Advances in Psoriasis
A Multisystemic Guide
Jeffrey M. Weinberg
Mark Lebwohl
Editors
Second Edition
123
Contents
1Introduction to and History of Psoriasis and
Psoriasis Therapy���������������������������������������������������������������������������� 1
John B. Cameron and Abby S. Van Voorhees
2Pathophysiology of Psoriasis/Novel Pathways������������������������������ 9
Jeremy M. Hugh and Jeffrey M. Weinberg
3Psoriasis: Clinical Review and Update������������������������������������������ 19
Ivan Grozdev and Neil J. Korman
4Psoriasis: Epidemiology, Potential Triggers,
Disease Course���������������������������������������������������������������������������������� 27
Ivan Grozdev and Neil J. Korman
5Topical Therapy I: Corticosteroids and
Vitamin D Analogues ���������������������������������������������������������������������� 39
Eric J. Yang and Shari R. Lipner
6Topical Therapy II: Retinoids, Immunomodulators,
and Others���������������������������������������������������������������������������������������� 51
Lyn C. Guenther
7Topical Therapy II: Retinoids, Immunomuodulators,
and Others/Ultraviolet Therapy for Psoriasis ������������������������������ 71
Kristen M. Beck and John Koo
8Laser Therapy in Psoriasis�������������������������������������������������������������� 93
Quinn Thibodeaux and John Koo
9Traditional Systemic Therapy I: Methotrexate
and Cyclosporine������������������������������������������������������������������������������ 103
Erin Boh, Andrew Joselow, and Brittany Stumpf
10Traditional Systemic Therapy II:
Retinoids and Others ���������������������������������������������������������������������� 119
Vignesh Ramachandran, Ted Rosen, Misha Koshelev,
and Fareesa Shuja Sandoval
11Apremilast���������������������������������������������������������������������������������������� 141
Jerry Bagel and Elise Nelson
12Etanercept���������������������������������������������������������������������������������������� 145
Andrew F. Alexis and Charlotte M. Clark
v
vi
13Adalimumab for Psoriasis �������������������������������������������������������������� 153
Cooper B. Tye and Jennifer C. Cather
14Infliximab, Golimumab, and Certolizumab Pegol������������������������ 173
Jacob A. Mojeski and Robert E. Kalb
15Ustekinumab������������������������������������������������������������������������������������ 201
George Han, Caitriona Ryan, and Craig L. Leonardi
16Guselkumab�������������������������������������������������������������������������������������� 213
Deep Joshipura, Brooke Rothstein, and David Rosmarin
17Tidrakizumab ���������������������������������������������������������������������������������� 225
George Han
18Risankizumab���������������������������������������������������������������������������������� 235
Erica B. Lee, Deeti J. Pithadia, Kelly A. Reynolds,
and Jashin J. Wu
19Secukinumab for the Treatment of Inflammatory
Skin and Joint Disease �������������������������������������������������������������������� 243
Jason E. Hawkes and Avishan Vishi Hawkes
20Ixekizumab �������������������������������������������������������������������������������������� 253
Caitriona Ryan and Roisin O’Connor
21Brodalumab�������������������������������������������������������������������������������������� 263
Annika S. Silfvast-Kaiser, Dario Kivelevitch, So Yeon Paek,
and Alan Menter
22Biosimilars for Psoriasis������������������������������������������������������������������ 279
Sarah Lonowski, Nirali Patel, Nika Cyrus,
and Paul S. Yamauchi
23Research Pipeline I: Oral Therapeutics for Psoriasis������������������ 291
D. Grand, K. Navrazhina, J. W. Frew, and J. E. Hawkes
24Research Pipeline II: Upcoming Biologic Therapies�������������������� 303
Ahuva D. Cices and Jeffrey M. Weinberg
25Pediatric Psoriasis���������������������������������������������������������������������������� 311
Starling Tolliver, Amber N. Pepper, Salma Pothiawala,
and Nanette B. Silverberg
26Challenges in Psoriasis Treatment: Nail, Scalp,
and Palmoplantar Involvement������������������������������������������������������ 343
Jeffrey J. Crowley
27Psoriasis and Comorbidities����������������������������������������������������������� 363
Philip M. Laws and Richard B. Warren
28Summary of Published Treatment Guidelines������������������������������ 399
Vignesh Ramachandran, Abigail Cline,
and Steven R. Feldman
Index���������������������������������������������������������������������������������������������������������� 415
Contents
1
Introduction to and History
of Psoriasis and Psoriasis Therapy
John B. Cameron and Abby S. Van Voorhees
Abstract
The history of psoriasis has had a long and
complicated path. With initial challenges in
recognizing this disease, psoriasis was misunderstood in ancient times as documented in the
Bible as well as in other ancient texts. At first
mistakenly thought to be leprosy or other infectious processes such as impetigo, those with
psoriasis were ostracized from their communities. It was only in the mid 1800s that Camille
Gibert clarified psoriasis as a papulosquamous
disease. Remarkable progress in our understanding has occurred over the millennium,
some a result of scientific investigation while
other has come as a consequence of serendipity.
Even in the just the past decade we continue to
refine our understanding of the immune dysregulation that causes this condition.
Given the poor characterization of this disease, those with psoriasis also suffered from a
lack of effective treatments. We review the
history of the treatments that have been
employed. Starting with Fowler’s solution,
sometimes the treatments had significant tox-
J. B. Cameron
Department of History, Old Dominion University,
Norfolk, VA, USA
A. S. Van Voorhees (*)
Department of Dermatology, Eastern Virginia
Medical School, Norfolk, VA, USA
e-mail: vanvooas@evms.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_1
icity. The use of tar and anthralin, while still in
use today by some, were some of the first
modalities to provide care. Early observations
by Goeckerman and Ingram demonstrated the
benefit of combining these topical treatments
with ultraviolet B light to allow for enhanced
efficacy. In the 1970s both methotrexate and
PUVA photochemotherapy were developed,
allowing for the outpatient care of psoriasis.
Systemic and topical retinoids followed, as
did narrowband UVB. It was however, the serendipitous discovery of the benefit of cyclosporine that truly allowed us to understand the
importance of the immune system in this disease. Drugs first targeting T cells were then
followed by those targeting TNF, and now
more recently those targeting IL17 and IL23.
With each new achievement in the understanding of psoriasis, the ability to more finely target the abnormalities of the immune system
has improved, and with that, the efficacy of
our newest agents has greatly expanded.
Key Learning Objectives
1. To understand the evolution of the understanding of the pathogenesis of psoriasis
2. To understand the evolution of the treatment paradigm for psoriasis
3. To describe the evolving understanding
of the diagnosis of psoriasis over time
1
J. B. Cameron and A. S. Van Voorhees
2
History of Psoriasis
BL
O
SP
ch R
ild
G
IN od
ho
OD
water
WI
old N
a
PH
L
EG
Sanguine Phlegmatic
choleric Melancholic
N
y
R bille)
LEellow
e
bil
LY
HO )
(yello CH
wo O
r
SU
M
You M
th
ER
COLD
AU
T
ma UM
tur
k
Fire
ty
HOT
i
MELA
(bla NC
c
The Bible Book of Leviticus, chapters 13 and 14.
Arikha, N (2007) Passions and Tempers. Harper
Perennial, New York. Also Crissey, JT, Parish, LC, Stelley,
WB (1981) The Dermatology and Syphilology of the
Nineteenth Century. Praeger Scientific, New York,
pp. 4–5.
air
R
TE e
g
An understanding of disease overall and, skin disease in particular, has been a unique part of modern
times. Previously those with psoriasis were often
mislabeled, poorly regarded, and suffered as a consequence. Symptoms were often considered the disease itself, and consequent progress in treatment
was limited by this lack of understanding of the disease and its cause. The history of psoriasis therefore
requires an appreciation of how the understanding
of disease has progressed over time and the often
serendipitous findings of treatment options.
Pre-scientific societies often viewed disease
as resulting from a violation of the sacred order,
the malignant influence of magic or the breaking
of a taboo. For example the entire thirteenth
chapter of the Book of Leviticus concerns how
the priests may determine if an outbreak on the
skin is leprosy and the fourteenth chapter concerns which animals (lambs and birds) shall be
sacrificed to purify the victim.1
The first cultures that developed notions of
rational science were China and Greece. Western
medicine finds its roots in the Greek belief that disease results from natural causes, that in some way
the balance or integrity of the body has been disrupted. Treatment, therefore, consisted in restoring
that balance or integrity. Hippocrates may be the
father of western medicine but the most influential
founder was more likely Galen of Pergamon (130–
200 CE) To Galen the human body was a very
complex organism made up not just of the four
humors but also of gradations of dry and moist and
hot and cool.2 Treatment of disease was not limited
to bleedings and purges but also included the use of
lotions designed to restore health. Galen’s system
was so completely accepted that only in the nineteenth century would the humors and miasma disappear from medical belief to be replaced by the
germ theory of disease.
MOIST
earth
DRY
DIAGRAM OF HUMOURS, ELEMENTS,
QUALITIES, AND SEASONS
I dentification of Psoriasis as a Unique
Disease
It is extremely difficult to tease out the history of
psoriasis and its treatment in the ancient world
because of confusion between psoriasis and
many other diseases. Furthermore in the past the
names assigned to diseases and symptoms were
arbitrary and inconsistent. Identification of psoriasis in Egypt is especially difficult because of
confusion between the disease and leprosy in
later times.3 However, since extensive examination of Egyptians mummies would indicate that
leprosy was not present in Egypt before the common era, it is possible that psoriasis was mislabeled as leprosy.
We face similar problems of terminology in
Greek medicine. The Corpus Hippocraticum
contains precise descriptions and treatments for
many recognizable diseases of the skin.4 Again, it
is likely that much of what was referred to as leprosy was in fact psoriasis. The appearance of true
leprosy early in the common era compounded the
confusion and sometimes lead to harsh treat-
1
2
Pusey WA (1933) History of Dermatology. Charles
C. Thomas, Baltimore, pp 11–17.
4
Pusey WA (1933) History of Dermatology. Charles
C. Thomas, Baltimore, pp 19–25.
3
1
Introduction to and History of Psoriasis and Psoriasis Therapy
ments for those with psoriasis since lepers were
often isolated and forbidden to associate with
non-leprosy population.
The first indisputable reference to psoriasis
comes from the fifth and sixth books of Aulus
Cornelius Celsus, De Re Medica (circa 25 BCE-­
circa 50 CE) a Roman who compiled an extensive list of diseases and treatment for use by
estate owners.5 Celsus did not use the term psoriasis but rather describes it under the heading
impetigo.
After the collapse of Roman culture, the practice of scientific medicine in the west disappeared
and only returned as a part of the Renaissance.
Geronimo Mercurialis penned a summary of
what was known of skin diseases in 1572.6
Mercuralis lumped psoriasis in with other diseases as Lepra. He mentions several treatments
including wolf dung rubbed in with vinegar,
blood of a mountain goat as well as the rubbing
of psoriasis with cantharides.
Robert Willan (1757–1812) set out clear
and uniform nomenclature of skin diseases in
1809. However, his terminology unfortunately
perpetuated some confusion in that he called
psoriasis lepra vulgaris.7 That confusion would
end by mid-century when Camille Melchoir
Gibert (1792–1866) dropped lepra vulgaris
and used only psoriasis as the sole term for
the disease and his work made clear important
distinctions among papulosquamous diseases.8
Gibert’s successors improved the distinctions.
Hebra fully distinguished the clinical practice
of leprosy from psoriasis; Heinrich Auspitz
(1835–1886) noted bleeding points after removing scales (Auspitz sign); Heinrich Köebner
made an important contribution in 1872 when
Pusey WA (1933) History of Dermatology. Charles
C. Thomas, Baltimore, p. 28.
6
Sixteenth Century Physician and his Methods:
Mercurialis on Diseases of the Skin. Translated from De
Morbis Cutaneis et Omnibus Corporis Humani
Excrementis Tractatus, by Sutton RL Jr (1986) The Lowel
Press,Kansas City, Missouri.
7
Pusey WA (1933) History of Dermatology. Charles
C. Thomas, Baltimore, pp62ff.
8
Pusey WA (1933) History of Dermatology. Charles
C. Thomas, Baltimore, pp 81–82.
5
3
he delivered an address entitled, “The Etiology
of Psoriasis” pointing out the tendency of
prior trauma to produce psoriasis lesions. The
“Koebner Phenomenon” is still viewed as an
important indication of psoriasis.9 In 1898
Munro described the micro abscesses of psoriasis now called Munro’s abscesses. With the
addition in the early twentieth century of Leo
van Zumbusch of generalized pustular psoriasis
and Waranoff’s description of the pale halo now
called “woranoff ring,” accurate diagnosis of
psoriasis became commonplace.
History of the Treatment of Psoriasis
The history of the treatment of psoriasis has
been largely driven by serendipitous findings.
The late 1700s and 1800s included treatments
such as arsenic, chrysarobin and ammoniated
mercury. Anthralin and tar came into widespread
use in the first half of the twentieth century.
Starting in the 1950s topical steroids were developed followed by the arrival of methotrexate,
retinoids, and immunosuppressive medications
in the 1970s, 1980s and 1990s respectively. An
enhanced understanding of the pathogenesis of
psoriasis has allowed for more targeted drug
development in the twenty-first century. Our
therapeutic armamentarium now includes medications known as the biologics which target various aspects of the immune system allowing for
its regulation.
rsenic, Ammoniated Mercury
A
and Chrysarobin
During the eighteenth and nineteenth centuries
three topical agents are known to have been used
in the treatment of psoriasis. While probably first
developed by the ancient Greeks, arsenic solution was first utilized in dermatology in 1786.10
Crissey JT, Parish LC, Shelley WB (1981) The dermatology and syphilology of the nineteenth century. Praiger
Publishers, New York, pp 367–369.
10
Farber M, “History of the treatment of psoriasis,” J
9
J. B. Cameron and A. S. Van Voorhees
4
The first report of its use in psoriasis though was
attributed to Girdlestone in 1806. He is credited
with noting the efficacy of Fowler’s solution for
improving the lesions of psoriasis.11 Ammoniated
mercury, another topical agent was also used at
this same time.12 The use of this mercury in the
topical treatment of psoriasis has been attributed to Dr. Fox in 1880. It was championed as
well by Duhring. The use of both of these topical agents continued until the 1950s and 1960s
when concerns about their possible toxicity risks
and accidental poisonings caused their prohibition. The third topical agent that was identified
was chrysarobin. A serendipitous finding, it was
noted to be of benefit in the treatment of psoriasis
by Balmonno Squire in 1876. His patient, who
was using Goa powder to treat a presumed fungal
infection, was noted to have improvement of his
psoriasis. Kaposi in 1878 also published his experience with this topical approach to psoriasis.
acid, zinc oxide and ultraviolet light. For many
decades this combination was the mainstay of
psoriasis treatment in Europe.
Coal tar was also pioneered in the early 1900s.
In 1925 Goeckerman noted the beneficial effect
of the combination of coal tar with ultraviolet
light B radiation in the treatment of psoriasis.15
While the beneficial effect of sunlight on psoriasis had been long known, Goeckerman realized
that this effect might be enhanced if combined
with a topical photosensitizer. The success of this
approach was demonstrated by its widespread
use for many decades. While both the Goeckerman
protocol and the Ingram protocol were often
effective, the main limitation of these approaches
was that they were very time-intensive, requiring
patients to remain hospitalized for weeks each
year to control their disease.
Anthralin and Tar
The development of steroids both for systemic
and topical use revolutionized the treatments of
many diseases including psoriasis. First discovered in 1950, it was only two years later that the
potential role of this agent in a topical form was
demonstrated in psoriasis.16 Known as compound
F, hydrocortisone was beneficial in treating psoriasis. From this time to the present, topical steroids have continued to play a significant role in
reducing the inflammation in various cutaneous
conditions. Topical steroids continue to be the
most frequently prescribed medication in the
treatment of psoriasis today.
After the first identification of the potential benefit of chrysarobin, the 1900s were a time of its
further exploration. During the early part of this
century scientists learned how to convert chrysarobin to anthralin. The active agent was identified
as 2-methyl dithranol. During World War 1 when
natural supplies were interrupted the process of
synthesizing anthralin was discovered. It was
then in 1916 that Unna came to understand the
potential of this compound in the treatment of
psoriasis.13 In 1953, Ingram further refined the
treatment of psoriasis with anthralin.14 He demonstrated that treatment could be enhanced by
utilizing the combination of anthralin, salicylic
Amer Acad Dermaol 1992; 27: 640–5.
11
Bechet PE, “History of the use of arsenic in dermatology,” Arch Dermatol 1931; 23: 110–7.
12
Farber EM, “History of the treatment of psoriasis,” J
Amer Acad Dermatol 1992; 27: 640–5.
13
Unna PG” Cignolin als Heilmittel der psoriasis,”
Dermatol Wochenschr 1916; 62: 116–86. Fry L,”
Psoriasis,” 1988; 119: 445–561.
14
Ingram JT, “The Approach to Psoriasis,” Br Med J 1953;
2: 591–594.
Corticosteroids
Methotrexate and PUVA
Methotrexate was developed in the 1950s for the
treatment of malignancies. As seen with treatments before, it was only a short while before its
Goeckerman WH, “Treatment of Psoriasis,” Northwest
Med 1925; 24: 229.
16
Sulzberger MB, Witten VH, “The Effect of topically
applied coumpound F in select dermatoses,” J Invest
Dermatol 1952; 19: 101.
15
1
Introduction to and History of Psoriasis and Psoriasis Therapy
potential in the treatment of psoriasis was identified. In 1946 Farber developed aminopterin for
the treatment of leukemia. Five years later
Gubner noted its role in the treatment of psoriasis.17 While using this agent in the treatment of
Rheumatoid arthritis, he noted that his patient,
who concurrently had psoriasis, also had
improvement of his skin. A more stable derivative of aminopterin with less toxicity, methotrexate, was introduced in 1958 for the treatment of
psoriasis.18 This agent was subsequently approved
by the FDA for the treatment of psoriasis in 1972
after the first guidelines for its use were published.19 It continues to be an important agent in
the treatment of psoriasis today.
The efficacy of PUVA in the treatment of psoriasis was also demonstrated during the 1970s.
While the combination of ultraviolet light and a
photosensitizing compound had been used in the
treatment of vilitigo for hundreds of years in
Egypt and in India,20 the demonstration of its role
in psoriasis was novel. Ancient healers had those
with vitiligo ingest psoralen-rich foods such as
figs and limes and then exposed their skin to natural sunlight. It took however until 197421 to
demonstrate the effectiveness of the combination
of psoralen and artificial UVA light exposure
(320–400 nm) in psoriasis. Known as PUVA, this
therapeutic approach was a highly efficacious
approach for many patients with chronic psoriasis. PUVA was widely utilized since it allowed
patients to achieve control of their disease without incurring long inpatient hospitalizations.
17
Guber R, August S, Ginsbergerg V,” Therapeutic suppression of tissue reactivity; effect of aminopterin in
Rheumatoid arthritis and psoriasis,” Am J Med Sci 1951;
221: 176–182.
18
Edmondson W, Guy WB, “Treatment of psoriasis with
folic acid antagonist,” Arch Dermatol 1958; 78(2)
200–203.
19
Roenigk HH Jr, Maibach HI, Weinstein G, “Guidelines
in methotrexate therapy for psoriasis,” Arch Dermatol
1972; 105: 363–365.
20
Gupta AK, Anderson TF, “Psoralen photochemotherapy,” 1987; 17: 703–34.
21
Parrish Jam Fitzpatrick TB, Tanenbaum L, Pathak M,
“Photochemotherapy of psoriasis with oral methoxsalen
and longwave ultraviolet light,” New Engl J Med 1974;
291: 1207–1211.
5
However, in the late 1970s the first reports surfaced of cutaneous malignancies.22 Longitudinal
studies of the original cohort of patients in subsequent years confirmed this finding.23 Stern noted
the increase risk of SCC, BCC and potentially
melanoma skin cancer in those treated with high-­
dose exposures and long-term therapy. Concerns
about the potential risk of cutaneous malignancy
has limited the utilization of this modality over
the past decades.
arrowband UVB, Retinoids,
N
Vitamin D
As the potential risk of non-melanoma skin cancers associated with long-term use of PUVA
became increasingly apparent, discoveries continued and additional new approaches to treat
psoriasis came into prominence in the 1980s and
the 1990s. Parrish and Jaenicke identified what
has come to be known as narrowband UVB.24
They identified that the most therapeutically
effective wavelengths of UVB were those
between 300–313 nm, while the remaining wavelengths of UVB light contributed primarily to the
development of erythema. Subsequently, 311 nm
was identified as the most efficacious wavelength
for the clearance of psoriasis lesions.25 This
modality therefore allowed for clearance of the
skin with more limited risk of erythema; narrowband UVB has come to replace the broad-band
UVB phototherapy upon which it was based.
In the 1980s systemic retinoids previously
developed for acne and hyperkeratosis were also
Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA,
Fitzpatrick TB, et al, “Risk of Cutaneous Carcinoma in
patients treated with oral methoxsalen photochemotherapy for psoriasis,” New Engl J Med 1979; 300: 809–813.
23
Stern RS, Lange R, et al, “Non-melanoma Skin Cancer
Occurring in patients treated with PUVA Five to Ten Years
after First Treatment, J Invest Dermatol 1988; 91:
120–124.
24
Parrish JA, Jacnicke KF, “Action Sprectrum for phototherapy of Psoriasis,” J Invest Dermatol 1981; 76(5):
359–62.
25
Green C, Ferguson J, Lakshmipathi T, Johnson BE,”
311 nm UVB phototherapy-an effective treatment for psoriasis,” Br J Dermatol 1988; 119: 691–6.
22
J. B. Cameron and A. S. Van Voorhees
6
explored for their possible benefit in the treatment of psoriasis. The second-generation ­retinoid
etretinate, followed by the development of its
metabolite acitretin, were both shown to be beneficial.26 Etretinate was eventually removed from
the market given its lipophilic nature and consequent persistence in the subcutaneous fat.
Acitretin however, remains a systemic treatment
of psoriasis today. A third generation retinoid,
tazarotene was also developed as a topical agent
that continues to be utilized in the treatment of
psoriasis.
Vitamin D and its derivatives were investigated in the 1980s as well. Based on a chance
observation of a patient’s psoriasis skin improving with the administration of systemic Vitamin
D, the development of topically applied Vitamin
D derivatives began. While still not fully understood, these topical agents remain important in
the armamentarium of dermatologists when treating patients with psoriasis.27
Systemic Immunosuppressive
Medications
Understanding the importance of immunosuppression in the treatment of psoriasis was another
example of gains achieved by serendipitous findings. When cyclosporine was initially developed
in the 1970s the critical role of the immune system in the pathogenesis of psoriasis was not yet
appreciated. When transplant patients who coincidentally had psoriasis were placed on cyclosporine to prevent graft rejection they were noted to
have improvement of their skin lesions.28 The
efficacy of this treatment on the psoriasis helped
to identify the importance of T cells, and the
immune system more generally, in this disease.
Despite its demonstrated effectiveness FDA
26
Ellis CN, Voorhees JJ, “Etretinate therapy,” J Amer Acad
Dermatol, 1987; 16: 267–91.
27
Kragballe K, Beck HI, Sogaard H, “Improvement of
psoriasis by a topical Vitamin D3 analogue (MC 903) in a
double-blind study,” Br J Dermatol 1988; 119(2):
223–230.
28
Mueller W, Hermann B, “Cyclosporin A for psoriasis,”
New Engl J Med 1979; 301 (10): 555.
approval was delayed until the 1990s because of
concerns of possible risks associated with this
medication.29
The knowledge gained in the twenty first century from cyclosporine in the understanding of
psoriasis opened the door for the development of
medications that more specifically targeted the
immune system. A number of biologic agents
were initially developed which included those
targeting T cells as well as those targeting tumor
necrosis factor and IL 12/23. While heralded with
great promise, the T cell targeting compounds
alefacept30 and efulizumab31 have subsequently
been removed from the market because of potential side effects and/or lack of efficacy. However
the TNF inhibitors—adalimumab,32 etanercept,33
and infliximab34 and the IL-12/23 compound
ustekinumab35 have revolutionized the care of
patients with psoriasis. They have become mainstays in the treatment of this disease. The initial
assumption about ustekinumab was that the IL12
portion was the key blockade. Instead research
has now established that the IL23 inhibition is
most important in psoriasis. This has opened our
eyes to an ever-greater understanding of the
Griffiths CEM, DUBrtret L, Ellis CN, et al, “CIclosporin
in psoriasis clinical practice: an international consensus
statement,” Br J Dermatol 2004; 150 (Suppl 67): 11–23.
30
Ellis CN, Krueger GG, “Alefacept Study Group.
Treatment of CHorinc Plaque Psoriasis by selective targeting of memory effector T lymphocytes,” New Engl J
Med 2001; 345(4): 248–25.
31
Gordon KB, Papp KA, Hamilton TK, et al, “Efalizumab
for patients with moderate to severe plaque psoriasis: a
randomized controlled trial“JAMA 2003; 290 (23):
3073–80.
32
Menter A, Tyring SK, Gordon K, et al, “Adalimumab
therapy for moderate to severe psoriasis: a randomized,
controlled phase 3 trial,” J Amer Acad Dermatol 2007; 58:
106–15.
33
Leonardi CL, Powers JL, Matheson RT, et al, “Etanercept
Psoriasis Study group: Etanercept as monotherapy in
patients with psoriasis,” New Engl J Med 2003; 349 (21):
2014–22.
34
Chaudri U, Romano P, Mulcahy LD, et al,” Efficacy and
safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial,” Lancet 2001; 357 (9271):
1842–7.
35
Krueger GG, Langley RG, Leonardi C, et al, “A Human
interleukin-12/23 monoclonal antibody for the treatment
of psoriasis,” New Engl J Med 2007; 356: 580–92.
29
1
Introduction to and History of Psoriasis and Psoriasis Therapy
immune system and the key role of IL17 cells in
the immunologic cascade in psoriasis. With each
new class of medication developed, the role of
the immune system in psoriasis has become
increasingly apparent. This knowledge has
allowed for the development of IL17 inhibitors
including secukinumab36 and Ixekizumab,37 IL17
receptor blocker brodalumab,38 and IL23 inhibitors guselkumab39 and rizukizumab.40 New agents
targeting different sites of the inflammatory cascade are currently under development and may
further add to both our understanding of psoriasis
and our therapeutic armamentarium.
In addition to understanding the pathogenesis
of psoriasis we have also come to understand that
psoriasis is truly a disease of systemic inflammation. While long known that psoriasis can be
36
LangleyRG, Elewski BE, Lebwohl M, et al,
“Secukinumab in plaque psoriasis-results of two phase 3
trials,” NEJM 2014; 371(4): 326–338.
37
Gordon KB, Blauvelt A, Papp KA, et al, “Phase 3 trials
of Ixekizumab in Moderate to Severe Psoriasis,” NEJM
2016; 375(4): 345–356.
38
Lebwohl M, Strober B, Menter A, et al, “Phase 3 studies
comparing Brodalumab with Ustekinumab in
Psoriasis“NEJM 2015; 373: 1318–1328.
39
Reich K, Armstrong AW, Foley P, et al, “Efficacy and
Safety of guselkumab, an anti-interleukin-23 monoclonal
antibody compared with adalimumab for the treatment of
patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase 3,
double-blind, placebo- and active comparator-controlled
Voyage 2 trial,” J Amer Acad Dermatol 2017; 76(3):
418–431.
40
Gordon KB, Strober B, Lebwohl M, “Efficacy and
Safety of Risankizumab in Moderate to Severe plaque
psoriasis (UltiMMa-1 and UltiMMa-2): results from two
double-blind, randomized, placebo-controlled and
ustekinumab-controlled phase 3 trials,” Lancet 2018; 39:
650–661.
7
associated with psoriatic arthritis, we have
become more aware of the frequency with which
psoriasis patients suffer from other concurrent
illnesses such as inflammatory bowel disease,
diabetes and obesity. Patients with psoriasis have
also been shown to have an increased risk of cardiovascular disease including cardiovascular
death, and more frequently suffer from the metabolic syndrome, sleep apnea, renal disease and
others.
Thus, our understanding of psoriasis as well
as the knowledge of how to treat this disease has
become inextricably linked over time. With each
step forward therapeutically, more and more is
learned so that we enhance our understanding
this disease process. This new knowledge has
facilitated the development of medications with
which to treat psoriasis, thereby allowing patients
to achieve control of their disease. The expectation for treatment response has increased to levels unimaginable only ten years ago. Each step in
the understanding of the disease as well as its
possible treatments has been built upon the lessons learned previously. The National Psoriasis
Foundation has set target goals for those with
psoriasis of having a body surface area of 1 or
less while on treatment. With the vast array of
medications at our disposal and their ability to
allow for clearance of the skin, achieving clear or
almost clear skin has become an obtainable goal.
We may soon be entering an era where “the heartbreak of psoriasis” reigns no more.
Disclosures John B. Cameron Ph.D.—none
Abby S. Van Voorhees, MD—She has served as a consultant for the following companies:
Derm Tech, WebMD, Novartis, Lilly, UCB, Celgene.
—She has served as an investigator for Celgene, Lilly,
AbbVie.
2
Pathophysiology of Psoriasis/
Novel Pathways
Jeremy M. Hugh and Jeffrey M. Weinberg
Abstract
1. Psoriasis is a systemic inflammatory disease.
2. We now have an increased understanding of
the specific cytokines involved in the disease.
3. Therapies have been developed to target these
cytokines.
Key Learning Objectives
1. To learn the underlying pathophysiology of psoriasis
2. To learn how treatments were developed
with the increased understanding of
psoriatic pathways
3. To understand novel pathways elucidated for psoriasis
Psoriasis is a genetically programmed pathologic
interaction among skin cells, immunocytes, and
numerous biologic signaling molecules that is
triggered by environmental stimuli. The immune
response is a cellular one; type 1 (TH1) and
type 17 (TH17) T cells are activated by IL-12
J. M. Hugh
Department of Dermatology, University of Colorado,
Aurora, CO, USA
J. M. Weinberg (*)
Department of Dermatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: jmw27@columbia.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_2
and IL-23 secreted by antigen-presenting cells
(APCs) in the skin. Through various cytokines,
such as tumor necrosis factor (TNF) α, these
cells cause a chronic inflammatory state and
alter epidermal hyperproliferation, differentiation, apoptosis, and neoangiogenesis that produce the cutaneous findings seen in this disease.
The newer biologic therapies target the immunologic signaling pathways and cytokines identified in the pathogenesis of psoriasis and provide
notable clinical improvement. Further study in
the pathogenesis of psoriasis can help identify
targets for future therapies.
The last 30 years of research and clinical
practice have revolutionized our understanding
of the pathogenesis of psoriasis as the dysregulation of immunity triggered by environmental and
genetic stimuli. Psoriasis was originally regarded
as a primary disorder of epidermal hyperproliferation. However, experimental models and clinical results from immunomodulating therapies
have refined this perspective in conceptualizing
psoriasis as a genetically programmed pathologic
interaction among resident skin cells; infiltrating
immunocytes; and a host of proinflammatory
cytokines, chemokines, and growth factors produced by these immunocytes. Two populations of
immunocytes and their respective signaling molecules collaborate in the pathogenesis: (1) innate
immunocytes, mediated by antigen-presenting
cells (APCs)(including natural killer (NK) T
lymphocytes, Langerhans cells, and neutrophils),
9
10
and (2) acquired or adaptive immunocytes, mediated by mature CD4+ and CD8+ T lymphocytes
in the skin. Such dysregulation of immunity and
subsequent inflammation is responsible for the
development and perpetuation of the clinical
plaques and histological inflammatory infiltrate
characteristic of psoriasis.
Although psoriasis is considered to be an
immune-mediated disease in which intralesional
T lymphocytes and their proinflammatory signals trigger primed basal layer keratinocytes to
rapidly proliferate, debate and research focus on
the stimulus that incites this inflammatory process. Our current understanding considers psoriasis to be triggered by exogenous or endogenous
environmental stimuli in genetically susceptible
individuals. Such stimuli include group A streptococcal pharyngitis, viremia, allergic drug reactions, antimalarial drugs, lithium, beta-­blockers,
IFN-α withdrawal of systemic corticosteroids,
local trauma (Köebner phenomenon), and emotional stress. These stimuli correlate with the
onset or flares of psoriatic lesions. Psoriasis
genetics centers on susceptibility loci and corresponding candidate genes, particularly the psoriasis susceptibility (PSORS) 1 locus on the major
histocompatibility complex (MHC) class I region.
Current research on the pathogenesis of psoriasis
examines the complex interactions among immunologic mechanisms, environmental stimuli, and
genetic susceptibility. After discussing the clinical presentation and histopathologic features of
psoriasis, we will review the pathophysiology
of psoriasis through noteworthy developments,
including serendipitous observations, reactions
to therapies, clinical trials, and animal model
systems that have shaped our view of the disease
process. In addition to the classic skin lesions,
approximately 23% of psoriasis patients develop
psoriatic arthritis, with a 10-year latency after
diagnosis of psoriasis [1].
Principles of Immunity
The immune system, intended to protect its
host from foreign invaders and unregulated cell
growth, employs two main effector pathways—
J. M. Hugh and J. M. Weinberg
the innate and the acquired (or adaptive) immune
responses—both of which contribute to the
pathophysiology of psoriasis [2]. Innate immunity responses occur within minutes to hours of
antigen exposure but fail to develop memory for
when the antigen is encountered again. However,
adaptive immunity responses take days to weeks
to respond after challenged with an antigen.
The adaptive immune cells have the capacity to
respond to a greater range of antigens and develop
immunologic memory via rearrangement of antigen receptors on B and T cells. These specialized
B and T cells can then be promptly mobilized and
differentiated into mature effector cells that protect the host from a foreign pathogen.
Innate and adaptive immune responses are
highly intertwined; they can initiate, perpetuate,
and terminate the immune mechanisms responsible for inflammation. They can modify the
nature of the immune response by altering the
relative proportions of type 1 (TH1), type 2 (TH2),
and the more recently discovered type 17 (TH17)
subset of helper T cells and their respective signaling molecules. A TH1 response is essential
for a cellular immunologic reaction to intracellular bacteria and viruses or cellular immunity.
A TH2 response promotes IgE synthesis, eosinophilia, and mast cell maturation for extracellular parasites and helminthes as well as humoral
immunity, while a TH17 response is important for
cell-mediated immunity to extracellular bacteria
and plays a role in autoimmunity [3]. The innate
and adaptive immune responses employ common effector molecules such as chemokines and
cytokines, which are essential in mediating an
immune response.
Implicating Dysregulation
of Immunity
Our present appreciation of the pathogenesis of
psoriasis is based on the history of trial-and-error
therapies; serendipitous discoveries; and the current immune targeting drugs used in a variety
of chronic inflammatory conditions, including
rheumatoid arthritis, ankylosing spondylitis, and
inflammatory bowel disease. Before the mid-­
2
Pathophysiology of Psoriasis/Novel Pathways
1980s, research focused on the hyperproliferative
epidermal cells as the primary pathology because
a markedly thickened epidermis was indeed
demonstrated on histologic specimens. Altered
cell-­cycle kinetics were thought to be the culprit
behind the hyperkeratotic plaques. Thus, initial
treatments centered on oncologic and antimitotic
therapies used to arrest keratinocyte proliferation
with agents such as arsenic, ammoniated mercury, and methotrexate [4].
However, a paradigm shift from targeting epidermal keratinocytes to immunocyte populations
was recognized when a patient receiving cyclosporine to prevent transplant rejection noted clearing
of psoriatic lesions in the 1980s [5]. Cyclosporine
was observed to inhibit messenger RNA transcription of T-cell cytokines, thereby implicating
immunologic dysregulation, specifically T-cell
hyperactivity, in the pathogenesis of psoriasis [6].
However, the concentrations of oral cyclosporine
reached in the epidermis exerted direct effects
on keratinocyte proliferation and lymphocyte
function in these patients [7]. Thus, the question
was raised as to whether the keratinocytes or the
lymphocytes drove the psoriatic plaques. The use
of an IL-2 diphtheria toxin-­fusion protein, denileukin diftitox, specific for activated T cells with
high-affinity IL-2 receptors and nonreactive with
keratinocytes, distinguished which cell type was
responsible. This targeted T-cell toxin provided
clinical and histological clearing of psoriatic
plaques. Thus, T lymphocytes rather than keratinocytes were recognized as the definitive driver
behind the psoriatic plaques [8].
Additional studies have demonstrated that
treatments that induce prolonged clearing of psoriatic lesions without continuous therapy, such
as psoralen plus UVA irradiation, decreased the
numbers of T cells in plaques by at least 90%
[9]. However, treatments that require continual
therapy for satisfactory clinical results, such as
cyclosporine and etretinate, simply suppress
T-cell activity and proliferation [10, 11].
Further evidence has linked cellular immunity with the pathogenesis of psoriasis, defining
it as a TH1-type disease. Natural killer T cells
were shown to be involved through the use of a
severe combined immunodeficient mouse model.
11
They were injected into prepsoriatic skin grafted
on immunodeficient mice, creating a psoriatic
plaque with an immune response showing cytokines from TH1 cells rather than TH2 cells [12].
When psoriatic plaques were treated topically
with the toll-like receptor 7 agonist imiquimod,
aggravation and spreading of the plaques were
noted. The exacerbation of psoriasis was accompanied by an induction of lesional TH1-type
interferon produced by plasmacytoid dendritic
cell (DC) precursors. Plasmacytoid DCs were
observed to compose up to 16% of the total dermal infiltrate in psoriatic skin lesions based on
their coexpression of BDCA2 and CD123 [13].
Additionally, cancer patients being treated with
interferon alfa experienced induction of psoriasis
[14]. Moreover, patients being treated for warts
with intralesional interferon alfa developed psoriatic plaques in neighboring prior asymptomatic skin [15]. Patients with psoriasis who were
treated with interferon gamma, a TH1 cytokine
type, also developed new plaques correlating
with the sites of injection [16].
Intralesional T Lymphocytes
Psoriatic lesions contain a host of innate immunocytes, such as APCs, NK cells, and neutrophils,
as well as adaptive T cells and an inflammatory
infiltrate. These cells include CD4 and CD8
subtypes in which the CD8+ cells predominate
in the epidermis, while CD4+ cells show preference for the dermis [17]. There are two groups of
CD8+ cells: one group migrates to the epidermis,
expressing the integrin CD103, while the other
group is found in the dermis but may be headed
to or from the epidermis. The CD8+ cells residing
in the epidermis that express the integrin CD103
are capable of interacting with E-cadherin, which
enables these cells to travel to the epidermis and
bind resident cells. Immunophenotyping reveals
that these mature T cells represent chiefly activated memory cells, including CD2+, CD3+,
CD5+, CLA, CD28, and CD45RO+ [18]. Many
of these cells express activation markers such as
HLA-DR, CD25, and CD27, in addition to the
T-cell receptor (TCR).
12
T-Lymphocyte Stimulation
J. M. Hugh and J. M. Weinberg
psoriasis [20]. Furthermore, the cytokines produced from the immunologic response, such as
Both mature CD4+ and CD8+ T cells can respond tumor necrosis factor (TNF) α, IFN-γ, and IL-2,
to the peptides presented by APCs. Although correspond to cytokines that are upregulated in
the specific antigen that these T cells are react- psoriatic plaques [21].
ing to has not yet been elucidated, several antiIntegral components of the immunologic syngenic stimuli have been proposed, including apse complex include co-stimulatory signals,
self-­
proteins, microbial pathogens, and micro- such as CD28, CD40, CD80, and CD86, and adhebial superantigens. The premise that self-reactive sion molecules such as cytotoxic T-lymphocyte
T lymphocytes may contribute to the disease antigen 4 and lymphocyte function-­
associated
process is derived from the molecular mimicry antigen (LFA) 1, which possess corresponding
theory in which an exuberant immune response receptors on the T cell. These molecules play a
to a pathogen produces cross-reactivity with self-­ key role in T-cell signaling, as their disruption
antigens. Considering that infections have been has been shown to decrease T-cell responsiveassociated with the onset of psoriasis, this theory ness and associated inflammation. The B7 fammerits consideration. However, it also has been ily of molecules routinely interacts with CD28 T
observed that T cells can be activated without cells to co-stimulate T-cell activation. Cytotoxic
antigens or superantigens but rather with direct T-lymphocyte antigen 4 immunoglobulin, an
contact with accessory cells [19]. No single the- antibody on the T-cell surface, targets B7 and
ory has clearly emerged. Researchers continue to interferes with signaling between B7 and CD28.
search for the inciting stimulus that triggers the In psoriatic patients, this blockade was demonT lymphocyte and attempt to determine whether strated to attenuate the T-cell response and corT cells are reacting to a self-derived or non–self-­ related with a clinical and histologic decrease in
derived antigen.
psoriasiform hyperplasia [22]. Biologic therapies
that disrupt the LFA-1 component of the immunologic synapse also have demonstrated efficacy
T-Lymphocyte Signaling
in the treatment of psoriasis. Alefacept is a human
LFA-3 fusion protein that binds CD2 on T cells
T-cell signaling is a highly coordinated process and blocks the interaction between LFA-3 on
in which T lymphocytes recognize antigens via APCs and CD2 on memory CD45RO+ T cells and
presentation by mature APCs in the skin rather induces apoptosis of such T cells. Efalizumab is
than the lymphoid tissues. Such APCs expose a human monoclonal antibody to the CD11 chain
antigenic peptides via MHC I or II molecules for of LFA-1 that blocks the interaction between
which receptors are present on the T-cell surface. LFA-1 on the T cell and intercellular adhesion
The antigen recognition complex at the T-cell and molecule 1 on an APC or endothelial cell. Both
APC interface, in concert with a host of antigen-­ alefacept and efalizumab, 2 formerly marketed
independent co-stimulatory signals, regulates biologic therapies, demonstrated remarkable
T-cell signaling and is referred to as the immu- clinical reduction of psoriatic lesions, and alefanologic synapse. The antigen presentation and cept has been shown to produce disease remisnetwork of co-stimulatory and adhesion mole- sion for up to 18 months after discontinuation of
cules optimize T-cell activation, and dermal DCs therapy [23–25].
release IL-12 and IL-23 to promote a TH1 and
TH17 response, respectively. The growth factors
released by these helper T cells sustain neoan- NK T Cellss
giogenesis, stimulate epidermal hyperproliferation, alter epidermal differentiation, and decrease Natural killer T cells represent a subset of CD3+
susceptibility to apoptosis that characterizes the T cells present in psoriatic plaques. Although NK
erythematous hypertrophic scaling lesions of T cells possess a TCR, they differ from T cells
2
Pathophysiology of Psoriasis/Novel Pathways
by displaying NK receptors comprised of lectin
and immunoglobulin families. These cells exhibit
remarkable specificity and are activated upon recognition of glycolipids presented by CD1d molecules. This process occurs in contrast to CD4+
and CD8+ T cells, which, due to their TCR diversity, respond to peptides processed by APCs and
displayed on MHC molecules. Natural killer T
cells can be classified into two subsets: (1) one
group that expresses CD4 and preferentially produces TH1- versus TH2-type cytokines, and (2)
another group that lacks CD4 and CD8 that only
produces TH1-type cytokines. The innate immune
system employs NK T cells early in the immune
response because of their direct cytotoxicity and
rapid production of cytokines such as IFN-γ,
which promotes a TH1 inflammatory response,
and IL-4, which promotes the development of TH2
cells. Excessive or dysfunctional NK T cells have
been associated with autoimmune diseases such
as multiple sclerosis and inflammatory bowel disease as well as allergic contact dermatitis [26–28].
In psoriasis, NK T cells are located in the
epidermis, closely situated to epidermal keratinocytes, which suggests a role for direct
antigen presentation. Furthermore, CD1d is overexpressed throughout the epidermis of psoriatic
plaques, whereas normally, CD1d expression is
confined to terminally differentiated keratinocytes. An in vitro study examining cytokine-­based
inflammation demonstrative of psoriasis treated
cultured CD1d-positive keratinocytes with IFN-γ
in the presence of alpha-­
galactosylceramide
of the lectin family [29]. IFN-γ was observed
to enhance keratinocyte CD1d expression, and
subsequently, CD1d-­positive keratinocytes were
found to activate NK T cells to produce high levels IFN-γ, while levels of IL-4 remained undetectable. The preferential production of IFN-γ
supports a TH1-mediated mechanism regulated
by NK T cells in the immunopathogenesis of
psoriasis.
Dendritic Cells
Dendritic cells are APCs that process antigens in
the tissues in which they reside after which they
13
migrate to local lymph nodes where they present their native antigens to T cells. This process
allows the T-cell response to be tailored to the
appropriate antigens in the corresponding tissues.
Immature DCs that capture antigens mature by
migrating to the T-cell center of the lymph node
where they present their antigens to either MHC
molecules or the CD1 family. This presentation
results in T-cell proliferation and differentiation
that correlates with the required type of T-cell
response. Multiple subsets of APCs, including
myeloid and plasmacytoid DCs, are highly represented in the epidermis and dermis of psoriatic plaques as compared with normal skin [30].
Dermal DCs are thought to be responsible for
activating both the TH1 and TH17 infiltrate by
secreting IL-12 and IL-23, respectively. This
mixed cellular response secretes cytokines and
leads to a cascade of events involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that create the cutaneous lesions seen in
psoriasis [3].
Although DCs play a pivotal role in eliciting
an immune response against a foreign invader,
they also contribute to the establishment of tolerance. Throughout their maturation, DCs are
continuously sensing their environment, which
shapes their production of TH1- versus TH2-type
cytokines and subsequently the nature of the
T-cell response. When challenged with a virus,
bacteria, or unchecked cell growth, DCs mature
into APCs. However, in the absence of a strong
stimulus, DCs fail to mature into APCs and present self-peptides with MHC molecules, thereby
creating regulatory T cells involved in peripheral
tolerance [31]. If this balance between immunogenic APCs and housekeeping T cells is upset,
inflammatory conditions such as psoriasis can
result.
Cytokines
Cytokines are low-molecular-weight glycoproteins that function as signals to produce inflammation, defense, tissue repair and remodeling,
fibrosis, angiogenesis, and restriction of neoplastic growth [32]. Cytokines are produced by
J. M. Hugh and J. M. Weinberg
14
immunocytes such as lymphocytes and macrophages as well as nonimmunocytes such as endothelial cells and keratinocytes. Proinflammatory
cytokines include IL-1, IL-2, the IL-17 family,
IFN-γ, and TNF-α, while anti-inflammatory
cytokines include IL-4 and IL-10. A relative
preponderance of TH1 proinflammatory cytokines or an insufficiency of TH2 anti-inflammatory cytokines induces local inflammation and
recruitment of additional immunocyte populations, which produce added cytokines [33]. A
vicious cycle of inflammation occurs that results
in cutaneous manifestations such as a plaque.
Psoriatic lesions are characterized by a relative
increase of TH1-­type (eg, IL-2, IFN-γ, TNF-α,
TNF-β) to TH2-­type (eg, IL-4, IL-5, IL-6, IL-9,
IL-10, IL-13) cytokines and an increase in TH17type cytokines. Natural killer T cells stimulated
by CD1d-­overexpressing keratinocytes increase
production of proinflammatory IFN-γ without
effect on the anti-inflammatory IL-4. In addition to the cytokines produced by T cells, APCs
produce IL-18, IL-23, and TNF-α found in the
inflammatory infiltrate of psoriatic plaques. Both
IL-18 and IL-23 stimulate TH1 cells to produce
IFN-γ, and IL-23 stimulates TH17 cells. Clearly, a
TH1- and TH17-type pattern governs the immune
effector cells and their respective cytokines present in psoriatic skin.
Tumor Necrosis Factor α
Although a network of cytokines is responsible
for the inflammation of psoriasis, TNF-α has been
implicated as a master proinflammatory cytokine
of the innate immune response due to its widespread targets and sources. Tumor necrosis factor
α is produced by activated T cells, keratinocytes,
NK cells, macrophages, monocytes, Langerhans
APCs, and endothelial cells. Psoriatic lesions
demonstrate high concentrations of TNF-­α, while
the synovial fluid of psoriatic arthritis patients
demonstrates elevated concentrations of TNF-α,
IL-1, IL-6, and IL-8 [33]. In psoriasis, TNF-α
supports the expression of adhesion molecules
(intercellular adhesion molecule 1 and P- and
E-selectin), angiogenesis via vascular endothelial
growth factor, the synthesis of proinflammatory
molecules (IL-1, IL-6, IL-8, and nuclear factor κβ), and keratinocyte hyperproliferation via
vasoactive intestinal peptide [34].
A role for TNF-α in psoriasis treatment was
serendipitously discovered in a trial for Crohn
disease in which infliximab, a mouse-human
IgG1 anti–TNF-α monoclonal antibody, was
observed to clear psoriatic plaques in a patient
with both Crohn disease and psoriasis [35].
Immunotherapies that target TNF-α, including
infliximab, etanercept, and adalimumab, demonstrate notable efficacy in the treatment of psoriasis [36–38]. Tumor necrosis factor α is regarded
as the driver of the inflammatory cycle of psoriasis due to its numerous modes of production,
capability to amplify other proinflammatory signals, and the efficacy and rapidity with which it
produces clinical improvements in psoriasis.
IL-23/TH17 Axis
A new distinct population of helper T cells has
been shown to play an important role in psoriasis. These cells develop with the help of IL-23
(secreted by dermal DCs) and subsequently
secrete cytokines such as IL-17; they are, therefore, named TH17 cells. CD161 is considered a
surface marker for these cells [39]. Strong evidence for this IL-23/TH17 axis has been shown
in mouse and human models as well as in genetic
studies.
IL-23 is a cytokine that shares the p40 subunit with IL-12 and has been linked to autoimmune diseases in both mice and humans [3]. It is
required for optimal development of TH17 cells
[40] from a committed CD4+ T-cell population
after exposure to transforming growth factor
β1 in combination with other proinflammatory
cytokines [41, 42]. IL-23 messenger RNA is
produced at higher levels in inflammatory psoriatic skin lesions versus uninvolved skin [43],
and intradermal IL-23 injections in mice produced lesions resembling psoriasis macroscopically and microscopically [44]. Furthermore,
2
Pathophysiology of Psoriasis/Novel Pathways
several systemic therapies have been shown to
modulate IL-23 levels and correlate with clinical benefit [3]. Alterations in the gene for the
IL-23 receptor have been shown to be protective for psoriasis [45–47], and the gene coding
for the p40 subunit is associated with psoriasis
[45, 46].
Type 17 helper T cells produce a number of
cytokines, such as IL-22, IL-17A, IL-17F, and
IL-26; the latter 3 are considered to be specific
to this lineage [41]. IL-22 acts on outer body
barrier tissues, such as the skin, and has antimicrobial activity. Blocking the activity of
IL-22 in mice prevented the development of
skin lesions [48], and psoriasis patients have
elevated levels of IL-22 in the skin and blood
[49, 50]. The IL-17 cytokines induce the expression of proinflammatory cytokines, colonystimulating factors, and chemokines, and they
recruit, mobilize, and activate neutrophils [51].
IL-17 messenger RNA was found in lesional
psoriatic skin but not unaffected skin [52], and
cells isolated from the dermis of psoriatic skin
have been shown to produce IL-17 [53]. IL-17A
is not elevated in the serum of psoriatic patients
(unlike other autoimmune diseases) [54], and it
is, therefore, thought that TH17 cells and IL-17A
production are localized to the affected psoriatic
skin. Consistent with this concept is the finding
that treatments such as cyclosporin A and antiTNF agents decrease proinflammatory cytokines in lesional skin but not in the periphery
[55–57]. These cytokines released by TH17 cells
in addition to those released by TH1 cells act on
keratinocytes and produce epidermal hyperproliferation, acanthosis, and hyperparakeratosis
characteristic of psoriasis [3].
New therapies have been developed to target
the IL-23/TH17 axis. Ustekinumab is approved
for moderate to severe plaque psoriasis. This
treatment’s effect may be sustained for up to
3 years, it is generally well tolerated, and it may
be useful for patients refractory to anti-TNF
therapy such as etanercept [58]. Briakinumab,
another blocker of IL-12 and IL-23, was studied
in phase 3 clinical trials, but its development was
discontinued due to safety concerns [59]. Newer
15
drugs targeting the IL-23/TH17 axis include
secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab.
Genetic Basis of Psoriasis
Psoriasis is a disease of overactive immunity
in genetically susceptible individuals. Because
patients exhibit varying skin phenotypes, extracutaneous manifestations, and disease courses,
multiple genes resulting from linkage disequilibrium are believed to be involved in the pathogenesis of psoriasis. A decade of genome-wide
linkage scans have established that PSORS1 is
the strongest susceptibility locus demonstrable
through family linkage studies; PSORS1 is
responsible for up to 50% of the genetic component of psoriasis [60]. More recently, HLA-Cw6
has received the most attention as a candidate
gene of the PSORS1 susceptibility locus on the
MHC I region on chromosome 6p21.3 [61].
This gene may function in antigen presentation via MHC I, which aids in the activation of
the overactive T cells characteristic of psoriatic
inflammation.
Studies involving the IL-23/TH17 axis have
shown genetics to play a role. Individuals may be
protected from psoriasis with a nonsynonymous
nucleotide substitution in the IL23R gene [46–
48], and certain haplotypes of the IL23R gene are
associated with the disease [46, 48] in addition to
other autoimmune conditions.
Genomic scans have shown additional susceptibility loci for psoriasis on chromosomes 1q21,
3q21, 4q32–35, 16q12, and 17q25. Two regions
on chromosome 17q were recently localized via
mapping, which demonstrated a 6 Mb separation, thereby indicating independent linkage
factors. Genes SLC9A3R1 and NAT9 are present in the first region, while RAPTOR is demonstrated in the second region [62]. SLC9A3R1
and NAT9 are players that regulate signal transduction, the immunologic synapse, and T-cell
growth. RAPTOR is involved in T-cell function
and growth pathways. Using these genes as an
example, we can predict that the alterations of
16
regulatory genes, even those yet undetermined,
can enhance T-cell proliferation and inflammation manifested in psoriasis.
Conclusion
Psoriasis is a complex disease whereby multiple
exogenous and endogenous stimuli incite already
heightened innate immune responses in genetically predetermined individuals. The disease process is a result of a network of cell types, including
T cells, DCs, and keratinocytes that, with the production of cytokines, generate a chronic inflammatory state. Our understanding of these cellular
interactions and cytokines originates from developments, some meticulously planned, others
serendipitous, in the fields of immunology, cell
and molecular biology, and genetics. Such progress has fostered the creation of targeted immune
therapy that has demonstrated remarkable efficacy in psoriasis treatment. Further study of the
underlying pathophysiology of psoriasis may
provide additional targets for therapy.
References
1. Gottlieb A. Psoriasis. Dis Manag Clin Outcome.
1998;1:195–202.
2. Gaspari AA. Innate and adaptive immunity and the
pathophysiology of psoriasis. J Am Acad Dermatol.
2006;54(3 suppl 2):S67–80.
3. Di Cesare A, Di Meglio P, Nestle F. The IL-23/Th17
axis in the immunopathogenesis of psoriasis. J Invest
Dermatol. 2009;129:1339–50.
4. Barker J. The pathophysiology of psoriasis. Lancet.
1991;338:227–30.
5. Nickoloff BJ, Nestle FO. Recent insights into the
immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest. 2004;113:1664–75.
6. Bos J, Meinardi M, van Joost T, et al. Use of cyclosporine in psoriasis. Lancet. 1989;23:1500–5.
7. Khandke L, Krane J, Ashinoff R, et al. Cyclosporine
in psoriasis treatment: inhibition of keratinocyte cell-­
cycle progression in G1 independent effects on transforming growth factor-alpha/epidermal growth factor
receptor pathways. Arch Dermatol. 1991;127:1172–9.
8. Gottlieb S, Gilleaudeau P, Johnson R, et al.
Response of psoriasis to a lymphocyte-selective
toxin (DAB389IL-2) suggests a primary immune,
but not keratinocyte, pathogenic basis. Nat Med.
1995;1:442–7.
J. M. Hugh and J. M. Weinberg
9. Vallat V, Gilleaudeau P, Battat L, et al. PUVA bath
therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis
for remittive therapy. J Exp Med. 1994;180:283–96.
10. Gottlieb A, Grossman R, Khandke L, et al. Studies of
the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol.
1992;98:302–9.
11. Gottlieb S, Hayes E, Gilleaudeau P, et al. Cellular
actions of etretinate in psoriasis: enhanced epidermal
differentiation and reduced cell-mediated inflammation are unexpected outcomes. J Cutan Pathol.
1996;23:404–18.
12. Nickoloff B, Bonish B, Huang B, et al. Characterization
of a T cell line bearing natural killer receptors and
capable of creating psoriasis in a SCID mouse model
system. J Dermatol Sci. 2000;24:212–25.
13. Gillet M, Conrad C, Geiges M, et al. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the
presence of dermal plasmacytoid dendritic cell precursors. Arch Dermatol. 2004;140:1490–5.
14. Funk J, Langeland T, Schrumpf E, et al. Psoriasis
induced by interferon-alpha. Br J Dermatol.
1991;125:463–5.
15. Shiohara T, Kobayahsi M, Abe K, et al. Psoriasis occurring predominantly on warts: possible involvement of
interferon alpha. Arch Dermatol. 1988;124:1816–21.
16. Fierlbeck G, Rassner G, Muller C. Psoriasis induced
at the injection site of recombinant interferon gamma:
results of immunohistologic investigations. Arch
Dermatol. 1990;126:351–5.
17. Prinz J. The role of T cells in psoriasis. J Eur Acad
Dermatol Venereol. 2003;17(suppl):1–5.
18. Bos J, de Rie M. The pathogenesis of psoriasis:
immunological facts and speculations. Immunol
Today. 1999;20:40–6.
19. Geginat J, Campagnaro S, Sallusto F, et al. TCR-­
independent proliferation and differentiation of
human CD4+ T cell subsets induced by cytokines.
Adv Exp Med Biol. 2002;512:107–12.
20. Kastelan M, Massari L, Brajac I. Apoptosis mediated by cytolytic molecules might be responsible for
maintenance of psoriatic plaques. Med Hypotheses.
2006;67:336–7.
21. Austin L, Ozawa M, Kikuchi T, et al. The majority
of epidermal T cells in psoriasis vulgaris lesions can
produce type 1 cytokines, interferon-gamma, interleukin-­2, and tumor necrosis factor-alpha, defining TC1
(cytotoxic T lymphocyte) and TH1 effector populations: a type 1 differentiation bias is also measured in
circulating blood T cells in psoriatic patients. J Invest
Dermatol. 1999;113:752–9.
22. Abrams J, Kelley S, Hayes E, et al. Blockade of
T lymphocyte costimulation with cytotoxic T
lymphocyte-­
associated antigen 4-immunoglobulin
(CTLA4Ig) reverses the cellular pathology of psoriatic plagues, including the activation of keratinocytes,
dendritic cells and endothelial cells. J Exp Med.
2000;192:681–94.
3
Psoriasis: Clinical Review
and Update
Ivan Grozdev and Neil J. Korman
Abstract
Plaque psoriasis is the most common and wellrecognized disease type. It affects more than
80% of patients. Sebopsoriasis is a term used
when lesions predominate on seborrhoeic
areas. Guttate psoriasis is characterized by an
acute generalized eruption of small, usually
less than 1 cm in diameter, erythematous scaly
papules, distributed as “droplets” over the
body. It is common in children and young
adults with a family history of psoriasis and
typically follows streptococcal infection of the
upper respiratory tract. Guttate psoriasis and
chronic plaque psoriasis are genetically similar
conditions with a strong association to the
PSORS1 genetic locus. Pustular psoriasis is a
group of inflammatory skin conditions characterized by infiltration of neutrophil granulocytes in the epidermis clinically manifested
with sterile pustules. The three typical pustular
forms are generalized pustular psoriasis, palmoplantar pustulosis, and acrodermatitis continua of Hallopeau. According to the European
Rare and Severe Psoriasis Expert Network
I. Grozdev (*)
Department of Dermatology, Brugmann University
Hospital, Brussels, Belgium
N. J. Korman
Department of Dermatology, University Hospitals
Case Medical Center, Cleveland, OH, USA
e-mail: njk2@case.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_3
consensus each subtype of pustular psoriasis is
subclassified on the basis of the presence/
absence of associated features. Erythrodermic
psoriasis is a severe form of psoriasis characterized by generalized inflammatory erythema
and scaling involving at least 75% of the body
surface area. Precipitating factors may include
inappropriate use of potent topical and systemic corticosteroids. Other clinical variants of
psoriasis are nail and inverse (flexural) psoriasis. In pediatric population, psoriasis presents
the same clinical types. However, lesions may
differ in distribution and morphology. In the
future, a more clearly defined clinical classification of psoriasis is needed to provide more
specific management of each psoriasis type.
Key Learning Objectives
1. To understand the clinical features of
psoriasis
2. To understand the different variants of
psoriasis
3. To understand the differential diagnosis
of psoriasis
Psoriasis can present in various patterns and
forms. Different classifications of the disease
have been proposed based on either its epidemiology, age of onset, clinical morphology, or
severity [1, 2]. However, the diagnosis is typi19
I. Grozdev and N. J. Korman
20
cally made by the recognition of the classic and
distinctive lesions—well-demarcated erythematous plaques with adherent silvery scales. These
correlate to the inflammation, vascular dilatation,
and altered epidermal proliferation and differentiation seen histopathologically. The most common sites include symmetric involvement of the
elbows, knees, lower back, and buttocks, but the
disease can involve any cutaneous surface. The
disease varies widely in severity and extent of
involvement. There are multiple types of psoriasis that have been classified based upon a combination of morphology, distribution, and pattern.
This section will review the clinical forms of the
disease along with some updates on its particular
subtypes.
Plaque Psoriasis
This is the most common and well-recognized
form of psoriasis, also known as psoriasis vulgaris. It affects more than 80% of patients. It is
characterized by sharply defined erythematous
scaly plaques, usually distributed symmetrically
over the extensor surfaces of the upper and lower
extremities, lower back and scalp [3]. There can
be variation in the intensity of erythema and
amount of scale. The size of the lesions varies
from coin-sized to palm-sized and larger. The
term nummular psoriasis is used if coin-sized
lesions predominate [4]. Additional features of
psoriatic plaques include the Auspitz sign as the
presence of pinpoint bleeding when the tightly
adherent scales are removed from the surface of
the plaque, and Woronoff ring as the presence
of a white ring around erythematous plaques
undergoing topical treatment or phototherapy [5,
6]. Psoriasis is well known to develop at sites of
physical trauma (scratching, sunburn or surgery),
which is the isomorphic or Koebner’s phenomenon [7] and occurs in 11 to 75% of patients
[8]. The term sebopsoriasis is used if lesions
predominate on seborrhoeic areas, occasionally
causing difficulties separating the disease from
seborrheic dermatitis [9]. Lesions of plaque
psoriasis are quite stable over time. The term
annular or polycyclic psoriasis is used if central
clearing of the lesions with an active border is
present. Psoriatic leukoderma defines the post-­
inflammatory hypopigmentation as the psoriatic
plaques regress. Pruritusis present is as many as
60–90% of psoriasis patients [10].
Guttate Psoriasis
Guttate psoriasis is characterized by an acute generalized eruption of small, usually less than 1 cm
in diameter, erythematous scaly papules, distributed as “droplets” over the whole body surface.
Usually, lesions occur over the trunk as the palms
and soles are spared. Guttate psoriasis is common in children and young adults with a family
history of psoriasis and typically follows streptococcal infection of the upper respiratory tract
or acute stressful life events [11]. It can appear
either de novo or as an acute exacerbation of preexisting psoriasis. This form of psoriasis may
resemble other cutaneous conditions like pityriasis rosea or secondary syphilis. The prognosis is
excellent in children as spontaneous remissions
are known to occur within weeks or months.
The risk of developing chronic plaque psoriasis
after a first episode of guttate psoriasis has been
estimated to be 25–40% [12, 13]. Guttate psoriasis and chronic plaque psoriasis are genetically
similar conditions with a strong association to
the PSORS1 genetic locus [14]. Although guttate
psoriasis is highly associated with streptococcal
infections, there is little evidence-­based data to
support treatment of these patients with antibiotics or tonsillectomy [15, 16].
Pustular Psoriasis
Pustular psoriasis is a group of inflammatory skin
conditions characterized by infiltration of neutrophil granulocytes in the epidermis clinically
manifested with sterile pustules. Historically,
the three typical pustular forms (generalized
pustular psoriasis, palmoplantar pustulosis,
acrodermatitis continua of Hallopeau) have
been integrated in the large spectrum of pustuloses. (Table 3.1).
3
Psoriasis: Clinical Review and Update
Table 3.1 Generalized and localized pustuloses (from
Camisa C, 2004, modified) [17]
Generalized variants
Von Zumbusch-type
Impetigo herpetiformis
Acute generalized
exanthematous pustulosis
Localized variants
One or more plaques
with pustules
Palmoplantar pustulosis
Annular (Subcorneal
pustular dermatosis of
Sneddon and Wilkinson)
Acrodermatitis continua
of Hallopeau
Keratoderma
blenorrhagicum
(Previously known as
Reiter’s syndrome)
SAPHO syndrome
(synovitis, acne, pustulosis,
hyperostosis, osteitis)
Generalized Pustular Psoriasis
This condition was described by Leopold von
Zumbusch. It is a severe form of psoriasis and can
be life-threatening. It may be preceded either by
plaque psoriasis or arise de novo. Withdrawal of
systemic steroids may trigger the disease. This form
of psoriasis is characterized by sterile pustules arising from the surface of large erythematous patches
of skin distributed over the trunk and extremities.
The pustules eventually dry and peel. In some
cases, these pustules may form confluent large lakes
of pus. Oral lesions may be present with pustules
or acute geographic tongue. The eruption is usually accompanied by systemic symptoms including
fever, chills, diarrhea, and arthralgias. Leukocytosis
and an elevated erythrocyte sedimentation rate are
commonly encountered. Generalized pustular psoriasis may be associated with polyarthritis and cholestasis from neutrophilic cholangitis [18]. It has
been reported that pustular psoriasis occurs in 9%
of psoriasis patients without psoriatic arthritis and
in 41% of patients with psoriatic arthritis [19].
Impetigo Herpetiformis
Originally described in 1872 by von Herba,
impetigo herpetiformis refers to a generalized
pustular eruption anytime during pregnancy in
21
a woman without prior history of psoriasis [20].
Resolution occurs with delivery. Recurrences
might be associated with menstruation and oral
contraceptives [21]. Some cases have been found
to have IL-36RN mutations, suggesting that
impetigo herpetiformis and generalized pustular
psoriasos are the same disease [22].
cute Generalized Exanthematous
A
Pustulosis
AGEP is a drug-triggered severe cutaneous reaction characterized by rapid development of nonfollicular, sterile pustules on an erythematous
base. A wide variety of drugs has been associated with thecondition, antibiotics being the most
common cause. Typically, within 48 h of ingesting the causative medication, there is acute onset
of fever and pustulosis with leukocytosis. In
severe cases, there can be mucous membrane and
systemic organ involvement [23]. In some AGEP
cases, the same IL-36RN mutations were found
as in generalized pustular psoriasis [24].
Localized Pustular Forms
Palmoplantar pustulosis is the most common
variant of pustular psoriasis. It is characterized
by pruritic or burning erythematous patches on
the palms and soles, within which multiple pustules develop. Initially, the pustules are yellow.
Later they turn dark brown, dry up and form
crusts that subsequently exfoliate leaving tender
and diffusely eroded surfaces [25]. Those patients
experience great impairment of their quality of
life with difficulty in walking and using their
hands. Some authors consider palmoplantar pustulosis to be a separate dermatologic disorder as
it affects predominantly female patients, has a
higher age of onset, is associated with cigarette
smoking (up to 100% of cases at onset), and
consistently responds poorly to topical therapy.
Palmoplantar pustulosis does not share the association of PSORS1 gene locus with plaque psoriasis, supporting the concept that these are distinct
entities.
I. Grozdev and N. J. Korman
22
Acrodermatitis continua of Hallopeau is a
rare, chronic, and recalcitrant pustular eruption
of the fingers and toes that is widely considered
to be a localized variant of pustular psoriasis. The
pustules are located on the fingertips or toes and
are very painful and disabling, often leading to
loss of function in the affected digits and substantial morbidity. Nail dystrophy and paronychial
erythema are typically seen [26].
Consensus Statement
of Phenotypes of Pustular Psoriasis
For clinical use, pustular psoriasis is still grouped
with psoriasis vulgaris. However, accumulating
data reveal that the two conditions are genetically
and phenotypically different, respond differently to
treatment. The European Rare and Severe Psoriasis
Expert Network was founded to define consensus
criteria for diagnosis and phenotypes of pustular
psoriasis, to analyze the genetics and pathophysiology, to prepare for prospective clinical trials [27].
According to the consensus of this expert group,
each subtype of pustular psoriasis is subclassified
on the basis of the presence or absence of associated features. Generalized pustular psoriasis is
defined as primary, sterile, macroscopically visible
pustules on non-acral skin, excluding cases where
pustules are restricted to psoriatic plaques. It can
occur with or without systemic inflammation, with
or without psoriasis vulgaris, and can be either a
relapsing (> 1 episode) or persistent (> 3 months)
condition. Palmoplantar pustulosis is defined as primary, persistent (> 3 months), sterile, macroscopically visible pustules on the palms and/or soles
and can occur with or without psoriasis vulgaris.
Acrodermatitis continua of Hallopeau is defined as
primary, persistent (> 3 months), macroscopically
visible pustules affecting the nail apparatus, with or
without psoriasis vulgaris.
ErythrodermicPsoriasis
Erythrodermic psoriasis is a severe form of psoriasis characterized by generalized inflammatory
erythema and widespread scaling involving at
least 75% of the body surface area [28]. It may
develop gradually or acutely during the course of
chronic psoriasis, but it may also be the initial
manifestation of psoriasis. Important precipitating factors for erythrodermic psoriasis may
include inappropriate use of potent topical and
systemic corticosteroids. Psoriatic erythroderma
is not substantially clinically different from
erythroderma caused by eczematous dermatitis,
seborrhoeic dermatitis, pityriasisrubra pilaris,
drug induced erythroderma, lymphoma, or leukemia. Associated findings may include lymphadenopathy, hypothermia, tachycardia, peripheral
edema, elevated erythrocyte sedimentation rate,
hypoalbuminemia, anemia, leukocytosis or leucopenia, elevations of lactate dehydrogenase,
liver transaminases, uric acid, and calcium [29].
Severe medical complications can develop due to
dehydration from extensive fluid and electrolyte
disturbances, protein losses, high-output cardiac
failure, and infection.
Manifestations of Psoriasis
in Specific Locations
Scalp Psoriasis
The scalp is a very common location for psoriasis. Plaques typically form on the scalp and along
the hair margin. Many patients discover they
have psoriasis because of a dandruff-like desquamation. When the scalp is the only location of
psoriasis, it may be difficult to distinguish from
seborrheic dermatitis. The term sebopsoriasis is
used in such cases [9]. The scales can firmly be
attached to the scalp hair. This particular variety
is called pseudotinea amiantacea and is more
frequent in children [30]. Scarring alopecia may
develop in some patients [31].
Nail Psoriasis
The nails are commonly affected in patients with
psoriasis. In cases where skin lesions are absent
or equivocal, nail changes may be of assistance in
making the diagnosis of psoriasis. Two patterns
3
Psoriasis: Clinical Review and Update
of nail disorders have been shown to be caused
by psoriasis [32]. Nail matrix involvement can
result in features such as leukonychia, pitting, red
spots in the lunula and crumbling. Onycholysis,
salmon or oil-drop patches, subungual hyperkeratosis and splinter hemorrhages are classic
features of psoriasis nailbed involvement. Nail
psoriasis causes aesthetic and functional impairment, and is considered as an indicative of psoriasis joint involvement.
23
cum can develop psoriasiform skin lesions 1–2
months after the onset of arthritis. with involvement of the palms, soles, and the scalp [37]. The
psoriasiform patch has distinctive circular scaly
borders that develop from fusion of papulovesicular plaques with thickened yellow scale.
Pediatric Psoriasis
Approximately 30–50% of adults with psoriasis developed psoriasis before the age of 20.
Inverse (Flexural, Intertiginous)
The prevalence of childhood psoriasis has been
Psoriasis
reported to be up to 2% [38].
Although children present with the same cliniInverse psoriasis affects the skin fold areas cal types of psoriasis seen in adults, lesions may
including the axillae, submammary regions, glu- differ in distribution and morphology. Plaque
teal cleft, retroauricular, and inguinal folds [33]. psoriasis is the most common type of psoriasis in
Obese patients often have this form of psoriasis children. Typical erythematous plaques with
involving their excess skin folds [34]. Thin well-­ overlying white scales are often thinner and
demarcated erythematous patches without des- smaller. Lesions tend to develop more often on
quamation are the typical skin lesions. Usually the scalp, face, and flexural areas. Young children
the patches are superficially eroded with fissur- usually present with a diaper rash that is irresponing in the body folds. Inverse psoriasis may occur sive to irritant diaper dermatitis treatment [39].
alone but is more frequently accompanied by
Guttate psoriasis is the second most common
plaque psoriasis elsewhere. In cases where it is type of psoriasis in childhood. It could be trigthe only location of psoriasis, inverse psoriasis gered by a beta-hemolytic streptococcal or viral
may be confused with bacterial, fungal, or can- infection, and tends to resolve spontaneously
didal intertrigo. Scrapings or cultures are then within 3–4 months of onset. It has been reported
needed to exclude infection.
that a proportion of children with guttate psoriasis eventually develop plaque psoriasis [40].
Pustular psoriasis is seen in 1.0–5.4% of children with psoriasis. Other less common types of
Rare Forms and Some Specific
Locations
psoriasis in children are inverse psoriasis, palmoplantar psoriasis, isolated facial psoriasis, linear
Geographic tongue also known as benign migra- psoriasis, erythrodermic psoriasis. Nail changes
tory glossitis may be seen in psoriatic patients, have been reported in up to 40% of children with
especially in patients with generalized pustular psoriasis. Approximately 7% of all patients with
psoriasis. It is characterized by erythematous juvenile idiopathic arthritis appear to have juvepatches surrounded by a white line and loss of nile psoriatic arthritis [41].
Children suffering from psoriasis have higher
filiform papillae on the dorsum of the tongue
[35]. The lips can be affected in psoriasis but prevalence of comorbidities, including obesity,
this should be differentiated from discoid lupus diabetes, hypertension, rheumatoid arthritis,
erythematosus and desquamative cheilitis [36]. Crohn’s disease and psychiatric disorders, comIf psoriasis only affects the glans, the most com- pared to children without psoriasis [42].
Overall, 13% to 27% of children have modermon site of involvement is the proximal part [30].
It should be differentiated from erythroplasia of ate to severe disease, with a 10% body surface
Queyrat. Patients with Keratoderma blenorrhagi- area affected, and may warrant the use of systemic
I. Grozdev and N. J. Korman
24
Table 3.2 Differential diagnosis of variants of psoriasis
(modified from Lisi P 2007) [44]
References
Clinical variant
Guttate psoriasis
1. Griffiths CEM, Christophers E, Barker JNWN, et al.
A classification of psoriasis vulgaris according to phenotype. Br J Dermatol. 2007;156:258–62.
2. Dogra S, Mahajan R. Psoriasis: epidemiology, clinical
features, co-morbidities, and clinical scoring. Indian
Dermatol Online J. 2016;7(6):471–80.
3. Lebwohl M. Psoriasis Lancet. 2003;361:1197–204.
4. Van de Kerkhof PCM. Clinical features. In: de
Kerkhof PCM V, editor. Psoriasis. 2nd ed. London:
Blackwell; 2003. p. 3–30.
5. Bernhard JD. Clinical pearl: Auspitz sign in psoriasis
scale. J Am Acad Dermatol. 1997;36(4):621.
6. Varma S, Finlay AY. The Woronoff ring in psoriasis.
Br J Dermatol. 2003;148910:170.
7. Diani M, Cozzi C, Altomare G. Heinrich Koebner
and his phenomenon. JAMA Dermatol. 2016;
152(8):919.
8. Boyd AS, Neldner KH. The isomorphic response of
Koebner. Int J Dermatol. 1990;29(6):401–10.
9. Naldi L, Gambini D. The clinical spectrum of psoriasis. Clin Dermatol. 2007;25:510–8.
10. Szepietowski JC, Reich A. Pruritus in psoriasis: an
update. Eur J Pain. 2016;20(1):41–6.
11. Naldi L, Peli L, Parazzini F, Carrel CF, Psoriasis
Study Group of the Italian Grouo for Epidemiological
Research in Dermatology. Family history of psoriasis, stressful life events, and recent infectious disease
are risk factors for a first episode of acute guttate
psoriasis: results of a case-control study. J Am Acad
Dermatol. 2001;44:433–8.
12. Martin BA, Chalmers RJ, Telfer NR. How great is
the risk of further psoriasis following a single episode of acute guttate psoriasis? Arch Dermatol.
1996;132:717–8.
13. Pfingstler LF, Maroon M, Mowad C. Guttate psoriasis
outcomes. Cutis. 2016;97(2):140–4.
14. Asumalahti K, Ameen M, Suomela S, et al. Genetic
analysis of PSORS1 distinguishes guttate psoriasis and palmplantar pustulosis. J Invest Dermatol.
2003;120:627–32.
15. Owen CM, Chalmers RJ, O’Sullivan T, Griffiths
CE. A systematic review of antistreptococcal interventions for guttate and chronic plaque psoriasis. Br J
Dermatol. 2001;145(6):886–90.
16. Dupire G, Droitcourt C, Hughes C, et al.
Antistreptococcal interventions for guttate and
chronic plaque psoriasis. Cochrane Database Syst
Rev. 2019;3:CD011571.
17. Camisa C. The clinical variants of psoriasis. In:
Camisa C, editor. Handbook of psoriasis. 2nd ed.
New York: Blackwell; 2004. p. 7–36.
18. Viguier M, Allez M, Zagdanski AM, et al. High frequency of cholestasis in generalized pustular psoriasis. Evidence for neutrophilic involvement of the
biliary tract. Hepatology. 2004;40:452–8.
19. Aslanian FMNP, Lisboa FFCB, Iwamoto A, Carneirot
SCS. Clinical and epidemiological evaluation of pso-
Palmoplantarplaques
psoriasis
Palmoplantar
pustulosis
Generalized pustular
psoriasis
Erythrodermic
psoriasis
Nail psoriasis
Inverse psoriasis
Scalp psoriasis
Differential diagnosis
Pityriasis versicolor, Pityriasis
rosea, Secondary syphilis
Hand eczema, Contact
dermatitis, Dermatophytosis
Pompholyx, Dermatophytosis
Acute generalized
exanthematous pustulosis
Atopic dermatitis, Drug
reactions, Cutaneous T-cell
lymphoma, Ichthyoses
Dermatophytosis, Drug
reactions, Phototoxic
reactions
Candida infection,
Erythrasma, Seborrhoeic
dermatitis, Contact allergic
dermatitis, Benign familial
pemphigus (Hailey-Hailey
disease)
Seborrheic dermatitis, Contact
allergy, Ringworm
therapy. Along with the conventional treatment
options, biologics such as tumour necrosis factor
(TNF)-alpha inhibitor etanercept and the p40
inhibitor ustekinumab are approved in the United
States for severe plaque psoriasis in children. In
most European countries, adalimumab, another
TNF-alpha inhibitor, is also approved [43].
Differential Diagnosis of Psoriasis
The clinical presentation of psoriasis is usually
sufficient to make the diagnosis. Its differential
diagnosis includes other common skin diseases
(Table 3.2):
Conclusion
The continuous genetic and other experimental
research on psoriasis, along with the numerous
therapeutic studies in large psoriasis populations,
should come out with even more clearly defined
types of psoriasis. This would help for better
managing the disease and its course.
3
Psoriasis: Clinical Review and Update
riasis: clinical variants and articular manifestations. J
Eur Acad Dermatol Venereol. 2005;19:141–2.
20. Oumeish OY, Parish LJ. Impetigo herpetiformis. Clin
Dermatol. 2006;24:101–4.
21. Chaidemenos G, Lefaki I, Tsakiri A, Mourellou
O. Impetigo herpetiformis: menstrual exacerbations for 7 years postpartum. J Eur Acad Dermatol
Venereol. 2005;19:466–9.
22. Sigura K, Oiso N, Iinuma S, et al. IL-36RN mutations
underlie impetigo herpetiformis. J Invest Dermatol.
2014;134:2472–4.
23. Szatkowski J, Schwartz RA. Acute generalized exanthemateous pustulosis (AGEP): a review and update.
J Am Acad Dermatol. 2015;73(5):843–8.
24. Navarini AA, Simpson MA, Borradori L, et al.
Homozygous missense mutation in IL-36RN in general pustular dermatosis with intral oral involvement
compatible with both AGEP and general pustule psoriasis. JAMA Dermatol. 2015;151:452–3.
25. Misiak-Galazka M, Wolska H, Rudnicka L. What do
we know about palmoplantar pustulosis? J Eur Acad
Dermatol Venereol. 2017;31(1):38–44.
26. Seghal VN, Verma P, Sharma S, et al. Acrodermatitis
continua of Hallopeau: evolution of treatment options.
Int J Dermatol. 2011;50(10):1195–211.
27. Navarini AA, Burden AD, Capon F, et al. European
consensus statement on phenotypes of pustular psoriasis. J Eur Acad Dermatol Venereol.
2017;31(11):1792–9.
28. Singh RK, Lee KM, Ucmak D, et al. Erythrodermic
psoriasis: pathophysiology and current treatment perspectives. Psoriasis (Auckl). 2016;6:93–104.
29. Boyd AS, Menter A. Erythrodermic psoriasis: precipitating factors, course, and prognosis in 50 patients. J
Am Acad Dermatol. 1989;21(Part 1):985–91.
30. Ayala F. Clinical presentation of psoriasis.
Reumatismo. 2007;59(1):40–5.
31. van de Kerkhof PCM, Chang A. Scarring alopecia and
psoriasis. Br J Dermatol. 1992;126:524–5.
32. Schons KR, Knob CF, Murussi N, et al. Nail psoriasis: a review of the literature. An Bras Dermatol.
2014;89(2):312–7.
25
33. Khosravi H, Siegel MP, Van Voorhens AS, et al.
Treatment of inverse/intertriginous psoriasis:
updated guidelines from the Medical Board of the
National Psoriasis Foundation. J Drugs Dermatol.
2017;16(8):760–6.
34. Wang G, Li C, Cao T, Liu Y. Clinical analysis of 48
cases of inverse psoriasis: a hospital-based study. Eur
J Dermatol. 2005;15:176–8.
35. Meier M, Sheth PB. Clinical spectrum and severity of
psoriasis. Curr Probl Dermatol. 2009;38:1–20.
36. Zhu JF, Kaminski MJ, Pulitzer DR, Hu J, Thomas
HF. Psoriasis: pathophysiology and oral manifestations. Oral Dis. 1996;2:135–44.
37. Suong J, Lenwohl M. Psoriasis – clinical presentation. In: Psoriasis and psoriatic arthritis. An integrated
approach. Gordon KB, Ruderman EM (eds.), Springer
Berlin, 2004: 67-72.
38. Burden-Teh E, Thomas KS, Ratib S, et al. The epidemiology of childhood psoriasis: a scoping review. Br
J Dermatol. 2016;174(6):1242–57.
39. Bronckers IM, Paller AS, van Geel MJ, et al. Psoriasis
in children and adolescents: diagnosis, management
and comorbidities. Pediatr Drugs. 2015;17(5):373–84.
40. Mercy K, Kwasny M, Cordoro KM, et al. Clinical
manifestations of pediatric psoriasis: results of a multicenter study in the United States. Pediatr Dermatol.
2013;30(4):424–8.
41. Schwartz G, Paller AS. Targeted therapies for pediatric
psoriasis. Semin Cutan Med Surg. 2018;37(3):167–72.
42. Mahe E. Childhood psoriasis. Eur J Dermatol.
2016;26(6):537–48.
43. Thaci D, Papp K, Marcoux D, et al. Sustained long-­
term efficacy and safety of adalimumab in pediatric
patients with severe chronic plaque psoriasis from
a randomized, double-blind, phase III study. Br J
Dermatol. 2019 Apr 24;181(6):1177–89. https://doi.
org/10.1111/bjd.18029.
44. Lisi P. Differential diagnosis of psoriasis. Reumatismo.
2007;59(Suppl 1):56–60.
4
Psoriasis: Epidemiology, Potential
Triggers, Disease Course
Ivan Grozdev and Neil J. Korman
Abstract
Worldwide prevalence rates of psoriasis range
from 0.6 to 4.8%. The disease tends to have a
bimodal distribution of onset with the major
peak occurring at age of 20–30, and a later
smaller peak occurring at age of 50–60. While
there are many potential triggers of psoriasis,
infections are an important trigger and up to
half of children with psoriasis have an exacerbation within 2 weeks following an upper
respiratory infection. Psychological distress is
a causative or maintaining factor in disease
expression for many patients with psoriasis.
Other well-documented triggers for flares
include trauma, alcohol and smoking, as well
as obesity. Plaque psoriasis is usually chronic
with intermittent remissions. Plaques may
persist for months to years at the same locations; however, periods of complete remission
may occur.
I. Grozdev (*)
Department of Dermatology, Sofia Medical Faculty,
Sofia, Bulgaria
N. J. Korman
Department of Dermatology, University Hospitals
Case Medical Center, Cleveland, OH, USA
e-mail: njk2@case.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_4
Key Learning Objectives
1. To understand the epidemiology of
psoriasis
2. To examine the triggers of psoriasis
3. To understand the clinical course of the
disease
Epidemiology
Worldwide prevalence rates of psoriasis range
from 0.6 to 4.8% [1, 2]. Women and men are
equally affected. The prevalence of the disease
varies depending on the climate and ethnicity,
although these relationships are complicated.
The Caucasian population of Europe and the US
are affected equally by psoriasis [3, 4]. The disease is uncommon in the Mongoloid race. Asian
Americans have a prevalence of between 0.4%
[5] and 0.7% [6]. African-Americans have a
prevalence of 1.3% [7], while American-Indians
have prevalence of 0.2% or less [6]. Psoriasis
is absent in certain populations such as South
American Indians and Australian Aborigines
[8], while in the Arctic Kasah’ye its prevalence
is 11.8% [9]. A positive correlation between latitude and psoriasis prevalence would be expected
given the efficacy of ultraviolet light as a treatment [10]. However, Jacobson et al. identified 22
population-­based surveys, case-control studies,
27
I. Grozdev and N. J. Korman
28
and reviews on psoriasis prevalence rates from
numerous regions around the globe and found no
correlation between absolute latitude and psoriasis prevalence [11]. These findings suggest that
other factors or a combination of factors may
play a role in the frequency of psoriasis rather
than latitude alone. Differences in the prevalence
rates of psoriasis between two areas of the same
continent (West Africa prevalence rates of 0.05–
0.9% compared to South Africa prevalence rates
of 2.8–3.5% [12]) suggest that genetic factors
play an important role [13].
Although new onset psoriasis occurs in all
age groups from newborns to age 108 [14], the
disease tends to have a bimodal distribution of
onset with the major peak occurring at age of
20–30, and a later smaller peak occurring at age
of 50–60. Patients with early age onset of psoriasis are more likely to have a family history
of psoriasis, the course of the disease tends to
be more unstable with frequent remissions and
relapses, the disease tends to be more resistant
to treatment and more severe disease tends to be
more common. Late age onset psoriasis tends to
have a more stable chronic clinical course, and is
more likely to be associated with psoriatic arthritis, nail involvement and palmoplantar pustular
involvement [15, 16]. The mean age of onset of
psoriasis varies from study to study, but nearly
75% of patients with psoriasis have an onset
before the age of 40, and 12% of patients have
the onset of psoriasis at age of 50–60 [17]. More
recent studies have indicated an increasing prevalence of childhood psoriasis [18]. The known
familial concentration of psoriasis indicates an
important role of hereditary factors; however a
67%-concordance in monozygotic twins suggests that environmental factors may also be an
important component of psoriasis [19].
Potential Triggers
Trauma
Trauma can trigger the exacerbation of psoriatic
lesions or the development of new lesions (this
is known as the Koebner phenomenon, originally
described by Heinrich Koebner in 1872). Trauma
as a trigger is more commonly seen in patients
who develop psoriasis at an early age and those
who require multiple therapies to control their
disease [20]. In clinical studies the prevalence
of the Koebner phenomenon may range from
24–51% of patients while in experimental studies among selected patients with severe psoriasis
and a history of the Koebner phenomenon, it was
observed in up to 92% of patients [21]. Factors
that may lead to the Koebner phenomenon include
acupuncture, vaccinations, scratches, removal of
adhesive bandages, insect and animal bites, burns
(thermal, chemical, electrosurgical), radiation,
incisions, cuttings, abrasions, tattoos, irritant and
allergic contact dermatitis, phototoxic dermatitis,
as well as skin diseases including acne, furuncles,
herpes zoster, and lichen planus. The “reverse”
Koebner phenomenon which occurs when
trauma within a psoriatic lesion causes clearing
of that psoriatic lesion has also been observed
[22]. Some treatment modalities for psoriasis are
based on the reverse Koebner phenomenon such
as electrodissecation, dermabrasion, cryotherapy,
and CO2-laser therapy.
Infections
Infections have long been recognized as important triggers for psoriasis exacerbations. Up to
half of children with psoriasis have an exacerbation of their disease within 2 weeks following
an upper respiratory infection [23, 24]. Infection
with streptococcus pyogenes has a well-known
association with guttate psoriasis [25]. Up to
85% of patients with an episode of acute guttate
psoriasis show evidence of a preceding streptococcal infection as demonstrated by positive
anti-­streptolysin-­O titers [24]. In another study,
84% of patients with guttate psoriasis had a
history of infection prior to occurrence of skin
lesions, and the majority of these patients (63%)
had a verified streptococcal pharyngitis [26].
Although pharyngeal origin of the infection is
most common, skin infection with streptococcus pyogenes can also lead to guttate psoriasis.
Streptococcal infections can elicit exacerbations
4
Psoriasis: Epidemiology, Potential Triggers, Disease Course
of other types of psoriasis and psoriatic arthritis as well. Patients with psoriasis develop sore
throats much more frequently than non-psoriatic
individuals and it is well documented that streptococcal throat infections can trigger the onset
of psoriasis, and such infections cause exacerbation of chronic psoriasis [27]. The study of 111
patients isolated streptococcus pyogenes in 13%
of patients with a guttate flare of chronic plaque
psoriasis, in 14% of patients with chronic plaque
psoriasis, and in 26% of patients with acute guttate psoriasis, while 7% of the patients in the
control group had streptococcus pyogenes isolated [28]. Although many reports suggest a possible role for antibiotics or tonsillectomy in the
treatment of guttate psoriasis [27, 29–33], the
data is controversial about the beneficial effect
of either intervention [34].
Superantigens such as streptococcal pyogenic
exotoxin [35–38] as well as peptidoglycan derived
from various different bacterial sources [39, 40]
can lead to the development of psoriasis due to
an abnormal response of the innate immune system towards the super antigen. Development and
use of experimental vaccines to treat psoriasis are
based on this hypothesis [41, 42]. Other microorganisms reported to be potential triggers for psoriasis include Staphylococci, Candida, H pylori
and Malassezia spp [25, 43] while infections with
Yersinia spp have been reported to induce psoriatic arthritis [25].
Another important potential triggering factor
for psoriasis is infection with the human immunodeficiency virus (HIV). The link between HIV
infection and psoriasis onset seems paradoxical
as the immunosuppression should lead to psoriasis improvement [44]. It is suggested that either
HIV could function as a super antigen or other
microorganisms, including opportunistic ones,
could develop in the host because of the immune
dysregulation [44]. The prevalence of psoriasis in
patients with HIV infection is nearly 5%, about
twice that seen in the general population. The clinical manifestations of psoriasis in HIV-­infected
patients are similar to those in non-HIV-­infected
patients. However, lesions of more than one subset of psoriasis are often found in the same HIV
patient [45]. For example, a patient with chronic
29
plaque psoriasis may go on to develop guttate or
pustular lesions. Psoriasis may occur at any time
in the course of an HIV infection and exacerbations tend to be longer and more frequent than
those in otherwise healthy psoriasis patients [46].
There is no observed relationship between psoriasis and the CD4 count. There is one report of
psoriasis remission in the terminal stages of the
acquired immunodeficiency syndrome [47] and
another report on complete resolution of erythrodermic psoriasis in an HIV and HCV patient,
unresponsive to anti-psoriatic treatments after
highly active antiretroviral therapy [48]. Rapid
onset of acute eruptive psoriasis, frequent exacerbations or resistance to conventional and biologic treatments should raise the possibility of
underlying HIV disease [48, 49]. It has been suggested that inflammation within psoriatic lesions
develops against unknown antigens and super
antigens of viral origin such as human papilloma
virus 5 (HPV5), human endogenous retroviruses,
Coxsackie adenoviruses, Arboviruses and others
[43, 50, 51].
Stress
Psychological distress is a causative or maintaining factor in disease expression for many patients
with psoriasis. In one study, over 60% of psoriasis patients believed that stress was the principal
factor in the cause of their psoriasis [52]. Farber
and colleagues surveyed over 5000 patients with
psoriasis and 40% reported that their psoriasis
occurred at times of worry and 37% experienced
worsening of psoriasis with worry [5]. In a more
recent study of 400 patients with newly developed
psoriasis, 46% of the patients with plaque psoriasis and 12% of the patients with guttate psoriasis
linked the onset of their disease with a life crisis,
including divorce, severe or life-­threatening disease of the patient or a family member, death in
the family, financial burden, dismissal, or harassment in school [53]. In another study among 50
psoriasis patients, stressful life events were seen
in 26% of the patients within 1 year preceding
onset or exacerbation of psoriasis, suggesting
the potential value of relaxation therapies and
30
stress management programs in the management
of patients with psoriasis [54]. Stress-induced
relapse rates of up to 90% have been reported in
children [23]. In an epidemiological study of 784
Greek psoriasis patients, stress was self-reported
as the main cause for psoriasis exacerbations by
60% of patients [55]. It was demonstrated that
“low level worriers” achieved clearing of their
skin with PUVA (psoralen plus ultraviolet-A) a
median of 19 days earlier than “high level worriers” undergoing the same treatment [56]. Other
studies reveal that cognitive-behavioral therapy
in conjunction with medical therapy can lead to
a significantly greater reduction in the severity
of psoriasis than medical therapy alone [57, 58].
The role that acute psychosocial stressors play in
altering hypothalamic-­pituitary-­adrenal (HPA)
responses in patients with psoriasis is an area of
controversy. Some data shows that stress-exacerbated psoriasis flares lead to decreased levels of
cortisol [59], while other fails to show such a correlation [60, 61]. The epidemiologic data linking
psychological stress and onset or exacerbation of
psoriasis is also controversial with some studies
supporting this association [62], while others do
not [63, 64].
Medications
Various medications used for concomitant diseases may influence psoriasis in terms of precipitating or worsening it. Drug-induced psoriasis
is defined as the development of psoriasis after
treatment with a medication that remits when that
medication is withdrawn, while drug-triggered
or drug-exacerbated psoriasis is defined as the
development of psoriasis after treatment with
a medication whose withdrawal does not influence the clinical course [65]. The time between
the start of the drug intake and the outbreak of
­psoriatic eruption may vary and depends on the
drug and is classified as follows: short (<4 weeks
between the start of the drug and the onset of psoriatic eruption), medium (>4 and <12 weeks), and
long (>12 weeks) [66]. Several medications may
trigger or worsen psoriasis. The most common
medications that have been reported to trigger
I. Grozdev and N. J. Korman
psoriasis include lithium, beta-blockers, non-steroidal anti-inflammatory drugs, tetracyclines, and
antimalarials [65, 67]. Several other medications
that have reported to worsen psoriasis include
angiotensin converting enzyme (ACE) inhibitors, terbinafine, clonidine, iodine, amiodarone,
penicillin, digoxin, interferon-alpha, and interleukin-2. The abrupt discontinuation of systemic
or superpotent topical corticosteroids can serve
as triggers of psoriasis although the frequency of
this association has not been studied. While these
observations suggest the possibility that certain
medications may trigger psoriasis worsening, no
controlled trials have proven an association.
Newly developed psoriasis has been reported
in patients taking TNF-alpha blockers for indications other than psoriasis, including Crohn’s disease and rheumatoid arthritis [68, 69].
Interferons play an important role in the
pathogenesis of psoriasis. Their use as medications such as IFN (α, β, γ) and imiquimod may
induce or worsen psoriasis [43, 70]. Additionally,
withdrawal of interferon use in hepatitis C commonly leads to improvement in psoriasis [71].
Alcohol and Smoking
Alcohol and smoking have both been implicated
as triggering factors for psoriasis exacerbations.
It is well documented that the prevalence of psoriasis is increased among patients who abuse
alcohol [72]. However, conflicting evidence
exists as to whether increased alcohol intake in
psoriasis patients is a factor in the pathogenesis
or whether having a chronic disorder like psoriasis leads to greater intake of alcohol in an attempt
to self-medicate. A study of 144 Finnish patients
with psoriasis demonstrated that alcohol consumption in the previous 12 months was linked
to the onset of psoriasis. This study suggests that
psoriasis may lead to sustained alcohol abuse and
that this alcohol intake may perpetuate the disease [73]. Qureshi et al. prospectively evaluated
the association between total alcohol consumption and risk of incident psoriasis in a cohort of
82,869 nurses [74]. Compared with women who
did not drink alcohol, the multivariate relative
4
Psoriasis: Epidemiology, Potential Triggers, Disease Course
risk of psoriasis was significantly higher for an
alcohol consumption of 2.3 drinks per week or
more. Moreover, examining the type of alcoholic
beverage, non-light beer intake was associated
with an increased risk of developing psoriasis
among women, while other alcoholic beverages did not increase this risk. Recently, a meta-­
analysis of case-control studies showed that the
overall odds ratio of psoriasis for drinking persons compared to those with non-drinking habits
was 1.531 (P = 0.002), suggesting that alcohol
consumption is associated with an increased
risk of psoriasis [75]. Further support of increasing alcohol abuse as a post-diagnosis condition
was seen in a case-control study of 60 Australian
twins who were discordant for psoriasis [76]. In
this study, no difference in alcohol consumption
between discordant twins, either monozygotic
or dizygotic, was discovered. The influence of
increasing alcohol consumption on the severity
of psoriasis has also been investigated and there
appears to be a tendency for heavy drinkers to
develop more extensive and severe psoriasis that
lighter drinkers [77].
Mortality related to alcohol use in psoriasis has
also been evaluated. A population-based study of
over 5000 patients followed for 22 years demonstrated that psoriatic patients have an increased
mortality rate when compared to a control group
[78]. However, this study did not account for
previous hepatotoxic psoriasis therapies or other
medical conditions, and used the most severe
psoriasis patients (those who required hospital
admission for their psoriasis), suggesting that
the elevated mortality rates attributed to these
patients may have been overstated. In summary,
alcohol consumption is more prevalent in psoriasis patients, and it may also increase the severity
of psoriasis. The association of alcohol with the
pathogenesis and exacerbation of p­ soriasis is less
clear. Prolonged alcohol abuse may lead to alcoholic liver disease, and in that way may decrease
treatment responsiveness and options, which may
prolong exacerbations.
Patients with psoriasis are more likely than
those without psoriasis to smoke. In a large
cross-­sectional study from Utah, 37% of psoriatic
patients acknowledged they were smokers com-
31
pared to 25% smokers in the general population
[79]. Although the Finnish study of 144 psoriasis patients, mentioned above, found no association between smoking and the onset of psoriasis
[73], another study of 55 women demonstrated
an increased smoking rate of psoriasis patients
compared to controls [80]. Naldi et al. examined
560 patients and showed that the risk for developing psoriasis was the greater in former smokers
and current smokers than in those who had never
smoked [81]. A hospital-based Chinese study
evaluated 178 psoriasis patients and 178 controls
and found a graded positive association between
the risk of psoriasis and the intensity or duration
of smoking [82]. Moreover, they showed that the
risk of psoriasis in smokers with the HLA-Cw6
haplotype was increased by 11-fold over non-­
smokers without the HLA-Cw6 haplotype demonstrating an additive effect of genetics on that
of smoking in inducing psoriasis. Gene-smoking
interaction was found also by Yin et al. [83]. In
a larger Italian study of 818 patients, those that
smoked greater than 20 cigarettes per day were at
a twofold increased risk for more severe psoriasis than those who smoked less than 10 cigarettes
per day [84]. The largest and most definitive
study investigating the association of smoking
with psoriasis was the Nurses’ Health Study II
which prospectively followed a cohort of over
78,000 US nurses over a 14 year time period.
They demonstrated a “dose-response” relationship for smoking and the risk of developing incident psoriasis [85] and that the risk of incident
psoriasis decreases nearly back to that of never
smokers 20 years after stopping smoking. In
addition, they also found that prenatal and childhood exposure to passive smoke was associated
with an increased risk of psoriasis.
Obesity
Numerous studies demonstrate an increased prevalence of obesity, defined as a body mass index
(BMI) ≥30 kg/m2, among patients with psoriasis
[79, 86–90]. The findings of a systematic review
and meta-analysis of multiple observational studies support an increased prevalence of obesity
32
in patients with psoriasis [90]. The pooled odds
ratio [OR] for obesity for patients with psoriasis
compared with a control group without psoriasis
was 1.66 (95% CI 1.46–1.89). Further support for
this link between psoriasis and obesity derives
from a review of over 10,000 patients with moderate to severe psoriasis enrolled in clinical trials of biologic therapies [86] where the average
BMI for all patients in the trials was 30.6 kg/
m2. There is also a correlation between obesity
and the severity of psoriasis [79, 87, 91]. In the
systematic review and meta-­analysis described
above, the risk for obesity was more pronounced
in patients with severe psoriasis (pooled OR
2.23, 95% CI 1.63–3.05) than patients with mild
psoriasis (pooled OR 1.46, 95% CI 1.17–1.82)
[91]. One study of 4065 individuals with psoriasis and 40,650 controls that was included in
the meta-analysis illustrated a progressive relationship between disease severity and obesity.
Among patients with mild (≤2% body surface
area [BSA]), moderate (3–10% BSA), and severe
psoriasis (>10% BSA), the prevalence of obesity
compared to controls increased by 14, 34, and
66%, respectively [91].
Children with psoriasis also have an increased
risk for obesity. In an international cross-­sectional
study of 409 children with psoriasis, children
with psoriasis were significantly more likely to
be obese (BMI ≥95th percentile) than controls
(OR 4.29, 95% CI 1.96–9.39) [92]. Similar to the
general population of patients with psoriasis, a
correlation between disease severity and obesity
was observed. Children with severe psoriasis had
a greater increase in risk for obesity than children
with mild disease (OR 4.92, 95% CI 2.20–10.99
versus 3.60, 95% CI 1.56–8.30).
More than one factor may contribute to
the association between obesity and psoriasis.
Although the negative psychosocial impact of
psoriasis was initially considered the sole reason for excess weight in patients with psoriasis
[79], more recent data suggest that obesity may
increase risk for psoriasis. In an analysis of data
collected from almost 80,000 women in the
Nurses’ Health Study II, increased adiposity and
weight gain were identified as strong risk factors
for psoriasis [93]. Compared to women with a
I. Grozdev and N. J. Korman
BMI of 21.0–22.9 kg/m2 at age 18, the multivariate relative risk for the development of psoriasis
for subjects with a BMI ≥30 kg/m2 at the same
age was 1.73 (95% CI, 1.24–2.41), and only 0.76
(95% CI, 0.65–0.90) for women with a BMI
<21 kg/m2.
Data on the effects of weight loss on disease
severity in psoriasis are limited. The first randomized trial designed to explore the effect of
weight loss on the severity of psoriasis found
a statistically non-significant trend towards
greater improvement in psoriasis (as assessed
by Psoriasis Area Severity Index [PASI] score)
in overweight or obese psoriasis patients who
were placed on a low-energy diet compared
with a similar group of patients who continued
to eat ordinary healthy foods [94]. The median
baseline PASI score for all patients (5.4) correlated with mild to moderate psoriasis, and during
the 16-week trial, patients allocated to the low-­
energy diet lost a mean of 15.8 kg compared with
a mean loss of 0.4 kg in the control group. By
study end, PASI scores were reduced by a mean
of 2.3 in the low-energy diet group compared
with only 0.3 in the control group. In addition,
improvement in the Dermatology Quality of Life
Index (a secondary outcome measure aimed at
assessing the change in the impact of psoriasis on
patient quality of life) was significantly greater in
the low-energy diet group.
Improvement in psoriasis following gastric
bypass surgery has been previously documented
[95–97]. The mechanism of this is unclear, but
may be related to alterations in the production of
pro-inflammatory and anti-inflammatory adipokines, or weight-loss related changes in cutaneous microflora that result in the elimination of
an antigenic stimulant [98]. However, worsening
of psoriasis has also occurred after weight loss
and weight loss surgery [99–101]. Further study
is therefore necessary to better understand the
effect of weight loss on psoriasis.
Obesity may impact the efficacy of some
psoriasis treatments [102]. A cohort study of
approximately 2400 patients receiving systemic
therapy for psoriasis (including conventional
and biologic agents) found that compared to
individuals with a BMI of 20–24 kg/m2, obese
4
Psoriasis: Epidemiology, Potential Triggers, Disease Course
subjects (BMI ≥30 kg/m2) were less likely to
achieve 75% improvement in disease severity
(odds ratio 0.62, 95% CI 0.49–0.79 at 16 weeks)
regardless of the type of therapy [103]. In addition, in a randomized trial of 61 obese patients
with moderate to severe psoriasis, weight loss
improved the response to cyclosporine (2.5 mg/
kg per day) [104]. The weight-based dosing regimen for ustekinumab, a newer treatment option
for psoriasis, is used to mitigate the reduction in
drug efficacy observed when the standard dose is
utilized in obese patients [102].
Estrogen
Elevated estrogen levels may serve as a trigger
for psoriasis in some patients. Reports of new
onset psoriasis at puberty, psoriasis worsened
by estrogen therapy, and psoriasis that may be
cyclical and related to menses, all suggest an
etiologic role for elevated estrogen levels [105].
However, there have also been reports of psoriasis occurring or being exacerbated at the onset of
menopause, which supports the opposite interpretation. These findings demonstrate that the
potential role of estrogen as a triggering factor
for psoriasis is not entirely clear. Additionally,
while some patients report a worsening of psoriasis during pregnancy, nearly twice as many report
improvement of their psoriasis during pregnancy
[106–108]. Relapse during the early postpartum
period is common. The mechanism by which
psoriasis tends to improve during pregnancy is
not well understood. However, there is now data
to suggest that the up regulation of Th2 cytokines
during pregnancy counteracts the effects of proinflammatory Th1 cytokines which are key players in the pathogenesis of psoriasis [77].
Disease Course
Psoriasis encompasses a spectrum of cutaneous
manifestations that varies from patient to patient
and even in the same patient over time. While the
majority of patients have chronic plaque psoriasis
throughout the typically lifelong course of their
33
disease, some patients may develop other variants including guttate, pustular, inverse or erythrodermic variants.
Plaque psoriasis is usually chronic with intermittent remissions. Plaques may persist for
months to years at the same locations; however,
periods of complete remission do occur. Psoriatic
plaques usually develop slowly over time. During
exacerbations, however, plaques tend to enlarge
more rapidly with an active peripheral edge of
increasingly intense erythema and scale along with
increases in plaque thickness. New psoriatic papules may arise in areas of normal skin surrounding
the established plaques and coalesce with these to
form increasingly larger plaques. Resolution of a
plaque typically begins at its center. The end result
of plaque clearance may be post-inflammatory
hypo- or hyper-pigmentation that gradually fades
giving way to normal-­appearing skin. Complete
remission of psoriasis for several years followed
by reoccurrence of disease can occur.
Traditionally, chronic plaque psoriasis has
been considered a single entity; however, recent
evidence demonstrates that patients with thin and
thick plaque psoriasis have differing clinical features [109]. In addition to cutaneous involvement,
plaque psoriasis may be associated with internal
involvement, including joints and extra-­articular
sites such as the eyes. Concomitant psoriatic
arthritis occurs in up to 30% of patients with cutaneous psoriasis [110]. In a minority of patients,
the symptoms of psoriatic arthritis appear before
skin involvement. The prevalence of ophthalmic
involvement in patients with cutaneous disease
is not known; however, it is thought to occur in
approximately 10% of patients [111]. Psoriasis
may affect almost any part of the eye, leading to
blepharitis, peripheral keratopathy, acute anterior
uveitis, posterior synechiae, conjunctivitis, and
cataract formation.
Guttate psoriasis may clear spontaneously
over weeks to months. There is a tendency
toward younger age of onset with elevated anti-­
streptolysin O (ASO) titer in patients with involuting course. Guttate psoriasis may become
chronic and progress to plaque psoriasis, particularly in patients with a family history of psoriasis [112].
34
Palmoplantar pustulosis, which is now considered a single entity distinct from pustular psoriasis, is a chronic disease which tends to remain
localized to the palms and soles. It is significantly
aggravated by extrinsic factors, such as stress,
smoking, and infections. It is less responsive to
standard treatment and is commonly associated
with sterile inflammatory bone lesions, such as
the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis).
Localized palmoplantar psoriasis presents
with sterile pustules found only on the palms
and soles that may be also seen with or without evidence of classic plaque type disease.
Generalized pustular psoriasis (von Zumbusch)
is a severe acute form of psoriasisin which small,
monomorphic sterile pustules develop in painful
inflamed skin which is triggered by pregnancy,
rapid withdrawal of corticosteroids, infections,
and hypocalcemia. It is complicated by systemic
symptoms of fever, chills, and fatigue, as well as
electrolyte derangements and liver abnormalities.
This variant requires aggressive treatment with
systemic immunosuppressive therapy. The mortality rate of generalized pustular psoriasis due
to sepsis is high without appropriately aggressive
treatment [77].
References
1. Naldi L. Epidemiology of psoriasis. Curr Drug Targets
Inflamm Allergy. 2004;3:121–8.
2. Lebwohl M. Psoriasis. Lancet. 2003;361:1197–204.
3. Toloza SM, Valle-Onate R, Espinoza LR. Psoriatic
arthritis in South and Central America. Curr Rheumatol
Rep. 2011;13(4):360–8.
4. Chandran V, Raychaudhuri SP. Geoepidemiology and
environmental factors of psoriasis and psoriatic arthritis. J Autoimmun. 2010;34(3):J314–21.
5. Farber EM, Nall ML. The natural history of psoriasis
in 5600 patients. Dermatologica. 1974;148:1–18.
6. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment.
Dermatol Clin. 1996;14:485–96.
7. Gelfand JM, Stern RS, Nijsten T, Feldman SR,
Thomas J, Kist J, Rolstad T, Margolis DJ. The prevalence of psoriasis in African Americans: results from
a population-based study. J Am Acad Dermatol. 2005;
52:23–6.
8. Shaefer T. Epidemiology of psoriasis. Review and the
German perspective Dermatology. 2006;212:327–37.
I. Grozdev and N. J. Korman
9. Eckes L, Ananthakrishnan R, Walter H. The geographic distribution of psoriasis [in German].
Hautarzt. 1975;26:563–7.
10. Okada S, Weatherhead E, Targoff IN, Wesley R,
Miller FW. International Myositis Collaborative
Study Group. Global surface ultraviolet radiation
intensity may modulate the clinical and immunological expression of autoimmune muscle disease.
Arthritis Rheum. 2003;48(8):2285–93.
11. Jacobson CC, Kumar S, Kimball A. Latitude and
psoriasis prevalence (research letter). J Am Acad
Dermatol. 2011;65(4):870–3.
12. Ouedraogo DD, Meyer O. Psoriatic arthritis in Sub-­
Saharan Africa. Joint Bone Spine. 2012;79(1):17–9.
13. Griffiths CE, Christophers E, Barker JN, Chalmers
RJ, Chimenti S, Krueger GG, Leonarid C, Menter
A, Ortonne JP, Fry L. A classification of psoriasis
vulgaris according to phenotype. Br J Dermatol.
2007;156:258–62.
14. Buntin D, Skinner R, Rosenberg E. Onset of psoriasis at age 108. J Am Acad Dermatol. 1983;9:276–7.
15. Henseler T, Christophers E. Psoriasis of early and
late onset: characterization of two types of psoriasis
vulgaris. J Am Acad Dermatol. 1985;13(3):450–6.
16. Ferrandiz C, Pujol RM, Garcia-Patos V, Bordas X,
Smandia JA. Psoriasis of early and late onset: a clinical and epidemiologic study from Spain. J Am Acad
Dermatol. 2002;46:867–73.
17. Holgate MC. The age-of-onset of psoriasis and the
relationship to parental psoriasis. Br J Dermatol.
1975;92:443–8.
18. Tollefson MM, Crowson CS, McEvoy MT, Maradit
Kremers H. Incidence of psoriasis in children:
a population-based study. J Am Acad Dermatol.
2010;62(6):979–87.
19. Farber EM, Nall ML. Genetics of psoriasis: twin
study. In: Farber EM, Cox AJ, editors. Proceedings
of the international symposium on psoriasis.
Stanford: Stanford University Press; 1971. p. 7–13.
20. Melski JW, Bernhard JD, Stern RS. The Koebner
(isomorphic) response in psoriasis: associations with
early age of onset and multiple previous therapies.
Arch Dermatol. 1983;19:655–9.
21. Weiss G, Shemer A, Trau H. The Koebner phenomenon: review of the literature. J Eur Acad Dermatol
Venereol. 2002;16(3):241–8.
22. Eyre RW, Krueger GG. Response to injury
of skin involved and uninvolved with psoriasis, and its relation to disease activity: Koebner
and ‘reverse’ Koebner reactions. Br J Dermatol.
1982;106(2):153–9.
23. Nyfors A, Lemholt K. Psoriasis in children: a short
review and a survey of 245 cases. Br J Dermatol.
1975;92:437–42.
24. Whyte HJ, Baughman RD. Acute guttate psoriasis and streptococcal infection. Arch Dermatol.
1964;89:350–6.
25. Norrlind R. The significance of infections in the
origination of psoriasis. Acta Rheumatol Scand.
1955;1(2):135–44.
5
Topical Therapy I: Corticosteroids
and Vitamin D Analogues
Eric J. Yang and Shari R. Lipner
Abstract
Key Learning Objectives
Psoriasis is a common disease affecting
1. To understand the mechanism of action
approximately 2% of the population worldof topical steroids and vitamin D
wide. Topical therapies play an integral role in
analogues
the treatment of patients with mild-to-­ 2. To understand the appropriate use and
moderate disease. The mainstays of treatment
efficacy of topical steroids and vitamin
are topical corticosteroids, vitamin D anaD analogues
logues, or a combination of the two. This
3. To understand the safety issues of topichapter will discuss the pharmacokinetics and
cal steroids and vitamin D analogues
mechanism of action of topical corticosteroids
and vitamin D analogues for the treatment of
psoriasis. Additionally, long-term adverse
effects of these medications, vehicle selection,
Topical Corticosteroids
potency, and combination use with other treatment modalities will also be discussed.
Topical corticosteroids (TCS) are a mainstay in
treatment of a wide range of inflammatory dermatoses. There are seven classes of topical steroids ranging from superpotent (class 1) to very
low-potency topical steroids (class 7). These
classes have been developed based on vasoconstrictor assays [1]. These vasoconstrictor assays
involve preparing the test corticosteroid in 95%
alcohol and then applying it to the volar surface
of a normal volunteer’s forearm. The alcohol is
left to evaporate and then the test area is covered
with an occlusive dressing for 16 h. Afterwards,
E. J. Yang
the area is washed off and vasoconstriction is
Chicago Medical School, Rosalind Franklin
University, North Chicago, IL, USA
assessed. The vasoconstrictive assay is reproducible and correlates well with the clinical efficacy
S. R. Lipner (*)
Department of Dermatology, Weill Cornell Medical
of TCS (Fig. 5.1).
College, New York, NY, USA
e-mail: shl9032@med.cornell.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_5
39
E. J. Yang and S. R. Lipner
40
Fig. 5.1 Topical
corticosteroid
CH2OH
21
18
12
HO
O
20
17
OH
11
13
19
1
16
9
14
2
8
15
3
7
5
O
4
Pharmacokinetics/Mechanism
of Action
Three factors determine the pharmacokinetics
and potency of a topical corticosteroid: the structure of the corticosteroid molecule, the vehicle,
and the skin onto which the corticosteroid is
applied [2]. Hydrocortisone is the central structure of most topical corticosteroids. Variations
are formed by placing hydroxyl groups onto the
11-β, 17-α, and 21 positions. Additionally, ketone
groups at the 3 and 20 positions and a double
bond into the 4 position of the glucocorticoid
nucleus distinguish between classes. Adding or
altering functional groups such as hydroxyl,
hydrocarbon, ester, fluoro, chloro, acetonide or
ketone groups at certain positions can vastly
impact the molecule’s pharmacokinetics [2]. The
alteration of hydroxyl groups modifies the molecule’s lipophilicity, solubility, percutaneous
absorption and glucocorticoid receptor binding
ability [2].
Glucocorticoid potency is increased by adding
a double-bond at position one, or with additional
fluorination or chlorination [2]. Additionally,
halogenation at the 6-α or 9-α position increases
glucocorticoid receptor binding activity [2].
Decreased mineralocorticoid activity, as in
6
d­examethasone, betamethasone and triamcinolone, is accomplished by the addition of a 16-α
methyl, 16-β methyl, or 16-α hydroxyl group.
Finally, epidermal enzymes cause de-­
esterification of topical corticosteroids into inactive metabolites. Increased potency can be
accomplished by inhibiting de-esterification
through halogenation at the 21 position.
Vehicle
The vehicle of a topical corticosteroid can influence percutaneous absorption and therapeutic
efficacy. When choosing a topical steroid, one
must first decide on the desired potency based on
the severity and the location of the skin disease.
Then, one must decide on the vehicle based on
the type of lesion to be treated, need for hydration
or drying effect, location and potential for irritation by components of the vehicle, and patient
preference. Lotions are often preferred for the
face, ointments work well for dry lesions, and
gels are more useful in hairy areas or for a drying
effect for wet lesions. Patients typically prefer
vehicles that are quickly absorbed, non-greasy,
and easy to apply [3], such as lotions and foams,
but patient preferences may vary greatly [4].
5
Topical Therapy I: Corticosteroids and Vitamin D Analogues
Potent and superpotent topical steroids should be
avoided on the thin skin of the face and intertriginous areas due to an increased risk of skin
atrophy.
The vehicle may alter the pharmacokinetics of
a topical steroid molecule, thereby affecting its
potency. A novel formulation for halobetasol propionate 0.01% lotion has demonstrated similar
efficacy for psoriasis as compared to halobetasol
0.05% cream despite a lower drug concentration
[5], due to increased drug delivery of the active
ingredient by the vehicle [6]. Propylene glycol
and alcohol, which are common solvents, can
affect percutaneous absorption by altering the
topical corticosteroid molecule’s solubility in the
vehicle. Propylene glycol enhances potency
through increasing penetration through the stratum corneum (Fig. 5.2).
For some agents, brand-name preparations are
not always equivalent to generics and may have
higher or lower potency. For example, Valisone
0.1% cream (Schering) and Kenalog 0.1% cream
(Westwood-Squibb) have both demonstrated
increased vasoconstriction over generics [2]. In
addition, Synalar 0.025% cream is also more
potent than generic fluocinolone acetonide
0.025% cream (Fougera and Company) [2].
However, Aristocort 0.025% cream and Aristocort
0.05% cream (Lederle Laboratories) are significantly less potent than generic triamcinolone
0.025 and 0.05% cream (Fougera and Company)
[2]. In general, generic vs. brand-name ointments
tend to be closer in vasoconstrictive assays than
creams. Additionally, there are differences
between different generic preparations as well as
different brand-name preparations of the same
topical corticosteroids [7].
Bioavailability and penetration of the topical
corticosteroid increase with inflamed or diseased
skin, as well as with increased hydration of the
stratum corneum. The thickness of the stratum
corneum is inversely proportional to the degree
of penetration of the topical corticosteroid. Very
occlusive agents, such as ointments, increase the
absorption of topical corticosteroids through
increased hydration of the stratum corneum [8].
41
Immunologic Mechanisms
Topical corticosteroids are closely involved with
all aspects of inflammation in the body, affecting
both adaptive and innate immunity. TCS have
been shown to decrease the number and function
of Langerhans’ cells, which are antigen presenting cells found in the skin important in initiating
immune responses. Neutrophils are decreased,
less adherent to vascular endothelium and have
decreased phagocytic function with corticosteroid use [9–11]. Similarly, leukocytes show
decreased antibody-dependent cellular toxicity
and natural killer cell function [12, 13]. In addition, the production of many cytokines is
decreased including interleukin (IL)-1, IL-2,
interferon (IFN)-γ, tumor necrosis factor and
granulocyte-monocyte-stimulating factor [2].
Topical steroids decrease the mitotic rate of
the epidermis, thereby causing thinning of the
stratum corneum and granulosum and flattening
of the basal layer [14]. TCS also cause atrophy of
the dermis through inhibition of fibroblast proliferation, migration, chemotaxis and protein synthesis. They have also been shown to cause
inhibition of fibroblast synthesis of both glycosaminoglycans and collagen [15–17].
Use in Psoriasis
The antiproliferative and atrophogenic characteristics of TCS are useful in treating psoriasis.
Topical corticosteroids are the mainstay of treatment and often first-line for the management of
mild to moderate psoriasis, as well as for intertriginous areas and genitalia, as these areas can
become irritated with the use of other topical
agents [18]. In general, for the treatment of localized plaque-type psoriasis, high potency or superpotent TCS are prescribed twice daily. Optimal
improvement with high potency TCS is often
achieved after 2 weeks. Superpotent TCS are recommended for the treatment of nail psoriasis [19],
whereas low-to-mid-potency TCS are typically
used for intertriginous and genital psoriasis [18].
E. J. Yang and S. R. Lipner
42
Fig. 5.2 Diagram of
steroid molecule. (Top)
Clacitriol chemical
structure, (Bottom)
Calcipotrience chemical
structure
Calcitriol chemical structure
22
21
20
18
12
24
23
27
OH
25
26
17
11
16
13
9
8
15
14
7
6
5
19
4
10
3
HO
1
2
OH
Calcipotriene chemical structure
OH
H
H
HO
OH
•H2O
5
Topical Therapy I: Corticosteroids and Vitamin D Analogues
Katz and colleagues in several studies indicated the efficacy of clobetasol ointment or betamethasone dipropionate ointment in clearing
plaque type psoriasis and found that remission
could be maintained by applying 3.5 g three times
a week [20, 21].In a placebo-controlled trial, Katz
et al. demonstrated that with maintenance therapy
consisting of 12 weeks of weekend-­only use of
betamethasone dipropionate ointment, 74% of
patients remained in remission as compared to
21% of the patients receiving placebo [22].
Occlusion can greatly increase penetration
and efficacy of TCS. Studies have demonstrated
that triamcinolone acetonide 0.1% ointment
under occlusion is more effective than clobetasol
propionate 0.05% cream twice daily or triamcinolone acetonide 0.1% ointment alone [23, 24].
Flurandrenolide (Cordran) tape is frequently prescribed due to its occlusive nature and has been
shown to be superior to twice-daily diflorasone
diacetate ointment in a randomized bilateral
comparison study of plaque-type psoriasis [25].
Clobetasol propionate lotion applied under occlusion with a hydrocolloid dressing (Duoderm ET)
once weekly also showed faster remission of psoriasis than unoccluded clobetasol propionate
ointment applied twice daily [26, 27]. Foams
have been found to have increased efficacy over
lotions of the same class of TCS when treating
the scalp [28, 29].
Combination with Other Therapies
In patients with psoriasis, vitamin D analogues
are frequently added at the onset, as there is a
synergistic effect with TCS. Topical corticosteroids work synergistically with light therapy as
well as many systemic agents. Psoriasis clears
faster when using psoralen plus ultraviolet A
(PUVA) with TCS versus PUVA alone. The addition of topical corticosteroids to cyclosporine
therapy also leads to more rapid clearance of psoriasis [30]. Topical steroids may also be combined with other topical agents, such as tazarotene
[31, 32], salicylic acid [33, 34], or anthralin [35],
providing increased efficacy due to increased
penetration.
43
Adverse Effects
Systemic adverse effects from topical corticosteroids are uncommon and are increased with young
age, liver disease, renal disease, the potency of the
drug, amount of skin surface involvement, the use
of occlusion, frequency of application and the
duration of treatment [2]. The liver metabolizes
corticosteroids and the kidneys excrete both
metabolized and unmetabolized corticosteroid
[36]. Infants and young children are particularly
predisposed to systemic adverse effects from TCS
due to a higher skin surface-to-­
body ratio,
increased cutaneous permeability, and immature
renal function [37]. Catch-up growth is expected
when topical corticosteroids are discontinued in
this population. Cushing’s syndrome and hypothalamic-pituitary-adrenal (HPA) axis suppression
has been noted in patients applying high quantities
of topical corticosteroids for prolonged periods of
time [38–40]. Screening for HPA axis suppression
is done using the 8 AM plasma cortisol level and
definitive diagnosis requires the cosyntropin test.
Local adverse effects are also rare but occur
more frequently than systemic adverse effects.
Cutaneous atrophy is the most commonly
observed side effect, and is characterized by telangiectasias, striae, hypopigmented, wrinkled or
shiny skin [41]. Striae are typically seen after
many weeks to months of topical steroid use; risk
factors include the potency of corticosteroid,
location of application, occlusion, and use in
infancy/childhood. “Corticosteroid phobia” is an
exaggerated and often irrational fear of using
topical steroids, and is common amongst patients
[42], often resulting in treatment nonadherence
[43]. Patients’ primary concerns often stem from
TCS “thinning the skin,” but a 2011 study by
Hong et al. demonstrated that appropriate long-­
term use of topical corticosteroids in children
with dermatitis does not cause skin atrophy [44].
Application of TCS may also result in perioral
dermatitis, characterized by erythematous papules in a periorificial distribution. Treatment for
perioral dermatitis consists of an oral tetracycline
in addition to a long taper with a non-fluorinated
topical corticosteroid, such as hydrocortisone
acetate cream.
E. J. Yang and S. R. Lipner
44
Prolonged use of topical glucocorticoids on
the eyelids can lead to glaucoma and cataracts,
and thus is not recommended [45]. These complications may also occur in patients who apply
TCS peripherally on their body, if inadvertent eye
contact occurs.
Allergic contact dermatitis to topical steroids
may occur and can be suspected when a patient
fails to respond to topical steroid therapy or flares
with topical steroid therapy [46, 47]. This allergy
may be to the vehicle or the actual corticosteroid
molecule, which can be confirmed with patch
testing. Topical corticosteroids often have a
delayed reaction and persist for at least 96 h, thus
requiring a delayed check [48].
Loss of clinical effect may occur with repeated
application of topical corticosteroids—known as
tachyphylaxis. This phenomenon occurs more
commonly with higher strength topical corticosteroids, but often subsides after a rest period of a
few days. There is no established regimen to prevent tachyphylaxis. A commonly recommended
regimen is twice daily application of TCS for
2 weeks followed by a 1 week rest period or
weekend-only application [49].
Vitamin d Analogues
Structure, Biosynthesis
and Mechanism of Action
Vitamin D as a treatment for psoriasis was first
discovered after a patient receiving oral vitamin
D for osteoporosis was cured of psoriasis [50].
Calcitriol, the active form of vitamin D3, was
found to inhibit the keratinocyte proliferation and
modulate the keratinocyte differentiation [51].
However, the therapeutic doses of oral vitamin
D3 for osteoporosis produce hypercalcemia and
hypercalciuria, thus limiting its practicality for
use in dermatology. As a result, topical vitamin D
analogues were developed to minimize the risk of
hypercalcemia, while maintaining the other beneficial cellular effects of vitamin D. There are
currently four vitamin D3 analogues out in the
market: calcipotriene, calcitriol, tacalcitol and
maxacalcitol.
The skin both synthesizes vitamin D (where
7-dehydrocholesterol is converted to vitamin
D3 in the presence of ultraviolet (UV) radiation)
and is a target organ for vitamin D activity.
Vitamin D receptors transduce the effects of 1,
25-dihydroxyvitamin D3 and have been identified
in keratinocytes, Langerhans’ cells, melanocytes,
fibroblasts and endothelial cells [52]. The vitamin D receptor (VDR) is activated by binding to
its ligand (1,25-dihydroxyvitamin D3) or a synthetic analogue such as calcipotriene or calcitriol.
This vitamin D receptor complex, in association
with the retinoid X receptor-α (RXR-α), then
binds to specific DNA binding sites called
Vitamin D Response Elements (VDREs), resulting in induction or repression of their target gene.
In addition to inhibiting the proliferation of keratinocytes and promoting epidermal differentiation, vitamin D promotes the formation of the
cornified envelope by increasing gene expression
and thereby increasing levels of involucrin and
transglutaminase [53].
Vitamin D also possesses anti-inflammatory
benefits. It has been shown to increase levels of
anti-inflammatory cytokine interleukin (IL)-10
and decrease levels of pro-inflammatory cytokine
IL-8in psoriatic plaques [54]. In addition, it has
been shown to inhibit the production IL-2 and
IL-6 by T cells, blocks transcription of interferon
(IFN)-γ and inhibits cytotoxic T cell and natural
killer cell activity [55].
Calcitriol
Calcitriol is the natural active form of vitamin D3.
Calcium metabolism is affected by calcitriol
through release of calcium from bone, decreasing
parathyroid hormone, increasing tubular resorption
of calcium in the kidney, and stimulating calcium
transport in the intestines. Thus, if applied excessively, calcitriol may result in hypercalcemia and
hypercalciuria. Calcitriol is available in an ointment form as Vectical (USA) and Silkis (Europe).
5
Topical Therapy I: Corticosteroids and Vitamin D Analogues
Calcipotriene (Calcipotriol)
45
Maxacalcitol (1α,25-dihydroxy-22-oxacalcitriol)
is available as Oxarol in Japan and has been
shown to be 10 times more potent than calcitriol
and tacalcitol in inhibiting keratinocyte
­proliferation and 60 times less calcemic than calcipotriene [56]. It has shown benefit in the treatment of psoriasis and has not posed a significant
risk of hypercalcemia.
roids in the treatment of psoriasis [57–59].
Calcipotriene applied twice daily has been shown
to be more effective than once daily applications,
without increased skin irritation [60, 61].
Calcipotriene is associated with slightly more
skin irritation than topical steroids, which rarely
leads to withdrawal of therapy [59].
In a study of 114 patients by Bruce et al., calcipotriene ointment was superior to fluocinonide
ointment in the treatment of plaque psoriasis
through 6 weeks [62]. A 2003 study of 258 psoriasis patients by Camarasa et al. in 2003 found
that though betamethasone dipropionate 0.05%
ointment was associated with slightly higher
global improvement than calcitriol ointment, a
statistically significantly higher proportion of
patients remained in remission following calcitriol therapy (48%) than betamethasone therapy
(25%) [63].
Calcipotriene may be used for intertriginous
psoriasis, though burning and irritation are commonly encountered [18, 60]. Less frequent application and alternation with low-potency topical
steroids in these areas may be less irritating.
Calcipotriene is an effective and well-tolerated
modality for treating scalp psoriasis, and in combination with other topical agents, may lead to
improved response to treatment. In long-term
studies, calcipotriene has been shown to be a safe
and effective therapy for the chronic management of psoriasis. Sustained disease improvement has been documented with twice daily use
for 1 year without elevation of serum calcium
levels [64].
Vitamin D analogues have been shown to be
effective and well-tolerated in children. In an
uncontrolled pilot study of 12 children under the
age of 15 with long-term follow-up of 106 weeks
by Park et al., patients showed significant
improvement in PASI scores compared to baseline, with no detected serious adverse effects or
hypercalcemia [65].
Indication for Psoriasis
Use with Other Treatment Modalities
Vitamin D analogues perform as well as midpotency steroids, but less well than superpotent ste-
Topical steroids are commonly used in conjunction with vitamin D analogues, as these therapies
Calcipotriene is a synthetic form of calcitriol. It
was the only vitamin D analogue that was available in the U.S. for many years. Its molecular
structure differs slightly from calcitriol, as it contains a double bond and ring structure in its side
chain which enables it to be metabolized much
more rapidly. As a result, it is less likely to cause
hypercalcemia than calcitriol. It is available
under ointment, cream, solution, and foam forms
under the trade names Dovonex (USA), Sorilux
(USA), Daivonex (Europe, Asia), Psorcutan
(Europe) and Dermocal (South America).
Tacalcitol
Tacalcitol’s (1,24(OH)2D3) structure is slightly
different from calcitriol, as it contains a hydroxyl
group at the 24-position rather than the
25-­position. Nevertheless, it has a similar affinity
for vitamin D receptors and similar therapeutic
effects. Tacalcitol is less selective than calcipotriene in its effect on calcium metabolism and has
been shown to induce hypercalcemia at equivalent doses to calcitriol. It is available under ointment, cream, lotion and solution forms in Japan
and under lotion and ointment forms in Europe as
Curatoderm.
Maxacalcitol
E. J. Yang and S. R. Lipner
46
have a synergistic effect when used in combination. Combination therapy of TCS with vitamin
D analogues improves the clinical response rate
and minimizes the side effects of both treatments
[60, 66, 67]. Topical steroids reduce or eliminate
the irritation associated with calcipotriene use.
Additionally, a study by Lebwohl demonstrated
that patients using superpotent topical steroids on
weekends and calcipotriene during the week
maintained a longer remission than patients using
superpotent topical steroids alone [68].
Formulations of a combination of calcipotriene and betamethasone dipropionate ointment
have demonstrated greater efficacy and a more
rapid onset of action compared to either medication alone [69]. This combination is highly effective for scalp psoriasis and is associated with
significantly fewer side effects than with calcipotriol alone [70, 71]. The foam formulation has
demonstrated superior efficacy for psoriasis as
compared to the gel formulation in previous studies [72]. The calcipotriol/betamethasone propionate combination is available in the ointment
(Daivobet, Taclonex), topical suspension
(Taclonex), and foam (Enstilar) forms.
Combining vitamin D analogues and phototherapy has also been shown to clear lesions more
rapidly than either entity alone and produces a
greater reduction in Psoriasis Area and Severity
Index (PASI) [73, 74]. Studies combining PUVA
with calcipotriene have also demonstrated
increased efficacy than when using PUVA alone
[75]. Total cumulative UVA exposure required
for clearance of psoriasis with vitamin D analogues is reduced, thus decreasing the risk of
developing skin cancer. Vitamin D analogues
should be applied following phototherapy, as the
application prior to UV radiation leads to
­degradation of vitamin D analogues and can alter
the transmission of UV light [76].
Calcipotriene has been shown to enhance psoriasis patients’ response to both acitretin [77] and
cyclosporine [78, 79], while allowing for lower
dosing and less toxicity. Calcipotriene paired
with methotrexate has also allowed for decreased
dosing of methotrexate and increased time to
relapse following the discontinuation of methotrexate [80]. Additionally, a study by Kircik
d­emonstrated that the combination betamethasone dipropionate 0.064% with calcipotriene
0.005% maintains the efficacy of etanercept after
a step down dose to 50 mg weekly from 50 mg
twice weekly [81]. Patients with inadequate
response to etanercept also demonstrated
improved efficacy with combination calcipotriol
and etanercept treatment [82].
Adverse Effects
Vitamin D analogues are typically well tolerated,
with the main side effects being application-site
burning and irritation. These symptoms are more
common on the thin skin of the face and in the
intertriginous areas, with irritation developing in
about 20% of patients treating those areas [83].
Irritation is self-limited and resolves quickly
once the drug is discontinued.
Patients are recommended to use less than
100 g of topical calcipotriene weekly [84], as
topical calcipotriene demonstrates a dose-­
dependent suppression of serum parathyroid hormone production and 1,25 dihydroxyvitamin D3
levels [65, 85]. Patients undergoing long-term
treatment exceeding 100 g of topical vitamin D
analogues weekly should have their serum parathyroid hormone and vitamin D levels checked.
Patients with renal disease are at increased risk of
developing hypercalcemia with topical vitamin D
analogue therapy, and thus may benefit from regular monitoring, even when applying less than
100 g per week.
References
1. Cornell RC, Stoughton RB. Correlation of the vasoconstriction assay and clinical activity in psoriasis.
Arch Dermatol. 1985;121:63–7.
2. Wolverton SE. Comprehensive dermatologic drug
therapy. Philadelphia: Saunders Elsevier; 2007.
p. 595–624.
3. Eastman WJ, Malahias S, Delconte J, DiBenedetti
D. Assessing attributes of topical vehicles for the
treatment of acne, atopic dermatitis, and plaque psoriasis. Cutis. 2014;94:46–53.
4. Hong CH, Papp KA, Lophaven KW, Skallerup P,
Philipp S. Patients with psoriasis have different
6
Topical Therapy II: Retinoids,
Immunomodulators, and Others
Lyn C. Guenther
Abstract
Tazarotene is the only topical retinoid
approved for treatment of psoriasis. Although
it is used primarily for plaque psoriasis, it may
be beneficial for palmoplantar and nail psoriasis. Use in combination with a mid- to superpotency topical steroid enhances efficacy and
reduces irritancy and the atrophogenic potential of steroids. Thrice a week use with a twice
weekly superpotent topical steroid may maintain improvement long-term. The once daily
fixed combination lotion containing the superpotent steroid halobetasol propionate and tazarotene 0.045% (Duobrii™) is convenient,
providing synergistic efficacy and unrestricted
duration of use until clearance occurs. Use of
tazarotene with broad band and narrow band
UVB can enhance efficacy and decrease the
cumulative dose of UV. Addition of tazarotene
to broadband or narrowband UVB, or PUVA
phototherapy enhances efficacy and decreases
the total dose of ultraviolet radiation. The calcineurin inhibitors pimecrolimus and tacrolimus and phosphodiesterase-4 inhibitor
crisaborole are not approved for treatment of
psoriasis, although they are efficacious and
L. C. Guenther (*)
Division of Dermatology, Western University, The
Guenther Dermatology Research Centre,
London, ON, Canada
e-mail: dgue@guenthermpc.com
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_6
well tolerated in the treatment of intertriginous, facial and genital psoriasis. The use of
tar and anthralin has declined with the development of cosmetically elegant, efficacious
treatments that do not stain the skin or clothing. Although coal tar contains many known
carcinogens, use in psoriasis has not been
associated with an increase in skin cancer.
Addition of tar to erythemogenic UVB does
not enhance efficacy.
Key Learning Objectives
1. To understand the mechanism of action
of topical retinoids, immunomodulators, and other topicals.
2. To understand the appropriate use and
efficacy of topical retinoids, immunomodulators, and other topicals.
3. To understand the safety issues of topical retinoids, immunomodulators, and
other topicals.
In addition to the commonly used topical corticosteroids and vitamin D analogues, there are
several other topical therapies which are used
in the management of psoriasis. Tazarotene, a
receptor-­selective topical retinoid, is the first
and only topical retinoid to be approved to
treat psoriasis. Topical tretinoin and isotreti51
L. C. Guenther
52
noin, two other ­retinoids, have been abandoned
due to the variable efficacy and irritancy of
tretinoin [1–5], and failure to show superior
efficacy of isotretinoin compared to placebo
[6]. The calcineurin inhibitors pimecrolimus
and tacrolimus are commonly used off-label
for intertriginous, facial, and genital psoriasis
[7]. Coal tar and anthralin were once in common use, however their use has declined with
the development of more cosmetically elegant,
efficacious agents [8].
Tazarotene
Tazarotene is available as a 0.05 and 0.1% gel
and cream [9] (Fig. 6.1).
Figure 6.1 also known as; Tazorac, Zorac,
Avage, 118292-40-3, tazaroteno, tazarotenum,
Suretin, Tazoral, AGN-190168. It is also available in a fixed combination lotion with halobetasol (Duobrii).
Tazarotene (marketed as Tazorac, Avage and
Zorac) is a prescription topical retinoid sold as a
cream or gel. Halobetasol propionate/tazarotene
lotion is a topical prescription superpotent steroid/retinoid combination. Tazarotene is approved
for treatment of psoriasis, acne and sun damaged
skin, while halobetasol/tazarotene is approved
for treatment of plaque psoriasis in adults. Unlike
other products that contain topical steroids, this
combination product does not have a limitation
on how long the product can be used.
S
C
C
N
O
O
Mechanism of Action
Tazarotene is a synthetic acetylenic retinoid
which is a prodrug. Its free-acid active metabolite
tazarotenic acid, binds to the nuclear retinoic acid
receptor (RAR) β and γ, weakly to RARα, but not
to retinoid X receptors (RXRs) [10]. RARγ is the
predominant subtype in the epidermis [11].
RARs affect gene transcription after forming heterodimers with RXRs [12]. Tazarotenic acid cannot be converted to other retinoids since it does
not contain isomerizable double bonds [10].
Tazarotene decreases inflammation and normalizes the abnormal keratinocyte hyperproliferation and differentiation seen in psoriasis [10].
The lymphocytic infiltrate in the dermis, number
of HLA-DR and intracellular adhesion molecule
(ICAM-1) positive cells in the epidermis and dermis, expression of epidermal growth-factor
receptor (EGFR), the hyperproliferative keratins
K16 and K6, skin-derived antileukoproteinase
(SKALP) and macrophage migration inhibitory
factor-related-protein-8 (MRP-8), keratinocyte
transglutaminase type 1 (TGase K), and involucrin, are reduced, and filaggrin expression in the
upper stratum spinosum and stratum granulosum
increased [10, 13]. SKALP is an elastase inhibitor [14] in the suprabasal layers of psoriatic epidermis, which is not present in normal epidermis
[15]. The enzyme TGase K and protein involucrin are involved in formation of the cross-linked
envelope and are prematurely expressed in psoriasis [16]. Tazarotene can also induce expression
of tazarotene-induced genes (TIG). TIG1 is a cell
adhesion molecule which promotes cell to-cell
contact and reduces keratinocyte proliferation
[17]. TIG2 is not anti-proliferative, but is involved
in keratinocyte differentiation [18, 19]. TIG3
regulates keratinocyte terminal differentiation
and cornified envelope formation through the
activation of type 1transglutaminase (TG1) [20].
Pharmacokinetics
Fig. 6.1 Also known as; Tazorac, Zorac, Avage, 118292-­
40-­
3, tazaroteno, tazarotenum, Suretin, Tazoral, AGN-­
The half life of tazarotene is 2–18 min [10].
190168 (Molecular Formula: C12H21NO2S. Molecular
Weight: 351.46194)
Tazarotene is converted via esterase metabolism
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
to its active metabolite tazarotenic acid which has
linear pharmacokinetics and a 1–2 h elimination
half-life [10]. Tazarotenic acid is then metabolized into inactive sulphoxide and sulphone
metabolites and more polar conjugate metabolites [10]. Fecal elimination peaks approximately
2.5 days after dosing and is for all intensive purposes complete by 1 week [21]. Urinary excretion is virtually complete by 2–3 days [21].
Tazarotene and tazarotenic acid do not accumulate in tissues [10]. In a study of 6 patients with
psoriasis, 4.54% of a 2 mg dose administered at a
concentration of 2.5 μg/cm2 was absorbed into
the stratum corneum, 1.38% into the epidermis,
and 0.97% into the dermis; 0.43% was recovered
in the feces and 0.33% in the urine [21]. The systemic absorption after an occluded 10 h 2 mg
application (2.5 μg/cm2) of tazarotene 0.1% gel
to the backs of 6 healthy males was 5.3% and
drug half life in blood and urine, 17–18 h [22].
Application of the 0.1% gel to 20% body surface
area (BSA) of healthy volunteers for 7 days
resulted in a mean Cmax +/− SD of tazarotenic
acid of 0.72 ± 0.58 ng/ml [23]. Low plasma concentrations of tazarotene (<0.15 ng/ml) and tazarotenic acid (0.05–6.1 ng/ml) were noted in
2.8% (2/72) and 47.2% (34/72) of patients treated
with 0.05% or 0.1% gel [24, 25]. In a similar
study, after 12 weeks of therapy only 1 psoriasis
patient had a low concentration (0.069 ng/ml) of
tazarotene, while 69.4% had detectable tazarotenic acid [26]. In two phase 3 cream studies, tazarotenic acid was found in approximately ½ of
the samples, with a highest concentration of
0.874 ng/ml [27].
Toxicology
In contrast to tretinoin, tazarotene and tazarotenic acid are not cytotoxic to Chinese hamster
ovary cells [28]. In addition, tazarotene is not
mutagenic [10]. In a 21-month mouse study, it
was not carcinogenic, however, in the hairless
mouse photocarcinogenicity study, similar to
other retinoids, it enhanced the photocarcinogenicity associated with ultraviolet irradiation [21].
53
Tazarotene 0.05% and 0.1% gels did not exhibit
phototoxic or photoallergic potential in healthy
adult Caucasians [29]. In common with other
retinoids, systemic tazarotene is teratogenic [10].
Topical tazarotene is contraindicated in pregnancy [30], although in clinical trials, healthy
babies were reported in all eight women who
inadvertently became pregnant [31].
Clinical Studies in Plaque Psoriasis
Clinical trials of tazarotene and other topicals are
summarized in Table 6.1. In the two phase 2 trials, 0.01% tazarotene aqueous gel was not found
to be efficacious, while 0.05 and 0.1% tazarotene
gels once and twice daily showed similar efficacy
with significant improvement in elevation, scaling, erythema and overall clinical severity of
plaques as early as 1 week [32]. Treatment-­
related adverse effects (primarily burning, pruritus, stinging, and erythema) occurred in 30% in
the first trial and 22.2% in the second trial. In the
second trial, up to 50% of plaques had erythema
of the surrounding skin.
In a phase 3, placebo-controlled study, once
daily tazarotene 0.05 and 0.1% gel for 12 weeks
had similar efficacy and were superior to vehicle
(p < 0.05) in all efficacy measures [24]. At the
end of treatment, 59% on 0.05% tazarotene gel
and 70% on the 0.1% gel had at least 50%
improvement. Twelve weeks after treatment discontinuation, 52% in the 0.05% group and 41%
in the 0.1% group continued to have at least 50%
improvement. Treatment related adverse effects
(AEs) consisted primarily of mild to moderate
local irritation. A small uncontrolled study
(n = 43) suggested that these AEs could be minimized without compromising efficacy, by short-­
contact application for 20 min followed by
washing with water [33]. Two phase 3 placebo-­
controlled cream studies involving 1303 patients
showed that tazarotene 0.05 and 0.1% creams
were significantly better than vehicle with regards
to overall assessment, global response to treatment, and reduction in plaque elevation and scaling [27]. One of the studies included a 12-week
L. C. Guenther
54
Table 6.1 Clinical trials of tazarotene in psoriasis
Study
Krueger
et al.
(1998)
[32]
# Patients
45 (with 90
bilateral
symmetrical
plaques)
Treatment
2 of: 0.01 or 0.05%
tazarotene (taz) gel, or
vehicle gel BID × 6 weeks
Krueger
et al.
(1998)
[32]
108 (with
216 bilateral
symmetrical
plaques) [31]
2 of the following: 0.05%
taz gel OD or BID, 0.1%
taz gel OD or
BID × 8 weeks then
8 weeks follow-up
Weinstein
(1997)
[24]
324 with 318
evaluable
[24]
Taz 0.05, 0.1% gel or
vehicle gel OD × 12 weeks
then 12 weeks follow-up
Taz 0.05 and 0.01% similar
and better than placebo in
all efficacy measures
(p < 0.05).59% on 0.05 and
70% on 0.1% had ≥50%
improvement. At
follow-up, 52 and 41%
respectively maintained
improvement.
Weinstein
et al.
(2003)
[27]
1303 in 2
studies
Taz 0.05 or 0.1% cream
(cr) or vehicle × 12 weeks
(with 12 weeks follow-up
in 1 study)
Taz 0.05 and 0.1% more
efficacious than vehicle.
12 weeks pooled data:
25.3% on vehicle, 41.1%
on taz 0.05 and 44.9% on
0.1% taz had an overall
lesional assessment ≤mild.
Lebwohl
et al.
(1998)
[26]
348 with 340
evaluable for
efficacy
Taz 0.05, or 0.1% gel OD
OR fluocinonide 0.05% cr
BID × 12 weeks with
12 weeks follow-up period.
At week 12, no significant
difference between taz
&fluocinonide. More rapid
relapse with fluocinonide
after treatment
discontinuation
Tzung
et al.
(2005)
[34]
23, but 19
evaluable
with 44
lesion pairs
Comparable efficacy at
week 12 Taz: Greater
maintenance of
improvement
Kaur et al.
(2008)
[35]
20
Taz 0.1% gel
OD + petrolatum, or,
calcipotriene 0.005% ung
BID × 12 weeks with
4 weeks follow-up
Left side: Taz 0.05% or
0.1% gel OD × 8 weeks
right side: Calcipotriene
0.005% BID
Kumar
et al.
(2010)
[36]
30, with 27
evaluable for
per protocol
Taz 0.1% gel OD right side
5% crude coal tar (CCT)
ung OD left
side × 12 weeks. 8 weeks
follow-up
Efficacy
0.01% taz: Minimal
efficacy. 45% on 0.05% gel
had ≥75% improvement
vs. 13% on vehicle.
(p < 0.05)
No significant differences
in ≥75% improvement
with Rx (range: 48% with
0.05% taz OD to 63% with
0.05% taz BID) or 8 weeks
follow-up
Comparable efficacy of OD
taz 0.1% & BID
calcipotriene. Greater
efficacy of calcipotriene
than OD taz 0.05%
No significant difference
between 2 sides (74.15%
ESI reduction with taz;
77.37% with CCT,
p > 0.05)
Safety
33% of plaques had Rx
related adverse effects
(AEs), especially
erythema and pruritus
Rx-related AEs in 22.2%
(burning, pruritus,
stinging, erythema; 13%
with 0.05% OD vs. 30%
with 0.1% BID).
Perilesional erythema in
½. Rx withdrawal due to
AEs in 5.1%.
Mild to moderate
irritation: Pruritus (8%
on vehicle, 17% on
0.05% taz, 23% on 0.1%
taz), burning (6, 15, 19%
respectively), erythema
(1, 7, 8% respectively).
Withdrawal due to AEs:
3, 10 and 12%
respectively
In the 2 studies, pruritus
on vehicle: 12.2 and
8.9%, vs. 16.1 and 7.1%
on taz 0.05%, and 29.4
and 15.6% on taz 0.1%.
Taz: More burning,
stinging, desquamation,
skin irritation, erythema
Taz: Mild to moderate
pruritus, burning,
erythema. Fluocinonide:
Minimal irritation.
Withdrawal due to AEs:
12% on taz 0.05,18% on
0.1% taz, 2% on steroid.
Irritation in 35% on taz
and 0% on calcipotriene
No discontinuation due
to AEs. No statistically
significant difference in
AEs between the 2 sides
AEs in 48.1% on taz, but
none on CCT
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
55
Table 6.1 (continued)
Study
Lebwohl
et al.
(1998)
[37]
# Patients
300 with 284
evaluable for
efficacy and
299 for safety
Dubertret
et al.
(1998)
[39]
398
Dhawan
et al.
(2005)
[41]
Green and
Sadoff
(2002)
[42]
10
Koo and
Martin
(2001)
[43]
73
Taz 0.1% gel
OD + mometasone furoate
0.1% cr OD, or,
mometasone furoate 0.1%
cr BID × up to 12 weeks
With 12 weeks follow-up if
clear by week 4 or ≥ 50%
better by week 12
Guenther
et al.
(2000)
[44]
120
Taz 0.1% + 0.1%
mometasone furoate OD or,
calcipotriene 0.005%
BID × 8 weeks +12 weeks
follow-up if clear at week 2
or 4, or week 8 ≥ 50%
better
259 with 229
evaluable
Treatment
Taz 0.1% gel OD +
(fluocinolone acetonide
0.01% cr or mometasone
furoate 0.1% cr or
fluocinonide 0.05% cr or
placebo [Glaxal®
base]) × 12 weeks
+4 weeks follow-up
Taz 0.1% gel alternate
evenings with: 1%
hydrocortisone, 0.05%
aclometasone dipropionate,
betamethasone valerate
0.1%, or placebo
Taz 0.1% cr OD + 0.12%
betamethasone valerate
foam OD × 12 weeks (open
label)
Taz 0.1% gel hs +/− am
steroid (fluocinonide 0.05%
ung, 0.1% mometasone
furoate ung, 0.05%
diflorasone diacetate ung,
0.05% betamethasone
dipropionate cr, 0.005%
fluticasone propionate ung,
or 0.05% diflorasone
diacetate cr) × 12 weeks
Efficacy
Taz + mometasone furoate
0.1% or fluocinonide
0.05% was superior to taz
0.1% + placebo after 2, 8
and 12 weeks. Similar
efficacy of fluocinolone &
placebo groups
Safety
Burning peaked at week
4 and was seen in 19%
in the taz + placebo
group compared to
7–15% in the
taz + steroid groups
Greater reduction in
elevation, scaling and
erythema with
taz + betamethasone
valerate. Median time to
50% improvement was
2 weeks vs. 4 weeks in the
other groups
2 clear at week 4. No AEs
4 clear at week 8.1 patient
did not have any
improvement
The greatest efficacy was
seen with betamethasone
dipropionate cr (50% mean
reduction vs. 20% with
monotherapy, p ≤ 0.001),
followed by mometasone
furoate ung (41%
reduction, p ≤ 0.05) and
diflorasone
Diacetate ung (38%
reduction, p ≤ 0.05).
Maximal improvement at
8 weeks
Greater, more rapid global
improvement, plaque
elevation and scaling with
taz + steroid vs. steroid
monotherapy (p ≤ 0.05 by
week 4 or 8)
Fewer treatment-related
AEs with steroids (36%
with hydrocortisone,
32% with aclometasone,
31% with
betamethasone) vs. 42%
with placebo
At week 2, ≥75%
improvement in 45% on
taz + steroid vs. 26% on
calcipotriene (p ≤ 0.05).
Also greater reduction in
BSA, elevation, scaling and
erythema
No AEs
The mometasone furoate
ung regime was best
tolerated (17% incidence
of drug-related AEs vs.
40% with taz
monotherapy). There
were no treatment-­
related withdrawals due
to AEs in the
mometasone furoate ung
regimen vs. 18% on taz
monotherapy
1 dermatitis on
mometasone.
Taz + steroid: 19% Rx
related AEs at week 4,
17% at week 8 and 0%
at week 12. Burning
11%, pruritus 11%,
irritation 9%, eruption
6%, new psoriasis or
exacerbation 6%
Greater AEs with
taz + steroid. [42% vs.
8% burning, 32% vs.
13% pruritus, 28% vs.
12% irritation, 25% vs.
7% erythema (p ≤ 0.05)
for each AE]
(continued)
L. C. Guenther
56
Table 6.1 (continued)
Study
Tanghetti
et al.
(2000)
[45]
# Patients
1393
Treatment
Taz 0.05% or 0.1% gel OD
for up to 12 weeks either as
monotherapy or in
combination with other
topicals (open label)
Efficacy
Increased efficacy with
adjunctive emollient and/or
corticosteroid
Adjunctive mid- or high
potency steroid is at least
as efficacious and often
superior to super potent
steroid
Marked reduction in
scaling, elevation and
overall lesional severity on
both sides (p < 0.0001)
with no difference between
the 2 sides. More
improvement of erythema
with clobetasol (p < 0.01)
At week 8, 52.5%, 33.3%,
18.6% and 9.7%
respectively had treatment
success (IGA clear/almost
clear + at least a 2-grade
improvement from
baseline)
Bowman
et al.
(2002)
[48]
15 with 28
lesion pairs
Taz 0.1% gel
OD + calcipotriene 0.005%
gel BID, or, clobetasol ung
BID × 2 weeks, then
4 weeks follow-up (open
label)
Sugarman
JL et al.
(2017)
[50]
212
Phase 2. Halobetasol
propionate (HP) 0.01%/taz
0.045% lotion vs. HP vs.
taz vs. vehicle OD x
8 weeks
Stein Gold
L et al.
(2018)
[51]
418
2 phase 3 studies HP/taz
lotion or vehicle od X
8 weeks
Lebowohl
MG et al.
(2019)
[52]
555
HP/taz lotion daily x
8 weeks, then as needed in
4 week intervals up to 24
continuous weeks.
Koo
(2000)
[53]
54 patients
with 108
target lesions
Broad band UVB 3×/week
½ body with +2/3: No
topical, vehicle, or taz 0.1%
gel OD × 2 weeks pre-UV,
then 3×/week
Time to 50% improvement
reduced by ½ (25 days vs.
53 days) cumulative UVB
reduced by 76%
Behrens
et al.
(2000)
[54]
10
½ body hs taz 0.05% gel or
emollient +311 nb UVB
5×/week
After 4 weeks, 64% PASI
reduction taz vs. 48%
At week 8, 35.8% (study 1)
and 45.3% (study 2) had
treatment success (IGA
clear/almost clear + at least
a 2-grade improvement
from baseline)
At week 24, 20.9%
discontinued treatment due
to lack of efficacy
Safety
Increased tolerability
with adjunctive steroid
more AEs with
monotherapy (22% at
week 4) vs. 13% with
mid- or high potency
steroid or 12% with
super-potent steroid
No Rx withdrawal due
to AEs no Rx-related
AEs with Clobetasol
Taz/calcipotriene:
Asymptomatic erythema
in 53%, peeling in 33%,
pruritus in 7 and
irritation in 7%
Application site pain,
pruritus, and erythema
most frequent with taz
(22.4%) and 0.2%HP/taz
(10.2%)
Comparable number of
patients on HP/taz
(3.4%) and vehicle
(3.2%) reporting ≥1AE
leading to
discontinuation vs.
12.2% on taz
monotherapy
Contact dermatitis
(6.3%), pruritus (2.2%)
and pain at the
application site (2.6%)
were the most common
treatment-related AEs
7.5% discontinued due
to treatment-emergent
AEs: Dermatitis (7
people), pruritus (7
people) and pain (6
people), being the most
common
Taz + UVB: No
photosensitivity or
phototoxicity 16.7% had
Rx-related AEs
(irritation, burning and
pruritus)
Mild irritation with taz,
but no phototoxicity
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
57
Table 6.1 (continued)
Study
Stege
et al.
(1998)
[55]
Dayal
et al.
(2018)
[56]
# Patients
20
Behrens
et al.
(1999)
[58]
12
½ body taz 0.05% gel or
vehicle + bath PUVA 4×/
week
Tzaneva
et al.
(2002)
[59]
31
Oral PUVA 4 × weeks
+0.1% taz gel (0.05% if not
tolerated) 1 lesion 1 side,
tacalcitol ung 1 lesion
opposite side
30
Treatment
0.1% taz gel or 5%
salicylic acid 1 week before
& during 3 weeks narrow
band (nb) UVB
2 target plaques on right
and left sides of body.
Right side treated with taz
0.05% gel + nbUVB BIW;
left side with nb UVB BIW
follow-up phase; treatment response was generally maintained after the drug was discontinued.
In this study, an overall lesional score of mild or
better was noted at the end of the 12 weeks treatment period and 12 weeks follow-up period in
24.4 and 21.8% respectively on vehicle, 41.7 and
33.4% respectively on 0.05% tazarotene, and
39.4 and 30.3% respectively on tazarotene 0.1%
cream. The skin-associated treatment-related
AEs including pruritus, burning, erythema, skin
irritation, stinging and desquamation were more
common in the tazarotene arms, particularly the
0.1% arm. In a steroid comparison study, after
12 weeks of therapy, tazarotene 0.05 and 0.1%
gels had comparable efficacy to fluocinonide
0.05% cream [26]. However, the psoriasis
returned faster in the steroid group. In those
patients who achieved an overall lesional score of
mild or better at the end of treatment, relapse to a
score of moderate or worse was noted at the end
of the 12 weeks follow up period in 18% in the
0.1% arm, 37% in the 0.05% tazarotene arm, and
55% in the fluocinonide arm (p < 0.05% between
Efficacy
Significantly faster and
greater efficacy in ½ body
treated with taz
Safety
At week 12, target plaque
score reduced by 99.64%
and 84.92% respectively
Complete clearance in
96.7% and 6.7%
respectively
16.4 +/− 2.8 and 23.33
+/− 1.2 sessions
respectively for clearance
Faster and greater efficacy
with taz. At 3 weeks,
76.5% median PASI
reduction vs. 58.5%.
(p < 0.05)
Similar efficacy with taz
and tacalcitol. Compared to
PUVA mono-therapy, the
cumulative UVA was less
with taz or tacalcitol
(p < 0.01)
Lesional irritation
6.67%, burning 3.33%,
pruritus 6.67% with taz
No statistically
significant difference
between the 2 sides
(p = 0.352)
No photo-toxicity. With
taz, mild irritation
(transient burning and
erythema)
Tacalcitol: 1 mild irritant
dermatitis, 1
hypertrichosis Taz: 7
had AEs (dryness,
irritant dermatitis,
pruritus, burning);
resolved after changed
to 0.05%
tazarotene 0.1% gel and fluocinonide). A small
right/left study showed similar efficacy of tazarotene 0.1% gel once daily + emollient once daily
and calcipotriene BID, and however tazarotene
was more irritating, but had a better maintenance
effect after treatment discontinuation (overall
severity p = 0.007, erythema p = 0.01, scaling
p < 0.001, elevation p < 0.001) [34]. In a small
open label right/left pilot study of 20 patients,
twice daily calcipotriene was also found to be
comparable to once daily 0.1% tazarotene, but
was more efficacious than once daily 0.05% tazarotene [35]. A small (n = 30) open-label right/
left study showed that tazarotene and 5% crude
coal tar ointment had similar efficacy as measured by erythema, scaling and induration (ESI)
[36].
Addition of a mid-potency corticosteroid
(mometasone furoate 0.1% cream) or high
potency cream (fluocinonide 0.05% cream)
improved efficacy and reduced adverse effects
[37]. At least 50% improvement was noted in
91% and 95% in the mid- and high-potency ste-
58
L. C. Guenther
roid arms respectively compared to 80% in the severity [46]. In another similar subset study
placebo arm. The cumulative rates of burning involving 246 patients switched from calcipotriwere only 61% as frequent in the mid-potency ene + steroid at baseline to tazarotene + steroid,
steroid arm (14%), and 52% as frequent in the 75% achieved at least 50% global improvement
high-potency steroid arm (12%) compared to the at the final visit (up to 12 weeks) [47]. A small
placebo arm (23% rate). Addition of a low-­ open-label right/left comparison pilot study
potency steroid (fluocinolone acetonide 0.01%) (n = 15) showed similar efficacy of tazarotene +
had minimal additive benefit. Tazarotene can also calcipotriene ointment, and the superpotent stereduce the development of steroid induced epi- roid clobetasol ointment [48].
dermal atrophy. In a 4-week long study of healthy
Tazarotene can be used to maintain improvevolunteers, epidermal thickness was reduced by ment. After a 6 weeks open-label treatment phase
43% with diflorasone diacetate ointment mono- with tazarotene 0.1% gel + clobetasol propionate
therapy vs. 28% when used in combination with 0.05% ointment, a double-blind 5 months maintazarotene 0.1% gel (p ≤ 0.003) [38]. Another tenance phase showed that those on tazarotene
study showed that combination therapy with taz- Monday, Wednesday, Friday + clobetasol
arotene 0.1% gel used alternate evenings with Tuesday, Thursday maintained 75% global
betamethasone valerate 0.1% enhanced efficacy improvement (p ≤ 0.001 vs. vehicle group,
and tolerance [39, 40]. The foam formulation of p ≤ 0.05% vs. tazarotene/vehicle), those on tazbetamethasone valerate (0.12%) was studied in a arotene Monday, Wednesday, Friday + vehicle
small open-label study involving 10 patients; all Tuesday, Thursday 50% improvement, and those
but 1 had improvement and 4 were clear at week on vehicle Monday, Wednesday, Friday + white
8 [41]. In an effort to determine the optimal ste- petrolatum Tuesday, Thursday, 25% improveroid to use with tazarotene, tazarotene monother- ment [49].
apy was compared to combination therapy with 3
A fixed combination of halobetasol propiodifferent high-potency and 3 different mid-to-­ nate (HP) 0.01% and tazarotene (taz) 0.045%
high-potency steroids [42]. Greatest efficacy was lotion had greater treatment success (i.e.
seen when tazarotene 0.1% gel was used in com- Investigator Global Assesssment (IGA) of clear/
bination with betamethasone dipropionate 0.05% almost clear with at least a 2-grade improvement
cream, followed by mometasone furoate 0.1% from baseline) at week 8 (52.5%) vs. HP (33.3%,
ung and diflorasone diacetate 0.05% ung. The p = 0.033), taz (18.6%, p < 0.001), and Vehicle
best tolerated regimen was the tazarotene + (9.7%, p < 0.001) in a phase 2, multicenter,
mometasone furoate 0.1% ung, making this regi- double-­blind study [50]. In two phase 3 trials, by
men the one with the optimal balance of efficacy week 8, treatment success occurred in 35.8%
and tolerability. Tazarotene 0.1% gel in combina- (study 1) and 45.3% (study 2) compared with
tion with mometasone furoate 0.1% cream once 7.0% and 12.5% on Vehicle (p < 0.001) [51]. A
daily was shown to be more efficacious than rapid onset of action was noted in both studies;
twice daily mometasone furoate cream [43] and by 2 weeks, HP/Taz lotion was statistically sigtwice daily calcipotriene 0.005% ointment [44].
nificantly superior to vehicle [50, 51]. In a 1-year
A large (n = 1393) open-label effectiveness open label study (n = 555) with a focus on safety,
study also showed that mid- to high potency ste- HP/taz lotion was applied daily for 8 weeks, then
roids were optimal potencies to be used in combi- as needed [52]. Those without an IgA of clear/
nation with tazarotene, and that superpotent almost clear at week 8 were treated for additional
steroids were not superior [45]. A subset of 166 4 weeks. At week 12, those with no improvement
patients were switched from calcipotriene +/− a in IGA from baseline were discontinued (4.7%).
steroid to tazarotene + a steroid. There was a sub- For the remainder of the study, patients were
stantial improvement in efficacy and patient sat- treated for 4 weeks with HP/taz if they had an
isfaction of these patients with 71% having at IGA of 2 or more at a visit, to a maximum of
least a 1 grade improvement in overall psoriasis 24 weeks continuous treatment. At week 24,
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
20.9% discontinued treatment due to lack of efficacy. The rate of adverse events was similar to
that in the pivotal trials, peaked at day 60 and
remained stable from day 90 until the end of the
study. Treatment-emergent AEs resulted in discontinuation of 7.5% of study participants.
Addition of tazarotene to phototherapy can
enhance efficacy and decrease he total dose of
ultraviolet (UV) radiation. Daily pre-treatment
with 0.1% tazarotene gel for 2 weeks, then three
times a week immediately after broad band UVB
treatment, increased the rapidity of improvement
and overall efficacy [53]. The time to reach 50%
improvement decreased from 53 days to 25 days
with an associated 76% reduction in median
cumulative UVB exposure (390 vs. 1644 mJ/
cm2). The time to reach 75% improvement was
28 days earlier. By day 81, 75% improvement or
better occurred in 50% on UVB monotherapy
versus 82% on UVB + tazarotene 0.1% gel. No
treatment related photosensitivity or phototoxicity were noted. Similar results were seen with
narrow-band (nb) UVB. In a small study (n = 10),
after 4 weeks of 5×/week nb UVB, the psoriasis
area and severity index (PASI) score decreased
from 18.3 to 6.5 (95% confidence interval (CI)
5.29–7.91) with the addition of tazarotene 0.05%
gel hs, compared to 9.5 (95% CI 7.70–11.70)
with emollient (p < 0.05) [54]. In a half body
study involving 20 patients, tazarotene in combination with nb UVB was more efficacious than
5% salicylic acid with nb UVB [55]. In an open-­
label trial (n = 30), a target plaque was picked
from similar sites on each side of the body [56].
Both sides were treated with nb UVB, but the
right side was also treated with topical tazarotene
0.05% gel. After 12 weeks of therapy, the mean
target plaque was reduced by 99.64% in the
taz + nb UVB side vs. 84.92 on the nb UVB
monotherapy side. Complete clearance was
achieved at the end of 12 weeks in 96.67% vs.
6.67%. Fewer treatment sessions were required
for clearance on the tazarotene side (16.40
=/−2.799 vs. 23. 33 =/−1.212. Tazarotene nb
UVB combination therapy was found to be similar to calcipotriene nb UVB combination therapy
in a study of 10 patients [57].
59
Psoralen ultraviolet A (PUVA) studies have
also shown added benefit with topical tazarotene.
In a ½ body bath PUVA study (n = 12), the side
treated with tazarotene improved faster and to a
greater extent [58]. After 3 weeks, the median
PASI reduction was 76.5% (95% confidence
interval (CI) 65–86) compared to 58.5% (95% CI
50–69). No phototoxic effects were seen. In an
oral PUVA study (n = 31) addition of tazarotene
gel or tacalcitol ointment resulted in faster clearing and 14 rather than 16 PUVA exposures [59].
linical Studies in Other Types
C
of Psoriasis (Palmoplantar, Nail)
Tazarotene is efficacious in the treatment of palmoplantar and nail psoriasis. In a 12-week randomized trial with 30 patients with palmoplantar
psoriasis randomized to once daily 0.1% tazarotene cream or 0.05% clobetasol propionate
cream, there was no significant difference in the
reduction in the erythema scaling fissures and
induration (ESFI) score between the two groups
(83.2 and 89.1% respectively) and complete
clearance (52.9 and 61.5% respectively) [60].
A double-blind, vehicle-controlled 24-week
study (n = 31) showed greater reduction in onycholysis (p ≤ 0.05% weeks 4 and 12) and pitting
(p ≤ 0.05 at week 24) in occluded and nonoccluded tazarotene 0.1% gel treated nails [61]. An
open-label study (n = 35) showed fingernail
improvement after only 4 weeks with nonoccluded tazarotene 0.1% gel applied to the nail
plates, nail folds and periungual skin [62].
Hyperkeratosis and oil drop changes responded
faster; pitting was the most persistent. After
12 weeks of treatment of fingernails and toenails,
the mean visual assessment score for onycholysis
decreased from 26 to 2, hyperkeratosis 25 to 2,
oil spots 18 to 3, and pitting 13 to 1 (p < 0.0001
for each change). A case report in a 6-year-old
child showed that 8 weeks treatment with nonoccluded 0.05% tazarotene gel improved nail psoriasis, especially hyperkeratosis [63]. Occluded
tazarotene 0.1% cream and clobetasol propionate
0.05% cream had similar efficacy in a double-­
L. C. Guenther
60
blind study of 46 patients with nail psoriasis [64].
Both treatments showed significant improvement
in onycholysis, hyperkeratosis, salmon patches
and pitting.
Application Tips
Since tazarotene is photostable, it can be applied
at any time of day [65]. When used in combination with a topical steroid, both compounds can
be used at the same time of day without adversely
affecting each other’s stability [66]. The gel and
cream formulations rub in well and do not stain.
Only a small quantity is needed; larger amounts
can increase the risk of irritation [67]. A cotton-­
tipped applicator to apply tazarotene and application of moisturizer around psoriatic lesions can
minimize perilesional irritation from inadvertent
application to unaffected skin. The gel and cream
should be dry before clothes are worn to minimize spread onto unaffected skin. The 0.05% formulation should be considered for individuals
with sensitive skin [67]. If irritation should occur,
use of the 0.05% cream formulation rather than
the gel, alternate day treatment, and short contact
treatment for as little as 5 min followed by a corticosteroid or emollient immediately after the
tazarotene has been washed off, should be considered [67].
opical Calcineurin Inhibitors
T
(Immunomodulators) Pimecrolimus
and Tacrolimus
Topical pimecrolimus is available as a 1% cream
and tacrolimus as a 0.03 and 0.1% ointment.
They were approved by the FDA in 2001 and
2000 respectively [68]. Pimecrolimus is a derivative of the ascomycin macrolactam while tacrolimus was isolated from the bacterial strain
Streptomyces tsukubaensis [68]. They are indicated to treat atopic dermatitis. Although they are
not FDA approved for the treatment of psoriasis,
they are efficacious in the treatment of intertriginous, facial and genital psoriasis [69]. (Fig. 6.2).
A macrolide isolated from the culture broth of
a strain of Streptomyces tsukabaensis that has
strong immunosuppressive activity in vivo and
prevents the activation of T-lymphocytes in
response to antigenic or mitogenic stimulation
in vitro.
Mechanism of Action
After binding to macrophilin-12, topical calcineurin inhibitors inhibit the calcium dependent
phosphatase calcineurin, which in turn results in
inhibition of translocation of nuclear factor of
activated T cells (NFAT) and down regulation of
cytokine synthesis [7].
Toxicity
Application site burning is the most frequent
adverse drug reaction [7]. The FDA issued a controversial lymphoma “black box” warning in
March 2006 [68]. This warning noted that,
although a causal relationship has not been
­established, rare cases of malignancy (e.g., skin
and lymphoma) have been reported in patients
treated with topical calcineurin inhibitors. A
study of 293,253 patients with atopic dermatitis,
did not find an increased risk of lymphoma associated with use of calcineurin inhibitors [70]. The
main factor associated with an increase risk of
lymphoma was disease severity [70]. A 2015
Cochrane review of tacrolimus found no evidence to support a possible increased risk of cancer [71].
In contrast to topical steroids, calcineurin
inhibitors are not atrophogenic [72]. Tacrolimus
has been shown to increase collagen synthesis
[73] and pimecrolimus to reverse skin atrophy
[74].
Clinical Studies in Psoriasis
In the treatment of plaque psoriasis, non-occluded
tacrolimus was effective in two small studies
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
Fig. 6.2 Also known
as: TACROLIMUS
MONOHYDRATE,
Protopic (TN),
109581-93-3, FK-506
monohydrate,
Tacrolimus (USAN/
INN), Tacrolimus
hydrate (JP16), F4679_
SIGMA (Molecular
Formula: C44H71NO13;
Molecular Weight:
822.03344)
61
H
H
O
H
O
O
H
H O
O
H
H
O
O
H
N
O
O
O
O
O
H
O
(one monotherapy [75] and one with concurrent
6% salicylic acid gel [76]) but not in another
[77], while occluded tacrolimus [75, 78] and
pimecrolimus [79] were. Studies in inverse psoriasis are summarized in Table 6.2. In one study
(n = 57), after 2 weeks of 1% pimecrolimus,
71.4% were clear/almost clear vs. 20.7% on vehicle (p < 0.0001) [80]. Only 1 patient on pimecrolimus had a treatment-related AE (paresthesia).
However a 4-week study did not show superiority
of pimecrolimus over vehicle [81]. In a small
study (n = 15), the mean total score for erythema,
scaling and thickness on the face, genitalia and
intertriginous area decreased from 6.88 at baseline to 0.37 after 60 days of tacrolimus 0.1% oint-
ment. Two patients experienced a warm sensation
in facial lesions after application. In an 8-week
open label study of 21 patients with intertriginous and/or facial psoriasis treated with 0.1%
tacrolimus, all patients had at least 75% improvement and 81% were clear [82]. In a study of 167
patients with intertriginous and/or facial psoriasis, by day eight 24.8% treated with 0.1% tacrolimus vs. 6% on vehicle were at least 90% better
(p = 0.004); by 8 weeks, the numbers had risen to
66.7 and 36.8% respectively (p < 0.0001) [83].
The face and intertriginous areas showed similar
improvement (42% with facial and 48% with
intertriginous lesions were clear) [84]. Similar
efficacy (47.6% clear) was seen in an open label
L. C. Guenther
62
Table 6.2 Studies of calcineurin inhibitors in inverse psoriasis
Study
Gribetz
et al.
(2004)
[80]
# Patients
57
Treatment
Pimecrolimus (P)
1% cream or
vehicle (V)
BID × 8 weeks
Kreuter
et al.
(2006)
[81]
80
P 1% cream or
calcipotriene (C)
0.005% or 0.1%
betamethasone
valerate (B) or
vehicle
(V) × 4 weeks
Matyin
Rzquerra
et al.
(2006)
[75]
15
0.1% tac
ung × 60 days
(open label)
Freeman
et al.
(2003)
[82]
Lebwohl
et al.
(2004,
2005) [83,
84]
21 intertriginous
and/or facial
psoriasis (2/21 face
only)
104 intertriginous
167 with
intertriginous and/or
facial psoriasis
0.1% tac
(tac) × 8 weeks
(open label)
Steele
et al.
(2005)
[86]
13 children
12 with 0.1% tac 1
with 0.03% tac
(retrospective
review)
Brune
et al.
(2007)
[87]
8 children with
intertriginous/11
with face and/or
intertriginous
psoriasis
0.1% tac
BID × 180 days
(open label)
0.1% tac ung or V
BID × 8 weeks
facial study (n = 21), although 5/10 with complete clearing had recurrences during 1 month of
follow-up [85]. Adverse effects of tacrolimus.
were not significantly different than in the placebo arm [83]. Studies in children have also
shown efficacy of tacrolimus in facial and intertriginous psoriasis [86, 87]. In one open label
study, marked improvement was noted in all 10
patients with long-standing genital and facial
psoriasis after 1 week of 0.1% tacrolimus ointment [88], and in another one (n = 12), male gen-
Efficacy
Clear/almost clear: Day 3:
14.3% on P, 0% on V,
p = 0.0477
Week 8: 71.4% on P, 20.7%
on V, p < 0.0001
Mean M-PASI score
reduction: B: 86.4%, C:
62.4%, P: 39.7%, V: 21.1%.
No significant difference
between B and C, P and C,
and P and V. B better than P,
p < 0.05 and V, p < 0.01. C
better than V, p < 0.01.
Erythema decreased from 2.9
at baseline to 0.19, infiltration
from 2.1 to 0.11 and
desquamation from 1.8 to 0.07.
(for each, p < 0.001) N.B.
includes face + genital psoriasis
Complete clearing in 81%
and 75–99% clearing in 19%
(N.B. includes 2 pts. with
only facial lesions)
48% with intertriginous
psoriasis on tac were clear vs.
14% on V (p < 0.001)
12/12 on 0.1% tac had
complete clearance within
2 weeks
No improvement in 1 patient
on 0.03% but difficulty with
adherence
Reduction in overall severity
incl. Face (1.63 to 0.71,
p < 0.0001) in the 8 who
completed
Safety
1 mild application site
paresthesia with P 1
moderate tenderness
with V. no withdrawal
due to AEs
P: 5/20 mild itching
and burning
C: 2/20 increased
erythema, warmth,
irritation
B: No AEs
V: 1/20 herpes
genitalis
2 had a transient
warm sensation
2 had itching and a
feeling of warmth
Burning in 8% on tac,
7.3% on V,
hyperesthesia in 4.5%
on tac and 0% on V,
itching in 7.1% on tac
and 1.8% on V. all NS
1 on 0.03% had
burning and irritation
Pruritus in 1
ital PASI decreased from 15.8 to 1.2 (p < 0.001)
after 8 weeks of twice daily tacrolimus 0.1%
ointment [89]. Success in male genital psoriasis
has also been reported with pimecrolimus [90]
Crisaborole 2% Ointment
Crisaborole 2% ointment is a phosphodiesterase­4 inhibitor approved for the treatment of mild-to-­
moderate atopic dermatitis. It is not approved for
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
treatment of psoriasis. In a double-blind vehicle-­
controlled study involving 21 individuals with
intertriginous, anogenital, or facial psoriasis,
after 4 weeks of therapy, the crisaborole arm had
66% improvement in the Target Lesion Severity
Scale (TLSS) compared to 9% improvement with
vehicle [91]. There were no application site reactions, atrophy or telangiectasia [91].
Tar
Although the German Guidelines [7] do not recommend tar for psoriasis treatment and describe
it as “obsolete,” tar is still widely used in many
parts of the world [92]. Tar has been used for
more than 2000 years and became standard treatment with ultraviolet B phototherapy after
Goeckerman’s report in 1925 [92]. There are 3
types of tar, coal tar, wood tar (pine, beech, birch,
juniper), and shale (ichthammols, bituminous
tars) [93]. Coal tar comes from coal distillation in
the manufacture of coke and contains approximately 10,000 compounds including polycyclic
aromatic hydrocarbons such as benzenes, naphthalenes, creosoles and phenols [94]. The temperature of the distillation and type of coal used
affect the final composition [95]. Liquor Carbonis
Detergens (LCD) is an alcoholic extract of coal
tar that can be mixed in cream, ointment or
lotions bases, usually in a concentration of
5–15% [94].
Mechanism of Action
Tar inhibits DNA synthesis which in turn results
in decreased epidermal proliferation [92]. It is
also said to be vasoconstrictive, antifungal, antiparasitic, and antipruritic [92].
Toxicity
Coal tar is malodorous, can stain hair and fabric
and unlike wood and shale tars, is photosensitizing at wavelengths of 330–550 nm [892. It can
also cause burning, stinging (“tar smarts”), fol-
63
liculitis, acneiform eruptions, irritation, allergic
contact dermatitis, erythroderma, tar keratoses
and keratoacanthomas [92]. Acute tar intoxication may occur if tar is ingested, or if large
amounts of tar are absorbed after topical application; erythrodermic psoriasis patients and young
children are at a higher risk [92]. Carcinogenicity
concerns arose after Sir Percival Pott, a London
surgeon, linked the increased risk of scrotal cancer in chimney sweeps to soot [96], however
there was no increase in the expected rate of skin
cancer a study of 719 patients with psoriasis [97]
and a 25-year follow-up study of 280 patients
treated with crude coal tar and UVB [98].
Clinical Studies in Psoriasis
Tar extract in oil was superior to the oil base in
5 subjects [99], however coal tar was significantly less effective than betamethasone valerate (38% mean PASI reduction vs. 69%) in
another study [100]. Concentrations of 1 and
6% crude coal tar have similar efficacy when
used with UVB [101]. Daily UVB and tar ointment three times a day for an average of 20 days
yielded good to excellent improvement in 95%
of 123 patients with remission rates of 2 months
to 8 years (average 1.7 years) [102]. In a similar
study, 60% of patients were still in remission
2 years after treatment [103]. With erythemogenic doses of UVB, a number of studies failed
to show increased efficacy with tar compared to
petrolatum [104–108]. Studies with suberythemogenic UVB showed less UVB energy and
fewer side effects with tar oil vs. emollients in
one study [109], faster improvement with 1%
crude coal tar in petrolatum vs. petrolatum
(22%/week vs. 14.7%/week, p < 0.0005) and
5% tar extract in oil vs. oil base (19.6%/week
vs. 11.4%/week, p < 0.0005) in another [107],
and no benefit in another [110]. Menkes et al.
showed similar efficacy of suberythemogenic
UVB with tar oil, and maximally erythemogenic
UVB with emollients in a study of 49 patients
with psoriasis, however the total UVB dose to
clearing was 44% less in the suberythemogenic
UVB with tar group [111].
L. C. Guenther
64
Anthralin
Anthralin (1,8-dihydroxyanthrone) was first synthesized in 1916 by Galewsky in Germany, after
chysarobine, a related compound from Goa powder produced from the araroba tree in Brazil, was
noted to be an effective treatment for psoriasis
[112]. In the 1930s Ingram used anthralin in
Lassar’s paste (petrolatum, salicylic acid, zinc
oxide, starch) with tar baths and UVB to treat
psoriasis [112]. The Ingram regimen was in common use for several decades, but is now rarely
used. Anthralin has also been formulated as an
ointment [112], gel [113] and in a cream base
which washes off easily and has minimal staining
[114]. Commercial formulations are no longer
available in Canada due to the development of
efficacious, convenient, more cosmetically
acceptable alternatives.
Mechanism of Action
In vitro, anthralin has been shown to inhibit DNA
replication and DNA repair synthesis [115],
interfere with mitochondria [116], decrease keratinocyte transforming growth factor-α expression
and epidermal growth factor (EGF) receptor
binding [117], inhibit leukotriene production by
neutrophils [118], and inhibit monocyte secretion
of interleukin (IL)-6, IL-8 and tumour necrosis
factor (TNF)-α [119].
Toxicity
Adverse effects include staining of skin, nails and
clothing due to oxidation of anthralin, burning,
and irritant and allergic contact dermatitis [112].
In order to minimize irritation, care should be
taken to avoid application to uninvolved skin and
intertriginous areas should not be treated.
Clinical Studies
The benefits of the Ingram regime in 2120
patients were reported by Maclennan and Hellier
in 1961; 95% were clear in a mean time of
15.2 days as inpatients and 19.5 days as outpatients [120]. Average clearance times in other
inpatient series have varied from 11.0 to 20 days
[112]. Short contact anthralin ointment with a
10 min to 1 h contact time was tried in an effort
to minimize staining and irritation [121]. It was
as effective as conventional treatment with
anthralin ointment [122], difluorosone acetate
[122], and twice daily calcipotriene [123]. If
anthralin is considered in the outpatient setting,
short contact application (20–30 min) with an
initial 1% concentration, increasing the concentration as tolerated, has been recommended [69].
Moisturizers and Keratolytics
Moisturizers and keratolytics such as salicylic
acid and urea are considered ‘Basic Therapy’ of
psoriasis [7], although there are no placebo-­
controlled studies supporting their use.
Moisturizers decrease scaling, limit painful fissuring and are anti-pruritic. Salicylic acid
should be not used to large areas since systemic
toxicity might occur, especially if applied to
>20% of the body surface, or to patients with
impaired renal or hepatic f­ unction [69].
Conclusions
Although tazarotene is efficacious as monotherapy, it is more commonly used in combination
with a topical steroid to enhance tazarotene’s tolerance, increase efficacy and decrease steroids’
atrophogenic potential [50, 124]. The once daily
lotion containing the superpotent steroid halobetasol propionate 0.01% and tazarotene 0.045%
(Duobrii™) is convenient with greater efficacy
and fewer AEs than tazarotene monotherapy.
There is no duration limitation in the U.S. labeling, although treatment should be stopped when
the skin is clear. Use of tazarotene with broad
band and narrow band UVB can enhance efficacy
and decrease the cumulative dose of UV. Although
phototoxicity was not noted in clinical studies, if
tazarotene is added to ongoing phototherapy, it
6
Topical Therapy II: Retinoids, Immunomodulators, and Others
might be prudent to reduce the UVB dose by
30–50% or UVA dose by 2 J/cm2 once scaling
and induration are reduced, since one study
showed that application of tazarotene for 2 weeks
prior to phototesting significantly decreased the
average UVB MED from 56.25 to 42.5 mJ/cm2
(p < 0.01) [125]. Palmoplantar and nail disease,
particularly nail bed disease, also respond to
tazarotene.
The topical calcineurin inhibitors particularly
tacrolimus, and phosphodiesterase-4 inhibitor
crisaborole do not cause atrophy and are efficacious and well-tolerated in the treatment of
inverse, facial and genital psoriasis.
The use of tar and anthralin has declined with
the introduction of more cosmetically elegant,
efficacious products. Several studies have questioned the efficacy of tar; there does not appear to
be any benefit of adding tar to erythemogenic
UVB.
References
1. Frost PF, Weinstein GD. Topical administration of
vitamin a acid for ichthyosiform dermatoses and psoriasis. JAMA. 1969;206:1863–8.
2. Fredriksson T. Antipsoriatic activity of retinoic acid
(vitamin a acid). Dermatologica. 1971;142:133–6.
3. MacDonald A, McMinn RM, Fry L. Effect of retinoic
acid in psoriasis. II. Long-term study. Br J Dermatol.
1972;87:256–60.
4. Orfanos CE, Schmidt HW, Mahrle G, et al. Retinoic
acid in psoriasis. Its value for topical therapy with
and without corticosteroid. Clinical, histological, and
electron microscopical studies on forty-four hospitalized patients with extensive psoriasis. Br J Dermatol.
1973;88:167–82.
5. Günther S. The therapeutic value of retinoic acid in
chronic, acute, guttate, and erythrodermic psoriasis.
Clinical observations on twenty-five patients. Br J
Dermatol. 1973;89:515–7.
6. Bischoff R, De Jong EM, Rulo HF, et al. Topical
application of 13-cis-retinoic acid in the treatment
of chronic plaque psoriasis. Clin Exp Dermatol.
1992;17:9–12.
7. Nast A, Kopp I, Augustin M, et al. German evidence-­
based guidelines for the treatment of Psoriasis
vulgaris (short version). Arch Dermatol Res.
2007;299:111–38.
8. Murphy G, Reich K. In touch with psoriasis: topical treatments and current guidelines. J Eur Acad
Dermatol Venereol. 2011;25(Suppl 4):3–8.
65
9. Guenther LC. Tazarotene, a receptor-selective topical retinoid, in the treatment of psoriasis. Today’s
Ther Trends. 1999;17(2):133–45.
10. Chandraratna RA. Tazarotene—first of a new generation of receptor-selective retinoids. Br J Dermatol.
1996;135(Suppl 49):18–25.
11. Elder JT, Fisher GJ, Zhang Q-Y, et al. Retinoic acid
receptor gene expression in human skin. J Invest
Dermatol. 1991;96:425–33.
12. Pfahl M. Nuclear retinoid receptors as central regulators of retinoid response pathways. In: Burgdorf
WHC, Katz SI, editors. Dermatology progress and
perspectives. New York: Parthenon; 1993. p. 155–9.
13. Esgleyes-Ribot T, Chandraratna RA, Lew-Kaya
D, et al. Response of psoriasis to a new topical retinoid AGN 190168. J Am Acad Dermatol.
1994;30:581–90.
14. Molhuizen HO, Alkemade HA, Zeeuwen PL,
et al. SKALP/elafin: an elastase inhibitor from
cultured human keratinocytes. J Biol Chem.
1993;268:1228–32.
15. Schalkwijk J, van Vlijmen IM, Alkemade JA, de
Jongh GJ. Immunohistochemical localization of
SKALP/elafin in psoriatic epidermis. J Invest
Dermatol. 1993;100:390–3.
16. Bernard BA, Asselineau D, Schaffar-Deshayes L,
Darmon MY. Abnormal sequence of expression of
differentiation markers in psoriatic epidermis: inversion of two steps in the differentiation program? J
Invest Dermatol. 1988;90:801–5.
17. Nagpal S, Patel S, Asano AT, et al. Tazarotene-­
induced gene 1 (TIG1), a novel retinoic acid receptorresponsive gene in skin. J Invest Dermatol.
1996;106:269–74.
18. Nagpal S, Patel S, Jacobe H, et al. Tazarotene-­
induced gene 2 (TIG2), a novel retinoid-responsive
gene in skin. J Invest Dermatol. 1997;109:91–5.
19. Zheng Y, Luo SJ, Zeng WH, Peng ZH, Tan SS, Xi
YP. Alteration of tazarotene induced gene-2 expression in psoriasis vulgaris. Nan Fang Yi Ke Da Xue
Xue Bao. 2008;28(10):1792–4.
20. Eckert RL, Sturniolo MT, Rans R, et al. TIG3: a
regulator of type 1 transglutaminase activity in epidermis. Amino Acids. 2009;36(4):739–46.
21. Marks R. Pharmacokinetics and safety review of tazarotene. J Am Acad Dermatol. 1998;39(4):S134–8.
22. Franz TJ, Lehman PA, Franz S, et al. Percutaneous
absorption of AGN 190168, a new synthetic retinoid, through human skin in-vivo (Abstr.). J Invest
Dermatol. 1992;98:650.
23. Tang-Liu DD, Matsumoto RM, Usansky JI. Clinical
pharmacokinetics and drug metabolism of tazarotene. Clin Pharmacokinet. 1999;37:273–87.
24. Weinstein GD, Krueger GG, Lowe NJ, et al.
Tazarotene gel, a new retinoid, for topical therapy
of psoriasis: vehicle-controlled study of safety,
­efficacy, and duration of therapeutic effect. J Am
Acad Dermatol. 1997;37:85–92.
25. Weinstein GD. Safety, efficacy and duration of
therapeutic effect of tazarotene used in the treatment
7
Topical Therapy II: Retinoids,
Immunomuodulators, and Others/
Ultraviolet Therapy for Psoriasis
Kristen M. Beck and John Koo
Abstract
Total-body ultraviolet therapy (UV) for
moderate-­to-severe psoriasis consists of narrowband and broadband-UVB, psoralen plus
UVA (PUVA—where psoralen can be ingested
orally or applied topically), inpatient phototherapy (i.e. Goeckerman Therapy, Ingram
therapy), non-office-based phototherapy (i.e.
use of commercial sunlamps/sunbeds or home
UVB for psoriasis treatment, heliotherapy, climatotherapy), and combined UVB/PUVA
with retinoid or biologic agents. For each type
of UV therapy discussed in this chapter, essential information regarding dosage and administration, efficacy (including comparator data
if available), short-term side effects, and long-­
term photocarcinogenic risks are discussed. A
well-balanced understanding of the advantages and drawbacks of each photo-­therapeutic
option can help phototherapy practitioners
optimize clinical outcomes as well as enhance
the quality of life for patients affected by this
chronic skin condition.
K. M. Beck (*) · J. Koo
Department of Dermatology, University of California,
San Francisco, CA, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_7
Key Learning Objectives
1. To understand the mechanism of action
and types of phototherapy for psoriasis.
2. To understand the appropriate use and
efficacy of phototherapy for psoriasis.
3. To understand the safety concerns of
utilizing phototherapy for psoriasis.
UVB Phototherapy
UVB phototherapy has been used worldwide
since the early 1900s. It consists of narrowband
UVB (NB-UVB) and broadband UVB
(BB-UVB), which are still the most commonly
chosen phototherapeutic options for patients with
psoriasis.
Dosage and Administration
The calculation of the initial UVB dose can be
done after assessment of the MED (the minimal
erythema dose that induces barely perceptible erythema on non-involved skin) or the Fitzpatrick
skin type of each patient [1]. Skin testing to determine MED can add significant time to the first
phototherapy visit. Therefore, dosimetry is often
based on estimation of Fitzpatrick skin types.
Subsequent dosing depends on response of psoriasis
71
72
and phototoxic reactions to previous doses. For
example, if a patient experiences mild-­to-­moderate
pruritus or discomfort (but no skin burns), he or
she should be treated with the same light dose until
these reactions resolve [1]. If skin burns or intense
skin inflammation (i.e. “beefy red” erythema,
severe pruritus, etc.) develops, light treatment
should be withheld from patients until the erythema completely resolves. In the latter case, phototherapists might consider the use of “cooling
procedures” to calm intense skin inflammation, for
example, with very potent topical steroids, before
cautiously re-instituting phototherapy. Skin that
recently experienced phototoxicity reactions is
often extra-sensitive to re-exposure to UVB. Please
see Tables 7.1 and 7.2 [2].
The optimal number of UVB exposures per
week is three, since less than three treatments per
week may result in lower efficacy, and more than
three treatments per week have not been consistently shown to be more effective [3]. Once
Table 7.1 Dosing guidelines for broadband ultraviolet B
According to skin type
Initial UVB
UVB increase after
dose, mJ/cm2
each treatment, mJ/
cm2
Skin type
I
20
5
II
25
10
III
30
15
IV
40
20
V
50
25
VI
60
30
According to MED
Initial UVB
50% of MED
Treatments
Increase by 25%
1–10
of initial MED
Treatments
Increase by 10%
11–20
of initial MED
Treatments
As ordered by
≥21
physician
If subsequent treatments are missed for
4–7 day
Keep dose same
1–2 week
Decrease dose
by 50%
2–3 week
Decrease dose
by 75%
3–4 week
Start over
MED Minimal erythema dose, UV ultraviolet.
Administered 3–5×/week. Reproduced with permission
from Menter et al. [2]
K. M. Beck and J. Koo
Table 7.2 Dosing guidelines for narrowband ultraviolet B
According to skin type
Initial UVB
UVB
dose, mJ/cm2 increase
after each
Maximum
treatment,
dose, mJ/
mJ/cm2
cm2
Skin type
I
130
15
2000
II
220
25
2000
III
260
40
3000
IV
330
45
3000
V
350
60
5000
VI
400
65
5000
According to MED
Initial
50% of
UVB
MED
Treatments Increase by
1–20
10% of
initial MED
Treatments Increase as
≥21
ordered by
physician
If subsequent treatments are missed for
4–7 day
Keep dose
same
1–2 week
Decrease
dose by 25%
2–3 week
Decrease
dose by 50%
or start over
3–4 week
Start over
Maintenance therapy for NB-UVB after >95%
clearance
1 ×/ week
NB-UVB for Keep dose
4 week
same
1 ×/ 2 week NB-UVB for Decrease
4 week
dose by 25%
1 ×/ 4 week NB-UVB
50% of
highest dose
MED Minimal erythema dose, NB narrowband, UV ultraviolet. Administered 3–5 ×/ week. Because there is broad
range of MED for NB-UVB by skin type, MED testing is
generally recommended. It is critically important to meter
UVB machine once weekly. UVB lamps steadily lose
power. If UV output is not periodically measured and actual
output calibrated into machine, clinician may have false
impression that patient can be treated with higher doses
when machine is actually delivering much lower dose than
number entered. Minimum frequency of phototherapy sessions required per week for successful maintenance as well
as length of maintenance period varies tremendously
between individuals. Above table represents most ideal situation where patient can taper off phototherapy. In reality,
many patients require 1 ×/ week. NB-UVB phototherapy
indefinitely for successful long-­
term maintenance.
Reproduced with permission from Menter et al. [2]
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
patients achieve marked improvement in their
psoriasis, then the therapeutic regimen can be
tapered slowly to once weekly. Since this maintenance therapy is less intensive and well tolerated,
it may be continued for as long as possible in
order to prevent recurrence of psoriasis [1, 3].
Figures 7.1, 7.2, and 7.3 are intended to
illustrate the office-based practice of UVB
­
phototherapy.
Efficacy
Rare comparator studies have documented a
much larger difference in efficacy between broadband and narrowband UVB than what is typically
observed in practice. In a study by Green et al.,
52 patients with plaque psoriasis treated with
NB-UVB achieved clearance in 6.6 weeks,
whereas 25 patients treated with BB-UVB
achieved clearance in 22 weeks [4]. At 1-year
73
follow-up, 38% of the NB-UVB cohort retained
clearance, compared with 5% of the BB-UVB
cohort. Such magnitude of efficacy difference
has not yet been replicated by other studies or in
the usual practice settings.
More moderate results are be found in another
study involving 22 patients with psoriasis who
received half-body exposure to BB- or
NB-UVB. After 3 weeks of treatment, clinical
resolution occurred in 86% of NB-UVB-treated
plaques and 73% of the BB-UVB-treated plaques
[5]. Long-term efficacy of NB-UVB was reported
by Karawaka et al., who reported that 56% of
their 52-patient cohort retained PASI 50 response
for at least 1 year after a 4-week course of
NB-UVB phototherapy [6].
The difference in efficacy between BB-UVB
and NB-UVB—where the latter is, to some extent,
superior as a treatment for psoriasis—deserves
explanation. Some of the UV rays emitted by
BB-UVB lamps (i.e. 254, 280, or 294 nm rays) are
Fig. 7.1 Nurse stations and light boxes for office-based UVB phototherapy
K. M. Beck and J. Koo
74
less effective than UV rays with longer wavelengths (i.e. 311 or 312 nm rays) at clearing psoriasis [7]. The 311 nm rays emitted by NB-UVB
lamps are capable of clearing psoriatic plaques
with a little as 0.4 times the MED. Furthermore,
NB-UVB therapy confers the benefit of causing
fewer phototoxic reactions for patients than
BB-UVB therapy at the same doses.
Side Effects and Safety
Side effects of UVB phototherapy include visible
erythema, burning, blistering, discomfort, and
post-inflammatory hyperpigmentation [1, 5, 8].
In addition, “over-exposure” to UVB has been
associated with precipitation of erythrodermic
psoriasis in two reported cases [9]. Do not perform UVB if the patient is erythrodermic or
near-erythrodermic.
Fig. 7.2 Eye protection for whole-body UVB irradiation
Fig. 7.3 Whole-body UVB irradiation using a stool to
increase lower-body exposure
Photocarcinogenicity of UVB
Phototherapy
Studies with mice have often not mirrored human
exposure to UVB. They should not be extrapolated at face value to determine the carcinogenic
risk of UVB phototherapy in humans. For
instance, UVB irradiation of 30 hairless, lightly
pigmented mice who are not cancer-prone for
30 weeks was linked with an 83% rate of SCC
development [10]. This study lacked a control
mice group. Moreover, the mice received UVB 5
days per week, while humans with psoriasis are
usually treated three times weekly.
In another study using hairless, lightly pigmented mice, all mice developed skin tumors,
while mice receiving 311 nm UVB developed
skin tumors earlier than mice treated with
BB-UVB [11]. Of note, some of the mice had
total-body exposure to UVB at doses that were
multitudes of the MED (also known as “supra-­
erythemogenic” doses). In humans, total body
use of supraerythemogenic doses not done since
intense UVB irradiation of non-involved skin is
likely to result in frequent, severe skin burns,
which can increase the risk of skin cancer.
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
Meanwhile, review of the worldwide literature
on human experience revealed no convincing data
of an increased photocarcinogenic risk of longterm UVB phototherapy for psoriasis. In a publication by Lee et al., no increased carcinogenic risk
associated with UVB phototherapy was appreciated in 10 out of the 11 studies that were reviewed
in the medical literature [12]. One exception is the
report featuring a 30-case/137-­control sub-cohort
from a large-scale Finnish study in psoriasis
patients, where the relative risk ratio of developing
SCC in patients with a history of UVB treatments
was 1.6. This risk is slightly elevated but turned
out to be not statistically significant.
In addition, there was no increased risk of skin
cancer in 484 Northern Irish patients who had at
least 18 NB-UVB exposures individually [13]. A
larger retrospective study involving 3886 patients
treated with UVB at a Scottish hospital found 27
BCC, 7 SCC, and 6 melanomas, which were
comparable to expected incidences for the 3
types of skin cancer, respectively, in the matched
populations [14]. In this study, only patients who
received both NB-UVB and PUVA had a higher
incidence of BCC [15] than the expected incidence [14] in the general Scottish population, but
not among those who received UVB alone [14].
In a follow-up study of 195 patients who
received either BB- or NB-UVB treatment for
psoriasis, only one patient developed melanoma
in situ. This patient’s tumor was diagnosed in the
same year phototherapy was instituted; hence, its
development may have been unrelated to the limited UVB exposure [16]. Another study followed
1908 Scottish patients who had long-term UVB
treatment for an average of 4 years. Remarkably,
the study found no incidence of melanoma or
squamous cell carcinoma (SCC) [17]. Ten
patients developed basal cell carcinoma (BCC)
mostly on the face compared with the expected
incidence of 4.7 in the matched population [17].
The predilection of BCC for the face attested to
the possible increase in solar exposure as an
uncontrolled variable, since patients with psoriasis often engage in this practice to augment
office-based phototherapy. In contrast, the face’s
patient is usually covered during whole-body UV
irradiation.
75
PUVA (Psoralen Plus PUVA)
Dosage and Administration
PUVA is the combination of the plant-originated
compound psoralen and UVA (320–400 nm) irradiation for the treatment of psoriasis. Available as
Oxsoralen Ultra® 10 mg capsules in the US, psoralen can be taken orally or diluted in a bath solution for topical administration within the hour
before UVA irradiation. In the beginning of their
treatment course, patients are encouraged to
undergo PUVA treatment thrice weekly. For the
purpose of maintaining marked improvement or
clearance of psoriasis, the number of weekly
office visits for PUVA can be tapered slowly to
once weekly, once every other week, or even a
less frequent schedule. Dosimetry of PUVA is
described in Tables 7.3 and 7.4 [2]. Information
about dosage following missed PUVA exposures
can be found in Table 7.5.
Please refer to Fig. 7.4 for an illustration of
“hands” PUVA (PUVA just for the hands) and to
Figs. 7.5, 7.6, 7.7, and 7.8 for an illustration of
bath PUVA.
Efficacy
Following activation by UVA irradiation, psoralen cross-links with DNA of various cell types
in psoriatic skin (i.e. keratinocytes, T cells, etc.)
to inhibit inflammation and cell proliferation. A
randomized, double-blind, placebo-controlled
trial involving 40 psoriasis patients revealed an
86% PASI 75 response rate in the PUVA arm versus 0% PASI 75 response rate in the UVA arm
after 12 weeks of therapy [18]. In another study,
Table 7.3 Dosing of 8-methoxypsoralen for oral psoralen plus ultraviolet A
Patient weight
lb
<66
66–143
144–200
> 200
kg
<30
30–65
66–91
>91
Drug dose, mg
10
20
30
40
Reproduced with permission from Menter et al. [2]
K. M. Beck and J. Koo
76
Table 7.4 Dosing of ultraviolet A radiation for oral psoralen plus ultraviolet A
Skin
type
I
II
III
IV
V
VI
Initial dose,
J/cm2
0.5
1.0
1.5
2.0
2.5
3.0
Increments, J/
cm2
0.5
0.5
1.0
1.0
1.5
1.5
Maximum dose,
J/cm2
8
8
12
12
20
20
Reproduced with permission from Menter et al. [2]
Table 7.5 Subsequent dosing protocol for PUVA
Number of missed
days
3–5
6–14
15–21
22–28
>28
Subsequent dosing
Continue routine dosing increase
Hold dose
Decreased dose by 25%
Decreased dose by 50%
Re-institute phototherapy and
dosimetry
Fig. 7.5 Oxsoralen Ultra® 10 mg capsules for bath PUVA
Adapted from UCSF Psoriasis Center with permission of
the author (JK)
Fig. 7.6 Boiled water to dissolve Oxsoralen Ultra***
10 mg capsules
study, both PUVA and NB-UVB irradiation were
done thrice weekly for a maximum of 30 expoFig. 7.4 PUVA for the hands/feet psoriasis or eczema
sures or clearance, whichever came first. In
another study of 28 patients with psoriasis, 54%
88.8% of 3175 patients with psoriasis achieved of the PUVA-treated cohort versus 78% of the
95–100% clearance after an average of 20 PUVA NB-UVB-treated cohort achieved clearance after
exposures [19].
a maximum of 30 exposures [21]. Interestingly,
When compared against NB-UVB photother- in this study PUVA was administered twice
apy, PUVA demonstrates inferior efficacy in weekly, which is not the optimal regimen to
small-scale studies but superior efficacy in large-­ achieve rapid clearance of psoriasis.
scale studies. A comparator trial involving only
In terms of a larger “head to head” comparison
17 patients reported a PASI score reduction of study, Gordon et al. treated 100 patients thrice
45% in the PUVA-treated cohort compared with weekly with either PUVA or NB-UVB photo77% in the NB-UVB-treated cohort [20]. In this therapy. Eighty-four percent of the PUVA-treated
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
77
et al. involving 93 patients showed an 84% clearance rate in the PUVA arm after 17.0 exposures
compared with 65% in the NB-UVB arm after
28.5 exposures [23]. Sixty-eight percent of the
PUVA-treated subjects versus thirty-five percent
of the NB-UVB-treated subjects remained in
remission for 6 months after treatments had
ended. Evidence from these large, randomized
trials seem to support superior efficacy of PUVA
over NB-UVB, especially with regard to duration
of therapeutic effects.
Side Effects
Fig. 7.7 Concentrated solution made by dissolving
Oxsoralen Ultra 10 mg capsules in hot water
Fig. 7.8 Measuring water level for bath PUVA. The
water level corresponding to 100 L is indicated on the
ruler
Dose-dependent effects of PUVA include skin
irritation, skin burns, and tanning. In addition,
ingestion of psoralen has been associated with
nausea, headaches, dizziness, and extremely rare
instances of psychiatric disturbance (i.e. insomnia, depression) [8]. To minimize nausea, patients
can try decreasing the dose of psoralen and/or
ingesting psoralen with food later in the day [8].
After decades of use, the association of PUVA
with an increased risk of cataracts has not been
substantiated in an evidence-based fashion [24].
The author (JK) feels that an ophthalmic examination is mainly useful for documenting the presence or absence of pre-existing cataracts.
Therefore, for the author (JK), even the presence
of pre-PUVA cataracts does not necessarily constitute an absolute contraindication for initiating
PUVA therapy. There is no convincing human
data after decades of worldwide use to prove that
PUVA increases the risk of cataracts, provided
that the patient is compliant with UVA eye protection measures for 24 hours after psoralen
ingestion.
Long-term exposure to PUVA is associated
with photoaging marked by premature cutaneous
degeneration and pigmentation [25].
cohort achieved clearance of psoriasis after 16.7
exposures compared with sixty-three percent of
NB-UVB-treated cohort after 25.3 exposures Photocarcinogenicity of PUVA
[22]. Moreover, the number of PUVA-treated
patients who retained clearance 6 months after Long-term UVA irradiation exposure has been
therapy was almost double that of NB-UVB-­ associated with melanocytic atypia (i.e. large,
treated patients [22]. A similar study by Yones angular hyperchromatic nuclei and binucleated
K. M. Beck and J. Koo
78
melanocytes) called “PUVA lentigines”, suggesting aberrant cellular kinetics [26]. A list of 25
PUVA follow-up studies conducted worldwide
can be found in Table 7.6. Out of 25 published
studies, 24 did not show an elevated risk of melanoma associated with long-term PUVA exposure.
However, one study published by Stern et al.
recorded an increased risk of cutaneous melanoma associated with PUVA. In this study, 1380
patients across the USA were monitored for up to
21 years during and after photochemotherapy.
During the first 15 years of follow-up, the relative
Table 7.6 Risk of melanoma associated with PUVA treatment
Authors (Year)
Honigsmann et al.
(1980) [27]
Lobel et al. (1981)
[28]
Lassus et al. (1981)
[29]
Lindskov (1983) [30]
Ros et al. (1983) [31]
Reshad et al. (1984)
[32]
Eskelinen et al.
(1985) [33]
Tanew et al. (1986)
[34]
Henseler et al. (1987)
[35]
Barth et al. (1987)
[36]
Cox et al. (1987) [37]
Torinuki & Tagami
(1988) [38]
Abdullah & Keczkes
(1989) [39]
Forman et al. (1989)
[40]
Bryunzeel et al.
(1991) [41]
Chuang et al. (1992)
[42]
Lever & Farr (1994)
[43]
Gritiyarangsan et al.
(1995) [44]
Maier et al. (1996)
[45]
McKenna et al.
(1996) [46]
Hannuksela et al.
(1996) [47]b
Cockayne & August
(1997) [48]
Follow-up
periods
(years)
1–5
Mean or
median
follow-up
Relative risk of
invasive
melanoma
a
a
Country
Austria
Number of
Number of melanoma
cases
subjects
418
0
Australia
489
0
a
a
a
Finland
525
0
1–3.6
2.2
a
Denmark
Sweden
United
Kingdom
Finland
198
250
216
0
0
0
1–6
0–7
0–7
3.5
4.1
4.8
a
1047
0
0–8
a
a
Austria
297
0
3.4–8.0
5.3
a
Europe
1643
1 invasive
0–11
8.0
a
Germany
6820
0
0–10
a
a
United
Kingdom
Japan
95
0
0–8
a
a
151
0
0–10
a
a
United
Kingdom
United
States
Netherlands
198
1 in situ
0–10
a
a
551
1 invasive
0–10
4.8
a
260
0
0–12.8
8.7
a
United
States
United
Kingdom
Thailand
492
0
0–14
5.4
a
54
0
6–15
11.2
a
113
0
2–14
6.2
a
Austria
496
0
0.4–17.2
6.2
a
Northern
Ireland
Finland
245
0
2–15
9.5
a
527
0
0–16
11
a
150
0
5–17
a
a
United
Kingdom
a
a
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
79
Table 7.6 (continued)
Number of
Number of melanoma
cases
subjects
1380
18 invasive
7 in situ
1 ocular
Follow-up
periods
(years)
0–24
Mean or
median
follow-up
19 [49]
0–21
16
0–18
14.7
Authors (Year)
Stern et al. (1997)
[49] & Stern (2001)
[50]
Country
United
States
Lindelof et al. (1999)
[51]
Sweden
4799
Hannuksela-Svahn
et al. (1999) [52]b
Sweden,
Finland
944
0
Relative risk of
invasive
melanoma
1975–1990:
1.0
1991–1996:
4.7 (1.4–16.1)
1996–1999:
7.4 (2.2–25.1)
M: 1.1
(0.4–2.3)
F: 1.0
(0.5–2.2)
M: 0.7
(0.0–3.8)
F: 1.3
(0.0–7.2)
Information not provided or not able to be calculated from data
Bath PUVA only
a
b
incidence of melanoma was not different than
expected in the general US population, based on
cancer statistics from the SEER (Surveillance,
Epidemiology, and End Results) Program [49].
In the next 5 years of follow-up, seven new cases
of melanoma were diagnosed, giving a relative
risk ratio of 5.4 [49]. The authors thus hypothesized that a period of latency exists before the
risk of melanoma related to long-term PUVA
treatment becomes recognizable.
Comprehensive knowledge of how SEER
derives its cancer statistics can influence how one
interprets Stern et al.’s results and the ­implications
of their study. SEER approximates melanoma
prevalence in the general US population based on
chart reviews of hospitals and “search of private
laboratory records” in designated regions, which,
as of 1990, comprised 9.6% of the total US population. Unlike systemic cancers for which SEER
database was primarily intended, many cases of
melanoma in situ and early-stage invasive melanoma are excised on an outpatient basis by practicing dermatologists without being registered
into any of the above databases [15, 53]. As a
result, data generated by SEER may underestimate the actual prevalence of melanoma in the
general US population. This could inflate the
melanoma risk for PUVA that was calculated in
Stern et al.’s study. Additionally, the study lacked
a matched control group to account for confound-
ing variables such as a history of sunburns, family history of skin neoplasm, other UV light
treatments, or medications that possess carcinogenic risk, etc.
An extension of the original study by five
more years followed the same cohort of 1380
PUVA-treated patients. The relative risk ratio
within this latest five-year period is 7.4, once
again based on cancer statistics from SEER [50].
In contrast, the largest PUVA study that has been
published to date was conducted in Sweden by
Lindelof et al., who examined a cohort of 4799
PUVA-treated psoriasis patients. The data published by Lindelof et al. revealed no increased
risk of melanoma compared to the general
Swedish population during an average
15–16 years of follow-up [51]. There was not
even an increased risk of melanoma in a sub-­
cohort of 1867 patients who were followed up for
longer than 15 years [51]—this is where Stern
et al. claimed to have observed an increased carcinogenic risk of PUVA. The prevalence of melanoma used to calculate relative risk ratio of
melanoma in Lindelof et al.’ study comes from
the Swedish Cancer Registry. It is likely to reflect
the actual prevalence in the Swedish population,
since reporting of melanoma diagnoses in
Sweden is compulsory, unlike the situation in the
USA where no melanoma-reporting requirement
exists.
80
Concerning the risk of NMSC, the results of
Lindelof et al.’s study supported an increased risk
of SCC associated with long-term PUVA use:
relative risk ratios were 3.6 for women and 5.6
for men [51]. Furthermore, analysis of the
1380-patient US PUVA cohort by Nijsten and
Stern revealed higher than expected incidences of
SCC and BCC compared to the general US population (based on SEER statistics). This NMSC
risk is particularly notable in patients with more
than 200 lifetime PUVA treatments [54].
Conversely, a follow-up study in 944 Swedish
and Finnish psoriasis patients treated only with
bath PUVA, not systemic PUVA, did not show
any increased risk of SCC or malignant melanoma after a mean follow-up period of 14.7 years
[52]. Whether different cellular mechanisms are
involved or the total UVA dose is lower, bath
PUVA appears to have less photocarcinogenic
risk than oral PUVA.
It is important to recognize that available data
about long-term safety of PUVA therapy mostly
come from studies involving Caucasians. Murase
et al. conducted the only review of PUVA-related
skin cancer incidence in non-Caucasian patients
with various photosensitive dermatoses. Their
analysis included 4294 long-term PUVA patients
who had at least 5 years of follow-up in studies
conducted in Japan, Korea, Thailand, Egypt, and
Tunisia. The relative risk of developing skin neoplasm in these patients compared to the general
dermatology oupatient population in each respective country where the PUVA follow up data
originated was 0.86 (with a confidence interval of
0.36–1.35). This means that the increased risk of
skin cancer related to long-term PUVA in Asian
and North African patients has yet to be demonstrated [55]. Further investigation into the protective nature of darker skin phototypes is needed.
Inpatient Photothearpy
Goeckerman Therapy
Formulated in 1925, Goeckerman’s eponymous
therapy is one of the oldest forms of phototherapy for the treatment of psoriasis [56] and
K. M. Beck and J. Koo
enjoyed widespread use in the USA until the
Diagnostically Related Groups (DRG) made
prolonged hospitalization for dermatologic conditions impossible. It is still considered by many
dermatologists as the gold standard treatment
based on high efficacy, safety of not requiring
any internal agents, and induction of prolonged
remission times. Furthermore, Goeckerman
therapy can be used to treat patients who have
failed a number of therapeutic modalities beyond
topical steroids, such as PUVA, UVB, and biologics [57].
Dosage and Administration
Goeckerman therapy is an intensive therapy
requiring all-day, everyday continuous participation for typically 4–6 weeks in a hospital unit or
psoriasis day care center (Figs. 7.9 and 7.10)
[58]. The treatment regimen begins each day with
UVB irradiation, since UV light will not penetrate after application of crude coal tar (CCT)
[59]. The second step is to lather the patient’s
skin with CCT in petroleum (Fig. 7.11), which
comes in 2%, 5%, and 10% preparations, and to
soak the patient’s scalp in 20% liquor carbonis
detergens (LCD) in Neutraderm lotion (Fig. 7.12)
[58]. Twenty percent LCD in Aquaphor ointment
is applied to the total body of each patient before
he/she leaves the facility. It is also sent home with
the patient to be done once more at bedtime. If
the patient’s condition is so severe that tar plus
UVB do not provide adequate control, then compounded anthralin and even topical PUVA can be
added [1]. Infrequently, truly recalcitrant psoriasis might necessitate the concomitant use of retinoids and topical vitamin D derivatives in order
to achieve clearance [1].
Efficacy
Goeckerman therapy has high efficacy for recalcitrant psoriasis, even when single or multiple
biological agents have failed to show improvements [57]. In a prospective study, 95% and
100% of 25 psoriasis patients who were treated
with Goeckerman therapy reached PASI 75 by
week 8 and week 12, respectively [60]. In another
study, clearance of psoriasis has been documented in 90% of 300 patients after only 18 days
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
81
Fig. 7.9 The common area for Goeckerman therapy patients at a psoriasis day care center, which often turns into a
therapeutic milieu (i.e. where the ambient supportive atmosphere is experienced by the patients as therapeutic)
Fig. 7.10 Physicians performing rounds on a patient undergoing Goeckerman therapy
82
K. M. Beck and J. Koo
Fig. 7.11 Nursing staff
applying crude coal tar
with occlusion to
psoriatic skin
of treatment. Eight-month remission was
recorded in 90% of these subjects [58]. It should
be noted that the second study featured a more
intensive treatment regimen than the commonly
encountered Goeckerman therapy: UVB and tar
therapy were administered twice daily, and
patients attended the program six instead of 5
days a week [58]. This may explain their significantly rapid clearance rate.
In 1979 DesGroseilliers et al. implemented a
modified design to render Goeckerman therapy
less time-intensive and more cost-effective. 200
patients were treated with coal tar application at
home plus office-based UVB irradiation the following day 5 days a week. After 1 month of treatment, 86% of patients in this cohort achieved
clearance of their psoriasis [61]. The mean
r­ emission duration of 5.1 months was calculated
based on 185 patients who experienced relapse
during the observation period [61]. However,
there were 15 patients in the study who did not
relapse during the entire observation period. Had
these 15 patients been included, the calculated
mean remission duration would have been longer
than 5.1 months.
ide Effects and Long-term Safety
S
Side effects of Goeckerman therapy include folliculitis and phototoxic reactions, which are can
be managed by dose adjustment of tar and
UVB. The pustules associated with Goeckerman
therapy can develop on non-involved skin and are
therefore distinct from pustular psoriatic lesions
[62]. Rarely, precipitation of erythrodermic
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
83
consists of a succession of tar bath, light treatment, and application of anthralin paste or ointment to involved skin. Adding crude coal tar to
anthralin has been shown to reduce skin irritation
without compromising antipsoriatic efficacy
[66]. In a retrospective study by De Bersaques,
275 psoriasis patients who were treated in a hospital with Ingram therapy achieved clearance
after an average of 25 days [65]. Patients did not
need another treatment or hospitalization for 8 to
11 months after therapy [65]. However, being a
single center study, these results might have been
influenced by loss to follow-up of patients who
sought care from other practitioners due to early
relapse.
Non-office-based Phototherapy
Commercial Tanning Therapy
Fig. 7.12 Nursing staff applying 20% liquor carbonis
detergens in Neutraderm lotion to a psoriasis patient’s
scalp
p­ soriasis has been documented in patients allergic to crude coal tar [63]. To investigate longterm safety, a 25-year follow-up study was
conducted in 280 psoriasis patients treated with
Goeckerman therapy over a 5-year period. The
results consisted of 1 melanoma, 22 BCC, 7 SCC,
and 3 tumors of unknown type [64]. Based on
cancer statistics from a matched population, there
was no increase in the risk of skin cancer in these
patients [64].
Ingram Therapy
Ingram therapy is the inpatient treatment of psoriasis with UV irradiation and anthralin, which
was introduced to dermatology in 1916 [65]. It
In commercial tanning facilities, phototherapy
for psoriasis can be conducted using “tanning
beds” that emit high-intensity UVA rays mixed
with small quantities of contaminant UVB. This
is different from office-based, outpatient UVB
phototherapy, where healthcare professionals frequently perform clinical assessments and light
dose adjustments. For 16 out of 20 psoriasis
patients treated with tanning beds, the initial
mean PASI score of 7.96 (+/− 1.77) was diminished to 5.04 (+/− 2.5) after 6 weeks of treatment
[67]. Even those who did not complete the entire
treatment course had a 23.5% improvement of
their PASI score [67]. Furthermore, most patients
reported significant improvements in health-­
related quality of life, while mild burning and
transient pruritus were infrequent and well tolerated [67].
There is controversy surrounding the existence of an association between exposure to commercial UV tanning devices (i.e. sunlamps,
sunbeds) and an increased risk of melanoma. In
2006 the International Agency for Research on
Cancer issued a detailed report on the photocarcinogenic risk of artificial UV exposure, which
addressed 23 case-control studies related to
indoor tanning and melanoma. The risks for
K. M. Beck and J. Koo
84
Table 7.7 Meta-analysis of all studies included
Exposure
Ever use
of indoor
tanning
facility
First
exposure
in youth
Exposure
distant in
time
Exposure
recent in
time
Number
of
studies
19
7
5
5
Heterogeneity
Summary
relative risk P-value
(95% CI)
χ2
H
1.15
0.013
1.37
(1.00–1.31)
a
1.75
(1.35–2.26)
0.55
1.49
(0.93–2.38)
0.018
1.10
(0.76–1.60)
0.81
Table 7.8 Meta-analysis of the cohort and population-­
based case–control studies included
Exposure
Ever use
of indoor
tanning
facility
First
exposure
in youth
Exposure
distant in
time
Exposure
recent in
time
0.91
1.65
0.67
Reproduced with permission from the IARC (2005) [68]
a
The degrees of freedom for the Chi-square are given by
the number of databases included minus one, not by the
number of studies
­ elanoma associated with “ever use” (any expom
sure to sunlamps/sunbeds in one’s lifetime), “first
use in youth” (exposure to sunlamps/sunbeds
starting at 35 years old or younger), “distant use”
(5 years or more from the time of the interview),
and “recent use” (less than 5 years from the time
of the interview) of indoor tanning devices were
compared and contrasted using reported relative
risk ratios. Meta-analysis of 19 of these 23 studies (Table 7.7) revealed a calculated summative
relative risk of 1.15 (95% confidence interval:
1.00–1.31) for “ever use” of indoor tanning facility [68]. The same relative risk becomes slightly
elevated to 1.17 (0.96–1.42) when data only from
cohort and population-based case-control studies
were employed for calculation (Table 7.8) [68].
In both meta-analyses the summative relative risk
is higher for first exposure in youth than for “ever
use” of indoor tanning facility and also higher for
“distant” exposure versus “recent” exposure [68].
In a systematic review of case-control studies,
6 out of 19 studies reported a dose-response relationship between tanning lamp/bed exposure and
melanoma risk [69]. Another review of 10 case-­
control studies reported that the odds ratios
spanned anywhere from 0.7 (0.5–1.0) to 2.9 (1.3–
6.4) for “ever use” versus “never use” (no exposure at all during one’s lifetime) of sunlamps/
sunbeds [70]. Of note, the dose-dependent risk
for invasive melanoma is likely to be more
Number
of
studies
10
5
2
2
Heterogeneitya
Summary
relative risk P-value
(95% CI)
χ2
H
0.011
1.540
1.17
(0.96–
1.42)
1.71
(1.25–
2.33)
1.58
(0.25–
9.98)a
1.24
(0.52–
2.94)
0.435
0.973
0.502
0.830
0.762
0.521
Reproduced with permission from the IARC (2005) [68]
The confidence interval is very wide because this analysis
includes only 2 studies, one of which has two estimates
a
p­ rofound in Caucasian female users with more
than 10 lifetime tanning sessions compared with
those having less than 10 sessions [71]. The
results of this study do not apply to Caucasian
male users, possibly due to the fact that they visit
tanning facilities less frequently than their female
counterparts [71]. In addition, this cut-off of 10
tanning sessions is an arbitrary proposal based on
the results of one study. More convincing data is
needed to establish a photocarcinogenic threshold for UV exposure through tanning devices.
Home UVB Therapy
Most devices employed in home phototherapy
emit UVB. This form of phototherapy is tailored
to patients with stable psoriasis and logistical difficulty, such as lack of time to do office phototherapy or no access to transportation to
dermatology practices with UVB capacity. In a
randomized trial involving 196 psoriasis patients,
70% of patients receiving home UVB therapy
reached PASI 50 compared to 73% in the outpatient group [72]. Short-term safety profiles were
not notably different between the groups [72].
Moreover, the burden of therapy (a function of
method and time commitment) was significantly
lower for home phototherapy patients than for
office-based outpatients [73].
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
85
Heliotherapy
UVB and Retinoid Therapy
Heliotherapy is the therapeutic use of sunlight to
treat psoriasis and other photosensitive dermatoses. There are not many large, randomized, controlled studies to determine the efficacy of
heliotherapy, let alone comparator studies involving other forms of phototherapy. In a study with
373 subjects, the rate of clearance of psoriasis
was 22% and that of PASI 75 response was 84%
after 1 month of treatment [74]. The median
remission time was 2.6 months (80 days) [74].
Short-term side effects are similar to other phototherapeutic modalities: skin burns, irritation, pruritus, erythema, heat, etc. Skin cancer risks
associated with long-term heliotherapy in patients
with psoriasis have not been studied.
Acitretin, an oral retinoid agent, has been shown
to enhance the efficacy of UVB phototherapy. In
an 8-week, randomized, comparator study involving 82 psoriasis patients, 60% of the combined
BB-UVB and acitretin cohort (re-UVB) versus
24% of the BB-UVB cohort reached PASI 75
[78]. Phototherapy was administered 3–5 times
weekly, and acitretin was available as 25 mg tablets taken once daily [78]. Treatment with acitretin 25 mg plus thrice weekly NB-UVB resulted in
75% improvement of psoriasis in 30 out of 40
patients from another study [79].
The phenomenon “delayed retinoid burn” was
described in 2011 after a psoriasis patient experienced a severe phototoxic reaction as a result of
adding acitretin 25 mg daily to a previously tolerated UVB dose [80]. Since acitretin induces cell
differentiation and leads to sloughing of keratin
layers from psoriatic plaques, the introduction of
acitretin in the middle of already ongoing phototherapy can lead to too much light penetration
causing phototoxicity to previously tolerated
dosimetry. Therefore, phototherapy providers
should consider reducing UV dose when starting
concomitant retinoid therapy. The authors recommended cutting UVB dose by 50% as soon as
acitretin is added, and gradually going back
toward the pre-acitretin UVB dose level if no
phototoxicity occurs [80]. How this is conducted
in each phototherapy provider’s office is a judgment call.
Climatotherapy at the Dead Sea
Climatotherapy is the exposure of skin to a special kind of climate for the treatment of psoriasis.
Its efficacy was established in a study involving
64 patients: PASI 75 response after 1 month of
climatotherapy at the Dead Sea was 75.9%, and
median duration of remission was 5.8 months
(23.1 weeks) [75]. Analysis of skin cancer data
from a cohort of 1738 Danish patients who were
followed up for an average of 6.1 years revealed
no association between climatotherapy and an
increased risk of melanoma [76]. There were,
however, 8 SCC and 28 BCC compared with 0.8
expected SCC and 6.6 expected BCC [76]. It was
later discovered that the subjects in this follow­up study had received more than three times the
necessary amount of UVB to achieve therapeutic
results [77]. This important information might
partially explain the significant difference
between observed and expected incidence of
non-melanoma skin cancer.
Combination Therapy
For patients with severe psoriasis based on large
BSA coverage and/or resistance to traditional
single therapies, combinations of therapies are
available as treatment options.
PUVA and Retinoid Therapy
Similarly, rapid improvement of recalcitrant psoriasis might be achieved by adding oral retinoid
agents to PUVA. In a study comparing the
­efficacies of combined PUVA plus acitretin one
mg/kg body weight/day (re-PUVA) versus PUVA
alone, clearance was achieved in 96% of the
combination cohort and 80% of the PUVA cohort
after 11 weeks of treatment [81]. Had the 48 subjects of this study undergone PUVA treatment
three instead of four times weekly, the clearance
rates in both arms might not have been as high
and their difference easier to appreciate.
86
Furthermore, another head-to-head comparison study between re-PUVA and re-UVB showed
100% clearance rate in the re-PUVA cohort compared with 93% in the re-UVB cohort after a
6-week treatment course [82]. Etretinate one mg/
kg body weight/day was used instead of acitretin.
Duration of therapeutic effects was longer for re-­
PUVA patients versus re-UVB patients [82].
However, this study was limited in its small size
(each cohort consisted of 15 patients) and by the
fact that PUVA or UVB was done twice weekly
for each combination therapy.
When photo(chemo)therapy was instituted at
the optimal treatment regimen (thrice weekly) in
60 psoriasis patients, clearance was achieved in
63.3% of the re-PUVA cohort versus 56.6% of
the re-UVB cohort [83]. The reported clearance
rates were lower in this study than in the previous
studies because acitretin was dosed at 0.3–0.5 mg
instead of 1 mg/kg body weight/day. In spite of
the dosing differences between these comparison
studies, all consistently proved that re-PUVA is
more effective at reducing clinical severity of
psoriasis than re-UVB combination therapy.
UVB and Biologics
UVB therapy can be added to biological agents to
expedite clearance of moderate-to-severe psoriasis. A six-week study involving 14 patients
showed that combined UVB and etanercept
helped patients achieve a 64 +/− 28.8% reduction
of their modified PASI scores compared with the
53.7 +/− 36.9% PASI score reduction in patients
treated with etanercept alone [84]. UVB was
given thrice weekly, and etanercept was dosed at
25 mg twice weekly. De Simone et al. performed
a single-arm, open label study in which 33
patients with moderate-to-severe psoriasis were
treated for 8 weeks with etanercept 50 mg once
weekly plus NB-UVB thrice weekly, after which
only etanercept was continued for another
4 weeks. At Week 4, 8, and 12 of treatment, PASI
75 was reached in 24.2%, 66.7%, and 81.8% of
the study participants [85].
The results of a single-arm, single-center,
open-label study involving 20 patients with
K. M. Beck and J. Koo
severe psoriasis were promising: after 12 weeks
of combined adalimumab 40 mg every other
week and NB-UVB three times weekly, 95% and
85% of the patients reached PASI 75 and clearance, respectively [86]. Moreover, 65% of
patients retained PASI 75 response 12 weeks following the end of treatment [86]. A similar but
larger trial (known by the acronym “UNITE”)
with NB-UVB thrice weekly plus etanercept
50 mg twice weekly also showcased high efficacy of combination therapy: at week 12, 84.9%
of 86 psoriasis patients reached PASI 75 [87].
There was also an equally important and significant improvement in health-related quality of life
in almost all the UNITE study subjects [87].
Photocarcinogenicity of Combination
Therapy
Oral retinoid agents can lower the skin cancer
risk associated with phototherapy through promotion of keratinocyte differentiation. There is a
case report of one patient on once daily acitretin
25 mg whose number of squamous cell carcinomas decreased while on acitretin and increased
when taken off acitretin [88]. In addition, the
results of a 15-year follow-up study in 135 psoriasis patients who received PUVA and acitretin/
etretinate for more than 6 months seemed convincing: the numbers of SCC diagnosed during
the time of using and not using acitretin/etretinate were 196 and 302, respectively [89]. The
adjusted incidence rate ratio of SCC was calculated to be 0.79, which implicates the potential of
oral retinoid agents to decrease non-melanoma
skin cancer risk in phototherapy patients [89].
Whether or not these agents have any effect on
melanoma risk is a question that has not yet been
addressed in the literature.
The carcinogenicity of combined phototherapy plus biological agents is an on-going concern. In 2011, Gamblicher et al. compared
psoriatic plaques that were treated with either
BB-UVB at two MED or combined BB-UVB at
two MED plus etanercept 50 mg one time in 11
study subjects. Punch biopsies of the treated
areas were taken at 1, 24, and 72 hours after
7
Topical Therapy II: Retinoids, Immunomuodulators, and Others/Ultraviolet Therapy for Psoriasis
87
Fig. 7.13 Excimer laser
therapy requires the
most powerful excimer
laser machine to
adequately treat
moderate-to-severe
psoriasis
BB-UVB treatment [90]. Immunohistochemical
analysis revealed increased expression of survivin (a tumor marker) and decreased activity of
cyclin D and p53 (regulators of tumor development) in BB-UVB-plus-etanercept-treated sites
compared with BB-UVB-monotherapy-treated
sites [90]. Large randomized controlled trials are
needed to determine if an increased risk of melanoma or NMSC exists in psoriasis patients treated
with combined photo(chemo)therapy and
biologics.
therapy can confer some skin cancer chemo-­
protective effects limited to the periods of retinoid use [92].
In terms of efficacy, both forms of UVB therapy are not as effective as Goeckerman or PUVA
but fare better than heliotherapy [91, 92, 94]. The
combination of UVB and oral retinoid or biological agents can lead to more successful therapy for
patients than any of these modalities alone.
Short-term side effects of UVB phototherapy are
well tolerated, and no studies so far have convincingly demonstrated any relationships
between long-term UVB treatment and an
Conclusion
increased risk of skin cancer. If office UVB is not
feasible, climatotherapy, commercial and home
All day, every day Goeckerman therapy is one of UV therapies should still be considered as useful
the most effective regimens for moderate-to-­ alternatives in the care of patients with psoriasis.
severe psoriasis, and it still maintains an appealFinally, excimer laser therapy, to which
ing safety profile [91, 92]. PUVA has been shown another chapter of this book is dedicated, has
to result in high clearance rates, but the associa- been conducted worldwide for more than 10 years
tion of PUVA with an increased risk of NMSC in to target recalcitrant plaque psoriasis (Fig. 7.13).
fair-skinned Caucasian patients has rendered it Current data on its efficacy revealed that fewer
less popular nowadays than narrowband UVB exposures to light are needed to induce remission
[92]. Until this date whether or not PUVA causes [95–98]. No signal regarding an increased risk of
an increase in melanoma risk is a controversial skin cancer from therapeutic use of excimer laser
topic due to contradictory results between a has been reported. Furthermore, excimer laser
United States 16-center study and numerous spares non-involved skin, so there is a possibility,
other studies primarily from Europe [49, 93]. in terms of cutaneous malignancy safety, that this
Fortunately, adding oral retinoid agents to PUVA targeted phototherapy may even be better than
88
traditional total-body irradiation exposure with
UVB or PUVA.
Authorship Responsibilities and Attributions
This manuscript represents valid work. Neither
this manuscript nor one with substantially similar
content under my authorship has been published
or is being considered for publication elsewhere.
Dr. John Koo and I (Kristen Beck) both have significant contribution to the manuscript. He has
agreed to designate me as the primary correspondent with the editors to review the edited typescript and proof, and to make decisions regarding
release of information in the manuscript to the
media, federal agencies, or both.
Financial Disclosure Both authors have no relevant
financial interest in this manuscript.
References
1. Gattu S, Pugashetti R, Koo JY. The art and practice
of UVB phototherapy and laser for the treatment of
moderate-to-severe psoriasis. In: JYM K, Lee CS,
Lebwohl MG, Weinstein GD, Gottlieb A, editors.
Moderate-to-severe psoriasis. 3rd ed. New York:
Informa Healthcare; 2009. p. 75–113.
2. Menter A, Korman NJ, Elmets CA, et al. Guidelines
of care for the management of psoriasis and psoriatic
arthritis: Section 5: Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol. 2010;62(1):114–35.
3. Do AN, Koo JYM. Initiating narrow-band UVB
for the treatment of psoriasis. Psoriasis Forum.
2004;10(1):1–6.
4. Green C, Ferguson J, Lakshmipathi T, Johnson BE.
311 nm UVB phototherapy--an effective treatment for
psoriasis. Br J Dermatol. 1988;119(6):691–6.
5. Coven TR, Burack LH, Gilleaudeau P, Keogh M,
Ozawa M, Krueger JG. Narrowband UV-B produces superior clinical and histopathological resolution of moderate-to-severe psoriasis in patients
compared with broadband UV-B2. Arch Dermatol.
1997;133(12):1514–22.
6. Karakawa M, Komine M, Takekoshi T, et al.
Duration of remission period of narrowband ultraviolet B therapy on psoriasis vulgaris. J Dermatol.
2011;38(7):655–60.
7. Parrish JA, Jaenicke KF. Action spectrum for
phototherapy of psoriasis. J Invest Dermatol.
1981;76(5):359–62.
8. Lee ES, Heller MM, Kamangar F, Park K, Koo
JYM. Current treatment options: phototherapy. Fut
Med. 2011:1–13. https://doi.org/10.2217/ebo.11.18.
K. M. Beck and J. Koo
9. Boyd AS, Menter A. Erythrodermic psoriasis.
Precipitating factors, course, and prognosis in 50
patients. J Am Acad Dermatol. 1989;21(5):985–91.
10. Flindt-Hansen H, McFadden N, Eeg-Larsen T, Thune
P. Effect of a new narrow-band UVB lamp on photocarcinogenesis in mice. Acta Derm Venereol.
1991;71(3):245–8.
11. Wulf HC, Hansen AB, Bech-Thomsen N. Differences
in narrow-band ultraviolet B and broad-spectrum
ultraviolet photocarcinogenesis in lightly pigmented hairless mice. Photodermatol Photoimmunol
Photomed. 1994;10(5):192–7.
12. Lee E, Koo J, Berger T. UVB phototherapy and skin
cancer risk: a review of the literature. Int J Dermatol.
2005;44(5):355–60.
13. Black RJ, Gavin AT. Photocarcinogenic risk of narrowband ultraviolet B (TL-01) phototherapy: early
follow-up data. Br J Dermatol. 2006;154(3):566–7.
14. Hearn RMR, Kerr AC, Rahim KF, Ferguson J, Dawe
RS. Incidence of skin cancers in 3867 patients treated
with narrow-band ultraviolet B phototherapy. Br J
Dermatol. 2008;159(4):931–5.
15. Whitmore SE, Morison WL. Melanoma after
PUVA therapy for psoriasis. N Engl J Med.
1997;337(7):502–3.
16. Weischer M, Blum A, Eberhard F, Rocken M,
Berneburg M. No evidence for increased skin cancer
risk in psoriasis patients treated with broadband or
narrowband UVB phototherapy: a first retrospective
study. Acta Derm Venereol. 2004;84(5):370–4.
17. Man I, Crombie IK, Dawe RS, Ibbotson SH, Ferguson
J. The photocarcinogenic risk of narrowband UVB
(TL-01) phototherapy: early follow-up data. Br J
Dermatol. 2005;152(4):755–7.
18. Sivanesan SP, Gattu S, Hong J, et al. Randomized,
double-blind, placebo-controlled evaluation of the
efficacy of oral psoralen plus ultraviolet A for the treatment of plaque-type psoriasis using the Psoriasis Area
Severity Index score (improvement of 75% or greater)
at 12 weeks. J Am Acad Dermatol. 2009;61(5):793–8.
19. Henseler T, Wolff K, Honigsmann H, Christophers
E. Oral 8-methoxypsoralen photochemotherapy
of psoriasis. The European PUVA study: a cooperative study among 18 European centres. Lancet.
1981;1(8225):853–7.
20. Snellman E, Klimenko T, Rantanen T. Randomized
half-side comparison of narrowband UVB and
­trimethylpsoralen bath plus UVA treatments for psoriasis. Acta Derm Venereol. 2004;84(2):132–7.
21. Dawe RS, Cameron H, Yule S, et al. A randomized
controlled trial of narrowband ultraviolet B vs bath-­
psoralen plus ultraviolet A photochemotherapy for
psoriasis. Br J Dermatol. 2003;148(6):1194–204.
22. Gordon PM, Diffey BL, Matthews JN, Farr PM. A
randomized comparison of narrow-band TL-01 phototherapy and PUVA photochemotherapy for psoriasis. J Am Acad Dermatol. 1999;41(5):728–32.
23. Yones SS, Palmer RA, Garibaldinos TT, Hawk
JLM. Randomized double-blind trial of the treatment
of chronic plaque psoriasis: efficacy of Psoralen-­
8
Laser Therapy in Psoriasis
Quinn Thibodeaux and John Koo
Abstract
Treatment options for psoriasis are numerous
and span a wide array of modalities. For mild-­
to-­moderate disease, topical therapy may be
adequate for complete control; however,
moderate-­to-severe disease often requires systemic agents or phototherapy. Laser therapy is
also a helpful tool in the armamentarium
against psoriasis. For localized disease that is
not adequately controlled with topicals or for
lesions in difficult-to-treat areas, laser therapy
may be an ideal treatment option. Lasers
enable the delivery of therapeutic radiation to
lesional skin only, thus sparing non-lesional
skin from any possible adverse events. Over
the past few decades, various lasing devices
have been demonstrated to be safe and effective treatment options for psoriasis. The most
commonly used devices include the 308-nm
excimer laser and the 585 or 595-nm pulsed
dye laser. Despite recent advances in targeted
biologic therapy, lasers continue to play an
important role in the management of psoriatic
disease.
Q. Thibodeaux (*) · J. Koo
Department of Dermatology, University of California
San Francisco, San Francisco, CA, USA
e-mail: John.koo2@ucsf.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_8
Key Learning Objectives
1. To understand the mechanism of action
and types of laser therapy for psoriasis
2. To understand the appropriate use and
efficacy of laser therapy for psoriasis
3. To understand the safety concerns of
utilizing laser therapy for psoriasis
Introduction
Psoriasis is a chronic inflammatory disorder of
the skin and nails that affects over 3% of adults in
the United States [1]. The most common form of
the disease is plaque psoriasis, which presents as
scaly, erythematous lesions frequently involving
the scalp, elbows, knees, umbilicus, and lower
back. First line therapies for mild to moderate
psoriasis include topical agents such as corticosteroids, vitamin D analogues, coal tar, and topical retinoids. For more severe disease, oral
systemic agents, injectable biologics, or phototherapy may be required for adequate control.
For localized disease or when limited plaques
are recalcitrant to other therapies, laser therapy
may be beneficial. When compared to non-­
lesional skin, psoriatic plaques are able to withstand greater doses of radiation without burning
or blistering. Treatment with lasers allows the
targeting of lesional skin with supraerythemo93
Q. Thibodeaux and J. Koo
94
genic doses (i.e. beyond the minimal erythema
dose) of radiation leading to increased efficacy.
Sparing of non-lesional skin helps to reduced
treatment-related adverse effects such as burning,
blistering, and hyperpigmentation. Laser therapy
is also ideal for difficult-to-treat areas such as the
scalp, lower legs, palms, soles, and intertriginous
regions.
Multiple lasers have been evaluated for their
efficacy and safety in the treatment of psoriasis.
In the following chapter, the literature regarding
excimer, pulsed dye, Nd:YAG, and carbon dioxide lasers will be reviewed.
Excimer Laser
Background
The excimer laser is the most widely-used targeted phototherapy device for psoriasis and is
also used in the treatment of other dermatologic
conditions including vitiligo, alopecia areata, and
cutaneous T-cell lymphoma. The device was
invented in 1970 and produces a monochromatic
wavelength upon the dissociation of “excited
dimers”, which gives the technology its name. A
xenon dimer was used initially; however, further
development resulted in a xenon-chloride (XeCl)
dimer that produced a 308 nm wavelength within
the ultraviolet B (UVB) spectrum (290–320 nm).
In 1997, Bónis et al. were the first to report the
use of excimer laser in the treatment of psoriasis.
They found that in comparison to treatment with
narrowband UVB (311 nm), the excimer laser
was able to clear plaques of psoriasis in less time
and with lower cumulative doses of radiation [2].
Mechanism of Action
The mechanism of action of excimer laser in psoriasis is thought to be multifactorial and is drawn
from studies analyzing other forms of UVB phototherapy. Numerous mechanistic theories have
been proposed and include shifting of lesional
cytokine profiles away from the Th1/Th17 axis,
inducing apoptosis in epidermal and dermal kera-
tinocytes and T lymphocytes, promoting local
immunosuppression, and inducing cell-cycle
arrest [3]. p53, a promotor of cell-cycle arrest and
apoptosis has been found to be elevated in
lesional skin following irradiation with excimer
laser [4].
Efficacy
A pair of early efficacy studies evaluated the differences between medium and high-dose treatment regimens. In the medium-dose study, 20
subjects received thrice weekly treatments for up
to 8 weeks. The treatment regimen allowed possible dose increments of 25–30% per treatment.
Of the 15 subjects who completed the protocol,
>95% clearance was seen in an average of 10.6
treatments with a mean remission time (<25%
disease recurrence) of 3.5 months [5]. The high-­
dose study treated 32 plaques in 16 patients with
doses of 8 and 16 times their MED (minimal erythema dose). Following this single high-dose
treatment, mean modified PASI scores decreased
from 6.31 at baseline to 3.875 at follow-up
2 months later (P = 0.002) with partial clearing
noted in 11 of the 16 after only 1 month [6].
The earliest large-scale study evaluating
excimer laser in plaque psoriasis recruited 124
patients from multiple centers. Subjects were
initially treated with an average of 3 MED and
then twice weekly with dose adjustments in
response to treatment. Seventy-two percent of
patients who completed the protocol experienced at least 75% improvement of their lesions
in an average of 6.2 treatments. In all, 84% of
patients achieved 75% improvement in less than
10 treatments, with 50% reaching clearance of
90% or higher [7].
In another large, open-label study, 120 patients
received an initial 3 MED dose followed by
increases of 1 MED per session. Treatments were
administered twice weekly for 3 weeks and then
weekly until clearance was attained. Within 10
treatment sessions, 65.7% of subjects had
achieved 90% improvement, with 85.3% reaching PASI90 after 13 sessions. The average length
of treatment was 7.2 weeks [8].
8
Laser Therapy in Psoriasis
A smaller study evaluated 26 patients with
macular-type and 14 patients with chronic plaque
psoriasis. After an average of 13.7 treatment sessions, PASI improvements of 90.12 +/− 10.12%
and 77.34 +/− 17.04% were noted in the macular
and plaque groups, respectively [9].
Safety
Judicious use of the excimer laser has proven to
be a safe treatment option for psoriasis with no
serious or long-term side effects reported.
Common adverse events are similar to those of
more generalized phototherapy but are limited to
the areas receiving radiation. These common
reactions include pain, burning, erythema, blisters, erosions, and hyperpigmentation and are
typically mild and self-resolving [7, 8]. Although
no studies exist on the relationship between the
treatment of psoriasis with excimer laser and skin
carcinogenesis, a retrospective cohort study of
over 5000 Korean patients with vitiligo found no
increased risk of actinic keratosis, non-melanoma
skin cancers, or melanoma [10]. This relationship
is likely to hold true for the treatment of psoriasis
as well, as no reports have surfaced of an
increased risk of skin cancer, even anecdotally,
despite over 20 years of use.
Dosing/Protocols
To the authors’ knowledge, little data exists comparing the efficacies of various treatment
­regimens. In general, initial dosages are based on
either a predetermined MED or by the induration
of individual plaques. The MED is determined by
applying increasing dosages of radiation to
healthy, non-psoriatic skin and observing the first
dose that creates a well-demarcated, minimally
erythematous macule. In the earliest large, open-­
label study, initial dosages were one to three
times the MED, regardless of plaque characteristics [7]. Other studies have utilized the induration
component of the mPASI score to determine the
initial dose for specific plaques independent of
the patient’s skin type. Subsequent doses are then
95
altered in response to changes in induration [11].
In general, doses are increased or decreased
based on response to therapy or the development
of adverse events. Treatments should be separated by at least 48 h, and generally occur two to
three times per week in most protocols.
While the above protocols are most commonly
used, other, more aggressive treatment algorithms have also been implemented successfully.
Reports include a patient who achieved PASI 79
after only two treatments using a plaque-based
sub-blistering dosimetry [12] and a cohort of 13
patients whose global PASI scores decreased by
42% 8 weeks after a single “TURBO” dose of 10
times their MED [13]. Higher fluences were
noted to be more efficacious early in the development of the excimer laser, and Asawanonda et al.
were the first to report quicker clearance and longer remission of psoriasis with high dose (8 and
16 times MED) versus medium (2, 3, 4, and 6
times MED) and low (0.5 and 1 times MED) dose
treatments [14].
Few maintenance strategies have been evaluated. One protocol involved reducing the frequency of treatments after achieving PASI 75 to
once per week for 4 weeks, then once every
other week for 4 weeks, and then to one final
treatment 4 weeks later. With this regimen, none
of the five patients treated experienced >50%
PASI worsening during the 3-month taper [15].
In general, remission times of 3–4 months have
been reported following discontinuation of therapy [5, 6, 14].
ther Morphologies and Special
O
Populations
In addition to chronic plaque psoriasis, treatment
with excimer laser has also shown efficacy in
other forms of psoriasis as well, including palmoplantar pustulosis [16, 17], TNF-alpha inhibitor-­
induced palmoplantar pustular psoriasis [18],
inverse psoriasis [19, 20], scalp psoriasis [21,
22], and palmoplantar psoriasis [21, 23–25]. A
side-by-side study with 10 patients compared the
efficacy of excimer laser to topical PUVA for the
treatment of palmoplantar psoriasis and found
Q. Thibodeaux and J. Koo
96
near equivalent reductions in PASI after 5 weeks
(−63.57% for excimer; −64.64% for topical
PUVA) [26].
The safety and efficacy of excimer laser has
also been demonstrated in a pediatric population [27].
Pulsed Dye Laser
Background
The pulsed dye laser (PDL) is a lasing device that
is comprised of various combinations of organic
dyes mixed in solvents. These combinations are
“pumped” by an external high-energy source that
Adjuvant Therapies
excites the dye molecules, leading to the pulsed
emission of radiation at a wavelength of 585 or
The safety and efficacy of excimer laser has been 595 nm. At this wavelength, oxyhemoglobin acts
shown to increase with the concomitant use of as the main target within the skin. The pulsed dye
various topical medications. One right-versus-­ laser is mainly used in the treatment of vascular
left study compared twice weekly excimer treat- lesions such as port wine stains, hemangiomas,
ment to twice weekly excimer plus twice daily and telangiectasias; however, its efficacy in the
calcipotriene ointment. By week 6 the average treatment of psoriasis has also been evaluated.
PASI of the combination group (1.82 +/− 0.74)
was significantly lower than that of the monotherapy group (5.08 +/− 1.65). In addition to bet- Mechanism of Action
ter efficacy, the combination group also required
significantly less cumulative radiation [28]. The pulsed dye laser exerts its biological effects
Another study comparing excimer laser with based on selective photothermolysis, whereby a
concomitant flumetasone/salicylic acid oint- specific targeted tissue is preferentially destroyed
ment to excimer laser alone had similar results, leaving the surrounding tissues undamaged [32].
with the laser plus topical group experiencing In the case of PDL, the absorption of energy by
greater improvement in PASI scores with lower oxyhemoglobin leads to the destruction of the
average cumulative doses of phototherapy [29]. microvasculature. Because one of the defining
Combinations of various topicals in addition to histologic features of psoriasis is dilated and torexcimer have also been evaluated. One study tuous capillaries in the dermal papillae, PDL is
treated patients for 12 weeks with twice weekly able to treat psoriatic disease by ablating the vesexcimer laser in addition to alternating months of sels that supply blood, oxygen, and nutrients to
twice daily clobetasol spray and calcitriol oint- skin lesions.
ment. Of the 30 patients enrolled, 83% achieved
Reductions in plaque severity scores have
PASI75 by week 12 [30].
been correlated to decreases in plaque microvesExcimer laser has also been evaluated as an sel area following PDL treatment, with more
adjuvant therapy to PUVA treatment. One study clinically significant improvement seen in
evaluated 272 patients who were treated with plaques with larger pre-to-post treatment area
either PUVA four times weekly monotherapy or reductions [33, 34]. One early histologic study
PUVA four times weekly plus up to four suggested that a more tortuous or horizontal vasexcimer treatments within the first 2 weeks. cular pattern was associated with poorer response
Overall efficacy between the two treatments to treatment in comparison to more vertically oriwas equivalent, with 67.3% of the monotherapy ented vessels [35]. Another immunohistochemigroup and 63.6% of the PUVA plus excimer cal evaluation found that the thermolytic effect of
group achieving PASI 90; however, the PUVA PDL treatment was limited to the superficial capplus excimer group achieved PASI 90 in almost illary bed and did not affect the deeper vessels in
half the treatment time (15 +/− 6 vs. 27 +/− the upper reticular dermis. In a similar pattern, a
7 days) and with significantly less cumulative reduction of CD4+ and CD8+ T cells was seen in
UVA exposure [31].
the papillary dermis but not in the epidermis or
8
Laser Therapy in Psoriasis
97
upper reticular dermis [36]. Although thermolysis of superficial capillaries occurs as a result of
plaque treatment with PDL, overall blood flow
continues to be significantly elevated when compared to uninvolved skin, suggesting that deeper
vessels are also involved in the pathogenesis of
psoriasis [37].
Another study compared the efficacy of PDL,
NB-UVB, and the combination of PDL plus
NB-UVB versus no treatment. It found that while
both modalities led to significant improvement
by week 13, there was no significant difference
between the two and the benefits of both modalities were not synergistic [44].
Efficacy
Safety
Hacker and Rasmussen were the first to report the
efficacy of PDL in chronic plaque psoriasis. They
treated a single plaque in 20 patients with fluences of 5.0, 7.0, and 9.0 J/cm2, leaving one
quadrant as an untreated control. Eleven (57%) of
19 patients experienced positive effects after a
single dose of the 9.0 J/cm2 fluence, with negligible improvement in quadrants treated with the
5.0 and 7.0 J/cm2 doses and no improvement in
the control quadrant [38]. Following this proof-­
of-­concept, Katugampola et al. recruited eight
patients with symmetric chronic plaque psoriasis
and treated one plaque with PDL every 2 weeks
for three sessions, leaving the corresponding control plaque untreated. At week 16, five of the
eight patients showed improvement of >/= 50%
of the treated plaque. One patient remained clear
after 10 months of follow-up [39]. Another early
study by Ros et al. found noticeable improvement in 6 of 10 treated patients after 1–3 sessions
[40]. Zelickson et al. treated 36 patients across
two treatment groups and found that PDL significantly improved plaque psoriasis in two to five
sessions. No significant difference was noted
between treatment with short (450 μs) and long
(1500 μs) pulse-widths [35].
Two studies have compared PDL to topical
active comparators. Each found that PDL significantly improved the targeted psoriatic plaques;
however, one study found the active comparator
to be superior (clobetasol propionate + salicylic
acid) while the other found the active comparator
to be inferior (calcipotriol/betamethasone) [41,
42]. One case series compared PDL to dermabrasion. Of the 11 patients treated with PDL, three
experienced complete remission in comparison
to five of six treated with dermabrasion [43].
Side effects of PDL are similar to those of other
light-based therapies; however, because the
modality directly targets and destroys the vasculature, more specific effects from the extravasation of red blood cells have been noted. The most
common adverse events seen with PDL include
petechia, purpura, pain, erosions, hyperpigmentation, hypopigmentation, and atrophic scarring
[39, 40, 44]. Aside from rarely reported events
of scarring, side effects are typically mild and
short-lived.
Other Morphologies
de Leeuw et al. demonstrated that PDL may
be effective for palmoplantar psoriasis. Their
study involving 41 patients treated once every
4–6 weeks found that 76% of participants
achieved >70% improvement in their lesions after
an average of 4.2 treatments with over 50% experiencing greater than 90% improvement [45].
Much of the research into PDL and psoriasis
has focused on the treatment of nail disease. A
study comparing the efficacy of PDL and PDT
(methyl-aminnolaevulinic acid occlusion for
3 hours followed by PDL as a light source) in
the treatment of nail psoriasis found significant
improvement in both nail matrix and nail bed
disease for both modalities, with no significant
difference noted between the two [46]. Another
small study of 5 patients treated with monthly
PDL for 3 months found improvements in both
nail matrix (mean NAPSI from 7.0 +/− 1.4 to 2.2
+/− 0.7) and nail bed (mean NAPSI from 14.6
+/− 2.5 to 0.5 +/− 0.5) lesions [47]. A larger study
involving 20 patients and 79 nails also showed
Q. Thibodeaux and J. Koo
98
significant improvement in both nail bed and nail
matrix NAPSI scores with no significant difference noted between longer (6 ms) and shorter
(0.45 ms) pulse durations [48]. In a randomized,
single-blind study involving 20 patients and 192
diseased nails, treatment with monthly PDL for
6 months resulted in significant improvement
in both nail matrix and nail bed disease. In the
treatment group, mean NAPSI scores decreased
from 25.45 +/− 5.38 at baseline to 4.95 +/− 4.03
1 month after the last treatment session [49].
Nd:YAG Laser
Background
The Nd:YAG laser is a solid-state device that utilizes a crystal of neodymium-doped yttrium aluminum garnet as a lasing medium. The laser
emits infrared radiation at a wavelength of
1064 nm and is used as an ablative device in multiple specialties including ophthalmology, oncology, urology, and dermatology; however, little
evidence exists for its use in the treatment of psoriasis. Because the laser is able to penetrate up to
7 mm into the skin, it was postulated that
improvement in psoriatic lesions could result
from the destruction of deeper vasculature
structures.
Efficacy
Ruiz-Esparza was the first to report the use of
Nd:YAG laser in psoriasis in a 1999 case series.
Using a 1320 nm Nd:YAG laser, he treated three
patients with four sessions each and noted
improvement in all irradiated lesions. No quantitative measurements or validated scales were
used in this report [50]. van Lingen et al. compared monthly treatment with 1064 nm Nd:YAG
to daily calcipotriol/betamethasone dipropionate
(CBD) ointment for 3 months in four patients
using an intrapatient left-to-right study design.
Application of CBD ointment was found to significantly improve plaques at weeks 4, 8, and 12
of the study. Nd:YAG laser treatment using two
different spot sizes significantly improved lesions
at week 4, but these improvements were not
maintained through the remainder of the study.
They concluded that the laser was not “of additional value in the array of treatment modalities
for chronic localized plaque psoriasis.” [51]
Nd:YAG laser has also been evaluated for the
treatment of psoriatic nail disease. Kartal et al.
treated 16 patients with three monthly sessions of
Nd:YAG and assessed for changes in NAPSI
scores. Patients’ mean NAPSI score decreased
from 26 +/− 7.2 at baseline to 22 +/− 6.6, 13 +/−
6, and 5.7 +/− 4.3 after treatment sessions one,
two, and three, respectively. NAPSI scores at all
timepoints were significantly improved from
baseline [52].
Carbon Dioxide Laser
Background
The carbon dioxide (CO2) laser is a high-­powered
lasing device that operates in the infrared spectrum with wavelengths generally ranging from
9.4 to 10.6 micrometers. At this wavelength,
water absorbs and converts the energy to heat,
leading to local tissue destruction. The device is
used in soft-tissue surgery in multiple medical
specialties and has rarely been utilized for psoriasis due to the high likelihood of adverse events
and plaque recurrence.
Efficacy
Békássy and Astedt were the first to report the
use of CO2 laser in the treatment of psoriasis.
Their case series included three patients who
underwent vaporization to approximately 1 mm
of multiple plaques after the administration of
local anesthesia. The lesions were allowed to heal
over 4–6 weeks, and remission times of 3–5 years
were reported; however, their recovery was complicated by two instances of bacterial superinfection that required systemic antibiotics [53]. Alora
et al. compared the effects of varying the depth of
ablation by using curettage, debridement, and
8
Laser Therapy in Psoriasis
increasing numbers of CO2 laser passes in separate quadrants of individual plaques. In one
cohort, five of six patients noted recurrence of
their entire plaque within 8 weeks, while the final
patient noted recurrence after 12 weeks. In the
second cohort, four of six patients experienced
relapse by 8 weeks, but two subjects experienced
no recurrence 4 months after treatment [54].
Another study compared the effects of CO2 laser
and electrodesiccation and curettage within a
single plaque. Asawanonda et al. found that treatment with CO2 laser and ED&C both significantly improved psoriatic lesions over controls at
4 months of follow up; however, this improvement was then lost 2 months later. No significant
differences were noted between treatment with
CO2 laser versus ED&C at any timepoint [55].
Safety
Adverse events have been frequently reported
with CO2 laser therapy and include secondary
wound infection, depigmentation, and hypertrophic scarring [53, 55].
Comparative Studies
One recent single-blinded left-to-right study
compared excimer laser to pulsed dye laser in the
treatment of nail psoriasis. Forty-two patients
underwent twice weekly excimer laser treatment
to right hand nails and pulsed dye laser (PDL)
once every 4 weeks to left hand nails. Mean
NAPSI scores in the excimer group improved
from 29.8 at baseline to 16.3 at week 24, while
mean NAPSI scores in the PDL group improved
from 29.5 at baseline to 3.2 at week 24. NAPSI
improvement in the PDL group was significantly
greater than in the excimer group with minimal
side effects [56]. Another study involving 22
patients with plaque psoriasis compared twice
weekly excimer laser versus PDL with salicylic
acid pretreatment every 4 weeks and found that
mean PASI improvement was higher in the
excimer-treated plaques (4.7 SD 2.1) than in the
PDL-treated plaques (2.7 SD 2.4) [57]. An intra-
99
patient left-to-right study comparing PDL and
Nd:YAG laser for the treatment of nail psoriasis
found no statistical difference between reductions in NAPSI scores between the two modalities when each was combined with calcipotriol/
betamethasone gel [58].
References
1. Rachakonda TD, Schupp CW, Armstrong
AW. Psoriasis prevalence among adults in the United
States. J Am Acad Dermatol. 2014;70(3):512–6.
2. Bonis B, Kemeny L, Dobozy A, Bor Z, Szabo G,
Ignacz F. 308 nm uvb excimer laser for psoriasis.
Lancet. 1997;350(9090):1522.
3. Wong T, Hsu L, Liao W. Phototherapy in psoriasis: a
review of mechanisms of action. J Cutan Med Surg.
2013;17(1):6–12.
4. Bianchi B, Campolmi P, Mavilia L, Danesi A, Rossi
R, Cappugi P. Monochromatic excimer light (308
nm): an immunohistochemical study of cutaneous t cells and apoptosis-related molecules in psoriasis. J Eur Acad Dermatol Venereol. 2003;17(4):
408–13.
5. Trehan M, Taylor CR. Medium-dose 308-nm excimer
laser for the treatment of psoriasis. J Am Acad
Dermatol. 2002;47(5):701–8.
6. Trehan M, Taylor CR. High-dose 308-nm excimer
laser for the treatment of psoriasis. J Am Acad
Dermatol. 2002;46(5):732–7.
7. Feldman SR, Mellen BG, Housman TS, Fitzpatrick
RE, Geronemus RG, Friedman PM, Vasily DB,
Morison WL. Efficacy of the 308-nm excimer laser
for treatment of psoriasis: results of a multicenter
study. J Am Acad Dermatol. 2002;46(6):900–6.
8. Gerber W, Arheilger B, Ha TA, Hermann J, Ockenfels
HM. Ultraviolet b 308-nm excimer laser treatment
of psoriasis: a new phototherapeutic approach. Br J
Dermatol. 2003;149(6):1250–8.
9. He YL, Zhang XY, Dong J, Xu JZ, Wang J. Clinical
efficacy of a 308 nm excimer laser for treatment of
psoriasis vulgaris. Photodermatol Photoimmunol
Photomed. 2007;23(6):238–41.
10. Bae JM, Eun SH, Oh SH, Shin JH, Kang HY, Kim
KH, Lee SC, Choi CW. The 308-nm excimer laser
treatment does not increase the risk of skin cancer in
patients with vitiligo: a population-based retrospective cohort study. Pigment Cell Melanoma Res. 2019;
11. Taneja A, Trehan M, Taylor CR. 308-nm excimer
laser for the treatment of psoriasis: induration-based
dosimetry. Arch Dermatol. 2003;139(6):759–64.
12. Debbaneh MG, Levin E, Sanchez Rodriguez R, Leon
A, Koo J, Rosenblum MD. Plaque-based sub-­blistering
dosimetry: reaching pasi-75 after two treatments
with 308-nm excimer laser in a generalized psoriasis
patient. J Dermatolog Treat. 2015;26(1):45–8.
9
Traditional Systemic Therapy I:
Methotrexate and Cyclosporine
Erin Boh, Andrew Joselow, and Brittany Stumpf
Abstract
This chapter will review the traditional systemic drugs, methotrexate and cyclosporine,
both of which are used in treating patients
with moderate to severe or recalcitrant psoriasis. The pharmacology and use of these drugs
in the treatment of patients with psoriasis will
be covered as well as the parameters to screen
patients, monitoring guidelines and adverse
effects associated with each.
Key Learning Objectives
1. To understand the mechanism of action
of methotrexate and cyclosporine.
2. To understand the appropriate use and efficacy of methotrexate and cyclosporine.
3. To understand the safety concerns and
appropriate monitoring for methotrexate and cyclosporine.
E. Boh (*) · A. Joselow · B. Stumpf
Department Dermatology, Tulane University School
of Medicine, New Orleans, LA, USA
e-mail: eboh@tulane.edu; ajoselow@tulane.edu;
boswald@tulane.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_9
Introduction
Psoriasis is a chronic inflammatory disease
affecting over seven million individuals. It can be
debilitating and associated with systemic co-­
morbidities such as arthritis, hypertension, hyperlipidemia and insulin resistance [1–3]. Recently,
it has been suggested that psoriasis may be associated with or part of metabolic syndrome [4–6].
In addition to topical therapy and phototherapy,
systemic agents, including a newly developed
class referred to as biologics, have been used for
its treatment. Systemic therapies are often
reserved for patients with moderate to severe
psoriasis. The goals of treatment are to quickly
clear or reduce psoriatic lesions, to make the
patient comfortable by alleviating symptoms and
to provide long-term maintenance with minimal
toxicity for the patient.
In the past, systemic therapy has been used for
those individuals with moderate to severe psoriasis as defined by greater than 10% body surface
area or debilitating disease. With the development of biologic agents, the treatment algorithm
has changed tremendously, giving us additional
therapeutic options that are potentially less toxic
to the liver, kidneys, and bone marrow and are
not teratogenic. There still remains a place for
traditional agents for some patients with moderate to severe disease. While the biologics have a
very good safety and efficacy profile, they have
not totally replaced traditional agents for the
103
E. Boh et al.
104
treatment of psoriasis. Traditional systemic therapies continue to play an important role in the
treatment of psoriasis with their oral route of
administration and low cost (compared with biologics) making them an important treatment
option in the appropriate patient.
Contraindications due to comorbid conditions,
insurance restrictions as well as cost may be limiting factors for the use of these biologic agents.
This chapter will review the traditional systemic drugs, methotrexate and cyclosporine, and
how they can be used as monotherapy or even
adjunctive therapy (combination therapy) in
treating patients with moderate to severe or recalcitrant psoriasis.
Methotrexate
Introduction
Methotrexate is the most widely used systemic
treatment for moderate to severe psoriasis. The
National Psoriasis Foundation and American
Academy of Dermatology recently published
detailed dosing and monitoring guidelines [7,
8]. Methotrexate is a synthetic analogue of folic
acid, which exhibits immunosuppressive as well
as anti-inflammatory properties. It has been
used successfully to treat psoriasis for over
50 years. While Gubner et al. in 1951 [9] first
reported clearance of psoriasis in cancer patients
Fig. 9.1 Structure of
methotrexate (Methotrex
ate|C20H22N8O5 https://
pubchem.ncbi.nlm.nih.
gov/compound/
Methotrexate. Accessed
June 14, 2019. Source:
U.S. National Library of
Medicine)
being treated with aminopterin, a precursor to
methotrexate, Edmunson and Guy first reported
methotrexate’s efficacy in treating psoriasis in
1958 [10]. The FDA approved methotrexate in
1972 for the indication of psoriasis [11].
Interestingly, it was not until the early 1980s
that methotrexate was approved for rheumatoid
arthritis. Since these early years, methotrexate
has become the “gold standard” for treating
moderate to severe psoriasis and psoriatic arthritis [12]. Over the years, dosing has been modified to minimize the toxicity associated with
methotrexate [7, 8].
Mechanism of Action
Methotrexate has anti-proliferative, anti-­
inflammatory and immunosuppressive actions.
As a synthetic analogue of folic acid, methotrexate competitively inhibits dihydrofolate reductase, an enzyme responsible for conversion of
folic acid to reduced folate (tetrahydrofolate)
(Fig. 9.1). Tetrahydrofolate is required for the
transfer of 1-carbon units in the thymidylate and
purine synthesis pathway [13]. This inhibition
blocks synthesis of deoxythymidylic acid, which
is required for DNA synthesis. As a consequence,
methotrexate causes the arrest of cell division in
the S phase.
Studies have shown that the anti-proliferative
effects of high-dose methotrexate can be reversed
H
H
N
N
N
N
N
N
H
N
O
H
N
H
O
O
O
O
H
H
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
105
by high doses of folic acid, thus supporting the standing, methotrexate appears to have multiple
mechanism of inhibition of DNA synthesis [13, mechanisms of action at play. Methotrexate has
14]. Low-dose methotrexate may exhibit other been shown to help restore a typical immune balmechanisms of action, including anti-­inflammatory ance of T-cells by lowering the level of Th1 and
and immunomodulatory effects. This observation Th17 cells and increasing Th2 and T-reg cells –
is supported by the widespread practice by derma- essentially shifting from a pro-inflammatory to
tologists and rheumatologists of administering low an anti-inflammatory T-cell phenotype [19].
doses of folic acid (i.e. 1 mg per day) to patients on
methotrexate to minimize adverse effects without
compromising efficacy [15].
Absorption and Bioavailability
While high-dose methotrexate inhibits DNA
synthesis, primarily through the inhibition of Methotrexate may be given orally, intramuscudihydrofolate reductase, lower doses as used in larly, subcutaneously or intravenously. Food
treatment of psoriasis have more anti-­intake does not influence absorption in adults but
inflammatory and immunomodulatory effects. may in children [14]. Once absorbed, methotrexThese anti-inflammatory effects seem to involve ate is actively transported into cells where it is
the formation of intracellular metabolites of metabolized into polyglutamate imidazole prodmethotrexate [13, 16].
ucts, which appear to be the more active drug.
Once absorbed, methotrexate is metabolized These products accumulate, resulting in increased
intracellularly to polyglutamate derivatives, adenosine contributing both to toxicity and effipotent inhibitors of a number of folate-dependent cacy [16]. Current data suggests that methotrexenzymes leading to the accumulation of intracel- ate is metabolized intracellularly, including in the
lular imidazole products. These inhibit adenosine liver, to form polyglutamate metabolites that
deaminase, ultimately resulting in accumulation exert effects on various tissues.
of adenosine [16]. Adenosine suppresses the
Peak levels are attained fairly rapidly, approxisecretion of inflammatory cytokines by macro- mately one hour after oral administration, slower
phages and neutrophils, as well as diminishes the relative to other modes of administration.
expression of adhesion molecules. Additionally, Absorption after ingestion may be affected by
adenosine, through binding to the A2 receptor, dosing: higher doses having incomplete or variexhibits potent anti-inflammatory effects by able absorption. Steady-state levels of methotrexinhibiting neutrophil leukotriene synthesis [13]. ate may be more reliable in smaller doses over the
Activated T cells play a pivotal role in psoriasis, course of 12–24 h one day per week. Plasma levand it appears that methotrexate not only inhibits els have a triphasic response. Once the drug is
DNA replication of these T-cells but also dimin- absorbed, plasma levels decrease rapidly within
ishes antigen-stimulated T-cell proliferation. By the first hour, reflecting distribution throughout
inhibiting mitogen-activated T-cells, these cells body tissues. The second phase of reduction
become more susceptible to apoptosis [17]. reflects renal excretion over the next 2–4 h.
Johnston et al. recently refuted this notion of Importantly, renal function such as glomerular filincreased susceptibility to apoptosis [18]. These tration and tubular secretion can significantly
authors propose that methotrexate exerts its affect blood levels. The final phase occurs through
effects through both folate-dependent (decreased slow release from the tissues over 10–27 h after
synthesis of antigen stimulated T-cells) and ingestion reflecting its half-life (T ½).
folate-independent mechanisms (altered adheApproximately 50% of methotrexate is transsion molecule expression through alterations in ported bound to plasma proteins. The free or
adenosine). Most likely, the benefits seen involve unbound portion is the active form of the drug.
both processes, and methotrexate should be Plasma levels can be affected by the binding of
viewed as an immunosuppressing and immuno- other drugs to these plasma proteins either
modulating agent. At this point in our under- ­displacing or blocking methotrexate, resulting in
E. Boh et al.
106
elevated blood levels. Drug interactions will be
discussed below.
Orally administered MTX has been found to
have a saturable intestinal absorption and nonlinear pharmacokinetics, with significant consequences on drug bioavailability and clinical
efficacy. The current evidence shows that parenterally administered MTX results in rapid and
complete absorption, higher serum levels, and
less variable exposure than oral dosing. The use
of parenteral MTX, particularly when administered as a subcutaneous (SC) injection, has
recently raised great interest in order to overcome
the limitations of oral MTX.
Various clinical experiences have suggested
that SC MTX is more effective than oral MTX and
may provide significant benefit even in patients in
whom oral MTX proved to be inadequate. The
increased efficacy of SC MTX resulting from
higher drug exposure compared with oral MTX
has been associated with a similar safety profile
and in various reports even with a lower frequency
of gastrointestinal complaints [20].
In the future, novel colloidal drug delivery
systems may provide advantages over prior formulations with improved skin permeability and
targeted delivery systems may improve efficacy,
and decrease toxicity in psoriasis patients [21].
psoriasis including specific guidance on dosing,
route of administration, risk and monitoring of
liver toxicity [8, 24].
There are several important parameters to
consider when choosing methotrexate as a form
of therapy. These include the severity of the disease, the patient’s co-morbidities such as associated arthritis, socioeconomic factors, and the
ability of the patient to participate in treatment.
As a general rule, methotrexate is suggested for
patients with at least 10% body surface area
(BSA) affected, who have failed or can no longer
perform topical therapy, or who have failed or
have contraindications to phototherapy. Absolute
and relative contraindications to methotrexate
therapy, listed in Table 9.1, should be reviewed
carefully and discussed with the patient prior to
initiation of the drug. Considerations for patient
selection should be based on patient history, laboratory findings and co-morbidities. Absolute
contraindications mandate an alternative form of
therapy. Methotrexate is a teratogen, and women
of childbearing potential should use birth control.
It is contraindicated in pregnancy as well as during breastfeeding. Men should also be counseled
on not impregnating a woman until 3 months off
therapy. Relative contraindications include Type
Table 9.1 Contraindications to methotrexate therapy
Use in Psoriasis
Methotrexate is FDA-approved for the treatment
of moderate and moderate-to-severe psoriasis in
adults and psoriatic arthritis [13]. The first treatment guidelines on the use of MTX in psoriasis
were published by Roenigk et al. in 1973 [22];
and, since that time, many newer treatment
guidelines for the use of methotrexate and other
systemic agents in psoriasis have been published
[7, 8, 14, 23]. The most recent guidelines for the
treatment of psoriasis with methotrexate were
published by the National Psoriasis Foundation
and by the American Academy of Dermatology
in 2019 [7, 8].
These guidelines, as well as a systematic
review of the literature, has led to evidence-based
recommendations on the use of methotrexate in
Absolute contraindications
Excessive alcohol consumption
resulting in liver damage
Alcoholic liver disease or other
chronic liver diseases,
including hepatitis B or C
Bone marrow abnormalities:
Anemia, thrombocytopenia,
leukopenia
Immunodeficiency
Nursing mothers
Pregnancy
Methotrexate hypersensitivity
Active infection
Relative
contraindications
Renal insufficiency
Advanced age
Alcohol
consumption:
History of or current
alcohol consumption
Peptic ulcer disease
Concomitant use of
hepatotoxic drugs
Family history of
inheritable liver
disease
Diabetes mellitus
Hyperlipidemia
Morbid obesity
Active infection
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
2 diabetes, insulin resistance, alcohol consumption, obesity and hypertriglyceridemia. As a general rule, these patients should be evaluated for
other treatments. Patients with relative contraindications can use methotrexate with appropriate
precautions. For instance, patients with peptic
ulcer disease may be treated with concomitant
proton pump inhibitor therapy. The decision to
treat should be based on the patient’s individual
situation.
While used to treat psoriatic arthritis for years,
the SEAM-PsA trial is only one of a few studies
that suggest methotrexate (20 mg/week) is beneficial as a monotherapy in treatment-naïve psoriatic arthritis patients or in combination with a
biologic [25].
Similarly, Appani et al., found methotrexate
initiation (>15 mg/week) resulted in significant
improvement in dactylitis along with other psoriatic arthritis symptoms [26].
Dosing
Methotrexate is generally given as a single
weekly oral dose administered over a 12 h period.
It is available as a 2.5 mg, 7.5 mg, 10 mg, 15 mg
tablets and an injectable 25 mg/ml solution.
Intramuscular or subcutaneous administration is
helpful when there is gastrointestinal intolerance
to oral dosing or if there are concerns regarding
patient compliance. Subcutaneous injection is
equally effective and can be self-administered at
home.
Dosing is equivalent whether the oral or
injectable form is used. Many practitioners give a
single test dose of 2.5 or 5 mg to evaluate for significant bone marrow suppression or acute
hepatic injury in susceptible patients. Although
there are no established maximum or minimum
dosages of methotrexate, weekly dosages usually
range from 7.5 to 25 mg.
After the test dose of 5 mg of methotrexate,
blood tests (complete blood count with platelets
and renal and liver function tests) are obtained
5–6 days later. If blood work is within normal
limits, treatment doses are started at 10–15 mg
once weekly. Methotrexate can be increased by
107
2.5–5 mg every 2–4 weeks until a response is
seen, up to approximately 25 mg weekly, the
maximum recommended dose.
There are published reports suggesting that
folic acid protects against gastric upset, nausea,
oral ulcerations and may even impact bone marrow toxicity, especially in rheumatoid arthritis
patients [15].
A recent study found drug-survival, the time
period of treatment with a specific drug before its
cessation, was significantly higher in those
patients whose methotrexate therapy was supplemented with folic acid compared to those who
received methotrexate alone (27.6 months vs
18.5 months, respectively) [27].
Therefore, a 1 mg per day folic acid supplement is recommended based on expert evaluation
[15]. Some practitioners recommend not taking
folic acid on the day patients dose with methotrexate, but the significance of this has not been
studied.
All dosing schedules should be adjusted to the
individual patient to obtain or maintain adequate
disease control with minimal side effects. In
order to ensure some degree of safety, monitoring
should be done on a continuous basis.
Vena et al. reviewed the current literature on
use of subcutaneous vs oral methotrexate for
patients with inflammatory arthritis and psoriasis
[20] .These authors concluded that current evidence indicates that SQ administration of MTX
is characterized by linear and predictable pharmacokinetics resulting in higher bioavailability
as compared with oral methotrexate, especially
with weekly doses of 15 mg. Subcutaneous MTX
is useful for those with GI intolerability or for
those individuals who have not gotten maximal
response from orally dosed levels of MTX.
Monitoring Guidelines
Prior to initiation of methotrexate treatment, the
patient should have pretreatment blood tests,
including liver function tests, creatinine, hepatitis
B and C screening, tuberculosis screening, a
complete medical history with emphasis on medications and co-morbidities, and a complete
108
Table 9.2 Monitoring methotrexate guidelines
Baseline
History and physical
Careful review of drug history and evaluation of low
risk versus high-risk patients
Laboratory
Complete blood count with differential and platelet
counts (CBC)
Comprehensive metabolic panel- renal and hepatic
(CMP)
Hepatitis B and C screening
Tuberculosis screening with PPD or blood test
Serum or urine pregnancy screening
On-going monitoring
Periodic review of drug history
Physical exam
Laboratory
CBC with differential and platelets q month for
3 months then every 3 months
CMP q month for 3 months, then every 3 months
Tuberculosis screening every year
physical examination performed. Patients should
be counseled on methotrexate and its potential
side effects. Documentation should include the
type of psoriasis, past treatments, patient’s quality of life measures, the body surface affected,
risk factors for hepatotoxicity and other potential
toxicities. Patients taking methotrexate should be
monitored regularly for potential organ toxicity.
Baseline and ongoing monitoring guidelines are
listed in Table 9.2.
Monitoring of the blood parameters should be
done approximately 2–4 weeks after adjusting
the dose. It is important to remain at the minimal
effective dose and to record the total cumulative
dose of methotrexate while maintaining disease
control and medication tolerance. It is also important to consider a liver biopsy in those patients on
long-term therapy, or those with significant risk
for hepatotoxicity.
While practitioners have their individual
styles of practice, it is advisable to perform a
periodic history and physical exam on patients on
methotrexate therapy to ensure the highest quality of care and to minimize potential adverse
events. If laboratory abnormalities occur, blood
tests may be repeated and more frequent monitoring may be necessary. Liver function tests
E. Boh et al.
Table 9.3 High risk factors for hepatic toxicity from
methotrexate
Risk factors
History of or current alcohol consumption
Persistent abnormal liver chemistry studies
History of liver disease, including chronic hepatitis B
or C
Family history of inheritable liver disease
Diabetes mellitus
Obesity
History of significant exposure to hepatotoxic drugs or
chemicals
Potential significant drug interactions
Lack of folate supplementation
Hyperlipidemia
should be drawn at a 5-day interval from the last
dose since values may be elevated 1 to 2 days
after ingestion of methotrexate. If a significant
persistent abnormality in liver chemistry develops, methotrexate therapy should be withheld for
1 to 2 weeks and repeat blood work should be
performed. Discuss with the patient if any new
medications were prescribed or other situations
have developed.
Liver Biopsy
Guidelines for liver biopsy in psoriasis patients
were published in 1998 and updated in the
American Academy of Dermatology (AAD)
guidelines for treatment of psoriasis in 2009 [23,
24, 28]. Initially, guidelines suggested liver
biopsy at the start of therapy and after every 1.5
gram cumulative dose thereafter [28]. The AAD
and National Psoriasis Foundation guidelines for
monitoring have been updated to differentiate
patients at low risk for hepatotoxicity from those
at high risk [7, 8]. Table 9.3 outlines those patients
at high risk for hepatotoxicity. For low-risk
patients, methotrexate can be initiated without
performing a baseline liver biopsy. A liver biopsy
should be performed after approximately a 3.5–
4.0 gram cumulative dose. High-risk patients
should obtain a liver biopsy after approximately a
300–600 mg cumulative dose to ensure a response
to therapy before subjecting the patient to the
risks of a biopsy. Table 9.4 summarizes the grading system proposed by Roenigk et al. for interpretation of liver biopsy histologic results [28].
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
Table 9.4 Evaluation of liver biopsy findings [25]
Grade
I
II
IIIA
Findings
Fatty infiltration; mild;
nuclear variability; mild;
portal inflammation
Moderate to severe fatty
infiltration; moderate to
severe nuclear variability;
portal tract expansion;
portal tract inflammation
and necrosis
Mild fibrosis; slight
enlargement of portal tracts
without disruption
IIIB
Moderate to severe fibrosis;
cirrhosis
IV
Cirrhosis
Disposition
Normal
Continue
methotrexate
Continue
methotrexate
Fibrosis
Discontinue
methotrexate
Repeat biopsy
sooner
Fibrosis
Discontinue
methotrexate
Cirrhosis
Discontinue
methotrexate
As a general rule, patients with grade I and II can
continue methotrexate. Those with grade IIIA
may cautiously continue therapy with more stringent monitoring if better alternatives are not
available. Only those patients without other
options should continue methotrexate. Patients
with grade IIIB and IV should discontinue the
drug regardless. It is important to closely work
with a hepatologist who is also up to date with the
current published guidelines.
Although noninvasive tests for monitoring
MTX-induced hepatic fibrosis have been studied
and shown to be useful in reducing the number of
liver biopsies, no single test has emerged as a
replacement for liver biopsy. A family of related
noninvasive tests for hepatic fibrosis is available;
these tests consist of panels of serum biomarkers
and patient biometrics that are put into patented
mathematical models that generate scores predictive of hepatic fibrosis.
The nonalcoholic steatohepatitis (NASH)
FibroSure test (LabCorp) is similar to the
FibroTest used for assessing fibrosis in Hepatitis
C infection but was specifically developed for
patients with NAFLD. With a computational
algorithm to provide a quantitative surrogate
marker of liver fibrosis, steatosis, and nonalcoholic steatohepatitis (NASH), the NASH
109
FibroSure test uses 10 biochemical markers in
combination with age, sex, height, and weight.
The NASH FibroSure test is reported to have a
sensitivity of 83% and a specificity of 78% in
detecting risk of significant fibrosis and a sensitivity of 71% and a specificity of 72% in identifying risk of significant steatosis in patients with
NAFLD [29].
Bauer et al. postulate that a liver biopsy cannot be entirely replaced by the NASH FibroSure
test; they do, however, support the idea that the
number of liver biopsies can be significantly
reduced by the use of noninvasive tests such as
the NASH FibroSure [30].
Adverse Effects
There are a number of common and uncommon
adverse effects reported with methotrexate usage.
Common minor complaints by patients include
fatigue, nausea, vomiting, headache and stomatitis. Many of these adverse effects are eliminated
by administration of folic acid. If gastrointestinal
symptoms persist, methotrexate can be administered by injection, subcutaneously or intramuscularly. Dosing may also be administered in divided
doses over a 24-h period. The three primary areas
of potential major toxicity include hepatotoxicity, myelopsuppression and pulmonary fibrosis.
Hepatotoxicity
There are both acute and chronic hepatotoxic
adverse effects. Acute hepatocellular damage, as
manifested by elevated liver enzymes, may result
from high blood levels of methotrexate. High
blood levels occur when the dose exceeds 25 mg
per week or when levels are increased by a significant drug interaction or displacement of
bound methotrexate by another medication.
Acute hepatocellular damage almost always
results in abnormal liver enzyme studies.
However, chronic damage to the liver may occur
even when liver blood studies remain normal.
Chronic hepatotoxicity results from the cumulative effects of methotrexate on the portal system
resulting in fibrosis. The histologic damage and
subsequent fibrosis can only be assessed by liver
E. Boh et al.
110
biopsy. As discussed above, biopsy of the liver
can be delayed in those patients who are at low
risk of hepatotoxicity but should be done at an
earlier interval if the patient is at high risk. The
histopathologic features of methotrexate-induced
liver toxicity resemble nonalcoholic steatohepatitis (NASH), a similar pattern observed in patients
who are obese, hyperlipidemic or diabetic.
Methotrexate likely aggravates preexisting
steatohepatitis.
As stated, the risk of methotrexate-associated
liver damage is increased in patients with preexisting risk factors such as obesity and hypercholesterolemia. While older studies estimate the
risk of elevated transaminases and elevations
twice the upper limit of normal as nearly 50%
and 17% respectively, recent studies suggest,
with appropriate monitoring and dosing, the risk
may be significantly lower [31].
In their recent review, Conway et al. [31]
noted a more accurate level of risk for elevated
transaminases and those elevated beyond twice
the upper limit of normal is likely closer to 20%
and 1% respectively.
Serum assays for assessing liver fibrosis, such
as the measurement of the amino-terminal peptide of procollagen III, have been used in Europe
as an alternative to liver biopsy but are not currently available in the United States [32].
Currently, there are no blood assays or diagnostic
tests adequate to monitor for chronic liver toxicity other than biopsy or FibroSure testing.
methotrexate therapy as well as monitor while on
therapy to minimize these risks. If anemia,
thrombocytopenia or leucopenia occurs acutely,
it can be reversed with folic acid administration
or in severe cases, folinic acid (leucovorin) rescue. High dose folic or folinic acid can be given
by mouth or intravenously at doses of 15 mg
every 6 h for 1 to 2 days or until the methotrexate
levels approach zero. Administration of daily
folic acid while on methotrexate may minimize
gastrointestinal and liver toxicity, but its impact
on the bone marrow toxicity remains controversial [15].
Pulmonary Fibrosis
Pulmonary fibrosis and interstitial pneumonitis
may uncommonly occur in patients with psoriasis
being treated with methotrexate, but is more common in patients being treated for rheumatoid
arthritis. Pulmonary fibrosis is more commonly
associated with high dose methotrexate therapy.
Patients should be monitored for signs and symptoms such as dry cough, dyspnea at rest and low-­
grade fever. Other very uncommon pulmonary
complications include cryptogenic organizing
pneumonia (COP), pleuritis and pleural effusions.
Drug Interactions
Methotrexate has many reported and presumptive
drug interactions that may result in decreased or
increased levels of methotrexate and potentiate
end-organ toxicity. Therefore, it is very important
Myelosuppression
Myelosuppression is potentially a very signifi- to take a complete medication history as part of
cant toxicity associated with methotrexate admin- pre-methotrexate screening. It is also important
istration. Methotrexate can cause leukopenia, to counsel patients regarding possible drug interthrombocytopenia and anemia. It is usually dose-­ actions, especially with regards to over-the-­
dependent and due to direct toxic action on the counter and commonly prescribed drugs.
bone marrow. Rarely, there is an idiosyncratic Table 9.5 has some of the common potential drug
myelosuppression, which occurs early in treatment. Idiosyncratic reactions may be more likely Table 9.5 Common drug Interactions with methotrexate
in patients with advanced age, renal insufficiency, Trimethoprim
Phenothiazines
underlying bone marrow disease, hypoalbumin- Sulfonamides
Salicylates
emia, concomitant medications or folate defi- Chloramphenicol
NSAIDs
Tetracyclines
Systemic Retinoids
ciency. For this reason, physicians administer the
Dapsone
Probenacid
test dose of methotrexate. It is imperative to
Phenytoin
Triamterene
screen patients appropriately before starting
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
interactions. There are numerous medications
that increase or decrease blood methotrexate levels either by displacing it from protein binding
sties, blocking its binding, and altering the
metabolism of it through the cytochrome P-450
system. Other medications may also have an
additive effect on end-organ damage.
and originally used as an immunosuppressive
agent in organ transplantation, it was first shown
to be effective for psoriasis in 1979 [33].
Cyclosporine primarily acts by inhibiting T-cell
function and interleukin IL-2 via binding to
cyclophyllin.
The original formulation (Sandimmune) had
considerable variations in absorption and bioavailability. Newer microemulsion formulations
(Neoral/ cyclosporine modified) have better and
more predictable bioavailability and are more
cost effective. Neoral was FDA approved in 1997
for psoriasis and rheumatoid arthritis.
Cyclosporine is considered safe and effective for
psoriasis. However, there is still reticence about
its use in psoriasis. It has a particularly useful
role in managing psoriatic crises due to its rapid
onset and its efficacy in treating psoriasis unre-
Cyclosporine
Introduction
Cyclosporine, a cyclic peptide of 11 amino acids,
was isolated from the soil fungus Tolypocladium
inflatum Gams in 1970 (Fig. 9.2). CSA is a highly
effective and rapidly acting systemic agent for
the treatment of psoriasis. Discovered in 1970
Fig. 9.2 Structure of
cyclosporine (Cyclospor
ine|C62H111N11O12 https://
pubchem.ncbi.nlm.nih.
gov/compound/5280754.
Accessed June 14, 2019.
Source: U.S. National
Library of Medicine)
111
O
O
H
N
N
H
O
O
N
N
H
O
N
N
O
O
N
N
O
N
N
H
N
O
O
O
H
H
H
O
E. Boh et al.
112
sponsive to other modalities, bridging to other
therapies, and treating psoriasis within a rotational scheme of other medications [34].
Appropriate patient selection and monitoring will
significantly decrease the risks of side effects.
Despite published guidelines for use in psoriasis, there still remains controversy and disagreement over treatment strategy and monitoring
[34]. In contrast to other traditional agents such
as methotrexate and hydroxyurea, cyclosporine is
not remarkably cytotoxic, does not suppress the
bone marrow and is not teratogenic. It does have
potential significant renal side effects, including
hypertension.
Numerous clinical trials have demonstrated
the efficacy of CSA in psoriasis. The original
studies evaluating CSA’s efficacy in psoriasis
provided evidence that psoriasis is a T-cell driven
immunologic disorder rather than a disorder of
altered keratinocyte growth and differentiation.
CSA given at 2.5 to 5 mg/kg/d for 12 to 16 weeks
leads to rapid and dramatic improvement in psoriasis in up to 80% to 90% of patients [35]. When
dosed at 3 mg/kg/d, CSA leads to a PASI 75
response in 50% to 70% of patients and a PASI
90 response in 30% to 50% of patients [36].
A large, well-conducted systematic review
published in 2016 found no significant difference
in efficacy between CSA and MTX in PASI or
PGA in the treatment of psoriasis [37].
transcription of proinflammatory genes, most
notably IL-2, and the up-regulation of the IL-2
receptor [38]. As a consequence, T-cell activation
and production of inflammatory cytokines is
impaired. It is now widely accepted that psoriasis
is mediated by these activated T cells and their
cytokine products. Cyclosporine appears to also
dampen expression of intercellular adhesion molecule (ICAM)-1 on keratinocytes and endothelial
cells. Cyclosporine also decreases tumor necrosis
factor, a key cytokine in psoriasis pathogenesis,
and suppresses the Th17 genes, IL-17, IL-22 and
the IL-23p19 subunit, all of which are overexpressed in psoriatic skin [39].
Absorption and Bioavailability
Cyclosporine is lipophilic and exhibits very poor
solubility in water. As a consequence, suspension
and microemulsion forms of the drug have been
developed for oral administration and for injection. The first formulation, Sandimmune, was
produced in 1983. It had variable and unpredictable bioavailability among patients secondary to
its high dependence on bile solubility. This was
improved by the introduction of a microemulsion
formulation, Neoral, in July 1995. Several other
cyclosporine modified formulations have subsequently been brought to market. The bioavailability of generic cyclosporine is approximately 30%
that may be slightly increased with some branded
versions. Cyclosporine capsules and liquid oral
Mechanism of Action
formulations are considered bioequivalent. There
Cyclosporine primarily acts by inhibiting T-cell are few published reports comparing bioavailfunction and interleukin (IL-2) [38]. After an ability and efficacy among different generic forantigen-presenting cell binds to a T cell, intracy- mulations although the perception that differences
toplasmic levels of calcium increase leading to in these agents exists is prevalent [40]. Since
calmodulin activation of calcineurin phospha- cyclosporine has a narrow therapeutic window,
tase. Calcineurin phosphatase dephosphorylates careful monitoring and consistency in generic
cytoplasmic nuclear factor of activated T cells formulations is required.
Cyclosporine is absorbed in the small intesallowing translocation into the nucleus and
enabling transcription of proinflammatory genes, tine with peak concentrations occurring from
including IL-2, IL-4, interferon gamma and 1–8 h. The absorption is dependent on bile salts,
increased with fatty foods. Metabolism is affected
transforming growth factor beta.
Calcineurin inhibition by a cyclosporine-­ with concurrent grapefruit juice ingestion [41].
cyclophilin complex prevents activation of calci- Cyclosporine distributes through multiple organ
neurin phosphatase, thus preventing downstream systems, including the skin, and can be found in
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
breast milk. It crosses the placenta but not the
blood brain barrier.
Cyclosporine is metabolized by the hepatic
cytochrome P-450 3A4 (CYP3A4) enzyme system, and almost completely excreted in bile
through the feces. The dose may need to be
reduced in patients with hepatic insufficiency but
not in renal insufficiency or with hemodialysis.
The elimination half-life of cyclosporine is about
19 h, and its metabolism is age-dependent with a
two-fold increase in half-life in adults compared
to children.
Use in Psoriasis
Cyclosporine is FDA approved for severe psoriasis, resistant/recalcitrant psoriasis and disabling
psoriasis. It has several advantages over other traditional oral agents- it has rapid onset of action
and it is weight based dosing. These features
allow for rapid control of flaring psoriasis.
Numerous studies have been published on cyclosporine evaluating its efficacy, its comparison to
methotrexate and etretinate, and its long-term
maintenance/remission data. In a randomized
study comparing methotrexate and cyclosporine
after 16 weeks, cyclosporine and methotrexate
appeared to be equally effective, with PASI 75
improvement being 71% and 60%, respectively
[37, 42]. In a study comparing the oral retinoid
etretinate with cyclosporine, PASI 75 ­improvement
was seen in only 47% of patients on etretinate
compared to 71% on cyclosporine [43].
Cyclosporine rapidly controls psoriasis, but rapid
withdrawal may result in rebound. Open label
studies evaluating discontinuation of cyclosporine
after one year of therapy with a gradual (1 mg/kg/
wk) taper or abrupt cessation were published in
1999 and 2001 [35, 44]. No significant rebound
was noted in either group, and the median time to
relapse was not significantly different. Since more
than 50% of patients will relapse after 4 months,
new treatments should be added at the time of
taper or once psoriasis returns.
According to recently published recommendations by the National Psoriasis Foundation,
cyclosporine should be used with caution and for
113
the more severe cases [34]. For reasons not totally
understood, dermatologists do not use cyclosporine often for recalcitrant psoriasis and view it
only as a rescue drug treatment. The drug is very
safe to use if proper patient selection is done,
with knowledge of the patient’s co-morbidities
and medications and with proper clinical monitoring. Since the drug is very effective with rapid
onset of action, offering dramatic clearance in as
little as 2–4 weeks, it can be used to clear patients
quickly allowing time to plan and transition to a
long-term maintenance regimen. It has also been
used successfully for erythrodermic and pustular
psoriasis. While cyclosporine’s beneficial effects
on psoriasis were first observed during trials for
rheumatoid arthritis, it is not as useful for arthritis as for psoriasis lesions.
While not approved for children or pregnant
women, cyclosporine has been used with good
results in these patient populations. It is considered category C and should be used with caution
in pregnancy and during lactation [45].
Cyclosporine has been associated with low birth
weight (<2500 gm) and prematurity (< 37 weeks)
when used in renal transplant patients. Limited
information is known about the effect of cyclosporine in pregnant women with psoriasis, who
typically are prescribed lower doses. Cyclosporine
does not appear to be a teratogen and has been
used in pregnant women with successful outcomes. Overall, it is the authors’ opinion that
cyclosporine is safe to use in high risk psoriasis
patients during pregnancy if the benefits far outweigh the risks in severely debilitating disease.
However, at this point in time, there are biologics
which appear to be safe to use in pregnancy [46].
If cyclosporine is used in a pregnant patient, the
mother and fetus should be carefully followed by
high-risk obstetrician. Cyclosporine has been
used in children and appears to be safe and efficacious [47]. Doses are similar to that used in the
adult population, 2.5–3.0 mg/kg per day in
divided doses. Treatment courses should be limited to 6-month intervals [34, 44]. Risks of malignancy and lymphoproliferative disorders seem to
be minimal in children treated for skin diseases
due to limited courses of therapy and dosages
that are below 5 mg/kg/day.
114
Cyclosporine is contraindicated in patients
with uncontrolled or difficult to control hypertension and in those individuals with significant
renal disease or frequent infections. Careful
attention should be paid to individuals with a personal history of cutaneous malignancies as cyclosporine can increase the numbers of skin cancers
over time. Particular caution should be given
with patients who have had extensive PUVA therapy (greater than 200 treatments) as the risk of
nonmelanoma skin cancers, particularly squamous cell carcinoma, and melanoma may be
increased [48]. As with methotrexate, the decision to use cyclosporine should be made based on
a patient’s individual situation.
Dosing
Generally, patients are treated with 2.5–3 mg/kg/
day, usually in divided doses. The package insert
suggests dosing at ideal body weight; but, in the
authors’ experience, dosing is subtherapeutic at
ideal weights in significantly obese patients.
Dosing may need to be adjusted, especially in the
first few weeks as bioavailability is variable and
may vary with different generics. Cyclosporine is
best absorbed on an empty stomach in children.
However, adult patients can take it with food but
should be consistent with dosing regimens, same
time and amount of food ingested. Absorption
may even be improved slightly with food in
adults. Levels may be decreased with grapefruit
juice [41] in both populations. Unlike transplantation patients, peak and trough levels do not
need to be routinely done to ensure adequate
blood levels in psoriasis patients. Levels may be
checked if there is a question of compliance or
issues with absorption. Cyclosporine therapy is
generally used on a short-term basis to control
severe flares, rarely more than 6–12 months.
Monitoring Guidelines
Prior to initiating cyclosporine therapy, the
patient should have pretreatment blood tests,
including creatinine, urinalysis, magnesium,
E. Boh et al.
tuberculosis screening, a complete medical history with emphasis on medications and co-­
morbidities, complete physical exam and baseline
blood pressure measurements. Patients should be
counseled on adverse effects and the need for
careful monitoring. Baseline and ongoing monitoring guidelines are listed in Table 9.6.
Frequent monitoring, especially for iatrogenic
hypertension and signs of renal insufficiency, is
required [34]. Usually office visits with repeated
counseling and education parallel the blood evaluation schedule. If warranted, patients can also
monitor blood pressure at home. The package
insert recommends stopping cyclosporine if the
blood pressure remains elevated after an attempt
to lower the cyclosporine dose on several occasions. Many practitioners initiate low dose amlodipine or other calcium channel blocker in
normotensive adult patients for renal protection
[49]. Because of possible permanent damage to
the kidney and loss of renal function in patients
on long-term therapy, cyclosporine is a drug that
requires careful patient selection and subsequent
monitoring to be used safely. Therefore, a careful
assessment of psoriasis disease severity is critical
when assessing the risk-benefit ratio of treatment
Table 9.6 Monitoring guidelines for cyclosporine
Baseline
History and physical
Careful review of drug history
Blood pressure evaluation
Laboratory screening
Complete blood count with differential and platelet
counts (CBC)
Comprehensive metabolic panel- renal and hepatic (CMP)
Hepatitis B and C screening
Tuberculosis screening with PPD or blood test
Serum or urine pregnancy screening
On going monitoring at q 2 weeks x 1 then q
4-weeks x 3 months then q 2 months
Periodic review of drug history
Physical exam
BP at every visit and home monitoring if warranted
Laboratory
CBC with differential and platelets at 2 weeks then q
month for 3 months then every 2 months
CMP at 2 weeks then q month for 3 months then every
2 months
Tuberculosis screening every year
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
with cyclosporine. With the wide availability of
other useful agents for psoriasis, it is reasonable
to consider an alternative if the blood pressure or
kidney function remains elevated after two readings. Patients on cyclosporine are also immunosuppressed and are more susceptible to infections,
bacterial, viral and fungal. Patients should be
examined and screened for these types of infection before as well as during treatment.
Adverse Effects
While the frequency and severity of side effects
is reduced when used at doses for psoriasis, the
major toxicities associated with cyclosporine
remain renal insufficiency and hypertension
Table 9.7. The most common side effects associated with cyclosporine administration include
headaches (15%), hypertrichosis (6%), and gingival hyperplasia, which is seen more frequently
in transplant patients but can uncommonly occur
in psoriasis patients. Other side effects include
hirsurtism, tremor, diarrhea, hypertriglyceridemia, hypomagnesemia, nausea/vomiting, paresthesias and influenza-like symptoms. Blood
abnormalities include hypomagnesemia, hyperlipidemia and hyperuricemia. As a consequence
of these potential abnormalities, magnesium and
uric acid l­evels should be obtained regularly.
Lipid monitoring is less frequently needed but
should be considered in patients on longer treatment periods. Rare side effects include neuroTable 9.7 Side effects of cyclosporine
Increased risk of
malignancies
Increased risk of infections
Renal impairment
Hypertension
Malignancies
Headache, tremor,
paresthesia
Cutaneous
Hypertrichosis
Gingival hyperplasia
Hyperbilirubinemia
Worsening acne
Increased risk of infection
Nausea/vomiting/
diarrhea
Flu-like symptoms
Myalgias
Lethargy
Hypertriglyceridemia
Hypomagnesemia
Hyperkalemia
115
logic complaints, including lowering the seizure
threshold, transient gastrointestinal complaints
and respiratory complaints of cough and rhinitis.
Nephrotoxicity
Nephrotoxicity is the most common and clinically significant adverse effect and can present as
acute azotemia or as a chronic, slowly progressive renal insufficiency or failure. Although
reversible changes in the kidney may be related
to the vascular effect, long-term therapy may lead
to permanent scarring with loss of renal function.
Therefore, it is very important to routinely monitor the renal function with a serum creatinine and
a urinalysis as well as the blood pressure in
patients on cyclosporine. It is important to
remember that elderly patients may have a
decrease in the glomerular filtration rate (GFR)
without a decrease in creatinine. Patients who are
on cyclosporine for a year are suggested to get an
annual GFR. This is not routinely done, since
patients do not usually remain on cyclosporine
for greater than a year at a time. Patients with
elevations of serum creatinine greater than 25%
from baseline on two occasions (separated by
2 weeks) should have a 25% to 50% decrease in
their dosage. If the creatinine level remains elevated, the cyclosporine dose should once again
be decreased by 25% to 50%. If after these
changes, the creatinine does not return close to
baseline, cyclosporine should be discontinued.
Hypertension
Hypertension is caused by renal vasoconstriction
and sodium retention, and usually presents early
in the course of treatment. Dose reduction or
addition of an anti-hypertensive such as amlodipine can ameliorate this adverse effect. Caution
the patient that they may experience dependent
edema, a side effect common to both cyclosporine and amlodipine. Since amlodipine has been
reported to be renal protective in the transplant
population on cyclosporine, the addition of amlodipine at this juncture is reasonable. In fact, many
clinicians familiar with using the drug will start
amlodipine at low doses such as 5 mg q day even
in normotensive individuals as a prophylactic
measure at onset of therapy [49].
E. Boh et al.
116
Table 9.8 Potential cyclosporine (CyA) drug-drug interactions
Drug class
Antiarythmics
CCBa
Diuretics
Antifungals
Antibiotics
Anti-HIV
Anti-malarials
SSRIb
Foods
Anti-neoplastic
Steroids
Increases CyA
Amiodarone
Diltiazem;verapamil
Thiazodes;furosemide
Azoles
Quinolones;cephalosporins
doxycycline
Protease inhibitors
Hydroxychloroquine
Fluoxetine;sertraline
Grapefruit
Imatinib;
Dexamethasone;methylpredniso
lone
Anti-convulsants
Others
Retinoids
Decreases CyA
Drug levels increased by CyA
Verapamil;diltiazem
Griseofulvin
Beta-lactams;
nafcillin;rifampin
Efivarenz
Phenytoin;phenobarbitol;
valproic acid
OCPc
Statins
Bexarotene
Calcium channel blockers; bSelective Serotonin Reuptake Inhibitors; coral contraceptive pills
a
Drug Interactions
Since cyclosporine is metabolized by the hepatic
CYP3A4 system, a variety of drug interactions
can occur. Table 9.8 has a list of some common
drug interactions seen with cyclosporine administration. Concomitant use of medications metabolized by the CYP3A4 system compete as
substrates and may increase serum levels and
potentiate toxicity. Induction or inhibition of the
enzyme may decrease or increase serum levels,
respectively. Foods usually do not affect cyclosporine levels but grapefruit juice increases levels of cyclosporine by CYP3A4 inhibition.
Interactions may also occur with over the counter
nutraceuticals, herbal and vitamin preparations.
For instance, St John’s wort may decrease cyclosporine concentrations. In patients who have
severe liver disease, metabolism may be
decreased, leading to higher drug levels. Although
heavy alcohol intake increase cyclosporine levels, mild to moderate alcohol consumption has
little effect.
Cyclosporine is an inhibitor of CYP3A4
affecting other drugs such as calcium channel
blockers, erectile dysfunction drugs, and statins.
Reports of serious rhabdomyolysis occurring in
patients who are concurrently treated with a
statin have been described [50]. Medications that
may potentiate renal toxicity such as aminoglycosides or nonsteroidal anti-inflammatory drugs
as well as medications that may elevate potassium levels should be restricted. Given the long
list of possible drug interactions, a thorough
medication history must be obtained for all
patients before initiating treatment, and patients
should be educated regarding the introduction of
new drugs with continued therapy.
As a general rule, drugs that alter the cytochrome P450 system should be introduced cautiously and potentially nephrotoxic drugs, such
as nonsteroidal anti-inflammatory drugs, aminoglycosides, ciprofloxacin, clotrimazole, and
fibrates that can impair renal function during
cyclosporine treatment should be avoided if
possible.
Summary
Both methotrexate and cyclosporine improve
psoriasis by decreasing inflammation and suppression of T-cell mediated production of inflammatory cytokines that are known to be pivotal in
the pathogenesis of psoriasis. While methotrexate and cyclosporine are safe and reliable treat-
9
Traditional Systemic Therapy I: Methotrexate and Cyclosporine
ments for psoriasis with proper patient selection
and monitoring, the risk of serious potential complications remains. Patients and physicians
should be aware of these side effects and discuss
risks and benefits prior to starting therapy. From
the physician’s perspective, careful selection of
the patient is paramount to eliminate potential
complications. From the patient’s perspective,
the importance of follow-up appointments and
appropriate, timely blood monitoring needs to be
understood. These agents may serve a useful role
in bridging patients onto biologics, in those
patients with a recent history of malignancy or in
those patients where biologics are contraindicated or not available (Table 9.8).
References
1. Gelfand JM, Neimann AL, Shin DB, et al. Risk of
myocardial infarction in patients with psoriasis.
JAMA. 2006;296:1735–41.
2. Takahashi H, Iizuka H. Psoriasis and metabolic syndrome. J Dermatol. 2012;39:212–8.
3. Myers WA, Gottliep AB, Maase P. Psoriasis and psoriatic arthritis: clinical features and disease mechanism. Clin Dermatol. 2006;24:438–47.
4. Henseler T, Christophers E. Disease concomitance in
psoriasis. J Am Acad Dermatol. 1995;32:982–6.
5. Neimann AL, Shin DB, Wang X, et al. Prevalence of
cardiovascular risk factors in patients with psoriasis. J
Am Acad Dermatol. 2006;55:829–35.
6. Mallbis L, Ritchen CT, Stahl M. Metabolic disorders
in patients with psoriasis and psoriatis arthritis. Curr
Rheumatol Rep. 2006;8:355–63.
7. Menter A, Strober BE, Kaplan DH, et al. Joint AAD-­
NPF guidelines of care for the management and
treatment of psoriasis with biologics. J Am Acad
Dermatol. 2019 Apr;80(4):1029–72.
8. Elmets CA, Leonardi CL, Davis DMR, et al. Joint
AAD-NPF guidelines of care for the management
and treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol. 2019
Apr;80(4):1073–113.
9. Gubner R, Augsut S, Ginsberg V. Therapeutic suppression of tissue reactivity: effects of aminopterin in
rheumatoid arthritis and psoriasis. Amer J Med Sci.
1951;221:176–82.
10. Edmunson WF, Guy WB. Treatment of psoriasis with folic acid antagonists. AMA Arch Derm.
1958;78:200–3.
11. Weinstein GD, Frost P. Methotrexate for psoriasis. A new therapeutic schedule. Arch Dermatol.
1971;103:33–8.
117
12. Weinstein GD. Methotrexate. Ann Intern Med.
1977;86:199–204.
13. Warren RB, Griffiths EM. Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin
Dermatol. 2008;26:438–47.
14. Carrerero G, Puig L, Dehesa L, Carrascosa J, et al.
Guidelines on the use of methotrexate in psoriasis.
Actas Dermosifiliogr. 2010;101:600–13.
15. Strober B, Menon B. Folate supplemantation during
methotrexate therapy for patients with psoriasis. J
Amer Acad Dermatol. 2005;53:652–9.
16. Cronstein BN, Naime D, Ostad E. The anti-­
inflammatory mechanism of methotrexate. Increased
adenosine release at inflamed sites diminishes leukocyte accumulation in an vivo and in vitro model of
inflammation. J Clin Invest. 1993;92:2675–82.
17. Genestier L, Paillot R, Fournel S, Ferraro C, Miossec P,
Revillard JP. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated
peripheral T cells. J Clin Invest. 1998;102:322–8.
18. Johnston A, Gudjonsson JF, Sigmundsdottir H, et al.
The anti-inflammatory action of methotrexate is not
mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin
Immunol. 2005;114:154–63.
19. Priyadarssini M, Chandrashekar L, Rajappa M. Effect
of methotrexate monotherapy on T-cell subsets in the
peripheral circulation in psoriasis. Clin Exp Dermatol.
2019 Jul;44(5):491–7.
20. Vena GN, Cassano N, Iannone F. Update on subcutaneous methotrexate for inflammatory arthritis and
psoriasis. Ther Risk Manag. 2018;14:105–16.
21. Rajitha P, Biswas R, Sabitha M, Jayakumar
R. Methotrexate in the treatment of psoriasis and
rheumatoid arthritis: mechanistic insights, current
issues and novel delivery approaches. Curr Pharm
Des. 2017;23:3550–66.
22. Roenigk HH Jr, Maibach HI, Weinstein
GP. Methotrexate therapy for psoriasis. Guideline
revisions. Arch Dermatol. 1973;108:35.
23. Gottlieb A, Korman N, Gordon K, Feldman S, et al.
Guidelines of care for the management of psoriaisis
and psoriatic arthritis, section 2: psoriatic arthritis;
overview and guidlelines of care for treatment with
an emphasis on the biologics. J Am Acad Dermatol.
2008;58:851–64.
24. Montaudie H, Sbidian E, Paul C, Maza A, et al.
Methotrexate in psoriasis: a systematic review of
treatment modalities, incidence, risk factors and
monitoring of liver toxicity. J Euro Acad Dermatol
Venereol. 2011;25(Suppl. 2):12–8.
25. Mease P, Gladman D, Collier D, et al. Etanercept and
methotrexate as Monotherapy or in combination for
psoriatic arthritis: primary results from a randomized, controlled phase III trial. Arthritis Rheumatol.
2019;71:1–13.
26. Appani SK, Devarasetti PK, Rajendra, et al.
Methotrexate achieves major cDAPSA response,
and improvement in dactylitis and functional sta-
Traditional Systemic Therapy II:
Retinoids and Others
10
Vignesh Ramachandran, Ted Rosen,
Misha Koshelev, and Fareesa Shuja Sandoval
Abstract
Some patients with psoriasis either do not
respond to or develop significant toxicities
fromwell-recognized first-line systemic therapies. However, a number of second-line systemic agents may be considered. For example,
acitretin is particularly effective in erythrodermic psoriasis, palmoplantar pustulosis, and generalized pustular psoriasis. Since acitretin does
not induce immunocompromise, it can be used
to manage psoriasis associated with HIV infection. Concomitant ultraviolet B (UVB) or psoralen plus ultraviolet A (PUVA) is synergistic
with acitretin. Although not FDA-approved to
treat psoriasis, hydroxyurea has demonstrated
efficacy for chronic plaque psoriasis and, in
short bursts, for flares of pustular psoriasis.
Mycophenolate mofetil is used to treat
moderate-to-severe chronic plaque psoriasis,
most often as a maintenance therapy.
6-­thioguanine is used to treat plaque psoriasis
and palmoplantar pustulosis which is resistant
to other systemic agents, but is not recomV. Ramachandran · T. Rosen (*)
Department of Dermatology, Baylor College of
Medicine, Houston, TX, USA
M. Koshelev
University of Texas, McGovern Medical School at
Houston, Houston, TX, USA
mended for long-term maintenance due to possible hepatotoxicity. Systemic tacrolimus is
best used to treat severe, recalcitrant plaque
psoriasis; nephrotoxicity limits long-term use.
Though usually used for rheumatoid arthritis,
leflunomide can also be considered in
treatment-­resistant chronic plaque psoriasis or
psoriatic arthritis. Penicillin V or erythromycin
are options for guttate psoriasis when the latter
is associated bacterial infection (usually of the
upper respiratory system). Apremilast, a newly
approved treatment for psoriasis and psoriatic
arthritis, does not induce immunosuppression,
has a good safety profile, does not require laboratory monitoring, and is available in a convenient oral formulation. Nevertheless, its lower
efficacy may limit utility.
Key Learning Objectives
1. To understand the mechanism of action
of retinoids and other oral agents used
in the treatment of psoriasis.
2. To understand the appropriate use and
efficacy of retinoids and other oral agents
used in the treatment of psoriasis.
3. To understand the safety issues and
appropriate monitoring for retinoids and
other oral agents used in the treatment
of psoriasis.
F. S. Sandoval
Westlake Dermatology, Austin, TX, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_10
119
V. Ramachandran et al.
120
Psoriasis affects 1 in 50 individuals with manifestations appearing in the skin, nails, and joints
[1]. Patients with psoriasis are most commonly
treated with topical agents, which is effective in
70–80% of patients [2]. Systemic treatments tend
to be reserved for patients with more than 10%
body surface area (BSA) involvement or severe
psoriasis of the scalp, palms and soles, genitalia,
or intertriginous sites. Even in this era of biologics, traditional systemic therapies remain both
useful and appropriate.These drugs offer comparatively inexpensive, oral alternatives with wellknown short and long-term risks [3]. Although
methotrexate and cyclosporine are recognized
first-line treatments for psoriasis, patients who do
not respond or who develop toxicities are candidates for alternative second-line systemic agents.
In this chapter, we provide a clinically-­oriented
summary of several second-line systemic agents
used in the treatment of psoriasis. Specifically, the
medications discussed herein are: acitretin, hydroxyurea, mycophenolate mofetil (MMF), thioguanine
(6TG), systemic tacrolimus, leflunomide, penicillin
V, erythromycin, and apremilast (Fig. 10.1, 10.2, and
10.3). In doing so, we hope to aid clinicians navigate
the myriad of alternative tradiational systemic treatment options within the patients’ clinical contexts
with an evidence-based understanding of best use
practices, side effects, monitoring, and efficacy.
factors within cells. However, beyond this, thehe
exact mechanism of action of acitretin in psoriasis is unknown though it is likely related to its
ability to decrease epidermal proliferation and
induce differentiation [4].
When Best to Use
Acitretin is one of the suggestedtreatments for
relatively stable generalized pustular psoriasis
and is an effective treatment for less acute patients
with exfoliative erythrodermic psoriasis [11]. It
is also a suggested traditional systemic for psoriasis in the setting of human immunodeficiency
virus (HIV) infection due to its lack of immunosuppression [12]. In palmoplantar pustulosis,
acitretin is commonly used to ameliorate hyperkeratosis and decreases pustulation. In acitretinresponsive patients with chronic plaque psoriasis,
it can be an effective maintenance ­therapy [11].
Acitretin can safely be combined with phototherapy to potentiate its efficacy. Additionally,
it may be used in combination with biologic
therapies, including etanercept (resulting in
reduced etanercept dosing) and adalimumab.
Randomized, controlled trial evidence is lacking
for its use in combination with other biologics
[13]. Although seemingly contraindicated by the
acitretin prescribing information which warns of
the risk of hepatotoxicity, acitretin and methoAcitretin
trexate have been combined when monotherapy
was inadequate, particularly in cases of generalized pustular psoriasis. It is crucial to monitor
FDA-Approved Indication(s)
liver function closely with this combination [4,
Acitretin is FDA-approved for the treatment of 14]. Acitretin has been used with cyclosporine
severe psoriasis in adults [4]. In women of child-­ for short-term treatment albeit with frequent
bearing potential, acitretin is only advised for non- monitoring of lipids. Acitretin has also been
pregnant individuals who do not respond to other combined with hydroxyurea to treat recalcitrant
psoriasis medications or have c­ ontraindications palmoplantar pustulosis.
to their use. The FDA recommends its prescription by physicians knowledgeable in the use of
systemic retinoids [4].
Dosage
Mechanism of Action
Acitretin interacts with with cytosolic proteins
and nuclear factors, which act as transcription
The general acitretin dose ranges from 10 to
50 mg daily, administered with meals [4, 15].
Generalized pustular psoriasis typically requires
an acitretin dose of 25–50 mg [8]. After clinical
response, the dose is tapered to 10–25 mg daily.
10 Traditional Systemic Therapy II: Retinoids and Others
121
O
OH
O
Acitretin
S
O
H
N
N
HO
N
H
NH2
N
H
H2N
Hydroxyurea
N
6-Thioguanine
HO
O
O
OH
O
N
O
O
O
O
O
HO
O
Tacrolimus
Fig. 10.1 Chemical structures of acitretin, hydroxyurea, 6-thioguanine, and tacrolimus; adapted from the package
inserts for the corresponding medications [4–7]
V. Ramachandran et al.
122
O
S
O
NH
H
N
O
+ –
O
NH
K
N
O
F
O
O
F
F
Leflunomide
Penicillin V
Potassium
OH
HO
HO
O
O
O
O
OH
O O
O
N
O
Erythromycin
OH
Fig. 10.2 Chemical structures of leflunomide, penicillin V potassium, and erythromycin; adapted from the package
inserts for the corresponding medications [7–10]
Exfoliative erythrodermic psoriasis requires an
acitretin dose of 25–50 mg daily [15].
Clinical trials have employed varying acitretin doses to treat chronic plaque psoriasis. A
daily dose of 25 mg or less minimizes adverse
events. Initiation of therapy should begin with
a low dose with progressive uptitration to avoid
an initial disease flare and to improve tolerability
[4, 15]. Maximal response is usually seen after
3–6 months of treatment [15].
Two randomized, controlled trials (8-week and
16-week) assessed the efficacy acitretin (10 mg,
25 mg, 50 mg, 75 mg) compared to ­placebo in the
treatment of moderate-to-severe plaque psoriasis
[13]. Low-dose treatment was defined as approximately 25 mg/day, whereas high-dose treatment
10 Traditional Systemic Therapy II: Retinoids and Others
Table 10.1 Frequency of selected adverse events
reported in clinical trials of acitretin [4, 15]
O
O
O
N
O
NH
Percent of patients
reporting event(s)
More than 75%
50–75%
O
S
O
123
25–50%
O
10–25%
Fig. 10.3 Chemical structure of apremilast (OTEZLA®)
was defined as approximately 50 mg/day. The
studies showed that, overall, low-dose acitretin is
not only safer than high-dose acitretin, but may
also be more efficacious in treating psoriasis.
Adverse Events
Acitretin is associated with a number of adverse
effects (Table 10.1). Many of the common events
are related to increased epidermis turnover, drying of the skin, and their related sequelae.
Recommended Monitoring
Obtain a history and physical examination, CBC
with platelets, BUN/Cr, LFTs, lipid profile, and a
pregnancy test if indicated before starting acitretin [14, 15]. The clinician should perform a physical examination and obtain a CBC with platelets,
BUN/Cr, LFTs, and lipid profile monthly for the
first 3–6 months, then every 3 months [14]. BUN/
Cr and CBC with platelets may be ordered every
other monitoring period if desired. Pregnancy
tests may be done monthly, if indicated.
Perils and Pitfalls
Acitretin is contraindicated in patients with
hypersensitivity to retinoids, chronically elevated
lipids, severely impaired kidney or liver function, nursing mothers, and pregnant women [4].
Less than 10%
Adverse event(s) reported
Cheilitis
Alopecia
Skin peeling
Rhinitis
Xerosis
Nail disorder
Pruritus
Rigors
Xerophthalmia
Xerostomia
Epistaxis
Arthralgia
Spinal hyperostosis
Erythematous rash
Hyperesthesia
Paresthesia
Paronychia
Skin atrophy
Sticky skin
Nausea
Abdominal pain
Decreased night vision
Headache
Myalgia
The average half-life of acitretin is 49 hours
and that of its isomer cis-acitretin is 63 hours;
however, in the presence of alcohol, etretinate,
whose average half-life is 120 days, can form.
Etretinate has been detected 2.1–2.9 years after
stopping therapy, most likely due to storage in
fatty tissue. This is why acitretin is contraindicated in women who plan to become pregnant
within 3 years of stopping the medication and is
given with extreme caution (if at all) in women of
child-­bearing potential. Patients are also advised
against donating blood from the initiation of
treatment to 3 years after discontinuation. Fetal
abnormalities reported with retinoid use include
meningomyelocele,
meningoencephalocele,
decreased cranial volume, and cardiovascular
malformations [4, 15].
Acitretin may interact with a number of medications. It interferes with the contraceptive effects
of the microdose progestin minipill [4, 15]. When
given with tetracyclines, the combination raises
the risk of increased intracranial pressure and
124
manifest pseudotumor cerebri [4]. Acitretin can
potentiate the glucose-lowering effects of glibenclamide and may reduce phenytoin protein binding. Acitretin should not be given with other oral
retinoids nor with excessive vitamin A supplementation to avoid hypervitaminosis A [4, 15].
Hepatobiliary abnormalities such as elevated
serum bilirubin and transaminases, toxic hepatitis, acute reversible hepatic injury, and cirrhosis
have been associated with acitretin [1]. In clinical trials, 66% of patients treated with acitretin had triglyceride elevations; of note, these
patients were likely to have increased alcohol
intake, diabetes mellitus, obesity, pre-existing
disturbances of lipid metabolism, or a family
history of these conditions. Acitretin-induced
serum triglyceride levels above 800 mg/dL have
been associated with fatal fulminant pancreatitis. Acitretin-­
induced pancreatitis without an
increase in serum triglycerides has also been
reported. Forty percent of patients treated with
acitretin in clinical trials had decreased HDL
levels and one-third had serum cholesterol elevations. Changes in lipid levels resolved after
stopping acitretin. Thromboembolic events,
acute myocardial infarction, and pseudotumor
cerebri have been reported, as have depression,
thoughts of self-­harm, aggressive feelings, and
other psychiatric symptoms. Adults receiving acitretin have rarely experienced abnormal
ossification.
V. Ramachandran et al.
after 1 month depending on clinical response; the
mean dose was 0.4 mg/kg/day. After 4 months,
the mean PASI reduction was 59.4% [18].
There are no head-to-head trials comparing
the effectiveness of acitretin to methotrexate or
cyclosporine in the treatment of chronic plaque
psoriasis, but it is the American Academy of
Dermatology’s general consensus acitretin is
a less effective monotherapy [15]. However, a
head-to-head comparison between cyclosporine
and etretinate, the pro-drug of acitretin which is
unavailable in the United States, demonstrated
cyclosporine was more efficacious in the treatment of severe plaque psoriasis [19].
Acitretin has been studied in the treatment of
palmoplantar pustulosis [11, 20]. A randomized,
open-label study of67 patients with palmoplantar pustulosis assessed the efficacy of acitretin.
Patients received 10 mg/day for 4 weeks followed
by dosage adjustment based on clinical response
for 8 weeks. After the 12 weeks, patients had an
average of 3.9 pustules compared to their average
of 57.8 at baseline [20].
Acitretin is more efficacious when combined with phototherapy [15]. A randomized,
controlledstudy of patients with moderate-tosevere psoriasis (20–80% BSA) assessed the
efficacy of broadband-UVB (bb-UVB) with
acitretin or placebo. Overall, combinational
therapy led to 74% reduction in psoriasis severity scores after 12 weeks comparedto 42% reduction in patients treatedwith acitretin alone and
35% reduction with UVB alone [21]. Another
Strength of Evidence
multicenter, randomized, controlled trial of 82
patients with severe psoriasis (chronic plaque or
Acitretin can be an effective short and long- examthematic-­type pustular variant) investigated
term therapy for chronic plaque psoriasis [16]. A the efficacy of acitretin plus UVB compared to
­multicenter trial of 37 adults treated with acitre- placebo plus UVB. Treatment-group patients
tin for psoriasis was conducted for 12 months took 35 mg acitretin daily for 4 weeks followed
with 10 mg dose adjustments (up or down, range by 25 mg acitretin daily plus BB-UVB [22].].
10–70 mg daily) occurring monthly. Seventy-­ PASI decreased on average by 79% with acitretin
nine percent of patients achieved PASI 75 [17]. and UVB compared to 35% in the control group
A prospective study enrolled 17 patients with (placebo and UVB). Median cumulative UVB
plaque psoriasis who had failed treatment with dose needed to reach 75% improvement was
methotrexate, cyclosporine, or PUVA, or had at 41% lower for the acitretin and UVB group than
least 10% BSA involvement to assess the efficacy for the placebo and UVB group [22]. It is imporof acitretin [18]. Acitretin was started at 0.3 mg/ tant to note these older studies utilize BB-UVB
kg/day and could be increased to 0.5 mg/kg/day in lieu of narrow-band (nb-UVB), which is the
10 Traditional Systemic Therapy II: Retinoids and Others
more readily available and commonly used UVB
regimen in most practices.
Combination therapy with biologics are limited. However, a randomized, controlled, double-­
blinded study investigated acitretin alone versus
etanercept alone versus acitretin with etanercept
for patients with moderate-to-severe plaque psoriasis. Over six months, twenty patients received
0.4 mg/kg oral acitretin daily, 22 patients received
25 mg etanercept subcutaneously twice perweek,
and 18 patients received 0.4 mg/kg oral acitretin
daily with etanercept 25 mg subcutaneously once
a week. Thirty percent of patients in the acitretin group achieved PASI 75, compared to 45% of
patients treated with etanercept alone and 44% of
patients treated with both etanercept and acitretin. Overall, it appears acitretin is less effective
than etanercept. Adding acitretin to etanercept
achieves an efficacy rate similar to that of etanercept alone. The results, however, may bedrug-­
dose-­dependent [23].
There are limited other clinical trial studies
assessing acitretin in psoriasis. A multicenter,
randomize, controlled, double-blinded trial of
108 moderate-to-severe plaque psoriasis patients
assessed the efficacy of acitretin alone (with placebo) or in combination with “total glucosides
of paeony” (TGP), a Chinese traditional herbal
medication. After 12 weeks, the treatment group
treated with added TPG achieved PASI 50 in
90% of patients compared to 70.5% in the control group (P < 0.05 [24]. Similarly, in another
randomized, controlled, double-blinded trial of
15 patients with moderate-to-severe plaque psoriasis were treated with acitretin with or without curcumin (main active constituent of the
rhizome of turmeric with various anti-inflammatory, ­
anti-­
proliferative, and anti-angiogenic
effects) nanoparticles. At the end of the study
period (12 weeks), higher percentages of patients
treated with the adjuctive curcumin nanoparticles
achieved PASI 50 (93% versus 66%), PASI 75
(43% versus 20%), and PASI 90 (36% versus
13%) compared to the control arm (all P < 0.001)
[25]. These results must be reproduced with
larger cohorts and assessed for possible unaccounted confounding factors to establish the
strength of this data.
125
Hydroxyurea
FDA-Approved Indication(s)
Hydroxyurea (HYDREA®) is FDA-approved as a
treatment for resistant chronic myeloid leukemia
and locally advanced squamous cell carcinomas
of the head and neck (excluding lip) in combination with concurrent chemoradiation [5]. Another
formulation of hydroxyurea (DROXIA®) is FDA-­
approved for reduce the frequency of painful crises and to reduce the need for blood transfusions
in adult patients with sickle cell [26].
Mechanism of Action
The precise mechanism of action of hydroxyurea in psoriasis is unknown [5, 15, 27, 28].
Hydroxyurea inhibits ribonucleotide reductase
and suppresses DNA synthesis, which is thought
to contribute to an anti-proliferative role in
psoriasis.
When Best to Use
Hydroxyurea has been given to patients with
moderate-to-severe chronic plaque psoriasis who
have received the recommended cumulative dose
of methotrexate or who cannot tolerate adverse
events related to methotrexate [29]. Hydroxyurea
has also been used with low-dose cyclosporine in
short-course therapy to treat recalcitrant, severe
psoriasis and with acitretin to treat recalcitrant
palmoplantar pustulosis [30]. Hydroxyurea
may also be beneficial in generalized pustular
­psoriasis [27].
Dosage
Hydroxyurea is initiated at a dose of 500 mg
twice daily, and increased to 3 g daily (total) as
tolerated. Dosing at 3–4.5 g weekly has also been
used [15, 27, 29]. The senior author has utilized
hydroxyurea as a short-term “rescue” drug during flares of von Zumbusch pustular psoriasis,
V. Ramachandran et al.
126
starting at 3 g as a daily dose and decreasing by
500 mg daily, for a 1 week total course.
Adverse Events
Hydroxyurea is associated with a number of
adverse events, most of which are related to cell
turnover/production of highly proliferative cell
types including the bone marrow and gastrointestinal tract (Table 10.2).
Recommended Monitoring
Before starting hydroxyurea, the clinician should
obtain a good history,perform a general physical
examination, and obtain laboratories (CBC and
pregnancy test) (if indicated) [9]. Weekly CBCs
are obtained until a stable dose is achieved.
Thereafter CBCs are obtainedmonthly as long
as treatment with this agent is continued. Repeat
physical examination, focusing on skin cancer
and checking for enlarged lymph nodes, should
be done biannually. Periodic pregnancy testing is
performed if indicated.
Table 10.2 Selected adverse events reported with the use
of hydroxyurea; events reported in psoriasis patients are
marked with an asterisk [9, 19, 20, 22, 23]
Myelosuppression, including anemia*, leukopenia*,
and thrombocytopenia*
Gastrointestinal symptoms, including diarrhea*,
aphthous ulcers*, nausea, vomiting, constipation,
anorexia, and stomatitis
Dermatological symptoms, including nail
pigmentation*, alopecia*, pruritus*, dermatomyositis-­
like skin changes, rash, and ulceration
Systemic symptoms, including edema*, asthenia,
chills, malaise, and fever
Neurologic symptoms, including hallucinations,
dizziness, headache, disorientation, and convulsions
Serum creatinine, BUN, and uric acid elevations with
temporary impairment of renal tubular function
LFT elevations
Rare pulmonary fibrosis
Rare dysuria
Nonfatal and fatal pancreatitis and hepatotoxicity,
severe peripheral neuropathy in HIV patients given
hydroxyurea with other antiretrovirals
Perils and Pitfalls
Hydroxyurea is contraindicated in patients with
known hypersensitivity to hydroxyurea and
in patients with leukopenia, severe anemia, or
thrombocytopenia. Additionally, it is also contraindicated during pregnancy and in nursing
mothers [5, 15]. Hydroxyurea may raise uric
acid levels and require changes in the doses of
uricosuric medications to prevent gout flares [5].
Severe peripheral neuropathy, fatal and nonfatal
pancreatitis, hepatotoxicity and fatal hepatic failure have been described in HIV patients given
hydroxyurea and didanosine with or without
stavudine [31]. These adverse events are rare in
normal hosts.
Patients given long-term hydroxyurea have
reportedly developed both lymphoma and nonmelanoma skin cancer. In patients treated with
hydroxyurea for myeloproliferative disorders,
secondary leukemia has developed. These
patients have also developed gangrene and vasculitic ulcerations, but most were simultaneously
receiving interferon. Self-limiting megaloblastic
erythropoiesis may occur early in the course of
hydroxyurea therapy.
Myelosuppression may occur in patients
treated with hydroxyurea. Leukopenia generally
occurs first, followed by anemia or thrombocytopenia. Bone marrow recovery is rapid when
treatment is stopped. Increased myelosuppression may be seen when hydroxyurea is used concurrently with radiotherapy or myelosuppressive
drugs [15].
Strength of Evidence
A comparative study of methotrexate to
hydroxyurea in 30 patients (15 in each treatment
group) assessed the efficacy of these treatments
for moderate-­
to-severe plaque psoriasis [29].
Patients had ≥20% BSA involvement and a PASI
of ≥10. In the methotrexate group, patients given
15 mg of the medication weekly for 4 weeks; the
dose was then increased up to 20 mg weekly
in patients with less than 25% PASI reduction.
Patients receiving hydroxyurea were given
10 Traditional Systemic Therapy II: Retinoids and Others
500 mg twice a day on two consecutive days for
1 week, then 500 mg three times a day on two
consecutive days for 3 weeks. After 4 weeks,
patients with ≤25% PASI reduction were given
500 mg three times a day on three consecutive
days. Overall, 10/15 patients (66.7%) treated
with methotrexate and 2/15 patients (13.3%)
treated with hydroxyurea achieved PASI 75
at 12 weeks (P < 0.05). Though most patients
treated with hydroxyurea did not achieve PASI
75, they did have a mean PASI reduction of
48.47% while experiencing fewer adverse events
than the methotrexate group [29]. However, a
short-term (8-week) comparative study of methotrexate (control) and hydroxyurea treatment
in 24 patients with moderate-to-severe plaque
psoriasis [28]. The results of this study demonstrated that although the PASI scores before
and after treatment in each group significantly
decreased (P < 0.05), there was no difference in
mean percentage change of PASI scores between
the groups (P > 0.05) [32].
A prospective study of 34 patients with
moderate-­to-severe plaque psoriasis, erythrodermic, or generalized pustular psoriasis refractory
to topical treatments and methotrexate underwent a regimen of hydroxyurea to assess its
efficacy in treating their condition [27]. Patients
were initiated on 500 mg hydroxyurea twice
daily. If hydroxyurea was tolerated and PASI
reduction was less than 25% after 2 weeks, it
was increased to 1.0 and 1.5 g on alternate days,
and then to 1.5 g daily as tolerated. If greater
than 95% clearance was achieved, treatment was
tapered over 4–8 weeks. Mean PASI reduction
was 76% at 10–12 weeks. Three patients developed leukopenia which recovered after discontinuing treatment. Five patients relapsed within
12 months [27]
A prospective, non-randomized sries of 31
patients (including 26 with history of systemic
psoriasis therapy) were given hydroxyurea 1.0–
1.5 g per day for mean follow-up of 36.1 weeks
(+/− 13.8). At or before 8 weeks, nearly 75%
of the cohort demonstrated adequate response
(defined ≥35% PASI reduction), and over50% of
patients showed >70% PASI reduction [33].
127
Mycophenolate Mofetil (MMF)
FDA-Approved Indication(s)
MMF is FDA-approved in combination with corticosteroids and cyclosporine to prevent organ
rejection in liver, heart, and kidney transplant
patients [34].
Mechanism of Action
MMF is hydrolyzed to its active metabolite,
mycophenolic acid, which inhibits de novo guanosine nucleotide synthesis and selectively suppresses lymphocyte growth and division [34]. As
a result, psoriasis, a T-cell mediated inflammatory disorder, is thought to be responsie to MMF
for this reason.
When Best to Use
MMF is utilized to treat moderate-to-severe
chronic plaque psoriasis in patients who cannot
tolerate any of the various first-line agents [35].
MMF can be given with cyclosporine, making it
useful as both a bridge and maintenance therapy
for patients needing cyclosporine for acute disease control [36].
Dosage
MMF can be given as 1.0–2.0 g twice daily [35].
Adverse Events
Psoriasis patients given MMF reported abdominal cramping, diarrhea, nausea, elevated LFTs,
severe hyperbilirubinemia, severe hypertension,
life-threatening hyperuricemia, life-threatening
hypokalemia, periorbital edema, urticaria, furunculosis, and pruritus [35, 37, 38]. Transplant
patients given MMF reported vomiting, genitourinary urgency, genitourinary frequency,
V. Ramachandran et al.
128
dysuria, sterile pyuria, headaches, insomnia,
peripheral edema, hypercholesterolemia, hypophosphatemia, and hyperkalemia [15, 34].
Recommended Monitoring
The clinician should obtain a history andphysical
examination. Baseline labs should includeCBC
with differential, serum chemistry panel, LFTs,
and pregnancy test (if indicated) before starting
MMF [15, 34]. After initiation of therapy, complete blood and platelet counts should be checked
weekly for 1 month, then every 2 weeks for
2 months, then monthly thereafter. It is wise to
also obtain serum chemistries and LFTs monthly,
a physical examination focusing on skin cancer
and lymph nodes biannually, and ongoing pregnancy tests (if indicated) [39].
disease [34]. Adults given prolonged courses of
MMF haveincreased risk of skin cancer, especially squamous cell carcinomas Fatal cases of
progressive multifocal leukoencephalopathy
(PML) with the use of MMF were reported in
patients with risk factors such as pre-existing
immune function impairment and treatment with
other immunosuppressants [39].
Strength of Evidence
A randomized, open-label clinical trial evaluated
the efficacy and safety of MMF versus methotrexate in patients with chronic plaque psoriasis (PASI score of at least 10) and a history of
inadequate response to topical therapies [35].
Seventeen patients received MMF 1 g twice daily
for 12 weeks. Fifteen patients received methotrexate 7.5 mg/week for 1 week, then 15 mg/week for
3 weeks, and then 20 mg/week for 8 weeks. Ten
Perils and Pitfalls
of 17 patients (58.8%) in the MMF group and 11
of 15 patients (73.3%) in the methotrexate group
MMF is contraindicated in patients with hyper- achieved PASI 75 (P > 0.05) [35].
sensitivity to MMF or mycophenolic acid, during
Another randomized open-label clinical trial
pregnancy, and in nursing mothers [34]. MMF evaluated the efficacy of MMF versus cyclospocan cause first trimester spontaneous abortions rine in chronic plaque psoriasis patients with a
and fetal malformations [25]. It can interact PASI score of at least 10 [28]. Sixteen patients
with acyclovir, ganciclovir, valganciclovir, pro- received MMF 1 g twice daily for 6 weeks. Then
benecid, xanthine bronchodilators, high-dose they received 500 mg MMF twice daily if they
salicylates, cholestyramine, phenytoin, antibiot- had 60% or greater PASI reduction, 1 g MMF
ics, calcium, iron, and aluminum or magnesium-­ twice daily if they had 25–60% PASI reduccontaining antacids [15]. Since the effects of tion, and 1.5 g MMF twice daily if they had
these other medications on MMF are varied, it 25% or less PASI reduction. Twenty-one patients
is recommended to consult the FDA-approval received 1.25 mg/kg cyclosporine twice daily for
documentation to assess impact on bioavailabil- the first 6 weeks, and then either 1.25 mg/kg once
ity and subsequent efficacy [34].
daily, 1.25 mg/kg twice daily, or 2.5 mg/kg twice
Patients given MMF have developed severe daily based on PASI reduction thresholds identineutropenia. Two percent of kidney and heart cal to those in the MMF group. After 12 weeks,
transplant patients and 5% of liver transplant mean PASI decreased from 22.4 to 10.6 in the
patients given MMF in clinical trials developed MMF group and from 24.6 to 6.6 in the cyclofatal infection/sepsis. Live attenuated vaccines sporine group [37].
should not be given to patients taking MMF [15,
Use of concomitant MMF and cyclosporine to
34]. Pure red cell aplasia, anemia, leukopenia, treat severe recalcitrant psoriasis was described
and thrombocytopenia have also been reported.
in nine patients who failed to clear on cyclospoBetween 0.4% and 1% of transplant patients rine alone or could not tolerate higher cyclogiven MMF with other immunosuppressive drugs sporine doses [36]. Three patients showed good
developed lymphoma or lymphoproliferative clinical improvement and four patients showed
10 Traditional Systemic Therapy II: Retinoids and Others
129
moderate disease control after a follow-up period When Best to Use
of 3–11 months. No additional toxicity was
seen after starting MMF in patients already tak- 6TG can be used to treat plaque psoriasis and
ing cyclosporine. Notably, this study included a palmoplantar pustulosis resistant to more compatient with erythrodermic psoriasis and another monly utilized systemic agents or when these
with generalized pustular psoriasis [36].
other agents are contraindicated [39]. It may be
An open-label pilot study involving 20 patients considered a third-line systemic traditional syswith psoriasis (PASI >10) assessed the efficacy temic treatment [39].
of enteric-coated mycophenolate sodium 720 mg
twice daily for 6 weeks followed by 360 mg twice
daily for another 6 weeks. By week six, none of Dosage
the patients achieved PASI 75. However, 8/20
(40%) of patients achieved PASI 50. By week 12, 6TG is given two to three times per week to
2/8 (25%) of patients achieved PASI 75. Some reduce the risk of myelosuppression [42, 43]. The
patients in the cohort did relapse (4/13 by week starting dose is 80 mg twice per week; the dose
12). Twenty-five percent (2/8) achieved a PASI is increased by 20 mg every 2–4 weeks [15]. The
75% in week 24 [40].
maximum dose is 160 mg given up to three times
Another study compared the efficacy of MMF per week.
to cyclosporine in 80 patients with chronic plaque
psoriasis via a prospective, sequential, cross-­
over, non-randomized, two-phase, open-label Adverse Events
study. Both treatments were efficacious, resulting in decreased in PASI scores from baseline. According to various reports, 22–68% of psoriaHowever, cyclosporine was faster to produce sis patients given 6TG develop myelosuppression
results and produced more significant decreases [43, 44]. Up to 12% of patients given the drug
in PASI scores (45.7%, 60.2% and 60.5% at 3, reported gastrointestinal adverse events, includ8 and 16 weeks respectively for mycophenolate ing nausea, vomiting, aphthous ulcers, gastric
mofetil compared to 89.7%, 95.3% and 95.3%, ulcers, gastroesophageal reflux, and dysgeusia
respectively, for cyclosporin) [41].
[15, 43, 44]. One quarter of patients treated with
6TG for psoriasis experienced LFT elevations
[15, 43]. Patients treated with this agent also
6-Thioguanine (6TG)
developed headaches, fatigue, photodermatitis,
herpes zoster, multiple warts, hyperuricemia,
hepatic veno-occlusive disease, portal hypertenFDA-Approved Indication(S)
sion, and non-melanoma skin cancer [15, 43, 44].
6-thioguanine (6TG) is FDA-approved to induce Psoriasis patients treated with 6TG have rarely
and sustain remission in patients with acute non-­ developed hepatotoxicity; in the event that this
lymphocytic leukemia, most commonly in com- adverse event does occur, stopping treatment
bination with other chemotherapeutic agents [6]. leads to resolution [6, 15, 42, 43].
It is not recommended for long-term treatment
due to a significant risk of hepatotoxicity.
Recommended Monitoring
Mechanism of Action
6TG is a purine nucleotide analogue that interferes with nucleic acid synthesis, curtailing cellular proliferation [6].
The clinician should obtain a history and physical
examination.Laboratory evaluation entails CBC
with differential, serum chemistry panel, LFTs,
hepatitis B and C tests, tuberculosis screening,
and pregnancy test (if indicated) before initiating
V. Ramachandran et al.
130
6TG therapy [6, 15]. After starting treatment, a
CBC with differentialshould be checked every
2–4 weeks, serum chemistries every 3 months,
and a physical examination focusing on lymph
nodes and skin cancer biannually; periodic pregnancy tests should be performed, if indicated [15].
Perils and Pitfalls
6-thioguanine is contraindicated in patients with
known hypersensitivity to the drug. It is also
contraindicated in patients with liver disease,
immunosuppression, anemia, leukopenia, and/
or thrombocytopenia. Pregnant patients and nursing mothers are also contraindicated from taking
6TG [6, 12].
The cytoplasmic enzyme thiopurine methyltransferase (TPMT) metabolizes 6TG and
other thiopurines [6, 44]. TPMT activity in
Caucasians varies based on genetic polymorphisms. Specifically, 10% of Caucasians have
intermediate TPMT activity and one in approximately 300 Caucasian individuals has no TPMT
activity [44]. Lower TPMT activity increases
the risk of myelosuppression in patients taking
6TG. Aminosalicylate derivatives, such as olsalazine, mesalazine, and sulfasalazine, may inhibit
TPMT [6, 15]. Life-threatening infections due
to 6TG-induced granulocytopenia have been
reported [3]. It has been recommended that physicians measure TPMT activity in all psoriasis
patients before starting 6-thioguanine to determine initial dosage and assess the risk of myelosuppression [37].
Strength of Evidence
A retrospective 4-year review of the treatment of
18 patients with moderate-to-severe plaque psoriasis treated with 6-thioguanine. Overall, 14/18
(78%) patients had more than 90% improvement; 3 patients (17%) had 50–90% improvement while only 1 patient had less than 50%
­improvement [44].
An open-label study of 14 patients with severe,
recalcitrant plaque psoriasis investigated the efficacy of pulse-dosing 6TG. Two-to-threetimes per
week (120 mg twice a week to 160 mg 3 times a
week) resulted in marked improvement in 10 of
14 (71%) patients [43].
A retrospestive study of 81 patients (76 plaque
psoriasis, 6 palmoplantar pustulosis) treated with
6TG was reported on to assess this medication’s
efficacy [45]. Overall, 78% of patients had complete or almost complete clearing, 11% had some
improvement, and 11% had little or no change in
their psoriatic lesions. Four out of five patients
with palmoplantar pustulosis had complete or
almost complete clearing. Patients maintained
their response for 3–145 months (mean = 33).
The most commonside effect was myelosuppression [45].
Case reports corroborate these findings, albeit
with limited strength of evidence [42, 46].
Systemic Tacrolimus
FDA-Approved Indication(s)
Oral tacrolimus is FDA-approved, in conjunction with corticosteroids, to prevent organ
rejection in patients with kidney, liver, or heart
transplants [7].
Mechanism of Action
Tacrolimus inhibits the phosphatase activity of
calcineurin and thereby suppresses T cell activation and proliferation via DNA replication [7].
When Best to Use
Systemic tacrolimus is best used to treat severe,
recalcitrant, chronic plaque psoriasis [47].
Evidence also exists for its use in lieu of cyclosporine in patients with increased cardiovascular
risk [47, 48].
10 Traditional Systemic Therapy II: Retinoids and Others
Dosage
Systemic tacrolimus is started at a dose of
0.05 mg/kg/day [7, 15, 47]. The dose can be
increased to 0.10 mg/kg/day after 3 weeks and to
0.15 mg/kg/day after 6 weeks [47, 48].
Adverse Events
The adverse effects associated with oral or intravenous (i.e. systemic) tacrolimus include: insomnia, tremors, headaches, altered sensory function,
muscle pains, pruritus, malaise or fatigue, photophobia, nausea, and diarrhea [47]. Tremor,
nausea, and abnormal renal function tests are
commonly reported in transplant patients whereas
hyperglycemia (and diabetes mellitus), hyperkalemia, hypertension, myocardial hypertrophy,
elevated LFTs, leukocytosis, dyspnea, anemia
(including red cell aplasia), edema, fever, nephrotoxicity, neurotoxicity and arthralgias were less
commonly reported in these patients when given
systemic tacrolimus [7, 15, 47].
Recommended Monitoring
At baseline, the provide should obtain a detailed
medical history and perform a physical examination. Baseline and repeat serum creatinine, potassium, and fasting glucose should be obtained and
evaluated regularly. Monitoring of metabolic and
blood components should be clinically guided
[47]. Since tacrolimus can increase blood sugar
levels when administered systemically, repeat
blood sugars (serum concentration and hemoglobin A1c must be obtained periodically. A
CBC count with differential, serum BUN and
creatinine levels, LFTs, and pregnancy test (if
indicated) should all be obtained before starting
systemic tacrolimus [9]. After starting treatment,
serial evaluations should be done of the patient’s
blood pressure, serum chemistries, BUN and
creatinine, LFTs, and pregnancy test (if indicated) [7, 15, 47]. A monitoring frequency has
not been firmly established. Even if asymptomatic, patients should be monitored for signs and
131
s­ ymptoms of hypertension alongside repeat measurements [15].
Perils and Pitfalls
Systemic tacrolimus is contraindicated in patients
with known hypersensitivity to tacrolimus or to
its metabolites and in nursing mothers [7, 15].
It causes fetal harm in pregnant animals [7, 15].
Transplant patients treated with tacrolimus have
an increased risk of developing lymphoma and
skin malignancies and an increased susceptibility
to infection [7]. Since psoriasis patients already
have an increased baseline risk of lymphoma,
this particular potential problem needs to be followed closely. The clinician must advise patients
to take oral tacrolimus consistently either with
or without food, as the presence of food affects
the drug’s bioavailability. The cytochrome P450
system metabolizes systemic tacrolimus, and it
therefore interacts with many drugs [15]. One
should not give systemic tacrolimus concurrently
with cyclosporine; discontinue one drug at least
24 hours before starting the other.
Strength of Evidence
A randomized, controlled trial evaluated the
safety and efficacy of systemic tacrolimus
(0.1 mg/kg/d titrated to response and side effects)
rcompared to placebo in 50 patients with severe
recalcitrant plaque psoriasis over the course of
nine weeks [48]. At the conclusion of the study
period, PASI scores decreased by 83% on average in the tacrolimus group compared to 47% in
the placebo group (P < 0.02) [48]. The most common side effects were diarrhea and paresthesias.
An open-label pilot study of 26 patients with
severe refractory plaque psoriasis investigated
the efficacy of oral tacrolimus (0.1 mg/kg/day
divided equally into two doses per day). Overall,
21/26 (80.37%) of participants hadimprovement
in mean PASI scores at the end of the trial. Of
these 21 patients with improvement, 19 achieved
at least PASI 75 and, of those, 11 scored PASI 90.
The most common adverse events experienced
V. Ramachandran et al.
132
were: diarrhea, abdominal pain, acral paraesthesia, and myalgia [49].
The combination of systemic evirolimus and
tacrolimus was shown to be effective in completely clearing refractory chronic plaque psoriasis in one post-transplant patient [50].
Leflunomide
FDA-Approved Indication(s)
Leflunomide is FDA-approved to treat active
rheumatoid arthritis in adults [8].
Mechanism of Action
Leflunomide inhibits de novo pyrimidine synthesis and thereby suppresses cell proliferation and
inflammation [8].
When Best to Use
Leflunomide can be considered for patients with
treatment-resistant, widespread, chronic plaque
psoriasis as a second-line systemic therapy or
psoriatic arthritis as a disease modifying antirheumatic agent [15, 51].
Dosage
Leflunomide should be started at 100 mg/day for
3 days, and then maintained at a dose of 20 mg/
day [8, 15, 51].
Adverse Events
The most common adverse events in patients taking leflunomide are diarrhea, nausea, upper respiratory tract infection, headache, hypertension,
and alopecia. Baseline LFTs arer recommended
as some patients may uncommonly experience
elevated liver enzymes [39]. Rarely, patients
taking leflunomide have rarely developed pancytopenia, agranulocytosis, thrombocytopenia,
Stevens-Johnson syndrome, and toxic epidermal
necrolysis [8].
Recommended Monitoring
The clinician should obtain history and perform
a physical examination. Additionally, at baseline,
providers should obtain CBC with differential
and LFTs. Pregnancy test (if indicated) may also
be obtained before starting leflunomide [39] After
starting treatment, a CBC with differential and
LFTs should be checked monthly for 6 months,
then every 6–8 weeks [8]. If indicated, ongoing
pregnancy tests should be checked [8].
Perils and Pitfalls
Leflunomide is contraindicated in patients with
hypersensitivity to leflunomide and in pregnant
or nursing mothers [8]. Hepatotoxicity and fatal
liver failure have been reported in patients treated
with leflunomide, and it is well worth noting that
concurrent methotrexate therapy increases the
risk of hepatotoxicity. Concurrent rifampin use
leads to increased and potentially toxic peak levels of leflunomide’s active metabolite [8].
Strength of Evidence
A randomized, placebo-controlled trial evaluated the safety and efficacy of leflunomide
compared to placebo in 109 patients with
active psoriatic arthritis and psoriasis with
≥3% BSA involvement … Seventeen percent
of the leflunomide-­
treated group achieved
PASI 75 compared to 8% in the placebo group
(P = 0.048). Additionally, 59% of leflunomidetreated patients achieved 20% in Psoriatic
Arthritis Response Criteria compared to 30% in
the placebo group (P < 0.0001) [51].
10 Traditional Systemic Therapy II: Retinoids and Others
133
Penicillin V and Erythromycin
Recommended Monitoring
FDA-Approved Indication(S)
No specific hematologic or biochemical monitoring is recommended for short-term therapy with
penicillin V or erythromycin [9, 10]. These medications have good safety profiles.
Among other indications, penicillin V and erythromycin are both approved to treat mild to moderate Streptococcus pyogenes-associated infections
[9, 10].
Mechanism of Action
Penicillin V inhibits biosynthesis of cell-wall
mucopeptides during cellular multiplication
in penicillin-sensitive microorganisms [10].
Erythromycin inhibits protein synthesis in susceptible microorganisms by binding to the 23S
ribosomal RNA molecule within the 50S subunit,
preventing elongation of peptide chains [9].
When Best to Use
Penicillin V or erythromycin can be used to treat
guttate psoriasis when the condition appears
related to or associated with a bacterial infection,
usually of an upper respiratory nature (classically
Streptococcal pharyngitis) [52–54]. If patients
present well after the episode of possible infection preceding guttate psoriasis antibiotic treatment may not be appropriate.
Dosage
Both antibiotics (penicillin V or erythromycin)
are given orally in a dosage of 250 mg four times
daily, for 14 days [54].
Adverse Events
Patients given penicillin V sometimes report
nausea, vomiting, abdominal pain, diarrhea, and
black hairy tongue [10]. Patients taking erythromycin often develop nausea, vomiting, abdominal pain, diarrhea, and anorexia [9].
Perils and Pitfalls
Penicillin is contraindicated in patients with
hypersensitivity to the drug; reported hypersensitivity reactions have been fatal [10].
Patients receiving penicillin V have developed
Clostridium difficile associated diarrhea. Highdose penicillin is rarely associated with leukopenia, anemia, thrombocytopenia, nephropathy, and
neuropathy [10].
Erythromycin is contraindicated in patients
taking terfenadine, astemizole, pimozide, or
cisapride due to increased risk of fatal ventricular arrhythmia and also in patients with hypersensitivity to erythromycin [9]. Patients taking
erythromycin have developed LFT abnormalities, hepatitis, pseudomembranous colitis, Q-T
interval, ventricular arrhythmias, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, pancreatitis, convulsions, and
reversible hearing loss [9].
While the association of Streptococcal infection of the pharynx is a well-known, forgotten in
examination may be perianal source of infection
which may lead to withheld antibiotics [55].
Strength of Evidence
A few antibiotic regimens have been studied in
the contex of guttate psoriasis, including pencillin V, erythromycin, rifampin (proposed to act
via anti-inflammatory effects), or combination of
these treatments (erythromycin plus rifampin).
These studies are largely limited to small and
uncontrolled investigations [52–59].
In 2019, a Cochrane Database systematic
review sought to assess the effects of antistreptococcal interventions for guttate and chronic
V. Ramachandran et al.
134
plaque psoriasis. The conclusion of this study
was that there was a major lack of well-designed
studies, limiting evidence to low-quality studies
with potential for various biases. Overall, the
efficacy and safety of antistreptococcal therapy in
the manangement of guttate and chronic plaque
psoriasis are uncertain and cannot be strongly
recommended at present [60].
Apremilast
FDA-Approved Indication(s)
Apremilast (OTEZLA®) is FDA-approved to
treat adults with active psoriatic arthritis and
patients with moderate-to-severe plaque psoriasis
who are candidates for phototherapy or systemic
therapy [61].
Mechanism of Action
Apremilast is a selective inhibitor of phosphodiesterase (PDE) 4, the predominant PDE in
inflammatory and immune cells, resulting in
increased intracellular levels of cyclic adenosine
monophosphate (cAMP) [62]. The increased levels of cAMP modulate the expression of inflammatory cytokines involved in the pathogenesis of
psoriasis. Inducible nitric oxide synthase, tumor
necrosis factor alpha (TNF-α), interferon gamma
(IFN-γ), interleukin (IL)-17A/F, IL-22, and
IL-23 are all decreased whereas IL-10, an anti-­
inflammatory cytokine, is increased [62, 63].
When Best to Use
There are several benefits to apremilast for
plaque psoriasis, manifesting in some general
principles for its best use. Since apremilast is
not immunosuppressive, it is useful in patients
with underlying/active infectious diseases
(e.g. viral hepatitis, tuberculosis) or those at
increased risk for infection (e.g. liver cirrhosis,
diabetes, intravenous drug users). In patients
with pre-existing disease-­associated (e.g. human
i­mmunodeficiency virus, acquired immune deficiency syndrome, malignancy) or iatrogenic
immunocompromised states (e.g. chemotherapy), apremilast is a valuable treatment [12].
Furthermore, apremilast may be a consideration
in patients for whom the side effects or contraindications of other biologic regimens (e.g.
infection, heart failure, demyelinating disorders)
exclude them from consideration [64].
Patients with psoriasis may have various
comorbidities necessitating numerous daily
medications [65]. In such patients, apremilast
may be beneficial due to its minimal interactions with cytochrome P450. Serum levels are
not increased inpatients taking medications that
inhibit cytochrome P450 [66, 67]. Additionally,
unlike other disease-modifying agents antirheumatic drugs, aprelimast does not exclude patients
with hepatic impairment [68]. In obese patients,
the side effect of weight loss may be beneficial in
treatment [61].
Apremilast’s oral formulation may also
improve adherence in patients with needle phobia
(or “needle-fatigue”), elderly patients, or those
facing impediments to social life or work activity
secondary to injections [69].
Dosage
Regardless of use, the FDA-approved daily dosage of apremilast is 30 mg twice daily [39].
This final recommended dosage is supported
by clinical phase II trials, which assessed clinical response to differing doses and frequency of
apremilast, showing that 30 mg twice daily was
the optimal regimen [70–72]. To improve the tolerability, gradual uptitration is advised in achieving the final recommended dose. The following
regimen is suggested [73]:
•
•
•
•
•
•
Day 1: 10 mg in the morning
Day 2: 10 mg in morning and 10 mg in evening
Day 3: 10 mg in morning and 20 mg in evening
Day 4: 20 mg in morning and 20 mg in evening
Day 5: 20 mg in morning and 30 mg in evening
Day 6 and thereafter: 30 mg in morning and
30 mg in evening
10 Traditional Systemic Therapy II: Retinoids and Others
135
Adults with severe renal impairment (end-­ not differ from the extremely low rates observed
stage renal disease stage 3b and above) are rec- in the ESTEEM 1 and 2 studies [77]. These
ommended to take 30 mg once daily. During the short- and long-term findings were corroborated
titration stage at the start of therapy, only the and validated by the LIBERATE studies [78, 79].
morning dose should be given [74].
Real-world investigation outside of clinical trials
also validate the strong safety profile found in
phase 3 trial data [80] (Table 10.4).
Adverse Events
Overall, the safety data does not seem to show
significant increase in serious infections, opporSince apremilast functions as an anti-­inflammatory tunistic infections, major cardiac events, organ
rather than an immunosuppressant, no increased damage, or malignancies. Additionally, there was
risk of opportunistic infections has been observed no change in laboratory abnormalities [75–79].
[68]. In the Efficacy and Safety Trial Evaluating
the Effects of Apremilast in Psoriasis (ESTEEM)
phase III trials (ESTEEM 1 and 2), adverse Recommended Monitoring
effects were compared in the 0–16-week period
(placebo-controlled) and assessed in the solely Apremilast has the added benefit of no required
apremilast exposure period (0–52 weeks) laboratory monitoring, such as liver and kid(Table 10.3) [75, 76].
ney function test, due to lack of organ-specific
The most common adverse events were diar- or cumulative toxicities with this medication
rhea, nausea, upper respiratory tract infection, [47]. However, monitoring patients for adverse
nasopharyngitis, and headaches (Table 10.2). sequelae of adverse effects is warranted.
Of these, the adverse events most different from Although the risk is low, patients with a history
the placebo group were: diarrhea and nausea. of depression, suicidal ideation, or history of suiLong-­term (0 to ≥156 weeks) investigation of cide should be closely monitoring for worsenpooled data from ESTEEM 1 and 2 showed no ing symptoms during therapy [69, 81]. Advising
new adverse events affecting ≥5% of the cohort patients, family members, and caregivers of these
were observed [77]. Overall, adverse events, seri- side effects is recommended. Additionally, the
ous adverse events, and adverse events leading to risk of weight loss warrants periodic body weight
drug discontinuation did not increase with long-­ checks, especially in underweight patients.
term drug use. Furthermore, the rates of major Clinically significant weight loss should prompt
cardiac events, depression, and malignancy did medication discontinuation [68, 81].
Table 10.3 Pooled adverse event data from the ESTEEM 1 and 2 phase III clinical trials for apremilast. AE = adverse
events
≥1 AE
≥1 severe AE
≥1 serious AE
≥1 AE leading
to drug
withdrawal
≥1 AE leading
to death
Placebo-controlled period (0–16 week)
Apremilast
Placebo
Placebo
ESTEEM 1
ESTEEM 1 ESTEEM 2
(n = 560)
(n = 136)
(n = 282)
157
82 (60.3%)
388 (69.3%)
(55.7%)
9 (3.2%)
6 (4.4%)
20 (3.6%)
8 (2.8%)
3 (2.2%)
12 (2.1%)
9 (3.2%)
7 (5.1%)
29 (5.2%)
Apremilast
ESTEEM 2
(n = 272)
185 (68.0%)
Apremilast-exposure period
(0–52 weeks)
Apremilast
Apremilast
ESTEEM 2
ESTEEM 1
(n = 380)
(n = 804)
633 (78.7%)
296 (77.9%)
12 (4.4%)
5 (1.8%)
15 (5.5%)
48 (6.0%)
34 (4.2%)
59 (7.3%)
33 (8.7%)
18 (4.7%)
27 (7.1%)
1 (0.4%)
0 (0.0%)
1 (0.1%)
0 (0.0%)
0 (0.0%)
1 (0.2%)
V. Ramachandran et al.
136
Table 10.4 Pooled side effect data from the ESTEEM 1 and 2 phase III clinical trials for apremilast
Diarrhea
Upper respiratory
tract infection
Nausea
Nasopharyngitis
Headache
Tension headaches
Placebo-controlled period (0–16 week)
Apremilast
Placebo
Placebo
ESTEEM 1
ESTEEM 1 ESTEEM 2
(n = 560)
(n = 136)
(n = 282)
20 (7.1%)
8 (5.9%)
105 (18.8%)
21 (7.4%)
6 (4.4%)
57 (10.2%)
Apremilast
ESTEEM 2
(n = 272)
43 (15.8%)
13 (4.8%)
Apremilast-exposure period
(0–52 weeks)
Apremilast
Apremilast
ESTEEM 2
ESTEEM 1
(n = 380)
(n = 804)
150 (18.7%)
55 (14.5%)
143 (17.8%)
35 (9.2%)
19 (6.7%)
23 (8.2%)
13 (4.6%)
12 (4.3%)
50 (18.4%)
20 (7.4%)
17 (6.3%)
14 (5.1%)
123 (15.3%)
108 (13.4%)
52 (6.5%)
52 (6.5%)
Perils and Pitfalls
9 (6.6%)
6 (4.4%)
1 (0.7%)
2 (1.5%)
88 (15.7%)
41 (7.3%)
31 (5.5%)
31 (5.5%)
63 (16.6%)
55 (14.5%)
22 (5.8%)
29 (7.6%)
mean change (−6.6%), and pruritus visual analogue scale (VAS) score decrease (−31.5%)
Patients with known hypersensitivity to apre- were significantly different in apremilast-treated
milast or any excipients in its formulation are patients compared to placebo-treated patients
contraindicated from this medication [82]. (5.3%, 17.0%, 3.9%, −2.1%, and − 7.3%, respec­
Concurrent use of cytochrome P450 activators tively) (all P < 0.0001) [75].
(e.g. rifampin) can lead to loss of efficacy [82].
Similarly, another phase III, multicenter,
The effects of apremilast on pregnancy, labor, double-­blind, placebo-controlled study (ESTEEM
delivery, and lactation in humans is unknown. 2) randomized 274 adults (2:1) to apremilast of
Although cases reports exist regarding its use in placebo. By week 16, the percentage of patients
pediatric patients, apremilast has not been stud- apremilast-treated patients achieving PASI-75
ied in this population and is off-label in this pop- (28.8%), PASI-50 (55.5%), sPGA score of 0 or
ulation [82].
1 (20.4%), DLQI mean change (−6.7%), and
Dose titration is important as the gastroin- pruritus VAS score decrease (−33.5%) were sigtestinal side effects are much prevalent when nificantly different in apremilast-­treated patients
not performed, leading to higher rates of drug compared to placebo-­
treated patients (5.8%,
withdrawal [73]. Xanthines, which are found in 19.7%, 4.4%, −2.8%, and − 12.2%, respectively)
caffeine, can increase cAMP through PDE inhi- (all P < 0.0001) [55]. The LIBERATE studies
bition. This can lead to increased risk of diarrhea validate these prior two studies’ findings over the
or other side effects [83].
long-term (104 weeks) [78, 79].
There is some evidence that apremilast is
Apremilast does not appear to be as efficacious
more effect in biologic-naïve patients reflected as other biologics as demonstrated by its lower
by a higher efficacy in this group of patients in PASI-75 scores compared to other biologics
the ESTEEM trials [75, 76].
[84, 85]. The German Society of Dermatology’s
consensus psoriasis treatment guidelines noting
the drug as the least efficacious biologic [86].
Strength of Evidence
Nevertheless, real-world multi-center studies
cite apremilast as a valuable part of the dermaA phase III, multicenter, double-blind, placebo-­ tologists’ armamentarium against psoriasis. One
controlled study (ESTEEM 1) randomized 844 such retrospective study of 148 patients noted a
adults (2:1) to apremilast or placebo. By week greater proportion of apremilast monotherapy
16, Psoriasis Area and Severity Index (PASI)- patients achieving response (PASI-75) (26/59,
75 (33.1%), PASI-50 (58.7%), static Physician’s 44.1%) compared to patients undergoing comGlobal Assessment (sPGA) score of 0 or 1 binational therapy (apremilast plus one of: pho(21.7%), dermatology life quality index (DLQI) totherapy, systemic therapy, biologic therapy)
10 Traditional Systemic Therapy II: Retinoids and Others
137
4. Soriatane [package insert]. Coral Gables: Stiefel
(33/89, 37.1%) (P = 0.396). However, the authors
Laboratories, Inc; 2011.
note this is partially due to the patients on com5. Hydrea (hydroxyurea). Food and Drug Administration.
binational therapy having more extensive/refracAccessed at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016295Orig1s047,s048Lbl.
tory disease or psoriatic arthritis (P < 0.001) [80].
pdf. March 2016. Retrieved on June 28, 2019.
The percentage of PASI-75 patients in this real-­
6. TABLOID [package insert]. Research Triangle Park:
world study is similar to the ESTEEM 1 and 2
GlaxoSmithKline; 2004.
trial data [75, 76].
7. Prograf [package insert]. Deerfield: Astellas Pharma
US, Inc; 2011.
Nevertheless, apremilast may be effectively be
8. Arava [package insert]. Bridgewater: Sanofi-Aventis
used in the real world as monotherapy or comU.S. LLC; 2011.
binational therapy, especially in biologic-naïve
9. Ery-Tab [package insert]. Thousand Oaks: Rebel
patients. This notion is complemented by evidence
Distributors Corp; 2010.
for apremilast use resulting in lower per-­patient 10. Penicillin V Potassium [package insert]. Sellersville:
Teva Pharmaceuticals USA; 2011.
per-month costs than biologic treatment [87].
Conclusion
Several factors should be considered when
selecting a regiment for a patient with psoriasis including pre-existing comorbidities, special
patient populations, resource-limited settings,
and adherence. Many treatments, particularly,
systemics have contraindications based on preexisting comorbidities or risks [12]. In this
chapter, we provide a clinically-oriented summary of second-­line traditional systemic agents
to navigate the myriad of treatment options.
Nevertheless, an important general principle is
that the best t­reatment is one the patient will be
adherent to [88–91]. This concept may be considered in deciding treatments. Additionally, combinational treatments with other modalities (e.g.
phototherapy) are often more efficacious.
References
1. Dogra S, Mahajan R. Psoriasis: epidemiology, clinical
features, co-morbidities, and clinical scoring. Indian
Dermatol Online J. 2016;7(6):471–80.
2. Schlager JG, Rosumeck S, Werner RN, Jacobs A,
Schmitt J, Schlager C, Nast A. Topical treatments for
scalp psoriasis. Cochrane Database Syst Rev. 2016
Feb 26;2:CD009687.
3. Le Moigne M, Sommet A, Lapeyre-Mestre M, Bourrel
R, Molinier L, Paul C, Montastruc JL. Healthcare cost
impact of biological drugs compared with traditional
systemic treatments in psoriasis: a cohort analysis in
the French insurance database. J Eur Acad Dermatol
Venereol. 2014 Sep;28(9):1235–44.
11. Warren RB, Griffiths CE. Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin
Dermatol. 2008 Sep-Oct;26(5):438–47.
12. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which patient: focus on special populations
and chronic infections. J Am Acad Dermatol. 2019
Jan;80(1):43–53.
13. Cather JC, Crowley JJ. Use of biologic agents in combination with other therapies for the treatment of psoriasis. Am J Clin Dermatol. 2014;15(6):467–78.
14. Smith J, Cline A, Feldman SR. Advances in psoriasis.
South Med J. 2017 Jan;110(1):65–75.
15. Menter A, Korman NJ, Elmets CA, Feldman SR,
Gelfand JM, Gordon KB, Gottlieb AB, Koo JY,
Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR,
Bhushan R. Guidelines of care for the management of
psoriasis and psoriatic arthritis: section 4. Guidelines
of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad
Dermatol. 2009 Sep;61(3):451–85.
16. Ormerod AD, Campalani E, Goodfield MJD, et al.
British Association of Dermatologists guidelines on
the efficacy and use of acitretin in dermatology. Br J
Dermatol. 2010;162:952–63.
17. Murray HE, Anhalt AW, Lessard R, Schacter RK, Ross
JB, Stewart WD, Geiger JM. A 12-month treatment of
severe psoriasis with acitretin: results of a Canadian
open multicenter study. J Am Ac ad Dermatol. 1991
Apr;24(4):598–602.
18. Werner B, Bresch M, Brenner FM, Lima
HC. Comparative study of histopathological and
immunohistochemical findings in skin biopsies from
patients with psoriasis before and after treatment with
acitretin. J Cutan Pathol. 2008;35:302–10.
19. Italian Multicenter Study Group on Cyclosporin in
Psoriasis. Cyclosporin versus etretinate: Italian multicenter comparative trial in severe plaque-form psoriasis. Dermatology. 1993;187(Suppl 1):8–18.
20. Lassus A, Geiger JM. Acitretin and etretinate in the
treatment of palmoplantar pustulosis: a double-blind
comparative trial. Br J Dermatol. 1988;119:755–9.
21. Lowe NJ, Prystowsky JH, Bourget T, Edelstein J,
Nychay S, Armstrong R. Acitretin plus UVB therapy for psoriasis. Comparisons with placebo plus
11
Apremilast
Jerry Bagel and Elise Nelson
Abstract
In 2014 apremilast was the first oral FDA
approved therapy in almost 20 years. Although
the efficacy of apremilast, PASI 75—33%
@ week 16 was inferior to the biologic
agents approved in its era, i.e. ustekinumab,
Adalimumab, PASI 75—71%, the safety of
apremilast resulted in many dermatologists
prescribing apremilast to their patients with
psoriasis. The reason for the expansive use of
apremilast is at least partially due to the following factors, no risks of malignancy, serious infections, no opportunistic infections, no
laboratory monitoring required.
Many psoriatics, in part to direct to consumer marketing, have been fearful of the side
effects of biologic agents, yet since topical
therapy was not providing adequate efficacy
they wanted a different option. In addition to
showing efficacy for plaque psoriasis, apremilast has also been studied and revealed efficacy in psoriatic arthritis (FDA approved),
psoriatic onychodystrophy, scalp psoriasis,
and palmar plantar psoriasis.
J. Bagel (*) · E. Nelson
Psoriasis Treatment Center of Central New Jersey,
East Windsor, NJ, USA
The Mount Sinai School of Medicine,
New York, NY, USA
The University of Pisa, Pisa, Italy
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_11
Key Learning Objectives
1. To understand the mechanism of action
of apremilast
2. To understand the appropriate use and
efficacy of the apremilast
3. To understand the safety issues of
apremilast
In 2014 the FDA approved apremilast for the
treatment of psoriasis and psoriatic arthritis.
Acetretin and cyclosporine were FDA approved
in 1996 and 1997 respectively. In this time frame
there were six biologic therapies approved, however, apremilast was the first new oral therapy in
almost 20 years.
As opposed to biologic agents which bind
extracellular targets i.e. TNF-alpha, IL-12, IL-23,
IL-17, apremilast is a small molecule which acts
intracellularly. The mechanism by which apremilast acts is by inhibiting the activity of phosphodiesterase 4 (PDE4). In inflammatory cells,
PDE4 catalyzes the conversion of cAMP to
AMP. The ratio of cAMP to AMP regulates the
transcription of either anti-inflammatory mediators or pro-inflammatory mediators. Higher intracellular concentrations of AMP result in a greater
transcription of pro-inflammatory mediators i.e.
IL-17, IL-22, TNF alpha and accordingly, less
transcription of anti-inflammatory mediators.
More specifically, an increase in intracellular
141
142
cAMP activates Protein Kinase A (PKA). PKA
activates certain transcription factors, but inhibits
NF-KB which is thought to decrease the amount
of pro-inflammatory mediators. Hence, by inhibiting PDE4, apremilast increases intracellular
cAMP and promotes anti-inflammatory transcription via the activation of the cAMP-response
element binding protein.
The FDA approval of apremilast was based on
two phase III clinical trials, ESTEEM 1 and 2.
The ESTEEM 1 and 2 randomized, placebo-­
controlled studies evaluated apremilast 30 mg
BID in adult patients with chronic moderate-to-­
severe plaque psoriasis, PASI ≥ 12, BSA ≥ 10,
PGA ≥ 3. Patients with a history of prior phototherapy, systemic, and biologic therapy were eligible to participate in the trial. The primary
endpoint was PASI-75 response at week 16.
In ESTEEM 1, 844 patients participated (562
apremilast, 282 placebo), with a mean age of 46
who had psoriasis for approximately 20 years.
The mean PASI = 19, BMI = 31, and over half
had prior systemic or biologic therapy. At week
16, PASI-75 was achieved by 33.1% in the apremilast cohort vs placebo which was 5.3%. In
addition, the PASI-50, PASI change from baseline, Scalp PGA = 0–1, NAPSI-50, and DLQI %
response was 59, 52, 47, 33, 70 in the apremilast
cohort vs 17, 17, 18, 15, 34 for placebo.
Evaluating psoriatic onychodystrophy there was
a 22% improvement in NAPSI scores within 16
weeks.
PASI-75 response was maintained through
week 32. In those patients who obtained a PASI-­
75 at week 32, there was an 80% improvement in
PASI through Week 52.
The most common adverse events reported in
>5% of patients in the apremilast cohorts were
diarrhea, nausea, upper respiratory tract infections, and headaches. There were no serious
opportunistic infections, the rates of malignancy
and laboratory abnormalities were comparable
between the apremilast cohort and placebo.
The LIBERATE study compared apremilast
to placebo and had an active control in etanercept. At week 16, PASI-75 for placebo, apremilast, and etanercept was 12%, 40%, and 48%
respectively. In this study apremilast was con-
J. Bagel and E. Nelson
tinued through week 104 without any increase
in adverse events noted.
There have been reports of weight loss associated with apremilast. In view of the fact that over
35% of patients have a BMI > 30, weight loss is
generally not a concern. However, for those thinner individuals and elderly, weight loss may be
an issue. In addition diarrhea and/or vomiting
may result in electrolyte imbalance especially in
those taking diuretics. Diarrhea is listed as a
warning, it tends to occur in the first two weeks
and resolve over time with continued dosing. It
can be severe, reduce dose/discontinue, if needed.
Many of the nuisance side effects i.e. headaches, diarrhea, nausea, and vomiting may be
ameliorated by prolonging the tapering period of
apremilast at the initiation of therapy i.e. instead
of a 5 day taper starting at 10 mg on day 1,
advancing to 30 mg bid on day 6, a 10 or 15 day
taper significantly decreases the incidence of
these nuisance side effects. There is a warning
related to depression, so it is important to exclude
patients with a history of major depressive
episodes.
Based on the phase 3 Palace 1–3 clinical trials
apremilast was FDA approved for psoriatic
arthritis. At week 16 apremilast yielded ACR
20 = 32%–41%, placebo = 19%. At week 260,
the ACR 20, 50, 70 for apremilast was 67%, 44%,
and 27% respectively. A significant number of
these subjects had been biologically experienced
and biologic-failures. ACR 20 = 23% response
rates in biologic failures was lower than biologically naive = 43% at week 16. Overall swollen
joint counts and tender joint counts decreased by
87% and 80% respectively over 260 weeks. In
addition 80% and 54% of subjects obtained dactylitis count = 0 and enthesitis score = 0 at 260
weeks of treatment.
While apremilast is not the most efficacious
treatment for psoriasis, it is popular due to its
safety profile. Based on its mechanism of action,
apremilast does not suppress any of the extracellular pro-inflammatory molecules as much as
monoclonal antibodies. By not suppressing as
much, there is no increase in serious infections,
hence, apremilast acts as an immunomodulating
agent not as an immunosupressive. There were
11
Apremilast
no serious opportunistic infections, no increase in
malignancy with cumulative experience, laboratory anomalies were infrequent and transient, and
in fact no laboratory monitoring is required.
In addition, a phase IV study evaluated apremilast 30 mg bid in adults with moderate-to-­
severe palmoplantar psoriasis. At week 32, 24%
patients randomized to apremilast were clear or
almost clear. In a post-hoc analysis of ESTEEM
1 and 2 and a phase II study approximately 48%
(n = 92) were clear or almost clear at week 16,
however the placebo rate was rather high with an
average of 27% (n = 52). Baseline PPPGA ≥ 3.
In a Phase III study in patients with moderate
to severe scalp psoriasis (SSA ≥ 20%) 43% of
patients treated with apremilast at week 16 were
clear or almost clear compared to placebo = 14%.
Scalp itch and whole body itch response was seen
in 47% and 45% of patients respectively.
In my experience, many patients who opt for
apremilast tend to be hesitant of biologic risk or
much less commonly needle phobic. However,
based on the data, if patients do not capture a 25%
improvement within 8 weeks there is not much
likelihood of treatment success. Expectations
with apremilast need to be defined letting patients
know that there are other more efficacious options
should apremilast not work for them.
Apremilast has not been evaluated in combination with biologics. Ustekinumab may clear
psoriasis, but not psoriatic arthritis as well. By
adding apremilast instead of methotrexate better
efficacy with less toxicity can be obtained. A
similar scenario with adalimumab, where the
joints may do well, but in patients who don’t
achieve full skin clearance, adding apremilast
instead of methotrexate may be helpful. In addition combining apremilast with ultraviolet B has
shown synergistic efficacy.
Bibliography
1. Bagel J, Nelson E, Keegan BR. Apremilast and narrowband ultraviolet-B combination therapy for treating moderate-to-severe plaque psoriasis. J Drugs
Dermatol. 2017 Oct 1;16(10):957–62.
2. Crowley J, Thaçi D, Joly P, Peris K, Papp KA,
Goncalves J, Day RM, Chen R, Shah K, Ferrándiz
143
C, Cather JC. Long-term safety and tolerability of
apremilast in patients with psoriasis: pooled safety
analysis for ≥156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad
Dermatol. 2017 Aug;77(2):310-7.e1. https://doi.
org/10.1016/j.jaad.2017.01.052. Epub 2017 Apr 14.
3. Danesh MJ, Beroukhim K, Nguyen C, Levin E, Koo
J. Apremilast and adalimumab: a novel combination
therapy for recalcitrant psoriasis. Dermatol Online J.
2015 Jun 16;21(6). pii: 13030/qt5gf406zs.
4. Duffin KC, Papp KA, Bagel J, Levi E, Chen R,
Gottlieb AB. Evaluation of the physician global
assessment and body surface area composite tool for
assessing psoriasis response to apremilast therapy:
results from ESTEEM 1 and ESTEEM 2. J Drugs
Dermatol. 2017 Feb 1;16(2):147–53.
5. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo
AO, Wollenhaupt J, Gladman DD, Hochfeld M, Teng
LL, Schett G, Lespessailles E, Hall S. Longterm (52-­
week) results of a phase III randomized, controlled
trial of apremilast in patients with psoriatic arthritis.
J Rheumatol. 2015 Mar;42(3):479–88. https://doi.
org/10.3899/jrheum.140647. Epub 2015 Jan 15.
6. Kavanaugh A, Gladman DD, Edwards CJ, Schett
G, Guerette B, Delev N, Teng L, Paris M, Mease
PJ. Long-term experience with apremilast in
patients with psoriatic arthritis: 5-year results from
a PALACE 1-3 pooled analysis. Arthritis Res Ther.
2019 May 10;21(1):118. https://doi.org/10.1186/
s13075-019-1901-3.
7. Langley A, Beecker J. Management of common side effects of apremilast. J Cutan Med
Surg. 2018 Jul/Aug;22(4):415–21. https://doi.org/
10.1177/1203475417748886. Epub 2017 Dec 31.
Review.
8. Nguyen CM, Leon A, Danesh M, Beroukhim K, Wu JJ,
Koo J. Improvement of nail and scalp psoriasis using
apremilast in patients with chronic psoriasis: Phase
2b and 3, 52-week randomized placebo-controlled
trial results. J Drugs Dermatol. 2016 Mar;15(3):
272–6.
9. Papp K, Reich K, Leonardi CL, Kircik L, Chimenti
S, Langley RG, Hu C, Stevens RM, Day RM, Gordon
KB, Korman NJ, Griffiths CE. Apremilast, an oral
phosphodiesterase 4 (PDE4) inhibitor, in patients
with moderate to severe plaque psoriasis: results of
a phase III, randomized, controlled trial (Efficacy
and Safety Trial Evaluating the Effects of Apremilast
in Psoriasis [ESTEEM] 1). J Am Acad Dermatol.
2015 Jul;73(1):37–49. https://doi.org/10.1016/j.
jaad.2015.03.049.
10. Paul C, Cather J, Gooderham M, Poulin Y, Mrowietz
U, Ferrandiz C, Crowley J, Hu C, Stevens RM, Shah
K, Day RM, Girolomoni G, Gottlieb AB.Efficacy
and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe
plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol.
2015 Dec;173(6):1387–99. https://doi.org/10.1111/
bjd.14164. Epub 2015 Nov 7.
12
Etanercept
Andrew F. Alexis and Charlotte M. Clark
Abstract
Key Learning Objectives
Etanercept is a soluble dimeric fusion protein
1. To understand the mechanism of action
that was the first anti-tumor necrosis factor
of Etanercept
(TNF-α(alpha)) drug to be approved for the
2. To understand the appropriate use and
treatment of psoriasis and psoriatic arthritis. It
efficacy of the Etanercept
is administered subcutaneously by self-­ 3. To understand the safety issues of
injection. As with other biologic drugs for
Etanercept
psoriasis, etanercept offers a targeted approach
to treatment that lacks end organ side effects
of traditional systemic therapies such as methotrexate, cyclosporine, or acitretin. With over
Introduction
8 years of postmarketing experience in psoriasis (and over 14 years since approval for modEtanercept was the first anti-tumor necrosis facerate to severe RA in 1998), a large body of
tor (TNF-α(alpha)) drug to be approved for the
safety data exists for etanercept. Here, we
treatment of psoriasis and psoriatic arthritis.
review the safety and efficacy of etanercept in
As a TNF-α(alpha) blocking agent, etanercept
the treatment of plaque psoriasis and psoriatic
modulates inflammatory processes of innate and
arthritis, with emphasis on published Phase 3
extrinsic immune responses, cell trafficking, and
and Phase 4 clinical trial data. Safety considacute and chronic inflammation that are abererations, recommended monitoring, and studrant in psoriasis. In this chapter, the safety and
ies of combination therapy are also discussed.
efficacy of etanercept in the treatment of plaque
psoriasis and psoriatic arthritis will be reviewed,
with emphasis on published Phase 3 and Phase 4
clinical trial data.
A. F. Alexis (*)
Department of Dermatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: aalexis@chpnet.org
C. M. Clark
Department of Dermatology, Columbia University
Medical Center, New York, NY, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_12
Background
Psoriasis is a chronic inflammatory disease, characterized by hyperkeratotic epidermal lesions
formed in response to T cell activation and the
145
146
associated release of proinflammatory cytokines
[1]. Although the exact pathogenesis of psoriasis remains to be fully elucidated, TNF appears
to play a key role in the inflammatory cascade
associated with psoriasis and psoriatic arthritis.
When compared to uninvolved skin, greater concentrations of TNF-α are expressed in the stratum
corneum of psoriatic lesions [2].
Etanercept is a TNF-α inhibitor and FDA
approved drug for the treatment of adult patients
with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or
phototherapy. Etanercept is also approved for the
treatment of other TNF mediated inflammatory
diseases such as rheumatoid arthritis, psoriatic
arthritis, ankylosing spondylitis, and polyarticular juvenile idiopathic arthritis.
Structure and Mechanism of Action
Etanercept is a soluble dimeric fusion protein
that includes two TNF-α receptors fused to the
constant region (Fc) of human IgG1, allowing
it to bind specifically with non-membranous
bound TNF-α [1, 3, 4]. Etanercept binds to and
inactivates TNF [3]. Furthermore, etanercept
modifies responses induced by TNF activity,
such as adhesion molecule expression (needed
for leukocyte migration) and blood cytokine
levels [5]. Therapy is administered as a subcutaneous injection by patients at home. The peak
absorption of etanercept is at 51 h, with a mean
half-life of 68 h [4].
Etanercept in the Treatment
of Psoriatic Arthritis
Psoriatic skin lesions typically precede the onset
of joint symptoms and therefore, dermatologists
can potentially diagnose psoriatic arthritis in
early stages through careful history and examination. Elevated TNF-α levels have been found
in psoriatic arthritis joint fluid in comparison
A. F. Alexis and C. M. Clark
to osteoarthritis controls [2]. Psoriatic arthritis
patients treated with etanercept have shown to
have significant reductions in cutaneous psoriasis
lesions as well as improvement of their arthritis
[1, 6]. Etanercept (25 mg SC twice-weekly) has
been shown to be efficacious in the treatment
of psoriatic arthritis as evidenced by significantly greater percentages of subjects achieving
a 20% or greater reduction in American College
of Rheumatology criteria (ACR20) scores [6].
Significant inhibition of radiographic disease
progression (measured by mean change in modified total Sharp score) has also been shown in
controlled clinical trials of etanercept in the treatment of psoriatic arthritis [6, 7].
Etanercept in the Treatment
of Psoriasis
The safety and efficacy of etanercept has been
shown in large double blinded placebo-controlled
trials [8–10]. Based on US and Global phase III
trial data the dosage approved by the US FDA for
the treatment of plaque psoriasis is 50 mg SC twice
weekly for 12 weeks followed by 50 mg SC thereafter. Statistically significant proportions of etanercept treated subjects achieved a 75% or greater
reduction in Psoriasis Area and Severity Index
(PASI 75) scores compared to placebo (Table 12.1)
[6, 7]. Clinically meaningful improvements in the
quality of life have also been demonstrated in psoriasis patients treated with etanercept [6].
After discontinuation of therapy, a gradual onset
of disease recurrence is observed. In one study,
median time to disease relapse (measured as ≥50%
loss of PASI improvement achieved from baseline
after 24 weeks of therapy) was 3 and 2 months, in
PASI 50 and PASI 75 responders, respectively [8].
Successful discontinuation and re-treatment with
etanercept has also been shown [8, 9].
Therapeutic efficacy after dosage reduction
at 12 weeks from 50 mg SC twice weekly to
50 mg once weekly is maintained by a majority of
patients as demonstrated by the percentage of sub-
12
Etanercept
147
Table 12.1 The US and Global Phase III psoriasis clinical trials; study design, baseline characteristics, and clinical
outcomes [6, 7]
Study design
Number of patients
Duration
Drug regimen
US Phase III clinical trial [6]
Multicenter (47 sites), randomized,
double-blinded, placebo-controlled,
parallel-group
672 patients were randomized, 652
participated in study treatment
24 weeks
1. Placebo (n = 166) for 12 weeks, then
etanercept 25 mg BIW for 12 more
weeks
2. Low dose (25 mg QIW) (n = 160)
3. Medium dose (25 mg BIW) (n = 162)
4. High dose (50 mg BIW) (n = 164)
Efficacy endpoints
Demographics
and baseline
clinical
characteristics
Duration of
psoriasis
(years)
PASI score
Affected body
surface area
(%)
Efficacy
Results
PASI 50
PASI 75
PASI 90
Mean PASI
improvement
Results
PASI 50
PASI 75
PASI 90
Mean PASI
improvement
a
Placebo
group
(mean)
Primary endpoint: PASI 75 at week 12
Secondary endpoints:
1. PASI 50 and 90 at week 12
2. Physician global assessment
3. Patient global assessment
4. Dermatology life quality index
High dose
Medium
Low dose
dose group group
group
(mean)
(mean)
(mean)
18.4 ± 0.9
19.3 ± 0.9
18.5 ± 0.9
18.6 ± 0.9
18.3 ± 0.6
18.2 ± 0.7
18.5 ± 0.7
18.4 ± 0.7
28.8 ± 1.4
27.7 ± 1.5
28.5 ± 1.6
29.9 ± 1.6
Placebo
group
Low dose
group
Medium
dose group
12 weeks
14%
4%
1%
14.0 ± 2.6
41%a
14%a
3%a
40.9 ± 2.4a
24 weeks
NA
33%
NA
NA
58%
25%
6%
50.3 ± 2.5
17.5 (range
1.4–51.2)
Etanercept
25 mg BIW
group
(median)
21.5 (range
0.8–64.6)
Etanercept
50 mg BIW
group
(median)
18.1 (range
0.8–60.5)
16.0 (range
7.0–62.4)
20.0 (range
10.0–95.0)
16.9 (range
4.0–51.2)
23.0 (range
7.8–95.0)
16.1 (range
7.0–57.3)
25.0 (range
10.0–80.0)
High dose
group
Placebo
group
Etanercept
25 mg BIW
group
Etanercept
50 mg BIW
group
58%a
34%a
12%a
52.6 ± 2.7a
74%a
49%a
22%a
64.2 ± 2.4a
12 weeks
9%
3%
1%
NA
64%b
34%b
11%b
NA
77%b
49%b
21%b
NA
70%
44%
20%
62.1 ± 2.5
77%
59%
30%
71.1 ± 2.2
24 weeks
NA
28%
NA
NA
NA
45%
NA
NA
NA
54%
NA
NA
P < 0.001 for comparison with placebo at week 12
P < 0.0001 for comparison with placebo at week 12
b
Global Phase III clinical trial [7]
Multicenter (50 sites), randomized,
double-blinded, placebo-controlled,
parallel-group
611 patients were randomized, 583
participated in study treatment
24 weeks
1. Placebo (n = 193) for 12 weeks, then
etanercept 25 mg BIW for 12 more
weeks
2. Etanercept 25 mg BIW (n = 196) for
24 weeks
3. Etanercept 50 mg BIW (n = 194) for
12 weeks, then etanercept 25 mg
BIW for 12 more weeks
Primary endpoint: PASI 75 at 12 weeks
Secondary endpoints:
1. PASI 50 and 90 at 12 weeks
2. Patient global assessment
Placebo
group
(median)
148
jects maintaining a PASI 50 or greater after “stepdown” therapy [8]. In addition, approximately
30% of the non-responders (those not achieving a
PASI 75) after 12 weeks of dose- reduction were
shown to achieve a PASI 75 by week 24, despite
continued reduced-dose therapy [8].
The long-term safety and efficacy of etanercept 50 mg twice weekly in patients with psoriasis has been investigated in a 96 week open-label
extension trial [11].
Significant improvement in psoriasis associated depression in patients treated with etanercept (compared to placebo) was demonstrated
in a study that included assessment of the Beck
depression inventory (BDI) and Hamilton rating
scale for depression (HAM-D) [12].
A recent retrospective study investigating
potential racial and ethnic differences found no
differences in safety and efficacy variables (including adverse event rates and improvements in body
surface area of involvement) between Caucasians,
African-Americans, and Hispanics [13].
Combination Therapy
Etanercept has been used safely in combination
with other agents to enhance or maintain efficacy.
Adjunctive topical calcipotriene 0.005% and
betamethasone dipropionate 0.064% ointment
[14], narrow-band UVB phototherapy [15], or
methotrexate [16, 17], has been reported in published trials. The above adjunctive therapies can
be considered in cases of waning or insufficient
efficacy with etancercept monotherapy. However,
potential risks and benefits must be considered
and appropriate monitoring is advised when combining therapies (especially those with potential
immunosuppressive and/or malignancy risks).
Safety
A general outline recommending risk assessment prior to commencing etanercept therapy, as
well as recommendations for specific monitoring
of symptoms and routine laboratory tests when
initiating and maintaining etanercept therapy, is
provided (Table 12.2) [4, 5, 18, 19].
A. F. Alexis and C. M. Clark
Table 12.2 Recommended risk assessment prior to
introduction etanercept therapy (a) and recommended
symptom and laboratory monitoring prior to initiating and
while maintaining etanercept therapy (b) [4, 5, 18, 19]
(a)
Contraindications
Concurrent live vaccination
History of etanercept-induced hypersensitivity
reactions
Use in those with Wegener’s granulomatosis receiving
immunotherapy (associated with higher incidence of
solid malignancies and does not improve clinical
outcome if compared to standard therapy alone)
Septicemia, or active infection
Relative contraindications/cautions
Pregnancy (pregnancy category B), inadequate data
for risk assessment for breast feeding, caution advised
Caution if CHF, especially CHF grade III–IV new
York heart association (NYHA)
Caution in patients with or at risk for demyelinating
disorders
Caution if HBV carrier
Personal history of frequent or recurrent infections,
including history of chronic open wounds. Caution if
TB risk, history of latent TB, or if patient travels or
resides to regions with endemic TB or mycoses
Caution if moderate to severe alcoholic hepatitis
Personal history of uncontrolled diabetes mellitus
History of malignancy within the past 5 years or in
patients with increased malignancy risk
History of blood disorders or myelosuppression
Caution in patient >65 years of age
Caution use in patients with concurrent
immunosuppressants- anakinra or abatacept is not
recommended with etanercept therapy
In patients with a significant exposure to varicella
virus, etanercept therapy should be temporarily
discontinued and considered for prophylactic
treatment with varicella zoster immune globulin
Caution in patients with latex allergy- the needle cover
of prefilled syringes and needle cover within needle
cap contain latex-derived components
(b)
Baseline monitoring
PPD (baseline and annually) or Quantiferon gold (for
latent TB) is required, along with CXR for exclusion
of active TB
Liver function test (baseline and every 2–6 months),
hepatitis B and C testing, complete blood count
(baseline and every 2–6 months), basic chemistry
(baseline and every 2–6 months), and optional
baseline antinuclear antibodies (ANA)
Monitoring of signs and symptoms
Discontinue etanercept therapy during active infection.
Consider empiric anti-fungal treatment for those at risk
for invasive fungal infections or for patients residing or
travelling to regions where mycoses are endemic
12
Etanercept
Table 12.2 (continued)
Discontinue etanercept 1–2 weeks prior to surgery,
and reinitiation of etanercept therapy 2 weeks after
uncomplicated surgical procedures
Discontinue etanercept therapy 4 weeks prior to and
reinitiate 4 weeks after vaccination (to prevent
decreased vaccination efficacy)
Discontinue etanercept therapy if malignancy
detected, with the exception of cutaneous basal cell
carcinoma
Periodic evaluation of signs and symptoms of
opportunistic infections
Yearly examination for skin cancer detection
If pregnancy occurs, discuss risks versus benefits
(pregnancy category B drug)
Consider risks versus benefits in patients with
cardiovascular co-morbidities
Provide annual inactivated influenza vaccination,
preferably prior to biologic therapy initiation
Monitor hepatitis B carriers for reactivation during and
several months after initiating etanercept therapy. If
reactivation occurs, consider discontinuing etanercept
and beginning anti-viral therapy
CHF congestive heart failure, PPD purified protein derivation, CXR chest X-ray
As with other anti-TNF therapies, serious
and opportunistic infections, (including bacterial, mycobacterial, fungal, viral, parasitic) have
been observed in patients receiving etanercept.
Reactivation of latent tuberculosis (TB) is a risk
for this class of biologics and therefore screening
for TB is required at baseline and annually [4,
5, 18, 19]. Fatal cases of reactivation of hepatitis B virus have also been reported and as such,
baseline screening for viral hepatitis is required
before initiation of treatment with etanercept [4,
5, 18, 19].
Other non-infectious considerations include
congestive heart failure (CHF) and demyelinating disorders. Worsening of CHF and rare
new onset cases of CHF have been reported in
patients taking etanercept [3–5, 19, 20]. In addition, there are rare reports of exacerbation or new
onset of demyelinating disorders among etanercept patients [4, 5, 19]. Therefore, TNF inhibitors, including etanercept should be considered
with caution in patients with pre-existing CHF or
demyelinating disorders [4, 5, 19].
149
Malignancies
Malignancies have been reported in patients using
etanercept and other anti-TNF agents. Rates of
malignancies among patients with anti-­TNF therapy have been analyzed using clinical trial data
and large rheumatologic disease and biologic
therapy databases [21–25]. Reported malignancies include lymphomas, non-­
melanoma skin
cancers (NMSC), leukemia, and rare cases of
Merkel Cell carcinoma [26].
Among adult psoriasis patients treated with etanercept in clinical trials (n = 4410) up to 36 months,
the observed rate of lymphoma was comparable to
that in the general population [5]. No cases were
observed in the etanercept- or placebo-­
treated
patients during the controlled portions of these
trials. However, in the controlled portions of etanercept trials in adult rheumatology patients - with
rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)—two lymphomas were observed among etanercept treated
patients versus 0 among control patients [5]. In
combined data of controlled and uncontrolled
portions of clinical trials of etanercept for adult
rheumatology patients (RA, AS, and PsA) representing 12,845 patient years of therapy, the rate of
lymphoma observed (0.10 per 100 patient-years)
was threefold higher than that expected in the
general US population based on the Surveillance,
Epidemiology, and End Results (SEER) Database
[5]. However, higher rates of lymphoma (up to
several-fold) have been reported in the RA patient
population compared to the general population [5].
Higher rates of non-melanoma skin cancer
have been observed among psoriasis patients
treated with etanercept. In controlled clinical
trials of adult psoriasis patients (n = 1245), the
rate of NMSC observed was 3.54 cases per 100
patient-years among those treated with etanercept versus 1.28 cases per 100 patient-years
among control patients [5]. Rare cases of Merkel
cell carcinoma have been reported in the post-­
marketing period [5]. For all etanercept patients
at risk for skin cancer, full body skin examinations are recommended [5].
150
Excluding lymphoma and NMSC, no difference in exposure-adjusted rates of malignancies
between etanercept and placebo-treated patients
have been observed in the controlled portions of
etanercept clinical trials (across all indications)
[5, 27].
In the pediatric population, malignancies
including lymphoma and leukemia have been
reported, particularly among children or adolescents taking concomitant immunosuppressive
agents [5].
References
1. Krueger JG. The immunologic basis for the treatment
of psoriasis with new biologic agents. J Am Acad
Dermatol. 2002;46(1):1–23. quiz 23–6
2. Gratch N, Alexis AF. Etanercept in dermatology and
off-label use. In: Weinberg JM, Buchholz R, editors. TNF-alpha inhibitors. Basel: Birkhauser Verlag
part of Springer Science and Business Media; 2006.
p. 55–63.
3. Weinberg JM. An overview of infliximab, etanercept,
efalizumab, and alefacept as biologic therapy for psoriasis. Clin Ther. 2003;25(10):2487–505.
4. Papp KA. The safety of etanercept for the treatment of plaque psoriasis. Ther Clin Risk Manag.
2007;3(2):245–58.
5. Enbrel: Enbrel® (etanercept) prescribing information.
Manufactured by Immunex Corporation. Marketed by
Amgen, Inc. and Pfizer, Inc. Thousand Oaks: Amgen;
2012.
6. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept
treatment of psoriatic arthritis: safety, efficacy, and
effect on disease progression. Arthritis Rheum.
2004;50(7):2264–72.
7. Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with
psoriatic arthritis following 2 years of treatment with
etanercept. J Rheumatol. 2006;33(4):712–21.
8. Papp KA, Tyring S, Lahfa M, et al. A global phase
III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J
Dermatol. 2005;152(6):1304–12.
9. Leonardi CL, Powers JL, Matheson RT, et al.
Etanercept as monotherapy in patients with psoriasis.
N Engl J Med. 2003;349(21):2014–22.
10. Gordon KB, Gottlieb AB, Leonardi CL, et al. Clinical
response in psoriasis patients discontinued from and
then reinitiated on etanercept therapy. J Dermatolog
Treat. 2006;17(1):9–17.
11. Tyring S, Gordon KB, Poulin Y, et al. Long-term
safety and efficacy of 50 mg of etanercept twice
weekly in patients with psoriasis. Arch Dermatol.
2007;143(6):719–26.
A. F. Alexis and C. M. Clark
12. Tyring S, Gottlieb A, Papp K, et al. Etanercept and
clinical outcomes, fatigue, and depression in psoriasis: double-blind placebo-controlled randomised
phase III trial. Lancet. 2006;367(9504):29–35.
13. Shah SK, Arthur A, Yang YC, Stevens S, Alexis
AF. A retrospective study to investigate racial
and ethnic variations in the treatment of psoriasis with etanercept. J Drugs Dermatol. 2011;10(8):
866–72.
14. Kircik LH. Topical calcipotriene 0.005% and betamethasone dipropionate 0.064% maintains efficacy
of etanercept after step-down dose in patients with
moderate-­
to-severe plaque psoriasis: results of an
open label trial. J Drugs Dermatol. 2011;10(8):
878–82.
15. Gambichler T, Tigges C, Scola N, et al. Etanercept
plus narrowband ultraviolet B phototherapy of psoriasis is more effective than etanercept monotherapy at 6
weeks. Br J Dermatol. 2011;164(6):1383–6.
16. Strober BE. Successful treatment of psoriasis and
psoriatic arthritis with etanercept and methotrexate
in a patient newly unresponsive to infliximab. Arch
Dermatol. 2004;140(3):366.
17. Strober BE, Clarke S. Etanercept for the treatment of
psoriasis: combination therapy with other modalities.
J Drugs Dermatol. 2004;3(3):270–2.
18. Lebwohl M, Bagel J, Gelfand JM, et al. From the
medical Board of the National Psoriasis Foundation:
monitoring and vaccinations in patients treated
with biologics for psoriasis. J Am Acad Dermatol.
2008;58(1):94–105.
19. Menter A, Gottlieb A, Feldman SR, et al. Guidelines
of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and
guidelines of care for the treatment of psoriasis
with biologics. J Am Acad Dermatol. 2008;58(5):
826–50.
20. van Lumig P, Driessen R, Berends M, Boezeman
J, van de Kerkhof P, de Jong E. Safety of treatment
with biologics for psoriasis in daily practice: 5-year
data. J Eur Acad Dermatol Venereol. 2012;26(3):
283–91.
21. Strangfeld A, Hierse F, Rau R, et al. Risk of incident
or recurrent malignancies among patients with rheumatoid arthritis exposed to biologic therapy in the
German biologics register RABBIT. Arthritis Res
Ther. 2010;12(1):R5.
22. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses
from a large US observational study. Arthritis Rheum.
2007;56(9):2886–95.
23. Wolfe F, Michaud K. The effect of methotrexate
and anti-tumor necrosis factor therapy on the risk of
lymphoma in rheumatoid arthritis in 19,562 patients
during 89,710 person-years of observation. Arthritis
Rheum. 2007;56(5):1433–9.
24. Pallavicini FB, Caporali R, Sarzi-Puttini P, et al.
Tumour necrosis factor antagonist therapy and cancer development: analysis of the LORHEN registry.
Autoimmun Rev. 2009;9(3):175–80.
Adalimumab for Psoriasis
13
Cooper B. Tye and Jennifer C. Cather
Key Learning Objectives
1. To understand the mechanism of action
of Adalimumab
2. To understand the appropriate use and
efficacy of the Adalimumab
3. To understand the safety issues of
Adalimumab
Introduction
Psoriasis is an immune-mediated inflammatory
disease that affects 2–3% of the population worldwide [1]. Psoriasis patients experience episodic
flares with few spontaneous remissions. Psoriasis
is characterized by scaling, erythema, and thickened plaques on the skin. In addition to physical
symptoms, psoriasis patients often experience
psychosocial issues and have poor health related
quality of life (HRQoL) [2]. Psoriasis is a complex disease, and onset results from a combination
of genes and the environment [3]. Additionally,
some patients with psoriasis develop psoriatic
C. B. Tye
UT Health San Antonio School of Medicine,
San Antonio, TX, USA
e-mail: tye@livemail.uthscsa.edu
J. C. Cather (*)
Mindful Dermatology, Modern Dermatology and
Modern Research Associates, Dallas, TX, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_13
arthritis, a painful and potentially debilitating
inflammatory arthritis (6–42% depending on the
population studied) [4]. Psoriasis is also associated with a number of comorbidities including
obesity, cardiovascular disease, diabetes (Type
II), psychiatric disorders, and metabolic syndrome [5–7]. Individuals with psoriasis may also
be at risk for other inflammatory diseases, such as
Crohn’s disease and Hidradenitis Suppurativa [8,
9]. A variety of treatment options are available
and patients with moderate to severe psoriasis are
candidates for systemic therapy [10, 11]. A number of biologic agents have been approved for
psoriasis and additional molecules are currently
being studied in clinical trials [12]. Here we
review adalimumab (brand name Humira), a fully
human monoclonal IgG1 antibody that blocks
tumor necrosis factor alpha (TNF-a), a cytokine
elevated in inflammation [13]. Adalimumab binds
both soluble and membrane-bound TNF-a and
blocks TNF-a interactions at the p55 and p75 TNF
cell surface receptors with high affinity.
Adalimumab
Adalimumab was first approved in 2002 for rheumatoid arthritis. Today, it is approved for 10 indications which include ankylosing spondylitis,
Crohn’s disease, fingernail psoriasis, hidradenitis
suppurativa (HS), juvenile idiopathic arthritis,
plaque psoriasis, psoriatic arthritis, rheumatoid
153
C. B. Tye and J. C. Cather
154
arthritis, ulcerative colitis, and uveitis [14, 15].
Adalimumab is given by subcutaneous injection,
with dosing dependent on indication. Adalimumab
is available as a single-use prefilled pen
(40 mg/0.8 mL) or a single-use prefilled syringe
(40 mg/0.8 mL or 20 mg/0.4 mL). Recently, a
citrate free formulation was approved which provides for a better patient injection experience.
Adalimumab was the third TNF-inhibitor
approved for psoriatic arthritis and psoriasis and
other approved TNF-inhibitors for these indications include etanercept (brand name Enbrel),
infliximab (brand name Remicade), and certolizumab (brand name Cimzia). Golimumab (brand
name Simponi), is a TNF-inhibitor only approved
for psoriatic arthritis.
A number of guidelines of care for psoriasis
have been published, including American
Academy of Dermatology guidelines, [16–18]
German guidelines, [19, 20] Canadian guidelines, [21] European guidelines, [22, 23], Italian
guidelines, [24] and British guidelines [25].
Consensus statements have also explored monitoring and vaccinations with biologics [26] and
monitoring comorbidities, [27] while others have
examined psoriasis treatment in a case-based
manner [28, 29]. A chapter in this textbook is
dedicated to exploring the guidelines of care.
Here we provide an overview of adalimumab
in psoriasis and psoriatic arthritis, as well as in
comorbidities including fingernail psoriasis,
hidradenitis suppurativa, and include a very brief
mention of inflammatory bowel disease. We
review the pivotal phase III clinical trials for psoriasis, psoriatic arthritis, fingernail psoriasis, and
hidradenitis suppurativa, and ongoing safety and
monitoring considerations. We also provide
insight into treatment of special populations as
well as biologic comparator studies. Biosimilar
data is included elsewhere in this text.
Adalimumab in Clinical Trials
for Psoriasis and Psoriatic Arthritis
A number of clinical trials have been conducted
for psoriasis and psoriatic arthritis. REVEAL
(Randomized controlled evaluation of adalim-
umab every other week dosing in moderate to
severe psoriasis trial), CHAMPION (Comparative
study of adalimumab versus methotrexate versus
placebo in psoriasis patients), and ADEPT
(Adalimumab efficacy and safety in psoriatic
arthritis). Additionally, a number of biologic
comparator trials have been performed which we
will briefly describe; however, full details are
provided in separate chapters in this book.
REVEAL
The pivotal phase III psoriasis trial, REVEAL,
was a 52-week, prospective multicenter, randomized, double-blind placebo-controlled trial of
1212 moderate to severe psoriasis patients,
designed to examine efficacy, safety, and tolerability of adalimumab [13]. The criteria for enrollment was similar to many biologics trials, where
individuals were at least 18 years old, had been
diagnosed with moderate to severe psoriasis for
at least 6 months, and had stable psoriasis for at
least the past 2 months. Here, moderate to severe
psoriasis was defined as 10% or more body surface area affected, a psoriasis area severity index
(PASI) of 12 or greater, or a physician’s global
assessment (PGA) of at least moderate severity at
the baseline visit. Treatment washout periods
were required and similar to other biologic trials:
topical therapy (2 weeks), phototherapy (2 weeks
for UVB phototherapy and 4 weeks for PUVA),
systemic therapies (4 weeks), and biologic therapies (12 weeks, or 6 weeks for efalizumab). Low
to mid-potency topical corticosteroids were permitted on the palms, soles, face, and intertriginous areas. All potential participants were
screened for latent tuberculosis, and if latent disease was present, individuals could enroll as soon
as appropriate chemoprophylaxis for tuberculosis was started. Patients with a history of chronic
recurrent infections, demyelinating disease, cancer, or lymphoproliferative disease were
excluded.
The 52-week study trial design included 3 different treatment periods. During the first
16 weeks (Period A), patients were randomized
2:1, adalimumab to placebo. The adalimumab
13
Adalimumab for Psoriasis
group received 80 mg adalimumab at week 0 followed by 40 mg adalimumab at week 1 and then
40 mg every other week thereafter for 15 weeks,
while the other group received placebo. Period B
was defined as weeks 16–32 and at week 16,
patients in the placebo arm received 80 mg adalimumab, followed by 40 mg adalimumab every
other week beginning in week 17. Also, at week
16, all patients achieving a 75% or greater
response rate were entered into a 17-week open
label extension, receiving 40-mg adalimumab
every other week. Those who did not achieve
PASI 75 were entered into a different open label
extension, receiving 40 mg every other week.
Period C, weeks 33–52, was FDA mandated to
examine loss of adequate response in patients
who had achieved PASI 75 at weeks 16 and 33. In
Period C this set of PASI75 responders were re-­
randomized 1:1 to adalimumab or placebo. Time
to loss of response and retreatment data were
obtained with this patient population.
At week 16, the primary efficacy endpoint of
at least a 75% improvement in PASI score
(PASI75) was reported as 71% of patients in the
adalimumab group compared to 7% of placebo
using intent to treat (ITT) analysis. In ITT, those
lost to follow-up are considered non-responders
in the analysis. PASI 90 and PASI 100 were
achieved by 45% and 20%, respectively, in the
adalimumab group at 16 weeks, compared to
only 2% and 1% in the placebo group. At week
24, 70% of all patients had achieved PASI 75. At
week 33, the loss of adequate response phase was
initiated. Patients randomized to placebo lost
response more frequently (28% compared to 5%
in the adalimumab group), and the time to loss of
adequate response was shorter in the placebo
group.
At 33 weeks in the REVEAL study, patients
who maintained a PASI75 while randomized to
adalimumab treatment (n = 290) at the primary
endpoint were further randomized to treatment
with adalimumab (n = 250) or placebo (n = 240).
At the end of the secondary endpoint of 52 weeks,
68% of individuals randomized to the adalimumab treatment group maintained clear or minimal diseased based on PGA, as opposed to 28%
of individuals in the placebo group [13].
155
Additionally, when looking at PASI scores, 79%
of adalimumab treated patients achieved PASI75
at 52 weeks, 54% achieved PASI90, and 32%
achieved PASI100. In the control group, 43% of
individuals achieved PASI75, 18% achieved
PASI90, and 8% achieved PASI100.
The REVEAL trial had an open label extension (OLE) period that enabled participants to
receive adalimumab therapy for approximately
3 years [30]. For those who achieved PASI75,
efficacy was well maintained over the 3-year
period, using a last observation carried forward
(LOCF) analysis. A subanalysis examined consequences of when therapy was stopped and
restarted with adalimumab [30]. Efficacy was
slightly higher for those who received continuous adalimumab therapy compared to the
retreatment group (75% compared to 73% at
week 108 using LOCF). Retreatment response
was greatest in patients who had experienced
PASI50 or greater at the time retreatment was
started.
Additionally, individuals who were part of the
REVEAL clinical trial, along with 3 other clinical trials, who achieved PASI <75 by 16 weeks,
achieved PASI50 to PASI <75 by 33 weeks, and
lost response at the end of the trial were eligible
to enroll in a long term OLE study. Patients who
completed 52 weeks of REVEAL were also eligible for this study. During the REVEAL OLE
study, patients received adalimumab 40 mg twice
a month for at least 108 weeks, and their responses
were analyzed relative to the REVEAL baseline.
At the end of the REVEAL OLE study, 88% of
treated patients achieved a PASI75, 57% achieved
a PASI90, and 38% achieved PASI 100. Also,
71% of these treated patients achieved a PGA of
clear or minimal.
Adalimumab was well-tolerated in the
REVEAL trail. The majority of adverse effects
(AEs) were mild to moderate. Less than 2% of
patients discontinued use due to adverse events
and there were no deaths. Infections included
upper respiratory tract infections, nasopharyngitis, and sinusitis. Injection site reactions were
more common in the adalimumab group, occurring in 3.2% of the adalimumab group compared
to 1.8% of the placebo group. Serious adverse
C. B. Tye and J. C. Cather
156
events (SAEs) were comparable in both groups at
16 weeks.
Because 16 weeks is not sufficient for identifying AEs, a 3-year extension provides more
insight into potential safety concerns. During the
3-year open label extension, adalimumab was
well tolerated [30]. There were 2 cases of tuberculosis, 5 candidiasis infections, and 2 deaths
(coronary artery disease in a 75-year old man and
unknown cause of death in a 47-year old man).
There were no cases of lymphoma, lupus-like
syndrome, or demyelinating disorders during this
period. One of the limitations of the open label
extension is that individuals whose dose escalated to 40- mg every week were considered off
protocol, and LOCF prior to dose escalation was
used in the analysis, although they were still
receiving adalimumab.
In addition to the physical symptoms of psoriasis, psoriasis can also impact an individual’s
ability to work [31]. The effect of adalimumab on
work productivity was examined using the Work
Productivity and Activity Impairment (WPAI)
questionnaire during the REVEAL trial [32]. At
16 weeks, adalimumab decreased psoriasis
related work productivity and activity impairment, and improvements in WPAI were seen in
the adalimumab treated group compared to the
placebo group, 15.5% and 11.1%, respectively.
Individuals who were unemployed and had high
scores of total work productivity impairment and
total activity impairment also had measurably
more severe psoriasis. When psoriasis symptoms
worsened, patients described increases in pain,
increased WPAI scores, and greater impairment
in mental and physical component summaries,
respectively [33].
A number of subanalyses were also conducted
from the REVEAL trial. One analysis examined
if there were any differences in adalimumab efficacy or safety between different patient subgroups during the initial 16 weeks of the trial
[34]. While improvement in psoriasis was seen
consistently across most subgroups, decreased
response to adalimumab occurred in patients
with greater weight or body mass index. This was
most apparent in obese individuals (BMI ≥ 30),
where 65% achieved PASI75, compared to 75%
of overweight individuals (BMI ≥25 but <30),
and 79% of individuals with a normal BMI (BMI
18.5 < 25). There were no significant differences
in SAEs between adalimumab and placebo across
subgroups. Subgroups examined included age,
sex, race, baseline weight intervals, baseline
body mass index, disease duration, baseline
severity, prior treatments and comorbidities.
Another subanalysis explored the effects of
comorbidities (e.g. hypertension, psoriatic arthritis, hyperlipidemia, obesity, depression, arthritis,
diabetes mellitus, and cardiovascular disease) on
patient reported outcomes [35]. Comorbidities
were associated with greater impairment in
HRQoL and work productivity, measured by the
Dermatology Life Quality Index (DLQI), Short
Form 36 (SF-36) health survey, and WPAI questionnaire. There were consistent improvements in
DLQI, SF-36 physical component summary
score, SF-36 mental components summary score,
and WPAI in the group receiving adalimumab at
16 weeks. In an analysis of a phase II study,
patients receiving adalimumab also experienced
a reduction of symptoms of depression compared
to the placebo group, measured by the Zung Self-­
rating Depression score [36].
Champion
Another psoriasis trial of interest, CHAMPION,
was conducted in Europe and Canada and
included a comparator arm of methotrexate as
well as a traditional placebo arm [37]. Patient
inclusion criteria and washout periods were similar to the REVEAL trial (described in detail
above) except patients were required to be methotrexate and TNF-inhibitor naïve. CHAMPION
was a randomized, double blind, double dummy
placebo-controlled trial, and 217 patients were
randomized 2:2:1 to adalimumab (40 mg every
other week after an 80 mg loading dose), methotrexate (7.5–25 mg weekly), or placebo.
The primary endpoint was patients achieving
a 75% improvement in PASI score at 16 weeks.
At week 16, 79.6% of the adalimumab group
achieved PASI75, compared to 35.5% of the
methotrexate group and 18.9% of the placebo
13
Adalimumab for Psoriasis
group. In addition, 16.7% of the adalimumab
group, 7.3% of the methotrexate group, and 2%
of the placebo group achieved PASI100. This
study has been acknowledged for using the traditional systemic therapy methotrexate as an active
comparator. It has also been criticized, because
the methotrexate arm was conducted for such a
short time period, and a successful methotrexate
regimen typically takes a longer period of time
and has additional dose modifications.
Many patients reported adverse events,
including 73.8% of the adalimumab group,
80.9% of the methotrexate group and 79.2% of
the placebo group. Most adverse events were
mild. Some (5% or 15 patients) withdrew from
the study, and 8 of the withdrawals were for
adverse events, including 1 from the adalimumab group, 6 from the methotrexate group, and
one from the placebo group. Elevated liver
enzymes were more common in the methotrexate group compared to the adalimumab or placebo groups, 9.1%, 1.9%, and 7.5% respectively.
An additional analysis of the CHAMPION trial
examined adverse event free days during the
comparator arm of the trial [38]. Those in the
adalimumab group experienced more adverseevent free days (36.9 days) compared to those in
the methotrexate (8.3 days) or placebo (6.7)
groups over the 16-week period. While these
data are encouraging, a limitation is the short
duration of the comparator arm, allowing only
those adverse events occurring within the first
16 weeks to be captured.
An analysis of the week 16 efficacy scores of
adalimumab compared to methotrexate and placebo stratified by baseline body mass index has
been published. At week 16, normal weight
(<25 kg/m2), overweight (25 to <30 kg/m2), and
obese (> = 30 kg/m2) patients on adalimumab
had PASI75 responses of 85%, 85.7%, and 61.3%
compared to 43.4%, 29.3%, and 26.1% with
methotrexate and 28.6%, 16.7%, and 0% for placebo. Additionally, at week 16, the PASI90
results were 70%, 53.6%, and 35.5% with adalimumab; 26.7%, 7.3%, and 8.7% with methotrexate, and 9.5%, 16.7%, and 0% for placebo. The
greatest DLQI improvements were seen in the
adalimumab treatment arms [39].
157
ADEPT
Adalimumab has also been studied in psoriatic
arthritis. ADEPT was a phase III randomized,
double-blind, parallel-group, placebo controlled
trial examining adalimumab efficacy and safety
in psoriatic arthritis patients [40]. Like other psoriatic arthritis trials, patients who had moderately
to severely active psoriatic arthritis and a history
of inadequate response to non-steroidal anti-­
inflammatory drugs (NSAIDS) were eligible to
participate. Patients were stratified by methotrexate use and psoriasis skin involvement (≥ 3%
BSA or < 3%). Approximately half of patients
were taking methotrexate at baseline. Patients in
the adalimumab arm received 40 mg adalimumab
subcutaneously every other week for 48 weeks. If
improvement was not seen at week 12 (defined as
at least a 20% decrease in both swollen and tender joint counts on 2 consecutive visits), participants could receive corticosteroids or disease
modifying anti-rheumatic drugs (DMARDS).
Primary endpoints were the American College of
Rheumatology 20% improvement (ACR20)
response at week 12 and changes in modified
total Sharp score (mTSS) of structural damage at
week 24. In addition, HRQoL was measured in
all patients. For those patients who also had 3%
or more body surface area of psoriasis, skin
improvement was also measured.
At 12 weeks, 58% of the adalimumab group
achieved ACR20, compared to 14% of the placebo group. Patients in the adalimumab group
had a modified Psoriatic Arthritis Response
Criteria (PsARC) response rate of 62% at week
12, and 60% at week 24, compared to placebo
rates of 26% at week 12 and 23% at week 24.
Adalimumab also inhibited joint destruction,
as is seen with the TNF-inhibitors etanercept and
infliximab [41]. Radiographs were taken at baseline, 24, and 48 weeks. The mean change in
mTSS at 24 weeks was −0.1 for patient receiving
adalimumab compared to 0.9 for those receiving
placebo. At 48 weeks, patients on adalimumab
showed a mean change in mTSS of −0.2. Erosion
scores were examined, and there was improvement in those receiving adalimumab (mean
change 0) compared to placebo (mean change
158
0.6). When joint space narrowing scores were
examined, there was a mean change of −2 in the
adalimumab group compared to 0.4 in those
receiving placebo.
Skin symptoms also improved in those
patients who also had psoriasis. Improvements in
health-related quality of life, fatigue, and disability, measured using the DLQI, SF-36, Functional
Assessment of Chronic Illness Therapy - Fatigue
(FACIT-Fatigue) Scale and HAQ DI were also
seen [42]. HAQ DI scores improved significantly
in patients receiving adalimumab compared to
the control group. At 24 weeks, patients with psoriatic arthritis treated with adalimumab saw
improvement of their HAQ DI score to 0.4, as
opposed to a score of 0.9 in the placebo group. In
addition, patients treated with 40 mg of adalimumab every other week showed a reduction rate
in their HAQ DI burden of 47% and 49% respectively at 12 and 24 weeks, while those in the placebo group had rates of 1% and 3% during the
same time frame.
Regarding safety data from the ADEPT trial,
adverse events were similar between the adalimumab and placebo groups at 24 weeks [40]. There
were 12 serious adverse events, 7 in the adalimumab group and 5 in the placebo group. Treatment
was discontinued by 4 individuals because of
adverse events, 3 in the adalimumab group and
1 in the placebo group. Alanine aminotransferase
levels (ALT) were elevated more frequently in
patients in receiving adalimumab, and in most
cases ALT elevations were transient, resolving
without discontinuing adalimumab. Elevated
ALT levels were observed in individuals taking
concomitant methotrexate, isoniazid, or alcohol.
At the end of the 24-week trial, participants
could continue into a 24-week open-label extension [43]. Adalimumab was given 40 mg subcutaneously every other week after week 24 for
24 weeks. Radiographs were taken at week 48,
and safety data was collected. Many (n = 285)
enrolled in the open-label extension, including
138 from the adalimumab arm and 147 from the
placebo arm. ACR responses were maintained at
48 weeks. Those on continuous adalimumab
therapy had ACR20, ACR50, and ACR 0 rates of
48%, 24%, and 20%, respectively at week 48.
C. B. Tye and J. C. Cather
ACR scores were obtained using an ITT analysis
in the open label extension. Skin improvement
was also maintained at 48 weeks in the adalimumab group, with response rates of 67%, 58%,
46%, and 33% for PASI50, PASI75, PASI90, and
PASI100, respectively. In the group receiving
placebo until week 24, improvement was seen at
week 48, with response rates of 61%, 54%, 33%,
and 31% achieving PASI50, PASI75, PASI90,
and PASI100.
Improvements in disability measurements
were also maintained at 48 weeks. When considering joint progression, patients receiving adalimumab the entire time had a mean mTSS of −0.1
at week 24, and − 0.1 at week 48, indicating sustained control of progression. For those in the
placebo group until week 24 that then received
adalimumab until week 48, mTSS were 0.9 and
1.0, respectively, indicating potential halting of
progression at week 48. Improvements were also
seen in joint erosion scores and joint progression
scores through 48 weeks.
Adalimumab was well tolerated during weeks
24–48, with the most common adverse events
being upper respiratory tract infections, nasopharyngitis, and injection site reactions. One
serious infection was reported (gastroenteritis)
and 10 other SAEs were reported. Elevated serum
transaminase levels were also reported in 9
patients. During the first 48 weeks there were no
deaths and no reports of tuberculosis or granulomatous infections, demyelination, lymphoma or
carcinoma, new antinuclear antibody formation,
drug-induced lupus, or congestive heart failure.
2-year data has also been published from the
ADEPT trial, providing a better understanding of
efficacy and safety in patients with psoriatic
arthritis [42]. The open-label extension of the
ADEPT trial was continued for 120 weeks, and
data were available for 144 weeks after the beginning of the ADEPT trial. ACR20, ACR50, and
ACR70 scores at week 104 were 57.3%, 27.8%,
and 29.9% respectively. PsARC response rates
were 65.9% at week 48 and 63.5% at week 104.
All analyses used LOCF. Improvements in
HRQoL and disability were also maintained.
Inhibition of radiographic progression was also
seen throughout the 144 weeks.
13
Adalimumab for Psoriasis
From baseline to week 48, 87% of adalimumab treated patients had no progression, and
79% of patients had no radiographic progression
at week 144, as evaluated with mTSS. At week
24, the mean change from baseline of mTSS was
−0.1 for the adalimumab treated group compared
to 0.8 of the placebo group. The adalimumab
treated group also had mean changes of mTSS of
0.1 and 0.5 at 48 and 144 weeks respectively. A
subanalysis of the ADEPT trial examined risk
factors that predict radiographic progression
[44]. Elevated baseline C-reactive protein (CRP)
(> = 1.0 mg/dl: odds ratio = 3.28) was a strong
independent risk factor for joint progression, and
treatment with adalimumab reduced the risk of
progression five-fold. Individuals taking adalimumab also experienced lowering of CRP levels
compared to controls.
Over the 2 years, adalimumab was well tolerated, and adverse events were similar to what is
expected in rheumatoid arthritis patients.
Throughout 2 years of exposure, there were 5
opportunistic infections, 1 patient had peritoneal
tuberculosis and 4 patients experienced oral candidiasis. Additionally, there was one case of non-­
Hodgkin’s B-cell lymphoma, 2 basal cell
carcinomas, and 1 neuroendocrine carcinoma of
the skin. There were no reports of central nervous
system demyelinating disease, lupus-like syndrome, congestive heart failure, or adalimumab-­
related allergic reactions.
Adalimumab for Special
Populations
Most clinical trials are conducted in adults, and
there is limited data about TNF-inhibitor use in
women of childbearing potential during pregnancy, in children, in the elderly, and in rare situations. Use of adalimumab in these special
populations is reviewed below.
Pregnancy and Lactation
Pregnancy can affect the severity of psoriasis, as
one-third of women experience improvement,
159
one-third experience worsening of disease, and
the remaining third see no change in their psoriasis [45]. Experts recommend using adalimumab with caution during pregnancy [46]. The
benefit/risk ratio is acceptable in first and second trimester for moderate to severe plaque
patients and must be re-evaluated in the third
trimester. Infants exposed to adalimumab in
utero should avoid live vaccines for 6 months.
Women who become pregnant while on adalimumab, or any biologic, are encouraged to enroll
in a pregnancy registry. Additionally, TNFinhibitors are not typically used during lactation
[47]. Interestingly, adalimumab has been studied during in vitro fertilization (IVF). Women
with lower levels of TNF-a had better success
rates with IVF, and there were no increases in
birth defects due to adalimumab treatment,
although the study was small (100 pregnant
women, 136 babies) [48, 49].
Pediatric
Psoriasis in children can be challenging to treat,
as few treatments have been studied in children.
Etanercept has been studied in a pediatric psoriasis population and is reviewed in this textbook
[50]. Adalimumab is approved in Europe for
pediatric psoriasis in ages 4 and older; however,
in the US, it is only approved for four pediatric
indications (Crohn’s Disease, Hidradenitis
Suppurativa, Uveitis and Juvenile Idiopathic
Arthritis) [15, 51]. A phase 3 double-blind, multiperiod trial was performed to evaluate the safety
and efficacy of adalimumab compared to weekly
methotrexate in children aged 4 up to 18 years of
age with severe psoriasis unresponsive to topical
therapies. Children received adalimumab based
on their weight with significant improvement in
PASI75 [52]. A real-life retrospective multicenter
analysis of children treated with adalimumab
over a 52-week period found that at week 16,
29.6% of patients achieved a PASI90, 55.5%
achieved a PASI75. Results were sustained over
24 weeks and did not differ between biologic
naïve and biologic exposed patients. No serious
infections were observed [53].
160
Elderly
C. B. Tye and J. C. Cather
Geriatric psoriasis patients pose additional management challenges. In the elderly, adalimumab
can be used as a first line therapy in patients with
more extensive disease [54]. It is important that
elderly patients are properly monitored, due to
the higher general incidence of comorbidities
which include cardiovascular disease, metabolic
syndrome, nonalcoholic fatty liver disease, infections and malignancies. Lymphoma rates in
patients with psoriasis 65 years of age or older
appear to be 3x higher than in age matched controls without psoriasis [55]. Additionally,
­nonmelanoma skin cancers are more common in
this demographic so skin cancer screening is
important.
The main endpoint for the study was the number of patients achieving a PGA-F score of ≤1
with a ≥ 2 grade improvement from their baseline [56]. Another secondary endpoint was the
amount of patients achieving a mNAPSI 75 [56].
Also, beginning at week 16, patients whose baseline BSA increased ≥25 were taken out of the
study to an escape period [56]. At 26 weeks in the
trial, patients’ mNAPSI and PGA-F scores were
evaluated. The study found that 49% of patients
receiving adalimumab achieved a PGA-F score
of clear or minimal, as compared to 7% of the
placebo group. 47% of adalimumab patients also
achieved a mNAPSI75 compared to only 3% of
the placebo group [15, 57]. A decrease in nail
pain in adalimumab treated patients was also
demonstrated in this study [15].
Fingernail Psoriasis
Hidradenitis Suppurativa
Adalimumab was studied for its effectiveness
in treating fingernail psoriasis using a phase 3,
multicenter, double-blinded, randomized,
placebo-­controlled trial with parallel-arm. To
be eligible for the study, patients must have had
moderate or worse severity plaque psoriasis,
ranked on the PGA scale, as well as moderate
or worse severity fingernail psoriasis, which
was graded on a 5-point Physician’s Global
Assessment of Fingernail Psoriasis (PGA-F)
scale. Eligible patients also had to have a
Modified Nail Psoriasis Severity Index
(mNAPSI), a scale that judges patients’ fingernail psoriasis based on the presence and severity of pitting, onycholysis, oil-drop dyschromia,
splinter hemorrhages, and hyperkeratosis, ≥8
with a BSA involvement of ≥10%, or else have
a mNAPSI of ≥20 with a BSA involvement of
≥5% [56].
During the trial, 217 patients were randomized to receive either adalimumab (n = 109) or
to a placebo group (n = 108). At week 0, patients
in the adalimumab group were given a loading
dose of 80 mg adalimumab, and then from week
1 on all patients in this group received 40 mg of
adalimumab subcutaneously every other week
[15, 56].
Hidradenitis Suppurativa is a chronic inflammatory disease characterized by recurrent, painful
sinus tracts, abscesses, and nodules [58]. Similar
to chronic psoriasis, HS is associated with
increased levels of inflammatory cytokines,
including TNF alpha [59], a delay in diagnosis,
and significant psychological and physiological
comorbidities [60]. Individuals with psoriasis
have also been shown to be more likely to also be
affected with HS [8].
Adalimumab has been studied for HS in the
PIONEER 1 and 2 studies which were the first
completed Phase 3 trials for HS [15, 61]. Briefly,
the induction dosing for patients with HS is the
same as inflammatory bowel disease patients and
the maintenance dosing, which starts on day 29,
is a weekly 40 mg subcutaneous injection.
Adalimumab is the only FDA approved therapy
for HS. The safety profile of adalimumab in the
PIONEER trials were consistent with other trials
[15, 61].
Generalized Pustular Psoriasis
In Japan, an open-label 52-week study examined
the safety and efficacy of adalimumab in 10
13
Adalimumab for Psoriasis
patients with generalized pustular psoriasis.
Induction was similar to current psoriasis dosing;
however, if needed the patients could increase to
80 mg every other week. Seven of the patients
(including 3 who dose escalated to 80 mg)
achieved clinical response at week 16 and 5
achieved clinical response at week 52 [62].
Inflammatory Bowel Disease (IBD)
Psoriasis and inflammatory bowel disease, especially Chron’s disease share several epidemiologic factors, genetic similarities, and
inflammatory cytokine profiles [63–65]. A
­retrospective US claims based study involving
5492 pairs of patients with moderate to severe
psoriasis and their age, gender, and geographic
based matched controls found that psoriasis
patients had approximately 3.5 fold increase
prevalence of IBD [66]. Additionally, a prospective study of women in the Nurses’ Health Study
1 and 2 (n = 174,476) evaluated the incidence of
psoriasis and IBD. There were 2752 women in
these two studies and in a pooled analysis the
women were found to have a four-fold increase in
Crohn’s disease but no increase incidence of
ulcerative colitis [67]. Patients with severe psoriasis and psoriatic arthritis have the highest risk
for Crohn’s disease and ulcerative colitis [68].
There are no known trials dedicated to the treatment of psoriasis patients who have concomitant
IBD. However, both adalimumab and infliximab
have demonstrated efficacy in psoriasis, psoriatic
arthritis, Crohn’s disease and ulcerative colitis
[69].
Hemodialysis
A case report involving a patient with psoriasis
being treated with infliximab required transition
to adalimumab due to pulmonary edema thought
secondary to intravenous fluids at time of infliximab infusion [70].
161
Biologic Comparator Trials
Briefly, we will discuss some of the important
plaque psoriasis trials in which a newer biologic
has been compared to adalimumab. More complete details of these trials can be found in the
chapters that focus on the comparator drug.
1. Guselkumab
Voyage 1 and 2 Trials compared the safety
and efficacy of guselkumab (an anti-IL23
monoclonal antibody) to adalimumab.
Additionally, data on withdrawal, retreatment,
adalimumab non-responders treated with
guselkumab, and maintenance data out to 1
year was obtained. Guselkumab demonstrated
superior efficacy compared to adalimumab
[71, 72]. A secondary analysis of the trial
results has been published for the difficult to
treat body regions, such as scalp, hands, feet,
and nails. Guselkumab was not superior to
adalimumab when looking at efficacy in nails;
however, it was superior for other difficult to
treat areas examined [73].
2. Ixekizumab
Two trials evaluated the efficacy of ixekizumab versus adalimumab for the treatment
of psoriatic arthritis: SPIRIT-P1 and SPIRIT-­
H2H. Full details are described in the
Ixekizumab chapter in this text.
In the SPIRIT-P1 trial, adult biologic naïve
patients with psoriatic arthritis achieved comparable ACR results at week 24 with ixekizumab or adalimumab. There was no added
value when methotrexate was used in combination with ixekizumab; however, adalimumab patients did better on combination
therapy [74].
SPIRIT-H2H directly compared ixekizumab and adalimumab with endpoint measures of ACR50 and PASI100 at week 24.
Again, ixekizumab scores for ACR50 and
PASI100 were not improved with concurrent
methotrexate use. However, adalimumab
again demonstrated improved efficacy in
C. B. Tye and J. C. Cather
162
these measures when combined with methotrexate [75].
3. Risankizumab
IMMvent, a phase 3, randomized, double-­
blind, active-comparator-controlled trial
investigated adalimumab vs risankizumab for
the treatement of moderate-severe plaque psoriasis [76]. Risankizumab showed significantly greater efficacy in providing skin
clearance compared to adalimumab.
Practical Considerations
for TNF-Inhibitors
There are a number of safety and practical considerations for all TNF-inhibitors, including adalimumab [10]. TNF-inhibitors are contraindicated in
patients with active, serious infections. Testing for
tuberculosis should be performed on all patients
who will be treated with ­
TNF-­
inhibitors. The
Centers for Disease Control (CDC) has released
guidelines regarding testing for tuberculosis [77].
Additionally, live vaccines should not be used in
patients receiving TNF-­inhibitors. Demyelinating
events, new onset or exacerbation of symptoms,
may also occur under TNF-blockade. Anti-TNF
therapy should not be used in patients with a history of demyelinating disease (e.g. multiple sclerosis, optic neuritis, and peripheral demyelinating
disease such as Guillain-Barre syndrome). Caution
should be used in patients with congestive heart
failure. Patients should also be screened for hepatitis B prior to receiving therapy, as TNF-blockers
may reactivate hepatitis B in patients who are carriers of the disease. Many individuals experience
injection site reactions, although most are minor
and the citrate free formula has improved patients’
injection experience. Malignancies, hepatotoxicity, and new onset psoriasis with anti-TNF therapy
are also considerations.
Prior to initiating systemic therapy, including
adalimumab, a physical examination should be
performed and a full medical history taken. It is
important to ask about age appropriate cancer
screening (pap smears, mammograms and colonoscopies), cancer history, infection history, vac-
cination history, as well as personal or family
history of inflammatory bowel disease history
and arthritis. A total body skin examination
should also be performed. Clinicians should also
inquire about social and lifestyle history, and
family planning if relevant. A number of labs can
also be requested, including a complete blood
count (CBC) and comprehensive metabolic panel
(CMP), Hepatitis screen (B and C), a human
immunodeficiency virus (HIV) screen if warranted, and a tuberculosis test upon initiation and
yearly. Once systemic therapy is initiated, monitoring patients on therapy is vital. Patients should
have periodic total body skin examinations as
well as a yearly evaluation for tuberculosis [10].
Safety Update
Leonardi et al. analyzed the long-term safety of
adalimumab from 18 clinical trials involving
3727 adults with plaque psoriasis. The cumulative exposure was 5429.7 patient years. The
adverse events remained stable with no new
safety signals [78].
In a recent review of safety registries involving adults with psoriasis, Strober et al. found that
across multiple registries the adalimumab safety
data was consistent with the long-term safety
data reported from the clinical trial experience
[79].
An analysis explored adalimumab safety in
23,457 participants across 71 global trials, rheumatoid arthritis (36 trials, n = 14,109), juvenile
idiopathic arthritis (3 trials, n = 212) ankylosing
spondylitis (4 trials, n = 1684), psoriatic arthritis
(4 trials, n = 837), psoriasis (13 trials, n = 3010),
and Crohn’s disease (11 trials, n = 3606) [80].
This analysis represented 12 years of adalimumab exposure, with 52.5% and 48.7% of
patients receiving concomitant immunosuppressant agents or concomitant systemic steroids,
respectively. The majority of patients (60%) were
rheumatoid arthritis patients, and approximately
two-thirds received concomitant therapy. The
most frequently reported serious adverse events
were infections, and these were most often seen
13
Adalimumab for Psoriasis
in the rheumatoid arthritis and Crohn’s disease
trials. Malignancy rates were as expected in
adalimumab-treated patients compared with the
general population. There was an increase in
lymphoma incidence in patients with rheumatoid
arthritis, but this increase was in the expected
range of rheumatoid arthritis patients not on anti-­
TNF-­therapy. Non-melanoma skin cancer rates
were elevated in rheumatoid arthritis patients,
psoriasis patients, and Crohn’s disease patients.
While there may be some distinct differences in
patient populations, no new safety signals were
revealed.
lack Box Warnings: Infection
B
and Malignancy
A series of warnings are detailed on the prescribing information of adalimumab, including black
box warnings for serious infections and malignancies [81]. Patients taking adalimumab are at
increased risk of serious infection, and many who
developed serious infections while taking adalimumab were also taking concomitant immunosuppressants
(e.g.
methotrexate
or
corticosteroids). Tuberculosis is a concern,
including active tuberculosis and reactivation of
latent tuberculosis. All patients should be
screened for latent tuberculosis prior to initiating
therapy. If latent tuberculosis is present, anti-TB
therapy should be initiated prior to beginning
adalimumab or any TNF-inhibitor. Because anti­TB therapy can increase liver function tests, and
in rare cases adalimumab can too, we wait a
month after beginning anti-TB therapy before
starting adalimumab. Compliance with tuberculosis prophylaxis is key. Consultation with an
infectious disease clinician for managing patients
with latent tuberculosis is recommended. Invasive
fungal infections (e.g. histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis) and opportunistic
bacterial (e.g. legionella, listeria) or viral infections have been reported. Patients presenting
with a serious infection should discontinue
adalimumab.
163
In the controlled portions of adalimumab trials across all indications, adalimumab treated
patients had a rate of serious infections of 4.3 per
100 patient years (n = 7973) compared to a rate of
2.9 per 100 patient years in placebo-treated
patients (n = 4848) [15]. These same trials
showed a reported active TB rate of 0.2 per 100
patient years. The rate of positive purified protein
derivative conversion in this same study was 0.09
per 100 patient years [15]. Through 16 weeks of
the REVEAL RCT trial, a rate of serious infections of 2.8% was observed in adalimumab
treated patients (n = 814) vs. a rate of 3.3% in the
placebo group (n = 398). From weeks 33–52, the
rates of infection among adalimumab treated
patients and the placebo group were 1.1%
(n = 250) and 2.4% (n = 240) respectively [13].
Tuberculosis rates for this study were 0.0% for
both groups at the 16-week mark, and 0.0% and
1.2% for the adalimumab and placebo treated
groups, respectively, from 33–52 weeks [13]. In
30 psoriasis clinical trials, there was a rate of
serious infection of 1.37% across 1403 adalimumab patients, as well as a rate of active tuberculosis of 0.18% [82]. The ESPIRIT rate of serious
infection per 100 patient years was 1.0 (n = 6045)
and the rate of active tuberculosis was <0.1 [83].
Malignancies have been reported in patients
taking TNF-inhibitors, including hepatosplenic
T-cell lymphoma (HSTCL), a rare and usually
fatal T-cell lymphoma almost exclusively
reported in adalimumab-treated males with
Crohn’s disease taking concomitant azathioprine
or 6-mercaptopurine. In the controlled phase of
adalimumab trials across all indications, an equal
number of malignancies, including lymphomas,
were seen in the adalimumab group compared to
the control group. These trials showed 0.7 malignancies per 100 patient years among 7973 adalimumab treated patients and 4848 placebo treated
patients. Lymphoma rates in these trials were
0.11 per 100 patient years [15]. In the REVEAL
RCT, both adalimumab and placebo treated
patients showed similar incidences of malignancies, with an incidence of 0.8 through 16 weeks
and 0.0 from weeks 33–52. No lymphoma was
seen in this RCT [13]. The ESPIRIT 8-year post
C. B. Tye and J. C. Cather
164
marketing malignancy incidence was 1.1 in adalimumab treated patients (n = 6405) and the lymphoma rate was <0.1 [83]. A publication
evaluating 13 adalimumab clinical trials for treatment of moderate to severe plaque psoriasis with
treatment for up to 5 years did not show cumulative toxicity and adverse event rates were stable
or decreased over time [82].
There was an increased rate of non-melanoma
skin cancer in adalimumab trials and it was more
prevalent in those patients with previous immunosuppressant therapy and psoriasis patients previously treated with PUVA. When considering
lymphoma, more cases of lymphoma were
observed in the TNF-blocker patients compared
to controls. In adalimumab trials, 3 lymphomas
occurred in 6693 adalimumab treated patients
compared to 1 in 3749 patients in the control
group, across 32 global trials. In 45 trials, the rate
of lymphoma was 0.11 per 100 patient years,
approximately three-fold higher than that of the
general population. Patients with chronic inflammatory disease states such as rheumatoid arthritis, psoriasis, psoriatic arthritis, hidradenitis and
inflammatory bowel disease may be at a higher
risk for lymphomas than the general population,
even in the absence of therapies. In fact, several
studies have suggested that there is no increased
risk for lymphoma when using TNF inhibitors to
treat these disease states [84–87]. More data is
needed at this time as post-marketing cases of
acute and chronic leukemia have also been
observed. Most patients who developed malignancies were also receiving concomitant
immunosuppressants.
It has been challenging to determine the relationship between infection and malignancy and
TNF-inhibitors. A meta-analysis examined 20
randomized, placebo-controlled psoriasis trials
of TNF-inhibitors, etanercept, infliximab, adalimumab, golimumab and certolizumab, with 6810
patients total [88]. There was a small increased
risk of infection (odds ratio 1.18) but no increased
risk of serious infection (odds ratio 0.7). There
was an increased risk of malignancy in the TNF-­
inhibitor group compared to the control group
(odds ratio 1.48 for all malignancies and 1.26
when nonmelanoma skin cancer was excluded).
Post-Marketing Safety Information
A number of additional safety signals have been
observed in post-marketing surveillance of adalimumab [81]. Hypersensitivity reactions may
occur, and anaphylaxis or angioneurotic edema
may be rare events. Allergic reactions were seen
in ~1% of patients taking adalimumab. There
have also been rare reports of hematologic reactions, including cytopenia, with TNF-therapy.
Adalimumab treatment may result in autoantibody formation, and in rare cases, the development of a lupus-like syndrome [89]. Demyelinating
disease [90], reactivation of hepatitis B infections,
and worsening of congestive heart failure have
been reported, underscoring the importance of
appropriate screening. Elevations in liver enzymes
were also reported. TNF-inhibitors are acceptable
for patients with Hepatitis B and C as long as
appropriate monitoring and/or antiviral therapy is
in place with hepatology and/or infectious disease
consultation [91, 92].
A number of adverse events have also been
reported in post-marketing surveillance [81].
These include gastrointestinal disorders (diverticulitis, large bowel perforations including perforations associated with diverticulitis and
appendiceal perforations associated with appendicitis, pancreatitis, ulcerative colitis [93], liver
failure, sarcoidosis, nervous system disorders
(demyelinating disorders and cerebrovascular
accident), respiratory disorders (interstitial lung
disease, including pulmonary fibrosis, pulmonary embolism), skin reactions (Stevens Johnson
Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types
including pustular and palmoplantar) [94, 95],
alopecia [96], and vascular disorders (systemic
vasculitis and deep vein thrombosis).
Adalimumab Pearls
1. Dose adjustments may be required.
There are 10 different indications for adalimumab and multiple different dosing regimens. Ryan et al. evaluated in patients with
psoriasis or hidradenitis the safety of weekly
13
Adalimumab for Psoriasis
versus every other week dosing and found
similar adverse event rates [97]. Additionally,
optimizing therapy with temporary dose escalation followed by de-escalation permitted the
achievement of long-term disease control in
patients treated out to 252 weeks [98]. Dose
escalation was not associated with additional
safety concerns. Individualization of therapy
with adalimumab has been attempted by evaluating serum trough levels in 51 patients over
time. Excellent responses were seen with
serum trough levels at 6.46 micrograms per
mL [99].
2. Adalimumab is the market leader for the
treatment of psoriasis with concomitant psoriatic arthritis but newer agents are also
effective.
Historically, TNF-inhibitors have been the
treatment of choice for individuals with both
psoriasis and psoriatic arthritis [4]. An indirect comparison using individual patient data
from randomized clinical trials involving
adalimumab (REVEAL and CHAMPION) as
well as trials comparing etanercept to placebo
found adalimumab significantly outperformed
etanercept in PASI, DLQI, Patient global
assessment, symptom and lesion resolution,
and adverse event [100].
TNF-inhibitors show synergy with methotrexate, and patients with higher BMIs tend to
do better on the monoclonal TNF inhibitors,
including adalimumab [101, 102].
Rotation within the TNF-inhibitor class is
possible, but there may be diminishing returns
after trying two different TNF- inhibitors. A
number of small studies have examined rotation within the TNF-inhibitor class. In one
study, 30 patients who failed etanercept were
transitioned to adalimumab [103]. Efficacy
was examined at weeks 12, 24, and 48, and
27%, 36%, and 54% achieved PASI75.
Adalimumab was well tolerated, and there
was no increase in adverse events for patients
receiving adalimumab who had previously
received etanercept. Another study examined
14 patients with inadequate responses to etanercept who were transitioned to adalimumab
[104]. At 16 weeks, 9/14 (64%) achieved
165
PASI 50, (of these 4 achieved PASI 75 and 1
achieved PASI 90). No serious adverse events
were reported.
A sub-analysis of BELIEVE was also conducted to examine efficacy of adalimumab in
patients treated previously with anti-TNF
agents [105]. BELIEVE was a double-blind,
randomized, controlled trial where patients
received 80 mg at week 0 and 40 mg every
other week of adalimumab with topical vehicle or topical calcipotriol/betamethasone
dipropionate once daily for 4 weeks and then
as needed [106]. The trial enrolled 703
patients, with 38.6% having prior anti-TNF
therapy compared to 61.4% who were naïve
to anti-TNF therapy. Nearly two-thirds
(61.7%) of patients with prior anti-TNF therapy achieved PASI 75 at week 16 compared to
71.17% of anti-TNF naïve patients.
Adalimumab was well tolerated, and adverse
events were similar between those with previous anti-TNF therapy and those without.
Another open-label phase IIIb trial, PRIDE
(an open-label access program to evaluate the
safety and effectiveness of adalimumab when
added to inadequate therapy for the treatment
of psoriasis), was conducted in Canada, and
examined adalimumab response in patients
who had not responded previously to other
psoriasis therapies [107]. The trial enrolled
203 patients in the 24-week trial. Patients
received 80 mg loading dose at week 0 and
40 mg every other week beginning at week 1,
for 23 weeks. At week 16, 70.9% achieved
PASI 75. Adalimumab was generally well tolerated with 9 patients reporting serious
adverse events.
As more experience and data is accumulated with the IL-17 inhibitors, there will be
erosion of the TNF-inhibitor market share
since they also address both psoriasis and psoriatic arthritis. Biomarkers are being evaluated as predictors for response to both
TNF-inhibitors and IL-17 antagonists [108,
109].
3. Adalimumab is my treatment of choice for
psoriasis patients or psoriatic arthritis patients
with hidradenitis suppurativa
166
Case series report success using adalimumab
for patients with psoriasis and concomitant
HS [110]. Remember, HS requires a much
higher dose of adalimumab so even if HS is
mild and psoriasis is the major reason for
therapy, consider the dosing regimen for HS
to ensure adequate disease control for both
diseases.
4. Adalimumab is my treatment of choice for
psoriasis and or psoriatic arthritis patients
with concomitant inflammatory bowel
disease
As described above, TNF-inhibitors are the
treatment of choice for patients with psoriasis
and concomitant psoriatic arthritis and inflammatory bowel disease.
5. Pediatric data is available for plaque psoriasis
and adalimumab is approved in the EU; however, it is not approved for psoriasis in the US
at this time.
6. Clinic experience with biologics are different
than clinical trial experience.
As with all psoriasis therapies, it is important to understand real-world patient experiences. A real-world drug survival
meta-analysis has been published (cut off for
study inclusion was Oct 2017). Thirty-seven
studies with 32,631 subjects were included
and drug survival for all biologics decreased
over time dropping from 66% at year 1 to
41% at year 4 for etanercept, from 69% to
47% for adalimumab, from 61% to 42% for
infliximab and from 82% to 56% for
ustekinumab [111]. A recent study examined
patient reported reasons for discontinuing
treatment [112]. Patients (n = 1095) with
moderate to severe psoriasis who received
systemic treatment were interviewed. Of
these, 200 patients received adalimumab in
the past and were asked why they discontinued it. The top three reasons for discontinuing
adalimumab were because it did not work
well enough (34%), worked well at first but
stopped working well (22%), or non-lifethreatening side effects (14.5%).
C. B. Tye and J. C. Cather
Complications of Not Treating
Psoriasis
The majority of moderate to severe psoriasis
patients are not being treated as suggested by
guidelines. A National Psoriasis Foundation survey showed that nearly 40% of patients surveyed
were not in treatment for their psoriasis [113]. Of
those who were in treatment, 57% of patients
with severe psoriasis were on topical therapy
alone, and only 3% of these patients had ever
tried phototherapy, a systemic therapy, or a biologic. In a chart review of dermatologists treating
10 or more psoriasis patients per month, 40% of
patients with severe disease received topical therapy alone [114]. Additionally, individuals with
psoriatic arthritis are also undertreated, with 59%
of patients diagnosed receiving no medication,
biologic or topical, for their psoriatic arthritis
[115].
There are complications of not treating psoriasis. Extensive psoriasis leaves an unresolved
inflammatory burden in skin. In addition, there is
an elevated systemic inflammatory burden that
impacts comorbidities. New data suggests that
treatment with TNF-inhibitors can reduce the
risk of myocardial infarction [116]. Gkalpakiotis
et al. have reported the results of their pilot study
looking at the beneficial effects adalimumab has
on biomarkers connected to cardiovascular disease [117]. A decrease in both E-Selectin and
IL-22 were seen after 3 months on adalimumab—
both are linked with cardiovascular disease and
more studies are needed to elucidate the importance of this affect.
In addition to physical complications, there
are also psychosocial implications. Untreated or
inadequately controlled psoriasis can impact
quality of life and physical functioning. Finally,
untreated psoriasis may have an economic impact
through time lost from work and reduced productivity while at work. There are a number of appropriate treatments for individuals with moderate to
severe psoriasis. Adalimumab is one of these
treatments and is a viable option for some.
13
Adalimumab for Psoriasis
Conclusion
Adalimumab, a member of the anti-TNF class of
biologics, is an appropriate treatment for individuals with psoriasis, with or without psoriatic
arthritis. Patients with psoriasis who have hidradenitis suppurativa or inflammatory bowel disease
can address all diseases with one medication.
Numerous clinical trials (e.g. REVEAL,
CHAMPION, ADEPT, SPIRIT-P1 and others)
have shown adalimumab to be efficacious and
well tolerated with a safety profile similar to others in the class. Adalimumab treatment also
improved HRQoL. As with all immunosuppressive therapies, appropriate screening and monitoring of patients on adalimumab is required.
Adalimumab is an important option within the
psoriasis treatment armamentarium.
References
1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J
Med. 2009;361(5):496–509.
2. Stern RS, Nijsten T, Feldman SR, Margolis DJ,
Rolstad T. Psoriasis is common, carries a substantial
burden even when not extensive, and is associated
with widespread treatment dissatisfaction. J Investig
Dermatol Symp Proc. 2004;9(2):136–9.
3. Capon F, Burden AD, Trembath RC, Barker
JN. Psoriasis and other complex trait dermatoses:
from loci to functional pathways. J Invest Dermatol.
2012;132(3 Pt 2):915–22.
4. Gottlieb A, Korman NJ, Gordon KB, Feldman SR,
Lebwohl M, Koo JY, et al. Guidelines of care for the
management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of
care for treatment with an emphasis on the biologics.
J Am Acad Dermatol. 2008;58(5):851–64.
5. Davidovici BB, Sattar N, Prinz J, Puig L, Emery P,
Barker JN, et al. Psoriasis and systemic inflammatory diseases: potential mechanistic links between
skin disease and co-morbid conditions. J Invest
Dermatol. 2010;130(7):1785–96.
6. Gelfand JM, Neimann AL, Shin DB, Wang
X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA.
2006;296(14):1735–41.
7. Neimann AL, Shin DB, Wang X, Margolis DJ,
Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad
Dermatol. 2006;55(5):829–35.
167
8. Kridin K, Shani M, Schonmann Y, Fisher S, Shalom
G, Comaneshter D, et al. Psoriasis and Hidradenitis
Suppurativa: A Large-scale Population-based Study.
J Am Acad Dermatol. 2018.
9. Najarian DJ, Gottlieb AB. Connections between
psoriasis and Crohn’s disease. J Am Acad Dermatol.
2003;48(6):805–21. quiz 22-4
10. Menter A, Gottlieb A, Feldman SR, Van Voorhees
AS, Leonardi CL, Gordon KB, et al. Guidelines
of care for the management of psoriasis and
psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of
psoriasis with biologics. J Am Acad Dermatol.
2008;58(5):826–50.
11. Pariser DM, Bagel J, Gelfand JM, Korman NJ,
Ritchlin CT, Strober BE, et al. National Psoriasis
Foundation clinical consensus on disease severity.
Arch Dermatol. 2007;143(2):239–42.
12. Johnson-Huang LM, Lowes MA, Krueger
JG. Putting together the psoriasis puzzle: an update
on developing targeted therapies. Dis Model Mech.
2012;5(4):423–33.
13. Menter A, Tyring SK, Gordon K, Kimball AB,
Leonardi CL, Langley RG, et al. Adalimumab
therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol.
2008;58(1):106–15.
14. Miller I, Lynggaard CD, Lophaven S, Zachariae C,
Dufour DN, Jemec GB. A double-blind placebo-­
controlled randomized trial of adalimumab in the
treatment of hidradenitis suppurativa. Br J Dermatol.
2011;165(2):391–8.
15. AbbVie Inc. (North Chicago I. HUMIRA Injection
Package Insert.
16. Coates LC, Kavanaugh A, Mease PJ, Soriano ER,
Laura Acosta-Felquer M, Armstrong AW, et al.
Group for Research and Assessment of psoriasis
and psoriatic arthritis 2015 treatment recommendations for psoriatic arthritis. Arthritis Rheumatol.
2016;68(5):1060–71.
17. Elmets CA, Leonardi CL, Davis DMR, Gelfand
JM, Lichten J, Mehta NN, et al. Joint AADNPF guidelines of care for the management and
treatment of psoriasis with awareness and attention to comorbidities. J Am Acad Dermatol.
2019;80(4):1073–113.
18. Menter A, Strober BE, Kaplan DH, Kivelevitch D,
Prater EF, Stoff B, et al. Joint AAD-NPF guidelines of care for the management and treatment
of psoriasis with biologics. J Am Acad Dermatol.
2019;80(4):1029–72.
19. Nast A, Kopp I, Augustin M, Banditt KB,
Boehncke WH, Follmann M, et al. German
evidence-­based guidelines for the treatment of psoriasis vulgaris (short version). Arch Dermatol Res.
2007;299(3):111–38.
20. Nast A, Kopp IB, Augustin M, Banditt KB, Boehncke
WH, Follmann M, et al. Evidence-based (S3) guide-
Infliximab, Golimumab,
and Certolizumab Pegol
14
Jacob A. Mojeski and Robert E. Kalb
Abstract
Psoriasis and psoriatic arthritis are common
chronic inflammatory disorders that cause
substantial physical, financial, and psychosocial burdens for patients. Biologic therapy for
these diseases has led to a major improvement
in the therapeutic armamentarium, and subsequently, patient quality of life. The tumor
necrosis factor alpha (TNFα) blocking class is
one family of biologic therapy that has provided significant relief for patients. Infliximab
was the first TNFα inhibitor approved for use
in the United States in 1998 while golimumab
and certolizumab pegol are more recent additions. With over 20 years of clinical experience using TNFα inhibitors, physicians may
employ these agents in a manner that maximizes efficacy while decreasing risks of
potential side effects. This chapter will provide a comprehensive review of the published
data on the safety and efficacy of infliximab,
golimumab, and certolizumab.
J. A. Mojeski · R. E. Kalb (*)
Department of Dermatology, School of Medicine
and Biomedical Sciences, State University at of
New York at Buffalo, Buffalo, NY, USA
e-mail: jacobmoj@buffalo.edu; kalb@buffalo.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_14
Key Learning Objectives
1. To understand the mechanism of action
of Infliximab, Golimumab, and
Certolizumab Pegol
2. To understand the appropriate use and
efficacy of the Infliximab, Golimumab,
and Certolizumab Pegol
3. To understand the safety issues of
Infliximab,
Golimumab,
and
Certolizumab Pegol
Introduction
The treatment of psoriasis and psoriatic arthritis
has undergone a revolution with the advent of
biologic therapy providing patients with more
treatment choices and greater hope for sustained
symptomatic relief [1, 2]. Infliximab, golimumab
and certolizumab are all part of the Anti-TNF
class of drugs. Although these drugs have similar
profiles, each have specific therapeutic qualities
that can be taken advantage of in the clinical setting. Infliximab and golimumab are known for
their rapid-onset of clinical efficacy while certolizumab has the added benefit of use during
pregnancy as minimal to no drug crosses the placenta or into breast milk.
173
174
J. A. Mojeski and R. E. Kalb
Infliximab (Remicade) is one of the more nent of the typical IgG antibody structure, cerwidely used tumor necrosis factor (TNF)-alpha tolizumab contains only a monovalent Fab
inhibitors, and has extensive clinical experience fragment of humanized anti-TNFa antibody [15].
in various immunologic conditions. It is a chime- Additionally, situated on the hinge region of the
ric human-murine monoclonal antibody, consist- drug are two polyethylene glycol chains, which
ing of human constant and murine variable confer its pegylated component (PEG) [16, 17].
regions and binds to both soluble and membra- Similar to other anti-TNF agents, Certolizumab
nous forms of TNF-alpha, thereby neutralizing has been FDA approved for multiple indications
the cytokine’s effect [3–6]. It was first approved in the treatment of various inflammatory disby the U.S. Food and Drug Administration (FDA) eases. The current list of approved conditions
for the treatment of moderate to severe Crohn’s includes moderate-severe rheumatoid arthritis,
disease in August of 1998. Its use was later axial spondyloarthritis, psoriatic arthritis, psoriaexpanded to include the following indications: sis, and Crohn’s disease [18]. Dosing is via sub-­
rheumatoid arthritis (11/1999), ankylosing spon- cutaneous injection and is typically standard
dylitis (12/2004), psoriatic arthritis (05/2005), throughout its indications. For psoriasis, it is
ulcerative colitis (09/2005), pediatric Crohn’s administered 400 mg Q2W and for psoriatic
disease (05/2006), psoriasis (09/2006), and pedi- arthritis dosing varies between 200 mg Q2W or
atric ulcerative colitis (09/2011) [7, 8]. For the 400 mg Q4W.
treatment of psoriasis and psoriatic arthritis the
drug is usually administered intravenously over 2
h, at a dosage of 5 mg/kg on weeks 0, 2, and 6, Mechanism of Action
followed by maintenance infusions every 8 weeks
thereafter [3, 9]. While the intravenous adminis- The specific mechanisms of immune-mediated
tration can be inconvenient, it is administered inflammatory diseases have yet to be fully eluciinfrequently and has the benefit of rapidly achiev- dated, however, the over-expression of tumor
ing high serum concentrations, therefore offering necrosis factor (TNF) is believed to play a pivotal
the potential for rapid and sustained improve- role. This is documented by extensive investigament [4, 6, 10, 11].
tion and confirmed by the efficacy of anti-TNF
Golimumab (Simponi, Simponi Aria) is biologics in treating these disorders [14, 19, 20].
another member of the TNF antagonist family Numerous in vitro and in vivo studies have conand available in subcutaneous injection (Simponi) tributed to the knowledge base behind TNF-alpha
or IV formulation (Simponi Aria). It is a fully inhibitors, and it has been proposed that apoptohuman IgG1k monoclonal antibody that targets sis, reduction of pro-inflammatory cytokines,
both transmembrane and soluble forms of TNF-­ down-regulation of adhesion molecules, and
alpha with high affinity and specificity [12, 13]. increases in circulating T regulatory cells are the
As of 2017, both formulations of golimumab main mechanisms of action behind the efficacy of
have been FDA approved for use in numerous TNF-alpha inhibition [3, 13]. Infliximab, goliminflammatory diseases, including moderate-­ umab and certolizumab exert their anti-­
severe
rheumatoid
arthritis,
ankylosing inflammatory effects by binding to the soluble
­spondylitis, and psoriatic arthritis either alone or and transmembrane forms of TNF-alpha. This
in combination with conventional agents. leads to inhibition of the induction of the inflamSubcutaneous golimumab has an additional indi- matory cascade and ultimately results in the rapid
cation for the treatment of ulcerative colitis [13, reduction in the number of cells at the site of
14]. Golimumab is self-administered as a 50 mg inflammation. Infliximab and golimumab have
or 100 mg subcutaneous injection once each the additional function of being able to induce
month or intravenously at 2 mg/kg for at weeks 0 complement-dependent
cytotoxicity
and
and 4 then every 8 weeks thereafter.
antibody-­
dependent cell-mediated cytotoxicity
Certolizumab Pegol (Cimzia) is a biologically through their Fc portions [20, 21]. Current develunique anti-TNF agent. Lacking the Fc compo- opments in the biology of the TNF receptor path-
14
Infliximab, Golimumab, and Certolizumab Pegol
way have suggested pleotropic effects. There are
two antagonizing TNF receptor pathways including the TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2) pathways. The TNFR1 pathway
signals most of TNF’s effects including inflammation and cell death and is expressed ubiquitously whereas the TNFR2 pathway is only
expressed through immune cells, endothelial
cells, and multiple CNS cells and provides
homeostatic function [22, 23]. Recently, alternative strategies in blocking TNF receptors are
being developed that target the TNF receptor-1
(TNFR1) pathway and augment the TNF receptor-­2 (TNFR2) pathway [22].
Importantly, the Fc region of an antibody,
which infliximab and golimumab contain, prolongs half-life and prevents premature degradation of biologic drugs. Certolizumab does not
contain this Fc portion. The covalent linking of
its PEG moiety to the hinge region of the antibody increases the half-life of the drug and
decreases
protease
sensitivity
[24].
Certolizumab’s safety profile during pregnancy
and breastfeeding is thought to be due to its distinctive lack of an Fc component. Because there
is no Fc region, the drug is unable to bind the
175
neonatal FcRn-mediated transfer across the placenta. Subsequently, minimal to no drug is delivered to the fetus of mothers being treated with a
certolizumab regimen [24–28]. This is a significant advantage if anti-TNF therapy is required in
a woman of child bearing potential.
fficacy for Psoriasis and Psoriatic
E
Arthritis
Infliximab
The first documented treatment response with
infliximab was published in a case report of a
patient with a long-standing history of Crohn’s
disease with concomitant severe psoriasis [29].
The patient received a single infusion of infliximab (5 mg/kg) and 4 weeks later there was a dramatic improvement in the severity of the
psoriasis.
Subsequently, a double-blind, randomized
trial was conducted in 2001 by Dr. Alice
Gottlieb’s research group (Fig. 14.1) [30]. The
trial enrolled 33 patients with clinically-defined
moderate-severe plaque psoriasis who were ran-
Infliximab Therapy
Week 0
Week 10
PASI 42
PASI 1.8
Fig. 14.1 Before and after 10 weeks of intravenous infliximab therapy. A significant reduction in plaques is demonstrated providing promising data of the benefits of infliximab in decreasing disease burden
J. A. Mojeski and R. E. Kalb
176
domized to receive either intravenous placebo or 5 mg/kg, or placebo administered at weeks 0, 2,
intravenous infliximab in either 5 mg/kg or and 6 [31]. At week 10, 72% and 88% of the
10 mg/kg dosages at weeks 0, 2, and 6. Three patients treated with 3 mg/kg and 5 mg/kg of infpatients withdrew from the study, one from each liximab, respectively, achieved a 75% or greater
treatment group. At week 10, 9 of the 11 (82%) improvement using the PASI evaluating system
patients in the infliximab 5 mg/kg group and 10 in comparison to only 6% of patients in the plaof the 11 (91%) patients in the infliximab 10 mg/ cebo group (p < 0.001). Furthermore, 46% of
kg group were considered responders (clear or patients treated with 3 mg/kg and 58% treated
almost clear rating according to the PGA) com- with 5 mg/kg reached a 90% improvement in
pared to only 2 of 11 (18%) receiving placebo PASI score compared to only 2% of the patients
(p < 0.01). Additionally, nine of 11 (82%) in the in the placebo group (p < 0.001). Quality of life
infliximab 5 mg/kg group and 8 of 11 (73%) in scores were also improved with the use of inflixthe infliximab 10 mg/kg group achieved at least a imab. This study was notable for rapid clinical
PASI 75 compared with only 2 of 11 (18%) in the improvement after only 2 weeks in each treatplacebo group (p < 0.05). In both infliximab-­ ment group [31].
treated groups, the median time to response was
In 2005 and 2007, data from two large phase
only 4 weeks. This trial provided promising data III multicenter, randomized, double-blind
for the high degree of clinical benefit and rapid placebo-­controlled studies emerged -- EXPRESS
time to response in the treatment of moderate-­ I and EXPRESS II (Fig. 14.2) [32, 33]. These
severe plaque psoriasis with infliximab. studies further demonstrated the dramatic effecNumerous randomized controlled trials followed tiveness of infliximab in patients suffering from
to confirm this initial success.
moderate-severe plaque psoriasis. In EXPRESS
In the multicenter, double-blind phase II I, patients were allocated to receive infusions of
SPIRIT trial by Gottlieb et al. in 2004, patients either 5 mg/kg of infliximab or placebo at weeks
with severe plaque psoriasis were randomly 0, 2, and 6, and then every 8 weeks thereafter to
assigned to receive infusions of either 3 mg/kg, week 46 [33]. Beginning at week 24, the patients
Infliximab phase III study efficacy
EXPRESS II
EXPRESS
82
% of Patients
80
57
78
58
78
61
56
45
55
43
34
n=301
n=276
n=281
PASI 75
n=150
n=141
n=134
PASI 90
Fig. 14.2 PASI response to IV infliximab therapy at weeks 10, 24, and 50. At week 10, approximately 80% of patients
in the EXPRESS and EXPRESS II trials achieved PASI 75. This response was largely maintained through week 24 with
82% of patients in the EXPRESS trial achieving PASI 75 and 78% achieving PASI 75 in the EXPRESS II trial
14
Infliximab, Golimumab, and Certolizumab Pegol
in the placebo group crossed over to receive infliximab treatments. Although remarkable clinical
improvements were noted at week 6 (after only
two infusions), by the end of the induction period
(week 10) 80% of patients treated with infliximab achieved PASI 75, with 57% reaching at
least a 90% improvement (PASI 90), and 26% of
patients achieving complete clearing of the skin
(a score of 0 in PASI). This is in comparison to
3%, 1%, and 0% in the placebo group, respectively (p < 0.0001). These responses were maintained through week 50, with 82% and 61% of
patients attaining a PASI 75 at weeks 24 and 50
(Figs. 14.3 and 14.4) [32]. Additionally, infliximab therapy was noted to have a significant
effect on nail manifestations of psoriasis, a
traditionally treatment-resistant disease. Nail
­
Psoriasis Severity Index (NAPSI) improvements
were noted as early as week 10 in infliximabtreated patients. At week 24, there was a 56%
mean decrease of the NAPSI in the infliximab
177
group, and this response was also maintained
through week 50 (p < 0.0001 for week 24)
(Fig. 14.5) [32].
The EXPRESS II trial also documented the
efficacy of infliximab in a placebo-controlled
protocol (Fig. 14.2) [33]. This trial compared the
efficacy of continuous therapy (every 8 weeks)
versus intermittent (as needed) maintenance regimens. Patients were randomized to induction
therapy at weeks 0, 2, and 6 with infliximab
3 mg/kg, 5 mg/kg, or placebo. At week 14, the
infliximab group was then further randomized to
continuous or maintenance regimens at their
originally designated dose. Through week 50,
this study demonstrated that the clinical response
to treatment was best maintained using continuous infliximab therapy compared to an as-needed
basis in both dosage groups. The median of the
average percent improvement in PASI from week
16 through week 50 was 89.6% in the 5 mg/kg
every 8-week group compared to 76.4% in the
Median Serum concentration of infliximab
through week 50 in week 10 responders
Infliximab 5 mg/kg
Median Serum Infliximab
Concentration (µg/mL)
100
10
1
< 0.1
0 2
Week
Infusion
6
10
14
22
30
38
46
50
Responders at Week 10 and
Maintain Response at Week 50 (n = 56)
Responders at Week 10 and
Do Not Maintain Response at Week 50 (n = 19)
Fig. 14.3 Difference in median serum infliximab concentration between responders and non-responders in EXPRESS
and EXPRESS II trials. As an independent predictor of treatment response, patients that responded to infliximab therapy
had a significantly higher median serum concentration of infliximab than nonresponders
J. A. Mojeski and R. E. Kalb
178
Infliximab therapy
Baseline
Week 24
Fig. 14.4 Clinical response to Infliximab. Another example of disease improvement on IV infliximab therapy during
the EXPRESS trials. A patient with significant baseline disease burden achieves almost a complete response after 24
weeks of infusions
as-needed group (p < 0.001). Similar results were
obtained for the 3 mg/kg group as well, with
80.6% improvement in the continuous group versus 72.4% in the as-needed group (p < 0.001).
Furthermore, the authors showed that a 5 mg/kg
dosage regimen achieved superior induction and
maintenance scores compared to the lower dosage. Patient assessments across treatment groups
were consistent with the PASI scores, as the continuous infusion of 5 mg/kg group reported the
greatest improvements in their DLQI quality of
life scores.
Also in 2005 and 2007, the IMPACT I and II
trials were conducted as randomized,
­double-­blind placebo-controlled studies enrolling patients with psoriatic arthritis in whom
prior therapy with at least one disease-modifying
anti-­rheumatic drug (DMARD) had previously
failed [34, 35]. In IMPACT I, patients were
assigned to receive infusions of either 5 mg/kg
of infliximab or placebo at weeks 0, 2, 6, and 14.
After week 16, patients initially assigned to
receive placebo were crossed over to receive infliximab, and all groups received 5 mg/kg of infliximab every 8 weeks through week 50. At week
16, 65% of patients treated with infliximab
attained an ACR20 response, compared to only
10% of placebo-­treated patients (p < 0.001). In
addition, 46% of the infliximab group produced
an ACR 50 response and 29% an ACR 70
response, where no placebo-treated patients
achieved either of these end points (p < 0.001).
Furthermore, at the 16-week evaluation 75% of
infliximab-treated patients were improved
according to the PsARC, compared to only 21%
of placebo-controlled patients (p < 0.001).
Additionally, although secondary endpoints the
infliximab group showed substantial improve-
14
Infliximab, Golimumab, and Certolizumab Pegol
179
Infliximab therapy
Baseline
Week 24
Fig. 14.5 Infliximab in patients with nail disease. Nail Psoriasis Severity Index (NAPSI) improvements were noted
during the EXPRESS and EXPRESS II trials. By week 24, a 56% mean decrease in NAPSI was achieved in the infliximab treatment group
ments in in psoriatic skin disease as well as the
percentages of patients suffering from the common complications of psoriatic arthritis, namely
dactylitis and enthesitis [34, 35].
The IMPACT II trial was a 54-week multicenter study designed to expand the published
clinical response data from the initial, 24-week,
double blind placebo-controlled period [36] with
an expansion of the number of enrolled patients
[35]. As previously reported, these results demonstrated significant improvements in the signs
and symptoms of psoriasis and psoriatic arthritis,
as well as quality of life and physical functioning
in patients through 1 year of treatment. Another
outcome assessed was attainment of a “major
clinical response,” which is defined as ACR 70
improvement for 24 consecutive weeks. At week
54, major clinical response was achieved by
12.1% of the infliximab-treated group. The
authors also demonstrated that 5 mg/kg is a suf-
ficient dose for a majority of patients. Dose escalation from 5 mg/kg to 10 mg/kg was assessed in
15 non-responders (patients who did not achieve
ACR 20). Interestingly, in the patients requiring
dose escalation, patients who had not achieved an
ACR 20 score before escalation did not achieve
ACR 20 despite doubling of the drug dosage.
Furthermore, dose escalation did not appear to
significantly improve PASI responses. Out of the
15 patients who receive dose escalations, only 12
had a baseline BSA of 3% or greater and were
therefore included in the PASI analysis. Five of
these patients achieved a PASI 75 at week 38 and
maintained that response through week 54.
Conversely, the seven patients who did not
achieve a PASI 75 response at week 38 were
unable to achieve the response after dose escalation. Overall, these studies show that infliximab
therapy significantly reduces the signs and symptoms of psoriatic arthritis in patients that were
180
resistant to other treatment modalities and these
benefits were sustained through 1 year of
therapy.
In August 2011, the first documented head-to-­
head, randomized trial (RESTORE 1) comparing
the efficacy and safety of infliximab versus methotrexate was published [37]. 868 methotrexate-­
naïve patients were randomized to receive 5 mg/
kg of infliximab at weeks 0, 2, 6, 14, and 22 or
15 mg weekly methotrexate with a dose increase
to 20 mg weekly at week 6 if the PASI response
was <25%. Patients with less than a PASI 50
response were allowed to switch treatment groups
at week 16. At week 16, a PASI 75 response was
achieved by 508/653 (78%) of infliximab-treated
patients compared to 90/215 (42%) of patients
receiving methotrexate, and this response was
maintained throughout the 26-week study
(p < 0.001). Key secondary endpoints, including
PGA, DLQI, and PASI 90 were likewise achieved
by a greater proportion of infliximab-treated
patients. More impressively, 46/63 (73%) patients
who switched from methotrexate to infliximab at
week 16 demonstrated a PASI 75 at week 26.
Although the incidence of severe adverse events
was slightly higher in the infliximab group (7%
vs. 3%), a majority of the serious adverse events
were infusion-related reactions, and the overall
adverse event incidence was comparable between
groups. The study demonstrated that infliximab
was both well tolerated and more efficacious than
methotrexate in patients with moderate-severe
plaque psoriasis. Moreover, infliximab was
proven to be a successful alternative agent in
patients who had previously failed methotrexate
therapy.
While all biologics have performed well in
short-term clinical trials, very limited direct comparisons between agents are available, particularly for psoriasis. However, since most studies
used similar designs and end points, limited comparisons from randomized controlled trials are
possible. Adalimumab and infliximab appear to
have similar efficacy, with 70–80% of patients
achieving a PASI 75 score at 12 weeks [9].
According to a systematic review by Rodgers
et al., infliximab is associated with the highest
probability of response on joint (ACR and
J. A. Mojeski and R. E. Kalb
PsARC) and skin (PASI) outcomes from
12–14 weeks [38]. Etanercept appears to be
slightly less efficacious than its counterparts,
demonstrating 50% of patients attaining a PASI
of 75 at 12 weeks. Authors of a recent network
meta-analysis concluded that, anti-TNF agents
may be slightly less efficacious compared to anti­IL17 and anti-IL12/23 inhibitors, but are more
effective than anti-metabolites such as methotrexate [39]. Anti-TNF agents have the advantage
in terms of a well-known long term side effect
based on over 20 years of experience.
Promising data was recently published in The
Lancet pertaining to the efficacy of a biosimilar
to infliximab known as CT-P13 which was
approved by the FDA in 2016 for all indications
of infliximab after its patent expired in 2015. A
treatment switch was performed in a Norwegian
52-week randomized, double-blind study known
as NOR-SWITCH. Patients were enrolled from
each inflammatory condition that infliximab is
currently indicated for including plaque psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative
colitis, rheumatoid arthritis, and ankylosing
spondylitis. In a 1:1 ratio, patients were either
continued on infliximab or switched to CT-P13
treatment with unchanged dosing regimen. The
study showed that switching therapy to this biosimilar was not inferior to continued treatment
with infliximab. However, the study was not powered sufficiently to suggest non-inferiority in
individual disease processes. With a cost-saving
of up to 69% when compared to infliximab, the
use of this drug and introduction of other biosimilars can significantly improve access to biologic
therapies and lessen the financial burden of these
medications [40].
One of the major advantages of infliximab is
that it has a weight-based dosing on a milligram
per kilogram basis unlike a majority of the TNF
antagonists used to treat psoriasis [41, 42]. This
allows for a more individualized patient-tailored
therapy, which is particularly important as
patients with psoriasis are typically above average weight [41, 42]. Additionally, a few studies
have demonstrated the continued efficacy of infliximab regardless of body mass index, whereas
the efficacy of fixed-dose TNF antagonists may
14
Infliximab, Golimumab, and Certolizumab Pegol
181
Infliximab: BMI and efficacy
100
Percent of Patients
78.3
77.5
80
74.4
60
40
20
5.0
0
1.7
n=231
n=60
Normal (<25)
n=121 n=373
Overweight (25-30)
2.6
n=155 n=519
Obese (≥30)
Body Mass Index
Placebo
Combined Infliximab Groups
Fig. 14.6 Infliximab and BMI. There is no significant difference between normal weight patients and obese patients in
achieving an efficacious response with fixeddose infliximab suggesting that there may be no need for weight-based
dosing
be compromised [41–43]. In one study in JAAD
(Fig. 14.6), there was no significant difference
between the number of patients who achieved an
efficacious response with a BMI greater than or
equal to 30 (74.4%) compared to those of normal
body weight (77.5%) [43].
Combination Therapy
Currently, there is some evidence to suggest that
patients with psoriasis may obtain an improved
response from combination therapy with infliximab and another therapeutic agent such as methotrexate, cyclosporine, acitretin, narrow-band
UVB (nb-UVB) phototherapy, azathioprine, and
apremilast [44–49]. A retrospective analysis of
23 patients receiving infliximab in combination
with methotrexate or azathioprine showed PASI
50 improvements by 91.3% of patients. A prospective study performed by Goedkoop et al.
showed that infliximab plus methotrexate therapy
decreased PASI score and biopsy findings from
the patients showed decreased angiogenesis and
cellular infiltration at 4 weeks of therapy [49].
Additionally, an open-label study (RESPOND
study) was conducted comparing the efficacy and
safety of methotrexate alone versus methotrexate
in combination with infliximab in patients suffering from psoriatic arthritis [50]. 115 methotrexate-­
naïve patients were randomly assigned to receive
either 15 mg/week of methotrexate plus infliximab 5 mg/kg at weeks 0, 2, 6, and 14, or methotrexate therapy alone (15 mg/week). At week 16,
86.3%, 72.5%, and 49.0% of patients receiving
combination therapy compared to 66.7%, 39.6%,
and 18.8% of patients receiving methotrexate
alone achieved ACR 20 (p = 0.021), 50
(p = 0.0009), and 70 (p = 0.0015) responses,
respectively. With regards to skin disease, patients
whose baseline PASI was 2.5 or greater, 97.1% of
those on combination therapy and 54.3% of those
on methotrexate alone experienced a 75% or
greater improvement in PASI scores (p < 0.0001).
Importantly, combination therapy was determined to be generally well-tolerated by the
patient population. In the infliximab plus methotrexate group, 46% had treatment-related adverse
182
events (2 serious AEs) while the methotrexate
alone group experienced 24% AEs (no serious
AEs). While the overall incidence of adverse
events was higher in the combination therapy
group, a majority of the events were mild to moderate. Overall, this study suggested potential benefit of combination therapy for patients with
psoriatic arthritis.
In 2010, the New England Journal of Medicine
published a randomized, double-blind trial comparing the efficacy of infliximab monotherapy,
azathioprine monotherapy, and the combination
of the two drugs in patients with Crohn’s disease
[51]. 508 patients with moderate to severe
Crohn’s disease were randomized to receive
either 5 mg/kg infliximab at weeks 0, 2, 6, and
then every 8 weeks thereafter, 2.5 mg/kg oral
azathioprine daily, or combination therapy with
the two medications (with the monotherapy
groups also receiving either oral or infusion placebos). At week 26, 56.8% of the patients receiving combination therapy were in steroid-free
clinical remission compared to 44.4% of those
receiving infliximab alone (p = 0.02) and 30.0%
receiving azathioprine alone (p = 0.006 for comparison with infliximab and p < 0.001 for comparison with combination therapy). At week 50, a
similar trend was obtained with 46.2% of patients
on combination therapy, 34.9% on infliximab
alone (p = 0.04), and 24.1% on azathioprine
alone (p = 0.03 for comparison with infliximab
and p < 0.001 for comparison with combination
therapy) maintaining clinical remission status.
Safety data was generally similar among groups
with serious infections occurring in 3.9% of the
combination group compared to 4.9% in the infliximab group and 5.6% in the azathioprine
group. While this study documented the incremental benefit of combination therapy for
Crohn’s disease, controlled data are lacking in
psoriasis. Only two randomized control trials
have been performed to date assessing efficacy of
combination therapy in plaque psoriasis with
both involving etanercept with methotrexate.
Each showed superior efficacy compared to etanercept monotherapy. Another trial known as
OPTIMAP is underway currently that will assess
the performance of adalimumab and methotrex-
J. A. Mojeski and R. E. Kalb
ate combination therapy [52]. Whether combination therapy with all TNF antagonists, including
infliximab, will be more effective in improving or
maintaining response are important questions to
be answered for patients with psoriasis.
As previously mentioned, maintaining the
high initial response with infliximab therapy for
a chronic disease such as psoriasis remains a
challenge. The mechanisms for loss of response
include antibodies to infliximab, tolerance to the
drug, and drug metabolism for individual
patients [7, 53–58]. Predictors of continued
response include serum levels of infliximab at
the time of infusion (Fig. 14.3) [32], as well as
effective trough plasma concentrations [57].
Approximately 10% of patients with Crohn’s
disease and rheumatoid disease in clinical trials
have developed antibodies [59], and reports of
up to one-third of patients with psoriatic disease
[33, 60]. Studies have established relationships
among antibody formation and low serum drug
levels or failure and loss of response in patients
with rheumatic and inflammatory bowel disease
[61–65]. In psoriasis, elevated levels of antibodies were discovered in non-responders, and
authors concluded that they appeared to play a
role in the lack or regression of response [33,
66, 67]. In one trial in particular, patients with
an initial response to infliximab positive for
antibodies to the drug at week 10 were less
likely to maintain a good response at 1 year than
their antibody-negative counterparts [33].
Recently, a retrospective cohort study of 93
patients receiving infliximab therapy for psoriasis was performed to assess dosing techniques
for prolonged infliximab response. The authors
confirmed that concomitant methotrexate use
was associated with increased time to discontinuation or dose escalation, likely due to its
ability to decrease the formation of anti-infliximab antibodies. Additionally, increased dosing
frequency, as compared to increasing the size of
the dose, lead to statistically significant increase
in time to discontinuation or dose escalation
[58]. Thus, in order to maintain response, physicians may either start with methotrexate in combination with infliximab or add methotrexate
during therapy.
14
Infliximab, Golimumab, and Certolizumab Pegol
Golimumab
Subcutaneous and intravenous golimumab have
shown impressive efficacy results in patients with
psoriatic arthritis. Although one may expect that
the effects of golimumab in the treatment of
plaque psoriasis are comparable to other TNF
antagonists with a similar benefit in psoriatic
arthritis, there are no published trials directly
assessing the effects of this medication in plaque
psoriasis to date. Therefore, it is not known how
golimumab compares to other TNF inhibitors in
the treatment of moderate to severe plaque
psoriasis.
With regards to psoriatic arthritis, In a randomized, placebo-controlled, multicenter clinical study (GO-REVEAL), 405 patients with
active psoriatic arthritis were enrolled and randomly assigned to receive subcutaneous injections of placebo, golimumab 50 mg, or
golimumab 100 mg every 4 weeks [68]. At week
14, 51% and 45% of patients receiving golimumab 50 mg and 100 mg respectively, achieved
an ACR 20 response, compared with only 9% of
patients receiving placebo therapy (p < 0.001).
At week 24, an ACR 20 response was observed
in 52% of patients in the 50 mg group and 61%
in the 100 mg group, versus 12% of patients
receiving placebo (p < 0.001). The trial continued and an impressive 279 patients completed
five total years of therapy. At the five-year conclusion of the study, ACR20, 50, and 70 scores
were 62.8–69.9%, 43.4–50.7%, and 30.8–
35.6%, respectively. This showed that golimumab not only made significant clinical
improvements for patients, but the therapy also
had significant longevity. Improvement in dactylitis and enthesitis scores, as well as nail psoriasis severity was evident. Patient’s PASI scores
were determined as a secondary endpoint and
showed improvement against placebo. In
patients who were suffering from at least 3%
BSA involvement of skin psoriatic disease, 40%
in the 50 mg golimumab group and 58% in the
100 mg golimumab group had at least 75%
improvement in their skin disease (PASI 75) by
183
week 14 [68]. This was compared to only a 3%
PASI 75 response in placebo-treated patients
(p < 0.001). This beneficial response was maintained through week 24 in both golimumab
groups (56% and 66% for 50 mg and 100 mg)
whereas only 1% of patients in the placebo
group reached a PASI 75 at this time marker
(p < 0.001). At week 104, data revealed a PASI
75 of 68.8% of patients in the 50 mg group and
76% in the 100 mg golimumab group [12, 68,
69]. However, the trial failed to show consistent
difference in PASI score in patients treated with
a golimumab regimen compared to patients with
baseline methotrexate use [69]. This study gave
significant evidence that subcutaneous golimumab improved the clinical signs and symptoms
of psoriatic arthritis, along with associated skin
and nail disease, as well as physical functioning
and quality of life [12, 68, 69].
Intravenous golimumab has had similar efficacy results as evidenced by the GO-VIBRANT
trial. In the phase III, randomized, double-blind,
placebo-controlled trial, patients with psoriatic
arthritis were assigned to IV placebo or golimumab at 2 mg/kg at weeks 0, 4, 12, and 20. A
primary endpoint of ACR20 response was
assessed and was achieved by 75.1% of patients
in the golimumab group compared to 21.8% of
patients in the placebo group (p < 0.001).
Additionally, greater mean changes were
observed in each of the secondary endpoints of
the study. ACR50 and ACR70 responses were
found in 43.6% and 24.5% of golimumabtreated patients compared to only 6.3% and
2.1% in ­
placebo group, respectively.
Additionally, 59.2% of golimumab-treated
patients enrolled in the study achieved PASI75
response compared to only 13.6% of placebo
patients. This study suggests comparable efficacy of both formulations of golimumab in the
treatment of psoriatic arthritis. Again, although
this gives some evidence toward the use of golimumab for the treatment of plaque psoriasis, a
randomized control study would be more effective to determine golimumab’s place in the management of the condition [70].
J. A. Mojeski and R. E. Kalb
184
Certolizumab
tions every 2 weeks and patients were assessed at
16 weeks and 48 weeks. At week 16, patients
Certolizumab has significant promise in the man- enrolled in CIMPASI I and II achieved PASI 75
agement of both moderate-severe plaque psoria- responder rates of 75.8% and 82.6%, respectively
sis and psoriatic arthritis. With regards to plaque in the certolizumab 400 mg group and 66.5% and
psoriasis, there have been three phase 3 trials 81.4%, respectively in the certolizumab 200 mg
(CIMPACT I, CIMPASI I, and CIMPASI II). The group. When compared to patients receiving only
CIMPACT trial compared certolizumab against placebo therapy, 6.5% of patients in CIMPASI-I
etanercept and placebo while CIMPASI I and II and 11.6% of patients in CIMPASI-II receiving
were solely placebo-controlled studies. The placebo achieved PASI 75 (P < 0.001). These
CIMPACT trial results showed that the use of results were largely maintained throughout the
certolizumab for patients with chronic plaque 48-week trial (Fig. 14.8). Additionally, pooled
psoriasis was associated with a significant differ- analysis of both trials showed impressive PASI
ence in PASI 75 scores compared to placebo. 100 response rates of 34.5% for certolizumab
Additionally, when directly compared to its anti- 400 mg and 28.5% for certolizumab 200 mg.
TNF counterpart etanercept, certolizumab End-points of Dermatology Life Quality Index
400 mg was superior to and 200 mg was non-­ and Physician Global Assessment also showed
significant improvement [71].
inferior to etanercept (Fig. 14.7) [28].
Certolizumab’s use in the management of psoIn the randomized-control CIMPASI I and II
trials patients were enrolled and assigned to 2:2:1 riatic arthritis was studied in a 4-year trial
treatment groups consisting of certolizumab (RAPID-PsA) performed in patients treated with
400 mg, certolizumab 200 mg (with loading and without concomitant DMARD therapy. The
doses of 400 mg at 0, 2, and 4 weeks) and pla- study was a double-blind and placebo-controlled
cebo. Each group received subcutaneous injec- study through 24 weeks, dose-blind to 48 weeks
100
Placebo (N = 57)
CZP 200 mg Q2W (N = 165)
CZP 400 mg Q2W (N = 167)
80
ETN (N = 170)
74.7%
Responder rate (%)
66.7% †‡
68.2%
†
†
61.3% †§
60
†
40
53.3%
†
20
*
5.0%
*
3.8%
0
0
2
4
8
12
16
Week
Fig. 14.7 Percentage of responders (PASI 75) in placebo, certolizumab and etanercept groups within the CIMPACT
trial. Certolizumab displays superiority to etanercept at 400mg Q2W dosing and non-inferiority at 200mg Q2W dosing
14
Infliximab, Golimumab, and Certolizumab Pegol
185
CIMPASI-1
Placebo (N=51)
CZP 200 mg Q2W
(N=95)
CZP 400 mg Q2W
(N=88)
Responder rate (%)
100
87.1%
75.8%†
80
†
60
*
40
*
†
*
20
0
*
0 2 4
6.5%
8
12
Placebo (N=49)
CZP 200 mg Q2W
(N=91)
CZP 400 mg Q2W
(N=87)
Responder rate (%)
100
CIMPASI-2
67.2%
66.5%†
†
80
†
60
0
20
24
28
32
40
82.6%†
81.3%
†
81.4%
78.7%
*
*
*
0 2 4
11.6%
8
12
16
20
100
24
28
Week
32
40
CZP 200 mg Q2W
(N=186)
CZP 400 mg Q2W
(N=175)
Responder rate (%)
Placebo (N=100)
80
48
83.6%
82.0% †
Pooled
48
†
40
20
†
16
†
†
60
†
76.7%†
70.7%
†
40
†
20
0
9.9%
*
0 2 4
8
12
16
20
24
28
Week
32
40
48
Fig. 14.8 CIMPASI-I and CIMPASI-II randomized control trail results. Patients randomized to both the certolizumab
200mg Q2W and certolizumab 400mg Q2W achieve significant benefit compared to patients in placebo group. Results
were maintained throughout 48-week trial period
and then open label until 216 weeks [72–76] In
the trial, 409 patients were randomized to complete 24 weeks of treatment with either certolizumab 200 mg every 2 weeks, 400 mg every
4 weeks, or placebo. ACR 20 response was significantly greater at 12 weeks (58.0% and 51.9%
vs. 24.3%, respectively (p < 0.001)) and PsARC
achievement was also significant against placebo
group at 24 weeks (78.3% and 77.0% vs. 33.1%
(p < 0.001) [72]. The study was continued over 4
years with exciting results. Of the 67% of patients
who completed 216 weeks of therapy, 60.4%
achieved a Disease Activity Index for Psoriatic
Arthritis low disease activity or remission with
an increase to 66.3% at 216 weeks. Additionally,
at four-years, resolution rates for enthesitis, dactylitis, and nail psoriasis were 71%, 81%, and
65% respectively [73, 74, 76].
Safety Considerations
Throughout their nearly two decades of clinical
use, the safety profile of TNF-inhibitors is well
characterized [2]. In clinical trials, infliximab,
golimumab, and certolizumab have been proven
to be generally well tolerated, however, due to
their down-regulatory effects on the immune sys-
186
J. A. Mojeski and R. E. Kalb
tem, all TNF antagonists have labeled warnings among patients involved in psoriasis trials (393
about the potential development of bacterial, patients with psoriatic arthritis and 1112 patients
viral, and fungal infections during treatment with psoriasis) were the lowest of all inflamma(9,77–79). While the most common adverse tory conditions examined. When examining these
events are mild, consisting of nausea, headache, data it is also important to note that inflammatory
upper respiratory tract infections, abdominal conditions have been associated with adverse
pain, fatigue, and fever, serious and sometimes reactions regardless of the effect of anti-TNF
fatal events have been reported [7, 77–79]. agents such as psoriasis and cardiovascular risk
Kavanaugh et al. reported that only 8.6% of [75].
patients treated with golimumab experienced a
serious adverse event up to 104 weeks [12].
Infusion-related reactions are also possible and Infusion-Reactions
were reported in about 20% of patients receiving
infliximab compared to only 10% in placebo Infusion-related reactions are unique to inflixgroups [31, 59]. These reactions included hyper- imab and golimumab as these are currently the
tension, hypotension, bronchospasm, chest pain, only TNF antagonists that are administered intradyspnea, pruritis, and fever [80, 81]. Infusion-­ venously. Infliximab infusions can be adminisrelated reactions may occur with all intravenously-­ tered within a hospital or a community setting
administered biologic agents, but because [82]. Typically, infliximab is administered over a
infliximab is a human-mouse antibody, anaphy- 2 hour time span, however, a prospective cohort
laxis is possible, although uncommon [2]. For study demonstrated that infliximab infusion can
golimumab, injection site reactions occurred in be safely administered over 1 hour in patients
8.9% of golimumab treated patients, but only with no past history of significant infusion reacwith 0.7% of all golimumab injections over tion [84]. IV Golimumab is administered over a
104 weeks of treatment [12]. Malignancy, auto- 30-minute period [70, 85]. A majority of the
immune disease, demyelinating disease, and con- infusion-­reactions are mild, consisting of flushgestive heart failure [13] serve as additional ing, dizziness, nausea, sweating, and increase in
concerns with the use of these agents, however temperature, typically occurring within the first
with appropriate screening and selection of 2 hours after treatment [31, 86–88]. However,
patients, the potential for development of these patients may develop antibodies to golimumab
more serious conditions declines. Also of impor- and infliximab which may lead to more serious
tant note, the adverse event data of many of the reactions, although rare, including shortness of
biologics are derived primarily from patients breath, hypo/hypertension, chest tightness, sympwith rheumatoid arthritis (RA) or inflammatory toms of anaphylaxis such as urticaria, and bronbowel disease (IBD) as they have the most chospasms. Additional reactions of arthralgias,
­long-­term and extensive data available [1, 38]. myalgias, headache, fatigue, and influenza-like
The generalizability of these findings in patients symptoms may occur as well ([32, 85, 86, 89,
suffering from psoriasis and psoriatic arthritis 90]). It has been estimated that infusion reactions
remains unclear. More recent data suggests the occur in 3–22% of patients receiving treatment
side effect profile may be more favorable in with infliximab for psoriasis [87]. Golimumab
patients with psoriatic diseases [1, 77, 82, 83]. appears to have a lower incidence of infusion-­
For certolizumab specifically, a study performed related reactions with 0.8% of patients experiencby Curtis et al. analyzed the side-­effect profile of ing a reaction through 24 weeks of the
the drug used on 11,317 patients across a multi- GO-VIBRANT study and 1.1% of patients
tude of inflammatory conditions including psori- treated with a combination of methotrexate and
asis, psoriatic arthritis, axial spondyloarthritis, golimumab in the GO-FURTHER study [85, 90]
rheumatoid arthritis, and Crohn’s disease [77]. Typically, symptoms can be monitored and will
These data show that the rates of adverse events resolve with minor analgesics or antihistamines.
14
Infliximab, Golimumab, and Certolizumab Pegol
If a severe reaction develops, infliximab should
be discontinued immediately with commencement of appropriate treatment [88]. Generally,
infliximab and golimumab treatment can be continued after a mild or moderate reaction. Attempts
have been made to reduce the probability of
infusion-­related reactions. Various agents have
been administered as pre-medications, including
intravenous steroids, acetaminophen, and antihistamines, however, most trials have failed to demonstrate a protective effect of premedications and
lead to doubt on whether their risk of potential
side effects is justifiable [84, 90–93].
Co-medication with disease-modifying therapies
[84, 94–96] and ensuring a reliable maintenance
schedule (opposed to an as-needed schedule)
[88] have been shown to reduce the risk.
Infection
Infections are serious complications that can
result from the use of TNF antagonists. While the
most common types reported are upper respiratory tract infections and urinary tract infections,
more serious infections such as cellulitis, pneumonia, abscesses, skin ulceration, pyelonephritis,
cholecystitis, and sepsis have occurred [12, 59,
68, 79]. Although observational studies and
meta-analyses of rheumatoid arthritis and inflammatory bowel disease randomized controlled trials have indicated an increased risk of serious
and non-serious infections [97–103], clinical
safety data specific for psoriasis and psoriatic
arthritis demonstrated only a very small increased
risk of overall infection with the short-term use
of biologics, without an increased risk in the
development of more serious infections [1].
Furthermore, the authors even suggested that the
increased risk of overall infection may be attributable to variations in follow-up time between
the treatment and placebo groups. Rheumatoid
arthritis and IBD patient populations are typically treated with the concomitant use of additional immunosuppressants and have a higher
background incidence of infection. These factors
are the likely explanations for an increased infection rate in these groups [97, 98]. By design,
187
patients with psoriasis receive monotherapy in
clinical trials [104–108]. Although the overall
risk for infection reached statistical significance,
it may have limited clinical implications as 97.6%
of the reported infections were non-serious, with
a large majority represented by upper respiratory
infections [1]. More surprisingly, Dommasch
et al. found a marginally statistically significant
decreased risk of serious infection [1]. There
were three reported cases of cellulitis in the placebo group, versus only one in the treatment
group. It is postulated that an improvement in
skin disease and a decreased amount of excoriations and breaks in the skin barrier are possible
explanations for this unexpected finding.
A significant concern of health practitioners is
the potential for the reactivation of tuberculosis
[7, 59, 60]. The risk of reactivation of latent TB
is, of course, dependent on the incidence of latent
infection [4]. From January 1998 to September
2002, the reported cumulative incidence for
patients in the USA was estimated at 54/100,000
for infliximab [109]. However, the reality of this
serious risk has lead to the introduction of pre-­
treatment screening procedures, which have successfully reduced the number of cases [99, 110].
It has been reported that reactivation occurs at the
greatest frequency within the first 12 weeks of
treatment [111, 112]. The mechanism by which
TB reactivation occurs is not fully understood.
Anti-TNF agents likely lead to apoptosis of active
CD8+ T cells. These cells, along with the cytokine TNF-alpha, are crucial for the maintenance
of granulomas and the lysis of host cells harboring intracellular invaders, such as Mycobacterium
tuberculosis. The anti-TNF agent etanercept is
associated with a lower risk of TB reactivation in
comparison to other anti-TNF agents. This may
be due to less inhibition of TNF-a as etanercept
binds solely soluble TNF-a whereas other anti-­
TNF agents bind tmTNF [3, 19]. There is also
some data to suggest that psoriasis itself is a risk
factor for the risk of TB infection [113]. Screening
for TB infection should include a full history and
physical exam. Additionally, patients require a
tuberculin skin test (TST), and/or interferon-­
gamma release assay (IGRA) with chest radiography occurring after positive screen [13,
188
113–115]. The CDC guidelines suggest that 3
months of isoniazid/rifapentine is the treatment
of choice in countries such as the USA with low
to moderate levels of latent infection. As of 2018,
this recommendation has been expanded from
only adults to patients aged 2–17 years and
patients with HIV infection and taking antiretroviral medications [116]. In the setting of active
TB, anti-TNF agents should be discontinued
immediately. There is still no conclusive evidence on when to re-start or initiate anti-TNF
therapy after treatment of active or latent TB
infection. A multi-disciplinary panel, the Italian
multidisciplinary task force for screening of
tuberculosis before and during biologic therapy
(SAFEBIO) reviewed the available evidence
from phase III randomized control trials in which
anti-TNF agents were studied. The panel evaluated latent TB infection, identification of individualized level of risk of TB reactivation, and
management of patients when TB reactivation
occurred. The panel recommended that biologic
agents could be initiated or resumed 1 month
after the treatment of latent or active TB. Since
the TST and IGRA will not be helpful for the
diagnosis of TB reactivation in these patients,
they need consistent clinical monitoring for signs
and symptoms of active TB [113].
Additional rare severe, opportunistic infections have also been reported, such as listeriosis,
coccidioidomycosis, and histoplasmosis along
with infections caused by Cryptococcus,
Aspergillus, and Pneumocystis [2, 79]. Although
the incidence of fungal infections were not significantly increased in clinical trials, based on
case reports and post-marketing surveillance
data, a fungal infection should be suspected if a
patient on biologic therapy develops a fever [13].
Viral infections are an additional concern, as
there have been reports of reactivated hepatitis B,
and worsening of hepatitis C [2]. All anti-TNF
agents carry a boxed warning regarding the reactivation of hepatitis B. Although these complications exist, a recent recommendation from a
JAAD literature review concluded grade C evidence for the use of hepatitis B and C screening.
Therefore, this can be left to clinical judgement
J. A. Mojeski and R. E. Kalb
and assessment of risk factors [117]. In the case
of a positive result, anti-TNF therapy should be
initiated only in combination with hepatitis treatment and close monitoring of liver enzymes and
viral DNA levels under the supervision of a specialist [118–121]. There is currently limited evidence on the safety of infliximab treatment in
HIV positive individuals as most of these patients
are excluded from trials with biologic agents [13,
117]. Caution is therefore advised when considering anti-TNF therapy in these high-risk individuals [122].
In addition to the aforementioned screening
measures, no live vaccinations should be administered to a patient undergoing TNF antagonist
therapy, and these agents should be withheld if
patients are given antibiotics and completely discontinued in the presence of severe infections, as
these patients have a higher propensity to develop
serious bacterial complications [123–125].
Despite the risk of infectious complications,
the overwhelming majority of these infections
are minor, consisting mainly of upper respiratory
infections [1]. JAMA published a multi-center,
retrospective study examining whether the use of
biologic agents was associated with an increased
risk of serious infections requiring hospitalization in comparison to non-biologic agents [126].
They determined that TNF-antagonists were not
associated with an increased risk of hospitalization for serious infections across multiple autoimmune diseases, including psoriasis and
psoriatic arthritis. However, it was noted that for
rheumatoid arthritis patients, infliximab was
associated with a higher rate of serious infection
when compared alone to non-biologics (adjusted
hazard ratio: 1.25, 95% confidence interval:
1.07–1.48) and when compared to the other TNF
agents, etanercept (aHR: 1.26; 95% CI: 1.07–
1.47) and adalimumab (aHR: 1.23; 95% CI:
1.02–1.48). Subgrouping of the TNF antagonists
was not performed for psoriasis specifically,
however the rate of serious infections for the biologics as a group compared to the non-biologics
was not significantly different. Baseline use of
glucocorticoids, however, was associated with a
significantly increased risk of serious infection
14
Infliximab, Golimumab, and Certolizumab Pegol
and hospitalization compared to no baseline use
of steroids.
An additional concern surrounding the
increased risk of infections is whether or not this
risk will further increase perioperatively, and
whether or not infliximab infusions should be
held for a certain period of time before a major or
minor surgery. Current recommendations from
many professional societies recommend withholding therapy prior to surgery. The therapy
may be withheld for 3–5 half-lives of the drug or
individualized to patient characteristics and surgery type. However, this is not without risk and
disease flares can lead to adverse functional outcomes and impair rehabilitation [127]. A retrospective study was conducted to assess the safety
of preoperative infliximab use before restorative
proctocolectomy and ileal pouch-anal anastomosis (IPAA) in patients suffering from ulcerative
colitis (UC) [128]. Although controversy exists
surrounding the risks of preoperative infliximab
[129–132], it was determined that short-term
postoperative and infectious complications were
similar between the group that had received infliximab within 12 weeks of the surgery (44.8%),
and those who had not (44.2%) [133]. In fact, a
trend toward lower rates of wound infection was
observed for the infliximab group (3.5%) compared to controls (19.2%). Another recent retrospective cohort performed on patients receiving
infliximab within 4 weeks of elective hip or knee
arthroplasty were not at an increased risk within
1 year compared to patients withholding therapy
[134]. While these results are promising, there is
still a need for prospective studies.
Malignancy
Similar to infections, meta-analyses and observational studies with TNF antagonists in the RA
population demonstrated an increased risk of
malignancy [97, 98, 135, 136], although there is
conflicting evidence [137–144]. Again, the same
argument holds true as above where the different
disease states and the combination of immunosuppressants in this population may have a syner-
189
gistic effect resulting in an increased risk of
infection and malignancy that may not be applicable to the psoriatic patient population [104–
108]. In fact, in a meta-analysis the authors
concluded that there was no statistically significant increased risk of malignancy in patients with
psoriatic disease on short-term biologic therapy
[1].
Overall, in the malignancies observed, 70.6%
were non-melanoma skin cancers [1]. Whether
this was an artifact of increased recognition as
the psoriatic lesions healed is uncertain.
Additionally, it has been proposed that a patient’s
psoriasis may inherently increase their risk for
developing lymphoma, further complicating the
analysis of biological agents [144, 145]. In the
golimumab trials, non-melanoma skin cancers
were also the most common, however colon cancer, prostate cancer, and small cell lung carcinoma were also observed, although infrequently
[12]. Furthermore, the results of randomized controlled trials show that 26% of malignancies
occur within 12 weeks from enrollment in
patients receiving TNF inhibitors, suggesting
pre-existence of the cancers before initiation of
biologic therapy [146]. Therefore, it is prudent
that patients undergo age and risk adequate
screening before initiation of treatment.
Another meta-analysis was performed on
patients enrolled on certolizumab therapy regimens for all approved indications. This study
determined a standardized incidence ratio (SIR)
of malignancy to be 1.03 (95% CI 0.87 to 1.20)
using the SEER database and an SIR of 1.45
(95% CI 1.23 to 1.69) when using the worldwide
GLOBOCAN healthy population data set for
patients taking certolizumab. The authors suggest
that, although the SEER data base is typically
used in biologic safety studies, GLOBOCAN
data may be more representative of the population and caution should be exercised when dealing with biologics and malignancy risk [18].
Overall, the short-term risk-benefit profile of
biologics in patients with psoriatic disease is
favorable. However, continued long-term studies
with larger patient populations are necessary in
order to adequately assess the risk of cancer and
J. A. Mojeski and R. E. Kalb
190
serious infection with chronic use of infliximab,
golimumab, and certolizumab.
Laboratory Data/Autoimmune
Disease
use of TNF antagonists [9, 13]. Because of this
increased risk, patients with MS along with their
first-degree relatives have been cautioned against
the use of the drugs [123, 124].
Dermatologic
Some studies have reported abnormalities in laboratory data associated with the use of infliximab. Various skin complications have been reported
In a randomized study by Reich et al., a signifi- with the use of anti-TNF agents, some of which
cant increase in liver enzymes, aspartate and ala- include, delayed hypersensitivity type reactions,
nine aminotransferases was observed [32]. lupus-like syndrome, bullous skin lesions,
Anti-TNF agents have been associated with a eczematous-­like purpura, annular lichenoid erupnumber of cases of liver injury, such as choles- tion, and leucocytoclastic vasculitis [79]. In additatic disease and hepatitis, with some life-­ tion, several eczematous eruptions have occurred
threatening
cases
reported
[147–149]. with the use of infliximab, however most reacAdditionally, an association has been made tions resolve with discontinuation of the offendbetween anti-TNF agents and the development of ing agent [155].
autoimmune hepatitis type 1 reactions. After disInterestingly, there are an increasing number
continuation of the anti-TNF agent, liver enzymes of cases documenting the paradoxical formation
return to normal values and harmful reactions of psoriasis during treatment with TNF inhibitors
such as hepatitis typically regress. Interestingly, [3, 134, 156–160], primarily in patients treated
anti-TNF agents have also been anecdotally used for other autoimmune diseases, such as Crohn’s
as rescue therapy in treatment-resistant primary disease and rheumatoid arthritis [133, 161]. It is
biliary cholangitis and autoimmune hepatitis likely that the pathophysiology involves the dis[147]. Other laboratory abnormalities including equilibrium of cytokines caused by the inhibition
hematological disturbances have also been noted, of TNF-alpha. It has been suggested that TNF-a
such as rare cases of aplastic anemia and pancy- normally inhibits plasmacytoid dendritic cell
topenia, which can further predispose the patient secretion of interferon-alpha (IFN-a), a known
to serious infections [2].
inducer of psoriasiform lesions. The upregulation
Additionally, due to its chimeric nature, inflix- of IFN-a that occurs in patients on anti-TNF-a
imab has been shown to result in the formation of therapy may result in the formation of skin disantibodies [79]. Most commonly, antinuclear ease in predisposed individuals [160, 162].
antibodies (ANA), antibodies to double-stranded Various treatments have been reported to be useDNA, and anti-cardiolipin antibodies have been ful in this situation, such as aggressive topical
reported [150–152]. Studies of Crohn’s disease therapy, the addition of methotrexate, acitretin,
show that 44% develop ANAs at some point dur- cyclosporine, phototherapy, or switching the
ing the course of their treatment with infliximab TNF agent [160, 163]. Most frequently used
[7, 59]. While the development of systemic lupus agents have been glucocorticoids and vitamin D
erythematosus (SLE) in patients undergoing bio- analogs for topical therapy and methotrexate,
logic treatment is rare, it is postulated that the glucocorticoids, and phototherapy for systemic
important role TNF plays in autoregulation may treatment. Complete discontinuation of all biobe linked with new signs of autoimmune disease logics is often unnecessary, and a change in the
in patients receiving anti-TNF agents [13, 153, TNF antagonist used should be considered if con154]. It is also noted that withdrawal of therapy ventional treatment fails. Ultimately, 30.7–100%
typically results in resolution of symptoms. of patients were able to continue on anti-TNF-a
Several demyelinating and neurologic events, therapy with adjuvant topical or systemic treatincluding exacerbations of pre-existing multiple ment [160, 162].
sclerosis (MS), have also been reported with the
14
Infliximab, Golimumab, and Certolizumab Pegol
Treatment Switches
There is evidence that a gradual decline in therapeutic efficacy occurs in some patients with TNF
antagonists, whether through decreased bioavailability of the drug or as a biological adaptation to
chronic blockade, such as the development of
anti-drug antibodies [7, 56, 164]. However,
switching to a different biologic agent has proven
effective in treatment-refractory patients. In
2007, JAAD published a retrospective study
involving the efficacy of infliximab in patients
who previously failed treatment with etanercept
[164]. Infliximab was initiated at 5 mg/kg and
administered on weeks 0, 2, 6, 14, and every
8 weeks thereafter. After only 12 to 14 weeks of
infliximab therapy, 17 of 19 (89%) patients
showed improvements in their PGA and
BSA. Fifteen (79%) still maintained adequate
control on infliximab at the time of study publication, although 10 patients required infliximab
dose escalation, with a majority of patients
requiring infusions every 6 weeks to maintain
continued response. In addition, safety data was
obtained and compared between the two TNF-­
antagonists. The use of infliximab was associated
with a possible increased incidence in adverse
events compared to etanercept (16 versus 5
events, respectively). However, a majority of
these events were considered minor.
A multicenter, open-label prospective study
(PSUNRISE) was conducted to evaluate the clinical response of an etanercept-to-infliximab
switch in patients with psoriasis unresponsive to,
or with a loss of response to, etanercept therapy
[55]. Patients were included who had a PGA
score of at least 2 despite 4 or more months of
treatment with etanercept. Patients received intravenous infusions of infliximab 5 mg/kg at weeks
0, 2, 6, 14, and 22. At week 10, 65.4% of patients
achieved a PGA score of 0 (clear) or 1 (minimal)
and 61.3% of patients maintained this response
throughout the 26 weeks. Moreover, there were
no unexpected side effects or safety concerns
experienced during this study. This trial demonstrates that patients with an inadequate response
to etanercept may achieve substantial benefit
after switching to infliximab.
191
As an important aside, treatment switches
from anti-TNF therapy for non-medical reasons,
such as job loss or change of insurance, has been
associated with deteriorating clinical outcomes.
In a 2017 study, disease flares, disease control,
and health care utilization was compared between
patients who were switched/discontinued and
those that continued their anti-TNF agent.
Switchers were further classified by those that
switched to another biologic therapy and those
that switched to conventional therapy. The data
included patients with inflammatory conditions
including plaque psoriasis, psoriatic arthritis,
spondylarthritis, IBD, and rheumatoid arthritis.
Importantly, the authors found that switchers/discontinuers had worse clinical outcomes, even if
the agent that was switched to was another biologic agent (165). This study suggests that physicians need to be careful in the management of
their patients with inflammatory conditions and
have considerable knowledge about the insurance
formularies and compliance of their respective
patients.
Conclusion
Infliximab has been clinically available for over
two decades and a large body of data exists proving its generally increased efficacy and fewer
adverse events over traditional agents in numerous inflammatory disorders, including psoriasis
and psoriatic arthritis. Although newer anti-IL17
and anti-IL12/IL23 agents may have similar or
slightly superior efficacy in the treatment of psoriasis, research has proven the effectiveness of
infliximab, golimumab, and certolizumab in
treating signs and symptoms of psoriasis, and
demonstrated their rapid and prolonged suppression of inflammation preventing long-term disease progression, especially in debilitating
disease such as psoriatic arthritis. Infliximab and
golimumab are unique in the IV formulations
providing a rapid onset of action. Certolizumab
has a unique treatment niche in women of child
bearing potential. No new or unexpected safety
issues have emerged over the years, and infliximab, golimumab, and certolizumab have been
shown to be well-tolerated when clinicians
192
appropriately select patients and adhere to adequate screening and monitoring guidelines. As
for long-term efficacy, there is a great need for
the development of predictive biomarkers to predict response to biologic therapy, and more data
is needed in order to fully characterize the role of
neutralizing anti-drug antibodies. Overall, the
risk-benefit profile of these medications is favorable, and at this time, cost appears to be the main
barrier to the more widespread and extensive use
of these biological agents. The development and
use of biosimilars may have the potential to
reduce these costs for patients.
References
1. Dommasch ED, Abuabara K, Shin DB, Nguyen J,
Troxel AB, Gelfand JM. The risk of infection and
malignancy with tumor necrosis factor antagonists
in adults with psoriatic disease: a systematic review
and meta-analysis of randomized controlled trials. J
Am Acad Dermatol. 2011;64:1035–50. https://doi.
org/10.1016/j.jaad.2010.09.734.
2. Smolen JS, Emery P. Infliximab: 12 years of experience. Arthritis Res Ther. 2011;13(Suppl 1):S2.
https://doi.org/10.1186/1478-6354-13-S1-S2.
3. Silva LC, Ortigosa LC, Benard G. Anti-TNF-alpha
agents in the treatment of immune-mediated inflammatory diseases: mechanisms of action and pitfalls. Immunotherapy. 2010;2:817–33. https://doi.
org/10.2217/imt.10.67.
4. Tak PP, Kalden JR. Advances in rheumatology: new targeted therapeutics. Arthritis
Res Ther. 2011;13(Suppl 1):S5. https://doi.
org/10.1186/1478-6354-13-S1-S5.
5. Gupta AK, Skinner AR. A review of the use of
infliximab to manage cutaneous dermatoses.
J Cutan Med Surg. 2004;8:77–89. https://doi.
org/10.1177/120347540400800202.
6. Gall JS, Kalb RE. Infliximab for the treatment of
plaque psoriasis. Biologics: Targets & Therapy.
2008;2:115–24.
7. Drosou A, Kirsner RS, Welsh E, Sullivan TP,
Kerdel FA. Use of infliximab, an anti-tumor necrosis alpha antibody, for inflammatory dermatoses. J Cutan Med Surg. 200(7):382–6. https://doi.
org/10.1177/120347540300700503.
8. Services U S D o H a H. FDA Approved Drug
Products, Remicade. In, 2011.
9. Herrier RN. Advances in the treatment of moderate-­
to-­
severe plaque psoriasis. Am J Health Syst
Pharm. 2011;68:795–806. https://doi.org/10.2146/
ajhp100227.
J. A. Mojeski and R. E. Kalb
10. Scallon B, Cai A, Solowski N, et al. Binding and
functional comparisons of two types of tumor
necrosis factor antagonists. J Pharmacol Exp
Ther. 2002;301:418–26. https://doi.org/10.1124/
jpet.301.2.418.
11. Smeets TJ, Kraan MC, van Loon ME, Tak PP. Tumor
necrosis factor alpha blockade reduces the synovial
cell infiltrate early after initiation of treatment, but
apparently not by induction of apoptosis in synovial
tissue. Arthritis Rheum. 2003;48:2155–62. https://
doi.org/10.1002/art.11098.
12. Weger W. Current status and new developments in
the treatment of psoriasis and psoriatic arthritis with
biological agents. Br J Pharmacol. 2010;160:810–20.
https://doi.org/10.1111/j.1476-5381.2010.00702.x.
13. Sfikakis PP. The first decade of biologic TNF
antagonists in clinical practice: lessons learned,
unresolved issues and future directions. Curr
Dir Autoimmun. 2010;11:180–210. https://doi.
org/10.1159/000289205.
14. Services U S D o H a H. FDA Approved Drug
Products, Simponi and Simponi Aria. In, 2013.
15. Lee JU, Shin W, Son JY, Yoo KY, Heo Y. Molecular
basis for the neutralization of tumor necrosis factor
a by Certolizumab Pegol in the treatment of inflammatory autoimmune diseases. Int J Mol Sci. 2017;18
https://doi.org/10.3390/ijms18010228.
16. Rivkin A. Certolizumab pegol for the management of
Crohn’s disease in adults. Clin Ther. 2009;31:1158–
76. https://doi.org/10.1016/j.clinthera.2009.06.015.
17. Bourne T, Fossati G, Nesbitt A. A PEGylated fab’
fragment against tumor necrosis factor for the treatment of Crohn disease: exploring a new mechanism
of action. Bio Drugs. 2008;22:331–7. https://doi.
org/10.2165/00063030-200822050-00005.
18. Services USD. O H a H. FDA approved drug products. Cimzia.
19. Bianchi L, Costanza G, Campione E, Ruzzetti M,
et al. Biomolecular index of therapeutic efficacy
in psoriasis treated with anti-TNF-a agents. G Ital
Dermatol Venereol. 2018;153:316–25. https://doi.
org/10.23736/S0392-0488.16.05427-4.
20. Mitoma H, Horiuchi T, Tsukamoto H, Ueda
N. Molecular mechanisms of action of anti-TNF­a agents -- comparison among therapeutic TNF-a
antagonists. Cytokine. 2018;101:56–63. https://doi.
org/10.1016/j.cyto.2016.08.014.
21. Blandizzi C, Gionchetti P, Armuzzi A. The role
of tumour necrosis factor in the pathogenesis of
immune-mediated disease. Int J Immunopathology
and Pharmacology. 2014;27:1–10. https://doi.org/10
.1177/03946320140270S101.
22. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatology. 2016;12:49–62.
https://doi.org/10.1038/nrrheum.2015.169.
23. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak
PP. Tumor necrosis factor antagonist mechanisms
of action: a comprehensive review. Pharmacol
15
Ustekinumab
George Han, Caitriona Ryan, and Craig L. Leonardi
Abstract
Ustekinumab is a fully human IgG antibody to
the common p40 subunit of interleukin-12 (IL12) and IL-23, which has shown considerable
efficacy in the treatment of psoriasis and psoriatic arthritis. This review examines the efficacy
and safety of ustekinumab for the treatment of
psoriasis in clinical studies to date.
Ustekinumab was shown to be highly effective
in the treatment of moderate-to-­severe psoriasis with sustained response for up to 5 years in
the majority of patients. Adverse events in
clinical studies to date have been for the most
part, mild and similar to that in placebo-treated
patients. Similarly, ustekinumab has shown
efficacy in psoriatic arthritis and in adolescent
psoriasis in patients ages 12 and up. While
early questions about major adverse cardiovascular events existed in relation to this class of
medication, the burden of evidence over the
clinical trial program and over a decade in clin-
G. Han (*)
Department of Derrmatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: george.han@mountsinai.org
C. Ryan
Department of Dermatology, Baylor University
Medical Center, Dallas, TX, USA
C. L. Leonardi
Department of Dermatology, Saint Louis University
School of Medicine, St. Louis, MO, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_15
ical practice has borne out that ustekinumab
remains a safe and effective treatment for psoriasis and psoriatic arthritis.
Key Learning Objectives
1. To understand the mechanism of action
of ustekinumab.
2. To understand the appropriate use and
efficacy of the ustekinumab.
3. To understand the safety issues of
ustekinumab.
Introduction
Ustekinumab (Janssen Biotech, Philadelphia,
PA) is a fully human immunoglobulin G1/kappa
(IgG1/κ) monoclonal antibody to the p40 subunit
common to interleukin-12 (IL-12) and IL-23,
which has shown efficacy in the treatment of
moderate-to-severe psoriasis and psoriatic arthiritis [1]. It was first approved for treatment of
plaque psoriasis in adults in the United States in
2009 and subsequently received approval to treat
psoriatic arthritis in 2013 and psoriasis in adolescents in 2017. It is also approved in Europe and
multiple other countries for psoriasis and psoriatic arthritis; and for use in psoriasis for ages 6
and up by the European Medicines Agency [2].
IL-12 and IL-23 are heterodimeric cytokines
201
202
which possess a common p40 subunit linked by a
disulfide bond to a unique chain, IL-12p35 and
IL-23p19, respectively [3, 4]. The p40 subunit
binds to the IL-12 receptor-beta1 (IL-12Rb1) on
the surface of T lymphocytes and natural killer
cells. Interleukin-12 is a potent inducer of
interferon-­
gamma (IFN-g), which promotes
T-cell differentiation toward a Th1 lineage, while
interleukin-23 is the major regulator of Th17
CD4 cells, a subset of T helper cells distinct from
Th1 and Th2 cells, defined by their ability to produce IL-17 [5]. Interleukin-23 stimulates IL-17A,
IL-17F and IL-22 production from Th17 cells
and mediates its effects through Janus kinase-2
(JAK2) and STAT3, leading to hyperproliferation
of keratinocytes and production of chemokines,
angiogenic factors (VEGF) and pro-­inflammatory
mediators such as tumor necrosis factor-alpha
(TNF-a), nitric oxide and IL-1b [6, 7]. As psoriasis was originally thought to predominately be a
Th1-cell mediated disease, ustekinumab was specifically developed to target IL-12; indeed, IL-23
was not even identified until after ustekinumab
was submitted to the FDA for approval. The
dichotomy of these two cytokines lies in their
upregulation of Th1 cells (for IL-12) and Th17
cells (for IL-23) [6, 8]. Interestingly, it has since
been shown that IL-12 may have little to do with
the pathogenesis of psoriasis [9, 10] and actually
inhibits IL-23 itself [11]. The concomitant inhibition of IL-23 was thus, a fortuitous result of targeting the p40 subunit [12, 13]. It is worthwhile
to note that a similar monoclonal antibody targeting the p40 subunit, briakinumab, was under
development but was withdrawn from clinical trials due to safety concerns relating primarily to
adverse cardiovascular risk [14].
Pharmacokinetics
In phase I studies in psoriasis, ustekinumab
showed linear pharmacokinetics with both
ascending single intravenous doses and ascending single subcutaneous doses of the drug [15].
After a single subcutaneous dose, ustekinumab
was slowly absorbed, reaching maximum concentration (tmax) between 7 and 14 days [16]. The
G. Han et al.
absolute bioavailability (F) of ustekinumab was
estimated to be 57.2% after a single subcutaneous dose, with an apparent volume of distribution
of 79-161 ml/kg at the terminal phase [17].
Steady-state concentrations were achieved by
week 28 in phase III studies in psoriasis, with
trough steady-state serum concentrations (ctrough)
showing dose proportionality. The median ctrough
in those taking 90 mg every 12 weeks was twice
that of those taking 45 mg in two phase III psoriasis studies (0.47 vs 0.21ug/ml in PHOENIX 1
and 0.49 vs 0.26ug/ml in PHOENIX 2), with no
evidence of accumulation with either dosage regimen. The metabolic pathway of ustekinumab
has not yet been fully elucidated. As a human IgG
monoclonal antibody, ustekinumab is most likely
degraded into small peptides and amino acids by
the reticuloendothelial system in the same manner as endogenous IgG. A combined analysis of
phase III studies in psoriasis calculated the mean
half-life to be 21.6 days [18]. A population based
approach was used to further characterize the
pharmacokinetic profile of ustekinumab based on
two phase III studies [1, 18, 19]. Mean values for
apparent clearance, apparent volume of distribution and absorption rate constant were 0.465 L/
day, 15.7 L and 0.354/day, respectively. Based on
the known bioavailability of ustekinumab, the
volume of distribution of ustekinumab was calculated to be approximately 8.9 L in a 90 kg psoriasis patient, suggesting that ustekinumab is
confined to the intravascular system, with limited
tissue distribution. Factors influencing variation
in apparent clearance and apparent volume of
distribution included body weight, diabetes mellitus (independent of weight) and anti-drug antibodies to ustekinumab [18]. The most significant
effect was caused by body weight, with an apparent clearance and apparent volume of distribution
approximately 55% and 37% higher, respectively, in those with a bodyweight of greater than
100 kg compared with those of 100 kg or less.
This emphasizes the importance of dose adjustment in those who have a higher bodyweight to
achieve a similar efficacy. None of the 28 concomitant medications analyzed had a significant
effect on the pharmacokinetic profile. 3.2% of
patients developed antibodies to ustekinumab,
15
Ustekinumab
which was associated with a mean increase in
apparent clearance of 35.5% in these patients.
In the US, the current licensed dosage regimen
is 45 mg of ustekinumab at baseline, 4 weeks and
every 12 weeks in those less than 100 kg in
weight, and 90 mg of ustekinumab at the same
intervals for those heavier than 100 kg. These
dosage recommendations were made based on
analyses of 10-Kg increments with a presumed
ideal cutoff point to separate response between
the lower and higher dose regimens [20].
203
of these cytokines at week 1 compared to baseline, the mRNA expression of IL-8, IL-18 and
IFN-γ was significantly decreased in the lesional
skin of those who had a sustained response of at
least 70% improvement in PASI at 3 separate
time-points (week 8, 12 and 16), compared with
those without sustained PASI improvement.
The effects of ustekinumab on lesional skin
and peripheral blood in a subset of psoriasis
patients were examined in a phase II psoriasis
study [22]. At week 12, a significant decrease in
median epidermal thickness correlated with a
reduction in cellular proliferation (Ki67) and
Pharmacodynamics
T-cell infiltration (CD3) by 84.3% and 70.7%,
respectively, in the combined ustekinumab group.
Two phase I studies have examined the pharma- Surprisingly, the level of IL-12p40, the target of
codynamics of ustekinumab in lesional psoriatic ustekinumab, increased 13-fold from baseline to
skin. The first examined the effect of intravenous week 12, before slowly decreasing to near baseustekinumab in 18 patients. There was a signifi- line levels by week 32. This was postulated to be
cant reduction in the expression of IFN-g, TNF-­ due to decreased clearance of non-functional cirα, IL-8, IL-10, IFN-γ-inducible protein-10 and culating complexes of ustekinumab-bound
monocyte chemotactic protein-1 (MCP-1) within IL-12p40. The expression of cutaneous lympho2 weeks of administration of the drug before clin- cyte antigen (CLA), which facilitates homing of
ical response and histological changes were evi- activated T cells to the skin, significantly
dent [21]. A significant reduction in total CD3+ T decreased from baseline in ustekinumab-treated
cells was observed in responders (those achiev- patients compared with placebo, while there was
ing a PASI-75 response) but not in non-­responders no change in expression of CD45RA, CD45RO,
by week 2. Levels of TNF-α were significantly CXCR3, CD25 or HLA-DR on T cells. The sysreduced in responders but not in poor responders, temic effects of ustekinumab were also investiwhile levels of IL-12p40 and IL-23p19 were gated in vitro in healthy donors using isolated
reduced in both populations, particularly in peripheral blood mononuclear cells in the absence
responders. When baseline genetic expression of or presence of recombinant IL-12 or IL-23 [22].
responders was compared to that of non-­ Ustekinumab inhibited up-regulation of IL-12R,
responders, mRNA expression of TNF-α was sig- IL-2Rα (CD25) and the co-stimulatory receptor
nificantly higher in responders and correlated CD40L, while reducing IL-12 and IL-23-induced
with the percentage improvement in PASI, sug- secretion of the pro-inflammatory cytokines IFN-­
gesting that this may be a predictor of treatment γ, TNF-α, IL-2 and IL-17A.
response. The second phase I study examined the
effect of subcutaneous ustekinumab in 21
patients. Punch biopsies were obtained from Clinical Efficacy
lesional skin 24 hours before, and 1 week after
IL-12/23 antibody administration, and the mRNA Two large scale phase 3, multicenter, randomexpression of various cytokines, including TNF-­ ized, double-blind, placebo-controlled, parallel
α, IFN-γ, IL-8, IL-18, IL-12/23p40 subunit, studies (PHOENIX 1 and PHOENIX 2) were
IL-23p19 subunit, IL-12p35 subunit, IL-10, performed to evaluate the subcutaneous adminisIP-10, RANTES and CCL-2 was measured using tration of ustekinumab in patients with moderate-­
real-time polymerase chain reaction. Although to-­severe psoriasis [1, 19]. In PHOENIX 1, 766
there was no significant change in the expression patients were randomized to receive 45 mg or
204
90 mg of ustekinumab at baseline, week 4, followed by every 12 weeks, or to receive placebo at
week 0 and 4, with crossover to receive either
45 mg of ustekinumab or 90 mg of ustekinumab
at week 12 [1]. Those in the initial ustekinumab
group who achieved a sustained PASI-75 at both
week 28 and 40 were re-randomized at week 40
to ongoing treatment or withdrawal from treatment for another 36 weeks until loss of response
(weeks 40–76). These patients were retreated
when they lost at least 50% of PASI improvement. At week 12, PASI-75 was achieved in
67.1% of those receiving 45 mg, and 66.4% of
those receiving 90 mg of ustekinumab compared
with 3.1% of those taking placebo, while PASI-­
90 was achieved in 41.6%, 36.7% and 2% of
these groups, respectively. Those receiving placebo, achieved similar response rates after crossover to active treatment. Maximum efficacy was
achieved at week 24, with PASI-75 responses of
76.1% and 85% for the 45 mg and 90 mg
ustekinumab groups, respectively. A significantly
higher proportion of those receiving maintenance
treatment maintained a PASI-75 response compared to those from whom treatment was withdrawn (p < 0.0001). Response rates stayed stable
up to 76 weeks in the maintenance group, with a
median time to loss of PASI-75 of 15 weeks. No
rebound flare was observed on discontinuation of
ustekinumab (defined as a PASI greater than
125% of baseline). Of the 195 patients who
recommenced ustekinumab after losing response,
85.6% reestablished a PASI-75 response within
12 weeks. Patient-determined quality of life, as
determined by DLQI, showed a similar improvement to objective assessments of disease severity,
with median changes in ustekinumab-treated
patients significantly greater than placebo-treated
patients at week 12. A subsequent analysis
showed that at 3 years, 79.8% of patients (601 of
753 patients) who received one or more dose of
ustekinumab remained in the study and that
80.9% (45 mg) and 82.7% (90 mg) of week 40
responders continuing treatment every 12 weeks
achieved a PASI-75 response [23].
In PHOENIX 2, a similar schedule was
followed over 52 weeks, with a total of 1230
G. Han et al.
patients randomized to receive 45 mg or 90 mg
of ustekinumab or placebo at baseline, week 4,
and then every 12 weeks or placebo at baseline
and week 4, followed by a placebo crossover to
receive 45 mg or 90 mg of ustekinumab (week
12–28) [19]. At week 28, partial responders
(those who had achieved greater than PASI50 but less than PASI-75), were randomized to
escalate dosing to every 8 weeks at their originally assigned dose, or to continue receiving
ustekinumab every 12 weeks (week 28–52). At
week 12, 66.7% of patients receiving 45 mg
ustekinumab, and 75.7% receiving 90 mg
ustekinumab achieved PASI-75, compared
with 3.7% receiving placebo, while PASI-90
was achieved in 42.3%, 50.9% and 0.7% of
these groups, respectively. There was also a
highly significant improvement in DLQI in the
ustekinumab treated patients compared with
the placebo group at week 12 (p < 0.0001).
Maximum PASI-75 response rates were
attained at week 20 (74.9% of the 45 mg group
and 83.5% of the 90 mg group). At week 28,
22.7% of patients in the 45 mg ustekinumab
group were partial responders compared with
15.8% in the 90 mg group. Independent predictors of partial response included increased
bodyweight, a history of non-­
response to
biologic agents, longer duration of psoriasis
and the presence of psoriatic arthritis. Partial
responders had a significantly higher incidence
of antibodies to ustekinumab (12.7%) compared to responders (2%), and serum trough
drug levels were two to three times lower than
those of responders. Escalation from a 12
weekly to an 8 weekly dosing regime resulted
in a four to five times increase in the mean
trough serum concentrations in partial responders between week 28 and week 52. In partial
responders who received dosing intensification of ustekinumab 90 mg every 12 weeks to
ustekinumab 90 mg every 8 weeks, there was
a significant increase in those achieving PASI75, compared to those who remained at a dose
of ustekinumab 90 mg every 12 weeks, with
response rates of 68.8% and 33.3%, respectively. There was no significant difference in
15
Ustekinumab
response, however, in those randomized to
receive 45 mg of ustekinumab every 8 weeks,
compared to those who continued to receive
45 mg every 12 weeks. Further data were gathered out to 5 years of follow-up, with patients
randomized to either 45 mg or 90 mg groups
where dosage and interval adjustments (from
q12 weeks to q8 weeks; from 45 mg to 90 mg)
were allowed at the discretion of the investigator. At week 244, the proportions of patients
achieving PASI 75 were 76.5% and 78.6%
for those who started in the 45 mg and 90 mg
groups, respectively; PASI 90 was achieved in
50.0% and 55.5% of patients in the 45 mg and
90 mg groups, respectively [24].
The first study to directly compare the efficacy
of two biologic agents in psoriasis was the
ACCEPT study, a single-blind randomized, parallel phase III study of 903 psoriasis patients
comparing the safety and efficacy of ustekinumab
with etanercept [25]. Patients were randomized
to receive ustekinumab 45 mg or 90 mg at baseline and at week 4 or etanercept 50 g twice
weekly for 12 weeks. There was no placebo arm
in this study. At week 12 PASI-75 was achieved
in 67.5% of those receiving 45 mg ustekinumab,
73.8% of those receiving 90 mg of ustekinumab
and 56.8% of those receiving etanercept, while
PASI-90 was achieved in 36%, 45% and 23% of
these groups, respectively. A PGA of cleared or
minimal was achieved in 65.1%, 70.6% and 49%
of the groups.
Psoriatic Arthritis
A randomized, double-blind, placebo-controlled,
Phase III study of ustekinumab was performed
in 615 patients with active psoriatic arthritis
(PSUMMIT-1) [26]. Patients who previously used
methotrexate and those who were using disease-­
modifying antirheumatic drugs (DMARDs) or
NSAIDs were allowed in the study but patients
with a history of TNF-α inhibitor use were not.
The primary endpoint was ACR20 at week 24. At
the end of 24 weeks, 22.8% patients on placebo
achieved ACR20 compared to 42.4% and 49.5%
205
of patients on ustekinumab 45 mg and 90 mg,
respectively. About half of the patients took
methotrexate during the study, which did not
influence the likelihood of attainment of ACR20
for ustekinumab vs. placebo, though the benefit
was likely to be slightly greater in patients who
were not using concomitant methotrexate.
A later trial was conducted (PSUMMIT-2)
which was a randomized, double-blind, placebo-­
controlled, Phase III study of ustekinumab in
psoriatic arthritis, with the notable difference
from PSUMMIT-1 that patients who had used
TNF-α inhibitors previously were now allowed
into the study [27]. A total of 312 patients were
studied, including 180 with prior exposure to
TNF-α inhibitors. For TNF-α-naïve patients,
ACR20 rates were similar to PSUMMIT-1—with
43.7% and 43.8% of patients achieving this
threshold for ustekinumab 45 mg and 90 mg,
respectively. However, the response rates for
patients who had previously been on TNF-α
inhibitors was somewhat lower—36.7% and
34.5% for ustekinumab 45 mg and 90 mg, respectively. Notably, the study was not powered to
assess for a statistically significant difference in
response rates between the two groups (TNF-α
experienced or naïve). Also interestingly, the
patients’ skin disease seemed to track along with
the psoriatic arthritis response, where patients
previously exposed to TNF-α inhibitors experienced a little over 10% lower achievement of
PASI-75 than patients who had never been on
that class of biologic.
Adolescent Patients
A randomized, double-blind, placebo-controlled
Phase III study was completed in adolescent
patients from 12–17 years of age [28]. The study
was conducted with a primary endpoint of PGA
0/1 and PASI 75 at week 12, with a long-term
extension to 1 year. A total of 110 patients were
studied and assigned to different dosing regimens, including a half-dose cohort. Patients
under 60Kg received 0.75 mg/Kg in the standard
dose (SD) group or 0.375 mg/Kg in the half-­
G. Han et al.
206
standard dose (HSD) group. Patients from greater
than 60 Kg to 100 Kg received 45 mg (SD) or
22.5 mg (HSD) and patients greater than 100 Kg
received 90 mg (SD) or 45 mg (HSD). Overall,
78.4% of patients in the HSD and 80.6% in the
SD group achieved PASI 75 compared to 10.8%
for placebo. 54.1% of patients in the HSD group
achieved PASI 90 compared to 61.1% of patients
in the SD group and 5.4% of patients in the placebo group. In the placebo-controlled period
(through 12 weeks), 56.8% of placebo, 51.4% of
HSD, and 44.4% of SD patients reported adverse
events. No major safety issues were observed different from the side effects seen from ustekinumab
in adults. Based on this data, the FDA approved
ustekinumab for patients above 12 years of age at
the standard dosing regimen.
Adverse Effects
There is a good deal of safety data for
ustekinumab available from a pooled longitudinal analysis of phase II and phase III clinical
trials in moderate-­to-­severe psoriasis [29–31] as
well as longer term registry databases, including
the Psoriasis Longitudinal Assessment Registry
(PSOLAR). Initial safety data was based on all
safety data available from the Phase 2 study,
PHOENIX 1 and 2 and the ACCEPT study, with
a total of 5 years’ of safety data. A total of 3117
patients had been followed for up to 4 years
(6791 patient-­
years). During the combined
12 week placebo-­controlled period of these studies, 50.4%, 57.6% and 51.6% of patients treated
with placebo, 45 mg of ustekinumab and 90 mg
of ustekinumab, respectively, experienced at least
one adverse event, while 1.4%, 1.6% and 1.4%
of patients in these groups experienced a serious side effect and 1.9%, 1.1% and 1.4% were
withdrawn from the study due to adverse effects.
The most common side effects were nasopharyngitis, upper respiratory tract infections, headache
and arthralgias. Rates of adverse events, serious adverse events, infections or adverse events
requiring discontinuation of treatment did not
increase with increased duration of treatment and
were comparable between ustekinumab doses.
Serious Infections
Based on animal models of cytokine deficiency
and patients with genetic mutations encoding
IL-12 and IL-23 or their receptors, there was particular concern about a theoretical increase in the
risk of serious infections or malignancy with the
advent of these agents. In animal models, IL-12
has been shown to be important in prevention
against mycobacteria, salmonellosis and toxoplasmosis and patients with a genetic deficiency
of the IL-12 receptor or the IL-12p40 subunit
have an increased risk of severe infections with
intracellular pathogens such as mycobacteria and
salmonella [32–36]. Experimental animal models of herpes viral infection, viral encephalitis,
viral hepatitis and aquired immunodeficiency
syndrome (AIDS), have also demonstrated a
central role for IL-12 in protecting against viral
infection [37–40]. Interleukin-12 also appears
to be important in defense against opportunistic
fungal infections, with increased susceptibility
to Cryptococcus neoformans infection observed
in p35−/− or p40−/−knockout mice and prevention of infection following the administration of
IL-12 [41, 42]. Similarly, IL-12p40−/− knockout mice did not control fungal proliferation and
dissemination and succumbed to infection following intravenous inoculation of yeast cells of
paracoccidioidomycosis.
Interleukin-23 is also believed to contribute to
immune protection in the skin, lung and gut.
Interleukin-23 and IL-17, however, have been
shown to be only marginally involved in primary
infections with pathogens that require TH1 immunity [43–47]. One study showed that blocking
IL-23 alone does not increase bacterial burden in
immunocompetent mice after BCG infection but
that blocking TNF-α or the p40 subunit results in
increased infectious burden [48, 49]. Interleukin-­
23p19 deficient mice showed significant mortality following a sub-lethal dose of intrapulmonary
Klebsiella
pneumoniae,
however,
while
IL-12p40-deficient, IL-12p35- deficient and
IL-17R-deficient mice also show increased susceptibility to infection following inoculation
[50]. Administration of IL-17 restored the normal
infectious response in IL-23p19-deficient mice,
15
Ustekinumab
207
but not completely in p40-deficient mice, sug- 55]. Patients with congenital deficiencies of
gesting the additional role of IL-12-induced IL-12p40 or IL-12R, however, do not appear to
IFN-g production in the immune defense to have an increased incidence of malignancy [35].
Klebsiella infection. Another experimental study Interleukin-23, in contrast, appears to promote
showed that IL-23 plays a critical role in the host tumor growth, suggesting that inhibition of this
defense to Pneumocystis Carinii [51]. Individuals cytokine may inhibit carcinogenesis [56].
with abnormalities of Th17 cell function, such as
There were no differences in the incidence
patients with hyper-IgE (Job’s) syndrome and of non-melanoma skin cancer (NMSC) or other
chronic mucocutaneous candidiasis, are more malignancies during the placebo-controlled
prone to infection with Staphylococcus aureus phases of usekinumab studies [31]. The rate of
and candida albicans.
NMSC was 0.7/100PY in the 45 mg group and
However, clinical studies to date have not 0.53/100PY in the 90 mg group (34 BCC and
shown an increase in serious infections with the 10 SCC) and higher among patients previously
use of ustekinumab [31]. In the pooled analysis, treated with psoralen-UVA [31, 57]. Long-term
the frequency of infection during the placebo-­ follow-up data showed rates of malignancies
controlled period of the studies in patients receiv- other than NMSC of 0.63/100PY in the 45 mg
ing placebo, 45 mg of ustekinumab or 90 mg group and 0.61/100PY in the 90 mg group, with
of ustekinumab, was 23.2%, 27% and 24.1%, a total of 42 malignancies over the course of the
respectively, while the rates of serious infection studies [31]. These rates were consistent with
were similar between the placebo (1.70/100PY) age-, race- and gender-matched rates expected in
and 90 mg (1.97/100PY) groups but lower in the the normal United States population according to
in the 45 mg group (0.49/100PY) [31]. The rates the Surveillance, Epidemiology, and End Results
of overall infection, serious infection and infec- (SEER) database. Furthermore, analysis of the
tions requiring antibiotic treatment remained PSOLAR database showed no increased maligstable or decreased over the 4 years, with rates nancy risk for ustekinumab in matched-control
serious infection of 0.8/100 patient years (PY) cohort.
and 1.32/100PY for patients treated with 45 mg
and 90 mg of ustekinumab respectively and were
consistent with expected rates in psoriasis patients Major Adverse Cardiovascular Events
using the Marketscan Database. No cases of
tuberculosis were reported in the pooled analysis, The withdrawal of a similar biologic treatment
but one man who had a previously negative puri- mechanistically, briakinumab, from clinical studfied protein derivative and QuantiFERON-TB ies generated some interest and concern regardGold screening tests, had a tuberculosis reactiva- ing the potential adverse cardiovascular effects of
tion after two doses of ustekinumab in a RCT of anti-IL-12p40 agents. A total of five MACE
Asian psoriasis patients [52].
(0.3%), including one cardiovascular death, were
reported in 1582 ustekinumab-treated patients
compared with no events in 732 placebo recipients (0%) during the placebo-controlled phases
Malignancy
of the pooled analysis [31]. All of these events
Animal studies have also suggested increased occurred in patients with three or more cardiotumorigenicity following inhibition of IL-12 vascular risk factors. All cardiovascular events
[53–55]. Interleukin-12 has shown anti-tumor were re-adjudicated externally at the four-year
and anti-metastatic activity in murine tumor follow-up safety analysis and a total of 34 MACE
models of melanoma, renal cell carcinoma and were identified, with four cardiovascular deaths
breast cancer, while IL-12 deficient mice have an [31]. The rate of MACE was 0.56/100PY and
increased incidence of UVB-induced skin tumors 0.46/100PY in the 45 mg and 90 mg groups,
and malignant transformation of papillomas [53– respectively. This was reported to be within the
208
G. Han et al.
expected range of such events for both the gen- showed a significantly higher risk of MACE in
eral US population and the psoriatic population, patients treated with anti-IL-12/23 agents comleading the sponsoring company to conclude that pared with placebo (odds ratio = 4.23, p = 0.04).
there was no apparent change in cardiac risk with The discrepancy between these meta-analyses
this agent. However, it is clear that numerically, a results from the use of different statistical methhigher number of MACE were observed in the ods to compare MACE rates. Risk difference is
placebo-controlled period in the ustekinumab-­ considered to be a more conservative measure
treated cohort compared to control.
in comparing rare events but has the potential to
Two subsequent meta-analyses have been introduce false negative results. This was chosen
performed to evaluate the effect of anti-IL-12/23 over the Peto odds ratio method by the authors
agents on cardiovascular risk [14, 58]. The first of the first study because 16 of the 22 studies
was an independent meta-analysis of 22 random- had zero events and would have been excluded
ized controlled trials (RCTs) comprising 10,183 from the analysis if the odds ratio was used,
patients to evaluate the effect of biologic agents possibly leading to selection bias [59]. A later
on cardiovascular risk in psoriasis patients [14]. meta-­analysis of a number of biologics including
Double-blind, placebo-controlled RCTs of anti-­ ustekinumab also used the Peto odds ratios, and
IL12p40 agents (ustekinumab and briakinumab) concluded that there was not a significant risk of
and TNF-a inhibitors (infliximab, etanercept and MACE with ustekinumab [60]. Somewhat reasadalimumab) were compared and absolute risk suringly, further studies of ustekinumab use in the
differences were used as an effect measure, mea- real world have not shown a significant increase
suring the excess probability of major adverse in MACE; a cohort study of over 60,000 patients
cardiovascular events (MACE, a composite end- from multiple databases was studied and no sigpoint of myocardial infarction, cerebrovascular nificant difference was found in the risk of develaccident, or cardiovascular death) in those receiv- oping atrial fibrillation or MACE after initiation
ing active treatment compared to those receiving of therapy with ustekinumab vs. a TNF-α inhibiplacebo. During the placebo-controlled phases tor [61]. While there is some disagreement in the
of the anti-IL-12p40 studies, 10 of the 3179 literature, the majority of currently-­available evipatients treated with anti-IL-12p40 therapies dence—after over a decade on the market—suphad a MACE compared with zero events in 1474 ports that there is no significant safety signal with
patients treated with placebo (risk difference 1.2 MACE for ustekinumab.
events/100PY, p = 0·12). In anti-TNF-a trials,
only one of 3858 patients treated with anti-TNF­a treatments had a MACE compared with one of Other Adverse Events
1812 treated with placebo (risk difference 0.05
events/100PY, p = 0.94). Although the apparent Although there was initial concern that IL-12
increase in MACE observed with patients receiv- blockade could result in skewing towards a Th2
ing anti-IL-12p40 antibodies was not statistically type cytokine profile, there was no evidence of
significant, the findings did raise questions about exacerbation of any atopic disease in these studthe cardiovascular safety of the anti-IL-12p40 ies. No cases of demyelination were reported
agents and the authors recommended heightened apart from a possible case in a patient who was
vigilance when commencing patients with car- retrospectively diagnosed with human immunodiovascular risk factors on ustekinumab. The sec- deficiency virus and profoundly lymphopenic at
ond meta-analysis examined the rate of MACE the time. Two cases of reversible posterior leukein patients in randomized, placebo-controlled, ncephalopathy syndrome were reported as well;
monotherapy studies of IL-12/23 antibodies one in a 65 year old with a history of alcohol
using the Peto one-step odds-ratio, an alterna- abuse who recovered fully from the episode and a
tive statistical method, as an effect measure. This 58 year old with a positive urine drug screen for
15
Ustekinumab
MDMA, benzodiazepenes, barbiturates, and
marijuana who also recovered fully [62, 63].
Laboratory Abnormalities
In phase I studies of ustekinumab in psoriasis, transient asymptomatic decreases in CD4+
T cells and CD16+/CD56+ natural killer cells
were observed in some patients but this was not
seen in phase II or III studies [15, 16]. In phase
II and III studies in psoriasis and in psoriatic
arthritis, the incidence of haematological and
biochemical abnormalities was low and similar between ustekinumab-treated and placebotreated patients. In the phase II study of psoriasis,
however, there was a non-significant trend of elevated non-fasting glucose levels in ustekinumabtreated patients (10%) compared with controls
(4%) (p = 0.23) [64]. This was not observed in
subsequent phase III studies in psoriasis and
ustekinumab was shown to have no effect on haemoglobin A1c levels.
Pregnancy and Lactation
Ustekinumab is pregnancy category B. The
product prescribing information states that
ustekinumab should be used during pregnancy
only if the potential benefit justifies the potential risk to the fetus [65]. Toxicology studies
on cynomolgus monkeys revealed no maternal
or fetal abnormalities following administration
of intravenous and subcutaneous doses of up
to 50 mg/kg during the period of organogenesis [65]. Post-­marketing data is an important
source of information for pregnancy risks and
outcomes. A publication from 2019 reported the
outcomes of 478 maternal pregnancies across all
indications of ustekinumab (including Crohn’s
disease and ulcerative colitis)—the majority
resulted in live births and the rates of live births,
spontaneous abortion, and congenital anomalies were consistent with the general population
[66]. The product prescribing information for
ustekinumab advises caution in administration
209
of ustekinumab to nursing mothers, where the
unknown risks to the infant from gastrointestinal exposure to ustekinumab should be weighed
against the known benefits of breast-feeding [65].
Ustekinumab is excreted in the milk of lactating
monkeys, and as endogenous IgG is excreted in
human milk, it is expected that ustekinumab will
be also be present. It is not known if ustekinumab
would be absorbed systemically through the
immature neonatal gastrointestinal tract after
ingestion.
Cautions for Patients Treated
with Anti-IL-12p40 Agents
There are no absolute contraindications to treatment with ustekinumab [65]. Treatment should
be deferred in patients with clinically important
active infections until the infection resolves or is
appropriately treated [65]. No increase in serious infections has been observed with the use of
ustekinumab, however, despite initial concerns
regarding longer half-life of the drug [31]. Patients
with evidence of active or latent tuberculosis
should be treated with anti-tuberculosis treatment prior to initiating treatment [65]. Current
evidence does not support use or avoidance of
ustekiniumab within populations at risk for major
adverse cardiovascular events. Ustekinumab has
no currently known drug interactions. Patients
should receive all age-­
appropriate immunizations recommended by current guidelines prior
to commencing ustekinumab and live vaccines
should not be administered during treatment. The
Bacillus Calmette-Guérin (BCG) vaccine should
not be administered for 1 year prior to or after
discontinuation of treatment [65].
Conclusions
The field of psoriasis research has been revolutionized by the increased understanding of the pivotal
role of the Th-17/IL-23 axis in disease pathogenesis. As the first non-TNF-α inhibiting biologic for
the treatment of psoriasis, ustekinumab signaled
210
G. Han et al.
the arrival of new therapeutic options for psoria- References
sis patients, offering more targeted treatment with
1. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy
better efficacy and favorable side effect profiles.
and safety of ustekinumab, a human interleukin-12/23
Ustekinumab, the only licensed anti-IL-12p40
monoclonal antibody, in patients with psoriasis:
agent, still plays an important role in the current
76-week results from a randomised, double-blind,
placebo-controlled trial (PHOENIX 1). Lancet.
therapeutic armamentarium for psoriasis although
2008;371:1665–74.
newer agents focused on inhibiting only IL-23 are
2. See URL: http://www.clinicaltrials.gov/ct2/results?
available. The infrequency of dosing afforded by
term=psoriasis; last accessed 21 June 2012.
the long half-life of the drug is particularly appeal3. Trinchieri G. Interleukin-12 and the regulation of
innate resistance and adaptive immunity. Nat Rev
ing to patients. Adverse events in clinical studies to
Immunol. 2003;3:133–46.
date have been for the most part, mild and similar
4. Oppmann B, Lesley R, Blom B, et al. Novel p19 proto that in placebo-treated patients. Long-term post-­
tein engages IL-12p40 to form a cytokine, IL-23, with
marketing data has not revealed any significant
biological activities similar as well as distinct from
IL-12. Immunity. 2000;13:715–25.
concerns for the use of ustekinumab, including in
5. Yao Z, Painter SL, Fanslow WC, et al. Human IL-17:
pregnant patients. The approval of ustekinumab in
a novel cytokine derived from T cells. J Immunol.
adolescents is another strong selling point of the
1995;155:5483–6.
medication, speaking to its efficacy, but also bring6. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J
Med. 2009;361:496–509.
ing a better dosing regimen to this population of
7. Lowes MA, Kikuchi T, Fuentes-Duculan J, et al.
young adults who certainly appreciate that aspect
Psoriasis vulgaris lesions contain discrete populaof treatment. Long-term follow-up safety data and
tions of Th1 and Th17 T cells. J Invest Dermatol.
the use of registries are important in examining the
2008;128:1207–11.
8. Nestle FO, Turka LA, Nickoloff BJ. Characterization
incidence of cutaneous and non-­cutaneous maligof dermal dendritic cells in psoriasis. Autostimulation
nancy in ustekinumab-treated patients, and curof T lymphocytes and induction of Th1 type cytorent evidence points to no risk with ustekinumab.
kines. J Clin Invest. 1994;94:202–9.
Taken together, there continues to be a role for
9. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased
expression of interleukin 23 p19 and p40 in lesional
ustekinumab in our armamentarium for treating
skin of patients with psoriasis vulgaris. J Exp Med.
psoriasis and psoriatic arthritis given its favour2004;199:125–30.
able dosing regimen, proven long-term safety track 10. Chan JR, Blumenschein W, Murphy E, et al.
record, and reliable efficacy.
IL-23 stimulates epidermal hyperplasia via TNF
Conflicts of Interest
G Han has served as an consultant, advisor, speaker,
or investigator for Abbvie, Athenex, Boehringer
Ingelheim, Bond Avillion, Bristol-­Myers Squibb,
Celgene, Eli Lilly, Novartis, Janssen, LEO
Pharma, MC2, Ortho Dermatologics, PellePharm,
Pfizer, Regeneron, Sanofi Genzyme, SUN
Pharmaceuticals, and UCB.
C Ryan has served as a speaker, advisory
board member, or investigator for Jansen-Cilag,
Pfizer, Galderma, and Abbott.
C Leonardi has served as a consultant, investigator, or speaker for: Abbott, Amgen, Anacor,
Celgene, Janssen, Eli Lilly, Galderma, Glaxo
Smith Kline, Incyte, Maruho, Merck, Pfizer,
Sandoz, Schering-Plough, Sirtris, Stiefel, Leo,
Novartis, Tolmar, Novo Nordisk, Vascular
Biogenics, Warner Chilcott and Wyeth.
and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med.
2006;203:2577–87.
11. Langrish CL, Chen Y, Blumenschein WM, et al.
IL-23 drives a pathogenic T cell population that
induces autoimmune inflammation. J Exp Med.
2005;201:233–40.
12. Murphy CA, Langrish CL, Chen Y, et al. Divergent
pro- and antiinflammatory roles for IL-23 and
IL-12 in joint autoimmune inflammation. J Exp Med.
2003;198:1951–7.
13. Cua DJ, Sherlock J, Chen Y, et al. Interleukin-23
rather than interleukin-12 is the critical cytokine
for autoimmune inflammation of the brain. Nature.
2003;421:744–8.
14. Ryan C, Leonardi CL, Krueger JG, et al. Association
between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis
of randomized controlled trials. JAMA. 2011;306:
864–71.
15. Kauffman CL, Aria N, Toichi E, et al. A phase I
study evaluating the safety, pharmacokinetics, and
clinical response of a human IL-12 p40 antibody in
16
Guselkumab
Deep Joshipura, Brooke Rothstein,
and David Rosmarin
Abstract
Introduction
Guselkumab is a fully human IgG antibody to
the p19 subunit of interleukin-23 (IL-23).
Guselkumab has potent efficacy in the treatment of plaque psoriasis with a favorable
safety profile, providing patients with a sustained response for 3 years in long term studies. In addition, there is growing evidence that
guselkumab is effective at treating psoriatic
arthritis. This review discusses the efficacy
and safety of guselkumab in the treatment of
plaque psoriasis and provides an update on the
published data available from clinical trials.
Guselkumab (Janssen Pharmaceuticals, Inc.,
Philadelphia, PA) is a fully human monoclonal
IgG1λ antibody that selectively binds to the p19
subunit of interleukin 23 (IL-23) [1] (Fig. 16.1).
It is currently FDA approved for the treatment of
moderate-to-severe plaque psoriasis. IL-23 is a
heterodimeric cytokine composed of subunits
p40 and p19 and found at high levels in the serum
and plaques of patients with psoriasis.
Ustekinumab (Janssen Pharmaceuticals, Inc.,
Philadelphia, PA) binds to the p40 subunit which
is common to both IL-12 and IL-23. In contrast,
guselkumab binds to the p19 subunit only, and
therefore IL-12 is not suppressed. IL-12 is a promoter of T-cell differentiation to Th1 cells
whereas IL-23 promotes the development of
Th17 cells which produce IL-17A, IL-17F, and
IL-22 [1]. These cytokines are crucial in the
pathogenesis of psoriasis and signal through the
Janus kinase (JAK) and signal transducers and
activators of transcription (STAT) pathway.
Key Learning Objectives
1. To understand the mechanism of action
of Guselkumab
2. To understand the appropriate use and
efficacy of the Guselkumab
3. To understand the safety issues of
Guselkumab
Structure and Mechanism
D. Joshipura · B. Rothstein · D. Rosmarin (*)
Tufts Medical Center, Boston, USA
e-mail: djoshipura@tuftsmedicalcenter.org;
BRothstein@tuftsmedicalcenter.org; drosmarin@
tuftsmedicalcenter.org
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_16
Pharmacodynamics
and Pharmacokinetics
Structurally guselkumab is a human monoclonal
IgG1λ antibody that selectively binds to the p19
213
D. Joshipura et al.
214
IL-23
Guselkumab
p19
Dendritic cells
T17 cell
p40
a
IL-17A
IL-17F
Keratinocyte
proliferation
b
T22 cell
IL-22
IL-23
Receptor
Macrophages
Naive T cell
membrane
When guselkumab binds to the p19 subunit of IL-23, and blocks its interaction with its receptor, the IL-23- mediated signaling pathway
and release of pro-inflammatory cytokines are consequently blocked.
Fig. 16.1 The mechanism of action of guselkumab in
plaque psoriasis. Release of IL-23 by activated dendritic
cells and macrophages. Once IL-23 binds to its cell surface receptor, it triggers differentiation, proliferation and
survival of T cells subsets. T17 cells include Th17, Tc17,
ILC3 and γδ T cells (reprinted with permission from
Springer nature)
subunit which is shared by the cytokines interleukin 23 (IL-23), and IL-39 [2]. IL-23 is a heterodimeric cytokine composed of p19 and p40 secreted
by activated dendritic cells and macrophages.
Once activated through interaction with its IL-23
receptor on T-lymphocytes, it induces differentiation of Th-17 and Th-22 cells (Fig. 16.1).
Activation of Th-17 cells leads to secretion of
IL-17 and IL-22 causing epidermal hyperplasia
and inflammation in psoriasis [3]. In patients
with psoriasis, administration of guselkumab
reduced serum levels of IL-17A, IL-17F and
IL-22 relative to pre-treatment levels on exploratory analysis of the pharmacodynamic markers
[2]. The role of IL-39 in psoriasis, if any, is
unclear.
The pharmacokinetics, pharmacodynamics,
safety, and tolerability of guselkumab were analyzed in a phase I clinical trial of 24 patients with
moderate-to-severe plaque psoriasis and 47
healthy controls [4]. The healthy participants
were administered a single intravenous (0.03–
10 mg/kg) or subcutaneous (10–300 mg) dose of
guselkumab, and the subjects with psoriasis were
administered a single subcutaneous dose of placebo or guselkumab (10, 30, 100, 300 mg).
Guselkumab exhibited linear pharmacokinetics
for both intravenous and subcutaneous doses
tested in healthy participants and subjects with
psoriasis. Mean terminal half-life (t1/2) was
15–17 days in patients with psoriasis and
12–19 days in healthy controls. Both the intravenous and subcutaneous forms of administration
were well tolerated in this study.
Following subcutaneous administration of
guselkumab 100 mg at 0, 4 and every 8 weeks,
the mean guselkumab steady-state trough serum
concentration was approximately 1.2 mcg/mL
[2]. After a single 100 mg subcutaneous injection, the absolute bioavailability was estimated to
be approximately 49% in healthy subjects. The
exact pathway through which guselkumab is
metabolized is not well characterized. As a
human IgG monoclonal antibody, guselkumab is
expected to be degraded similar to endogenous
IgG into small peptides and amino acids [2].
Development of anti-drug antibodies occur
due to normal immune response to a foreign protein. Formation of anti-drug antibodies can affect
half-life, increase elimination of the drug, and
decrease efficacy. A study done by Zhu et al.,
evaluated anti-drug antibodies (ADA) through
100 weeks of drug exposure from the pivotal
VOYAGE 1 and VOYAGE 2 trials. It was determined that 8.5% of subjects in these trials had
anti-drug antibodies [5]. Most of these patients
had low titers and the anti-drug antibodies were
often transient, with serum guselkumab concen-
16 Guselkumab
trations being comparable between ADA+ and
ADA- patients. Anti-drug antibodies did not
affect the efficacy of guselkumab. The incidence
of injection site reactions was low in patients
with and without anti-drug antibodies.
Clinical Efficacy
Guselkumab has been FDA approved since 2017
for the treatment of moderate-to-severe plaque
psoriasis in patients who are candidates for systemic therapy or phototherapy. This approval was
based on efficacy demonstrated in three large pivotal phase III clinical trials VOYAGE 1 [6],
VOYAGE 2 [7], and NAVIGATE [8]. The findings above were also supported by other trials
such as a phase I pilot study of guselkumab by
Sofen H et al. [9], a phase II (X-PLORE) [10]
trial, and a phase III trial conducted in Japan [11].
In a phase I trial of 24 plaque psoriasis patients
who were randomized to placebo or guselkumab
10, 30, 100 or 300 mg, PASI75 was achieved at
week 12 in 50% of patients on guselkumab
10 mg, 60% on 30 mg, 60% on 100 mg, and
100% on 300 mg. On skin immunohistochemistry, there was a reduction in epidermal thickness
as well as T-cell and dendritic cell infiltration.
There were also serum reductions in IL-17A levels in responsive patients [12].
In the phase II trial [10] of 293 moderate-to-­
severe psoriasis patients randomized to receive
guselkumab (5 mg at weeks 0 and 4 and every
12 weeks thereafter, 15 mg every 8 weeks, 50 mg
at weeks 0 and 4 and every 12 weeks thereafter,
100 mg every 8 weeks, or 200 mg at weeks 0, 4
and every 12 weeks thereafter), placebo, or adalimumab, significant improvement was observed
with guselkumab. At week 16, the proportion of
patients with a PGA score of 0 or 1 was 34%,
61%, 79%, 86%, and 83% in the guselkumab
groups, respectively, 7% in the placebo group,
and 58% in the adalimumab group. The proportion of patients achieving a PASI75 at week 16
was 44%, 76%, 81%, 79%, and 81% in the guselkumab groups, respectively, 5% in the placebo
group, and 70% in the adalimumab group. The
proportion of patients achieving a PASI90 at
215
week 16 was 34%, 34%, 45%, 62%, and 57% in
the guselkumab groups, respectively, 2% in the
placebo group, and 44% in the adalimumab
group. Guselkumab was effective through week
40; however, there was some loss of efficacy right
before the scheduled dose of guselkumab when
the injection was dosed every 12 weeks.
Guselkumab was well-tolerated and adverse
events were similar among the treatment groups.
This successful phase II study showed promising
evidence of the clinical efficacy of IL-23 inhibitors for the treatment of plaque psoriasis leading
to further studies in a phase 3 program.
VOYAGE 1
VOYAGE 1 was a phase III, randomized, double-­
blind, placebo- and active comparator- controlled
multinational trial (n = 837) conducted to confirm the efficacy and safety of guselkumab compared to adalimumab and placebo for the
treatment of plaque psoriasis [6]. Patients
≥18 years old who were candidates for systemic
therapy or phototherapy with moderate-to-severe
plaque psoriasis (characterized by Investigator
Global Assessment (IGA) score ≥ 3, Psoriasis
Area and Severity Index (PASI) score ≥ 12, and
body surface area (BSA) ≥ 10) for at least
6 months were included. Excluded patients were
those with severe progressive medical conditions
or cancers (except nonmelanoma skin cancer)
diagnosed within 5 years, history of active tuberculosis, and those who had received guselkumab
or adalimumab at any time.
Patients were randomized to receive guselkumab, adalimumab, or placebo for 16 weeks; at
week 16 the patients on placebo were crossed-­
over to receive guselkumab through week 48.
Co-primary endpoints were the proportions of
patients achieving an IGA score of clear/minimal
disease (IGA 0/1) and 90% or greater improvement in PASI score from baseline (PASI90) at
week 16 [6].
Clinical response of guselkumab was demonstrated against placebo for all the co-primary
and major secondary endpoints (all p < 0.001).
At week 16, 85.1% of patients in the gusel-
216
kumab group achieved an IGA score of 0/1
compared to 6.9% for placebo. Additionally, at
this same timepoint, 73.3% of patients in the
guselkumab group achieved PASI90 compared
to 2.9% in the placebo group. At week 16, guselkumab was superior to adalimumab in IGA 0/1
scoring (85.1% versus 65.9%), PASI 90 scoring
(73.3% versus 49.7%), and achievement of
PASI 75 (91.2% versus 73.1%) [6]. Guselkumab
was also superior to adalimumab at week 24 in
IGA 0/1 (84.2% versus 61.7%) and PASI90
(80.2% versus 53.0%) scoring. The superior
efficacy of guselkumab was also observed at
week 48 with a significantly higher proportion
of guselkumab patients achieving scores of IGA
0/1 (80.5% versus 55.4%) and PASI90 (76.3%
versus 47.9%). Patients randomized to placebo
achieved similar results to the guselkumab
group once they were crossed over [6].
D. Joshipura et al.
and then guselkumab was re-initiated in the placebo group once 50% clinical response was lost.
Adalimumab responders were switched to placebo at week 28 and guselkumab was initiated
once 50% clinical response was lost, whereas
adalimumab non-­responders stopped treatment at
the end of week 23 and guselkumab was initiated
at week 28 [7] (Table 16.1).
The co-primary end points were the proportions of patients on guselkumab achieving IGA
0/1 and PASI90 at week 16 as compared to
­placebo. At week 16, guselkumab was superior to
placebo with higher IGA 0/1 scoring (84.1% versus 8.5%) and PASI90 scoring (70.0% versus
2.4%) (Table 16.2). Similar to VOYAGE I, guselkumab was superior to adalimumab at week 16
both in IGA 0/1 (84% versus 68%) and PASI90
scoring (70.0% versus 46.8%). From weeks 28 to
48, better persistence of response was observed
in the guselkumab maintenance versus withdrawal group, with 88.6% of patients in the mainVOYAGE 2
tenance group sustaining a PASI90 response
compared to 36.8% of those in the withdrawal
VOYAGE 2, a phase III, multicentered, random- group (p < 0.001). The median time to loss of
ized, double-blind, placebo- and adalimumab PASI90 response was 23 weeks after the last
comparator-controlled study (n = 992), evaluated guselkumab dose. Of adalimumab non-­
the efficacy and safety of interrupted guselkumab responders who switched to guselkumab, 66.1%
treatment, as treatment gaps frequently occur in achieved PASI90 by the end of the study [7].
clinical practice [7]. In addition, VOYAGE 2
In a pooled analysis of VOYAGE 1 and
assessed the transition from adalimumab to VOYAGE 2, guselkumab was effective at treating
guselkumab, providing clinically relevant infor- disease-specific areas such as the scalp, hands,
mation about patients who switch biologics. The and fingernails [15].
inclusion/exclusion criteria were similar to
At week 16, significantly more patients on
VOYAGE 1 as stated above. The study consisted guselkumab compared to placebo achieved a
of a placebo-controlled period (weeks 0–16), an scalp-specific Investigator Global Assessment
active comparator-controlled period (weeks (ss-IGA) score of 0 or 1 (81.8% versus 12.4%).
0–28), and a randomized withdrawal and re-­ At week 16, 75.5% of patients on guselkumab
treatment period (weeks 28–72). Patients were achieved a Physician Global Assessment of hands
initially randomized to guselkumab 100 mg at and/or feet (hf-PGA) score of 0 or 1 compared to
weeks 0, 4, 12, and 20; placebo at weeks 0, 4, and 14.2% of placebo patients. Guselkumab was
12, then guselkumab at weeks 16 and 20; or superior to adalimumab at week 24 in achieving
adalimumab 80 mg at week 0, 40 mg at week 1, a score of 0 or 1 in both ss-IGA (85% versus
and every 2 weeks thereafter through week 23 68.5%) and hf-PGA (80.4% versus 60.3%). At
(Fig. 16.2 and Table 16.1). At week 28, patients week 16, more patients on guselkumab than plawho achieved PASI90 on guselkumab were re- cebo achieved a fingernail Physician Global
randomized to continue guselkumab or start pla- Assessment (f-PGA) score of 0 or 1 (46.7% vercebo (to simulate an interruption in treatment) sus 15.2%). Similar proportions of patients
16 Guselkumab
217
Active-comparator period
Placebo-controlled period
Randomized withdrawal and
retreatment period
Placebo-crossover period
Placebo → retreatment
R
Continue guselkumab 100 mg q8w
Guselkumab 100 mg weeks 0, 4. then q8w
NR
Continue guselkumab 100 mg q8w
R
R
Placebo
Guselkumab
100 mg
Placebo → retreatment
NR
Continue guselkumab 100 mg q8w
R
Adalimumab 80 mg at week 0 → 40 mg at
week 1, then q2w
Week 0
R
16
PE
SE
= Randomization
q2w = every 2 weeks
Responders
PE = Primary endpoint
Placebo → guselkumab 100 mg 0, 4, then q8w*
NR
Initiate guselkumab 100 mg 0, 4, then q8w*
24
SE
28
48
SE
SE = Secondary endpoint
q8w = every 8 weeks
R = 90% or greater improvement in Psoriasis Area and Severity Index (PASI 90)
Nonresponders
NR = < PASI 90 response
Fig. 16.2 Schema showing randomization of patients at baseline in VOYAGE II (reprinted with permission from
K. Reich et al)
achieved an f-PGA of 0 or 1 on guselkumab and
adalimumab (60.0% and 64.3% p = 0.11).
Improvement in difficult-to-treat areas such as
the scalp, palms, and soles, with about 70%
achieving complete clearance, led to significant
improvement in health-related quality of life.
In a pooled analysis of the 1829 patients from
VOYAGE 1 and VOYAGE 2, guselkumab was
superior to placebo and adalimumab in almost all
subpopulations of patients who were stratified
based on age, gender, weight, body mass index,
ethnicity, baseline disease features, and previous
treatments [16]. Guselkumab showed a more
consistent clinical response across all weight
quartiles compared to adalimumab. In patients in
the highest weight quartile of >100 kg, 78.3% of
guselkumab patients achieved an IGA of 0 or 1
compared to only 45.2% of adalimumab patients.
Improvements in the Dermatology Life
Quality Index (DLQI) were greater for guselkumab versus placebo at week 16 and for guselkumab versus adalimumab at week 24 [13]. The
proportion of patients who achieved a DLQI of 0
or 1, indicating no impact on quality of life, at
week 24 was higher with guselkumab compared
to adalimumab (58.9% versus 40.2%).
D. Joshipura et al.
218
Table 16.1 Dosing regimens from phase 3 VOYAGE 1
and VOYAGE 2 trials permission (reprinted with permission from Springer nature)
Trial
VOYAGE
1 [13]
Active
comparator
(ADA) period
PL-controlled
period (wks
0–16)
GUS wks 0
and 4 → q8w
PL wks 0, 4
and 12
ADA 80 mg
wk 0, 40mg
wk 1 →
40 mg q2w
VOYAGE
2 [14]
GUS wks 0
and 4 → q8w
PL wks 0, 4
and 12
ADA 80 mg
wk 0, 40mg
wk 1 →
40 mg q2w
Randomized
WD and
re-TX perioda
(wks 28–72)
PL
crossover
periodb
GUS q8w
continued
to wk 44
GUS wks
16 and 20
→ q8w to
wk 44
ADA
40 mg
q2w
continued
to wk 47
GUS at
wk 20
GUS at
wks 16
and 20
ADA
40 mg
q2w to wk
23; no TX
wks 24–28
NA
NA
NA
R: PLc or
GUS q8w
NR: GUS
q8w
R: PLc
NR: GUS
q8w
R: PLc
Maintenance and Recapture
Based on VOYAGE 1, clinical responses were
maintained through 100 and 156 weeks for
patients on guselkumab, with 82.1% and 82.8%
of patients achieving a PASI90 at these time
points, respectively. Similarly, IGA 0/1 was
maintained by 83.3% and 82.1% of guselkumab
patients at week 100 and 156, respectively.
Patients did have improvement in DLQI and
Psoriasis Symptoms and Signs diary scores at the
same time points [14]. In VOYAGE 2, patients
with ≥90% PASI scores were re-randomized to
continue guselkumab versus withdrawal and placebo. The treatment with guselkumab was
restarted upon losing ≥50% of PASI at week 28
or at week 72. Loss of PASI75 response was
associated with increased serum levels of IL-17A
from week 40, IL-17F from week 36, and IL-22
from week 44 onwards. Maintenance of response
was associated with suppression of serum levels
of IL-17A, IL-17F, and IL-22. If there is an interruption in treatment with guselkumab, there is a
slow relapse of psoriasis and restarting guselkumab can recapture the initial response in most
patients [17].
NAVIGATE
NR: GUS
study-wks
28 and 32
→ q8w
ADA adalimumab, GUS guselkumah 100 mg, NA not
applicable, NR PASI 90 non-responder, PASI 90 ≥ 90%
improvement in Psoriasis Area and Severity Index, PL
placebo, pts patients, qxw every x weeks, R PASI 90
responder, re(TX) re(treatment), WD withdrawal, wk/s
week/s, → indicates thereafter
a
VOYAGE 1 wks 16–48; VOYAGE 2 wks 16–28, prior to
randomized withdrawal and re-Tx through to wk 72
b
GUS-treated pts were re-randomized based on PASI
response at wk 28; NR = PASI < 90 and R ≥ PASI 90
c
Upon loss of ≥ 50% of the 28-wk PASI response, pts
were switched to GUS (100 mg at wk 0 and 4 → GUS
100 mg q8w)
In the NAVIGATE phase III trial, the efficacy of
guselkumab was analyzed in patients who did not
adequately respond to ustekinumab [8]. Inclusion/
exclusion criteria were similar to VOYAGE 1
except patients who had received ustekinumab
(as opposed to adalimumab) within 3 months of
study onset were excluded. The study started
with a 16-week open-label period where all the
randomized patients received on-label dosing of
ustekinumab (weight based dosing of either
45 mg or 90 mg) at week 0 and 4. At week 16,
inadequate responders (IGA ≥ 2) were randomized to guselkumab 100 mg at weeks 16, 20 and
every 8 weeks thereafter, or to continue
16 Guselkumab
219
Table 16.2 Efficacy of guselkumab along with HR-QOL outcomes at week-16 in pivotal VOYAGE 1 and VOYAGE 2
trials (reprinted with permission from Springer nature)
Trial
VOYAGE 1 [5,
13]
VOYAGE 2 [5,
14]
Regimen (no. of PASI (%
pts)
pts)
75b 90c
GUS (329)
91*† 73*†
IGA 0/1 (%
pts)b
ssIGA 0/1 (%
pts)a
85*†
83*
ADA (334)
PL (174)
73
6
50
3
66
7
70
15
GUS (496)
86*†
70*†
84*†
81*
ADA (248)
69
47
68
67
PL (248)
8
2
9
11
HR-QOL outcomes mean change
from BL [BL]
PSSD symptomd
DLQId
*
–42 [54]
–11*
[14]
–35 [54]
–9 [14]
–3 [48]
<–1
[13]
–40* [54]
–11*
[15]
–33 [54]
–10
[15]
–8 [59]
–3
[15]
ADA adalimumab, BL baseline value, DLQI Dermatology Life Quality Index, GUS guselkumab, HR-QOL health-­
related quality of life, IGA Investigator Global Assessment (0 = cleared; 1 = minimal), PASI Psoriasis Area and Severity
Index, PASI x improvement of ≥ x% from BL in PASI score, PL placebo, PSSD Psoriasis Symptoms and Signs Diary,
pts patients, qxw every x weeks, ssIGA scalp-specific IGA (0 = absence; 1 = very mild), UST ustekinumab
*
p ≤ 0.001 vs. PL; †p < 0.001 vs. ADA
a
Major secondary outcome GUS vs. PL. Assessed in pts with BL ss-IGA score of ≥2 who had a ≥ 2-grade improvement; included 277, 286 and 145 pts in the GUS, ADA and PL groups, respectively, in VOYAGE 1 and 408, 194 and
202 pts in VOYAGE 2. No statistical comparisons performed for GUS vs. ADA
b
Major secondary outcome for GUS vs. ADA
c
Co-primary endpoint for GUS vs. PL at wk 16 in the VOYAGE trials; major secondary endpoint for GUS vs. ADA
d
Major secondary outcome for GUS vs. PL: mean change from BL in PSSD symptom score assessed in 249, 274 and
129 pts in the GUS, ADA and PL groups, respectively, in VOYAGE 1 and 411, 201 and 198 pts in VOYAGE 2; mean
change from BL in DLQI score assessed in 322, 328 and 170 pts in the GUS, ADA and PL groups, respectively, in
VOYAGE 1 and 496, 248 and pts in VOYAGE 2
ustekinumab at week 16 and every 12 weeks
thereafter, while responders with IGA 0/1 continued to receive ustekinumab. The primary end
point of the trial was the number of visits at
which patients achieved an IGA score of 0 or 1
and at least a two-grade improvement relative to
week 16 from week 28 through week 40 [8].
Among randomized patients, the guselkumab
group had a significantly higher mean number of
visits at which patients had an IGA score of 0 or
1 and at least a two-grade improvement relative
to week 16 from week 28 through week 40 (primary end point) compared with the ustekinumab
group (1.5 versus. 0.7; p < 0.001). Furthermore,
at week 52, 51.1% of guselkumab patients compared to 24.1% of ustekinumab patients reached
a PASI90 [8].
ECLIPSE
A phase III, multicenter, randomized, double-­
blind, active comparator controlled study named
ECLIPSE compared the efficacy and safety of
guselkumab and the anti-IL17a inhibitor,
secukinumab, in adult patients with moderate-to-­
severe plaque psoriasis [18]. 1048 adult patients
with moderate-to-severe plaque psoriasis were
randomized to receive guselkumab or
secukinumab in a 1:1 ratio for 44 weeks.
The primary endpoint was the proportion of
patients who achieved a ≥ 90% improvement in
Psoriasis Area Severity Index score (PASI90) at
week 48. At week 48, guselkumab was superior
to secukinumab in achieving PASI90 (84.5% versus 70.0%; p < 0.001). Major secondary end-
D. Joshipura et al.
220
points were not met such as the superiority in
proportion of patients achieving a PASI75 in the
guselkumab group compared to the secukinumab
group at both week 12 and 48 (84.6% versus
80.2%; p = 0.062) [18].
Other Studies
Guselkumab was evaluated in a phase III randomized, double-blind, placebo-controlled study
in Japanese patients with moderate-to-severe
plaque psoriasis. Results were similar to
VOYAGE 1 and VOYAGE 2 in which approximately 70% of patients on guselkumab achieved
a PASI90 at week 16 [11]. Guselkumab was also
evaluated in 159 Japanese patients with palmoplantar pustulosis and showed superiority over
placebo [19].
Safety/Adverse Events
Placebo
422
Patients treated, n
15.9
Average weeks
of follow-up
128
Total patient-years
of follow-up
198 (46.9)
At least on
adverse events
Common advers eventsa
Nasopharyngitis
33 (7.8)
19 (4.5)
Upper respiratory
tract infection
Headache
14 (3.3)
Arthralgia
9 (2.1)
Hypertension
8 (1.9)
Injecton site
3 (0.7)
erythema
Diarrhoea
4 (0.9)
Pruritus
17 (4.0)
Injection site bruising
4 (0.9)
Back pain
8 (1.9)
Cough
5 (1.2)
Fatigue
6 (1.4)
Gastroehteritis
3 (0.7)
Adverse events leading
5 (1.2)
to discontinuation
Infections
90 (21.3)
Infections requiring
30 (7.1)
treatment
Serious adverse events
6 (1.4)
Guselkumab Adalimumab
823
16.2
581
16.1
255
179
407 (49.5)
291 (50.1)
65 (7.9)
41 (5.0)
54 (9.3)
20 (3.4)
38 (4.6)
22 (2.7)
18 (3.1)
10 (1.7)
20 (2.4)
16 (1.9)
12 (2.1)
26(4.5)
13 (1.4)
13 (1.6)
13 (1.4)
13 (1.6)
11 (1.3)
10 (1.2)
10 (1.2)
9 (1.1)
11 (1.3)
10 (1.2)
10 (1.2)
9 (1.1)
9 (1.1)
10 (1.2)
9 (1.1)
10 (1.2)
193 (23.5)
56 (6.8)
145 (25.0)
43 (7.4)
16 (1.9)
12 (2.1)
Overall guselkumab is well tolerated, and side Data are presented as n (%). aCommon adverse event are defined
effects are usually mild. In a pooled analysis of as those occurring in at least 1% of patients in the guselkumab
VOYAGE 1 and VOYAGE 2 through 100 weeks, group.
safety of guselkumab was assessed [20]. The
Fig. 16.3 Common adverse events noted in the pooled
most common adverse events (AE) reported were analysis of VOYAGE 1 and VOYAGE 2 phase 3 clinical
nasopharyngitis, upper respiratory tract infec- trials on guselkumab (Reprinted with permission from
tion, and headache. Arthralgias were reported in Reich et al.)
2.7% of patients on guselkumab compared with
2.0% and 2.1% of patients on adalimumab and tively. The proportion of patients with injection
placebo, respectively [20]. There were no differ- site reactions was higher in the adalimumab
ences in serious AEs between the groups group before the crossover to guselkumab (8.8%
(Fig. 16.3).
versus 0.8%). No events of Crohn’s disease were
Through week 52, guselkumab and adalim- reported and the rates of vulvovaginal (0.4%) and
umab treated patients had few adverse events and skin (0.2%) candidiasis and neutropenia (0.1%)
serious adverse events (262.45/100 PYs versus were low [20].
328.28/100 PYs and 6.2/100 PYs versus 7.77/100
PYs) (Fig. 16.4) Serious infections, non-­
melanoma skin cancers (NMSC), malignancy Pediatrics and Breastfeeding
excluding NMSC, and major adverse cardiovascular events (MACEs) were low for patients There have been reports of pediatric patients
treated with guselkumab and no increased signal treated with guselkumab [21, 22], though there
was seen with treatment from weeks 0 to 100 are no large studies evaluating safety in this
compared to just weeks 0 to 52 [20].
patient population. There is a lack of safety data
Injection site reactions were noted in 2.8% for patients who are pregnant receiving guseland 2.8% of patients at week 52 and 100, respec- kumab. Guselkumab was not detected in the milk
16 Guselkumab
221
Guselkumaba
Treated patients. n
Average weeks of follow-up
Total PYs of follow-up
Adverse events
Observed number of events
Incidence per 100 PYs
95% confidence interval
Adverse events leading to discontinuation
Observed number of patients
Incidence per 100 PYs
95% confiedence interval
Infections
Observed number of events
Incidence per 100 PYs
95% confiedence interval
Infections requiring treatment
Observed number of events
Incidence per 100 PYs
95% confiedence interval
Serious adverse events
Observed number of events
Incidence per 100 PYs
95% confiedence interval
Adalimumab
Through Week 52
Through Week 100
Before crossover b
After crossover c
1221
45.4
1221
89.0
581
45.1
500
51.7
1065
2084
502
496
2795
4384
1647
794
262.45
252.81–272.37
210.41
204.23–216.73
328.28
312.62–344.23
160.15
149.20–171.69
26
2.46
38
1.83
23
4.63
8
1.62
1.60–3.60
1.30–2.51
2.93–6.94
0.70–3.19
1070
100.47
1703
81.74
77.90–85.71
540
107.63
98.75–117.11
353
71.20
495
23.76
145
28.90
95
19.16
21.71–25.95
24.39–34.01
15.50–23.42
66
6.20
131
6.29
22
4.44
4.79–7.88
5.26–7.46
39
7.77
5.53–10.63
94.54–106.68
300
28.17
25.07–31.55
63.96–79.03
2.78–6.72
aIncludes patients randomized to guselkumab at baseline (n = 825) and those initially randomized to placebo who crossed over to receive
guselkumab at week 16 (n = 398) in VOYAGE 1 and VOYAGE 2. bInclude patents randomized at baseline to adalimumab before crossover
to guselkumab at the end of the active-comparator perod (week 52) in VOYAGE 1 and before crossover to guselkumab during the randomized withdrawal and retreatmet period (starting at week 28) (28-08.20) in VOYAGE 2. cIncludes patients randomized at baseline to
adalimumabafter crossover to guselkumab at the end of the active-comparator perod (week 52) in VOYAGE 1 and after crossover
to guselkumab during the random- ized withdrawal and retreatmet period (starting at week 28) in VOYAGE 2.
Fig. 16.4 Summary of adverse events per 100 patient years through 100 weeks of follow up. Data from the pooled
analysis from VOYAGE 1 and 2 (reprinted with permission from Reich et al.)
of lactating monkeys, though IgG is known to be
present in human milk [2]. It is not known if
guselkumab would be absorbed systemically
through an immature neonatal gastrointestinal
tract after breastfeeding.
Tuberculosis, HIV, and Live Vaccines
Patients should be screened for tuberculosis
(TB) prior to starting guselkumab. For patients
being treated for latent TB, they can be safely
started on guselkumab at the same time as the
patient receives the first dose of antitubercular
treatment. There is one case report of a patient
who is HIV positive who received guselkumab
with stable CD4 counts at 12 months [23]. As
for all psoriasis biologics, live vaccines are
contraindicated since there is an absence of
safety data.
Malignancy
Guselkumab does not target the activity of IL-12/
Th-1 helper cells. Furthermore, in certain situations IL-23 may promote tumor growth [24], so
in theory, use of guselkumab may be safe in
patients with cancer as guselkumab inhibits the
activity of IL-23; however there is an absence of
evidence in the literature on the use of guselkumab in patients with malignancy. Therefore,
guselkumab should be used with caution in this
patient population pending more data.
Inflammatory Bowel Disease
Guselkumab treatment is not associated with
new-onset or exacerbations of inflammatory
bowel disease (IBD) and may serve as a future
treatment modality [25]. The anti-IL12/IL23
D. Joshipura et al.
222
inhibitor ustekinumab [26] and anti-IL23 blocker
risankizumab have both been shown to improve
inflammatory bowel disease [27].
Psoriatic Arthritis
Hidradenitis Suppurativa
Hidradenitis suppurativa (HS) is a chronic
inflammatory debilitating skin condition characterized by development of painful abscess, cysts
followed by development of sinus tracts and scarring. An overactivity of IL-23/Th-17 pathway has
been hypothesized to play a role in the pathogenesis of HS [29]. Two case series evaluating the
use of guselkumab in patients with HS reported
benefit in some of the patients [22, 30].
Guselkumab and other IL-23 inhibitors are currently under further investigation as a treatment
option for patients with HS.
The efficacy of Guselkumab was studied in a
phase 2 clinical trial done in patients with active
psoriatic arthritis [28]. 149 patients were
included with ≥3 tender and swollen joints,
with C-reactive protein levels ≥3 mg/L
and ≥ 3% BSA of plaque psoriasis. Patients
were randomized to 2:1 to receive either guselkumab 100 mg at week 0, 4 and every 8 weeks
through week 44 or placebo. Patients receiving
placebo were subsequently crossed over to Patient Controlled Injector
receive guselkumab at week 24, 28 then every
8 weeks through week 44. An early escape to In the placebo-controlled double-blind phase III
open label ustekinumab was enabled in patients ORION study which evaluated guselkumab
with <5% improvement from baseline in both administered through a patient-controlled injecswollen and tender joints. Primary endpoint was tor (One-Press), the primary endpoints were
ACR20 response at week 24 which was achieved PASI90 and IGA of 0 or 1 at week 16 [31].
in 58% of patients on guselkumab versus 18.4% Patients also filled out the self-injection assessof placebo. 34% of patients on guselkumab ment questionnaire (SIAQ) and patient-­controlled
achieved ACR50 versus placebo at week 24 injection device questionnaire. Guselkumab was
compared to 10.2% of placebo patients, and superior to placebo in terms of PASI90 (75.8%
14% of patients had ACR70 response at week 24 versus 0.0%) and IGA of 0 or 1 (80.6% versus
compared to 2.0% of placebo patients. 60% of 0.0%). Injection site reactions were similar for
patients with prior anti-TNF-alpha exposure both placebo and guselkumab treated subjects.
achieved ACR20 versus 57.8% of anti-TNF-­ SIAQ post-dose scores were also favorable with
alpha naive patients at week 24.56.6% of patients rating the one-press device as easy/very
patients on guselkumab had complete resolution easy to use from weeks 0 to 28 (87%–100%) and
of enthesitis at week 24 versus 29% in the pla- were satisfied/very satisfied with the device
cebo group. Similarly, 55.2% of patients in the (81%–100%).
guselkumab group had complete resolution of
dactylitis at week 24 versus 17.4% in the placebo group. 23% of patients had achieved mini- Conclusion
mal disease activity at week 24 compared to
2.0% of patients on placebo [28]. While there is The IL-23 inhibitor guselkumab offers a targeted
some promising early data on the use of gusel- therapy for patients with moderate-to-severe
kumab for patients with psoriatic arthritis, there plaque psoriasis. The ability to achieve high effiis no evidence that guselkumab reduces radio- cacy with minimal safety risk and infrequent
graphic progression of disease. Furthermore, injections are major advantages of guselkumab.
more data is needed to determine the relative Therefore, the development of anti-p19 agents is
efficacy of guselkumab against first line FDA a significant advancement in the treatment of
approved agents for psoriatic arthritis which tar- psoriasis. The ability of guselkumab to treat psoget TNF-alpha and IL-17.
riatic arthritis and other comorbidities of psoria-
16 Guselkumab
223
placebo- and active comparator. J Am Acad Dermatol
[Internet]. 2017;76(3):405–17. Available from:
doi:https://doi.org/10.1016/j.jaad.2016.11.041.
7. Reich K, Armstrong AW, Foley P, Song M, Wasfi Y,
Randazzo B, et al. Efficacy and safety of guselkumab,
an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients
with moderate to severe psoriasis with randomized
withdrawal and retreatment: Results from the phase
III, double-blind, p. J Am Acad Dermatol [Internet].
Conflict of Interest
2017;76(3):418–31. Available from: doi:https://doi.
David Rosmarin has received honoraria as a conorg/10.1016/j.jaad.2016.11.042.
sultant for AbbVie, Celgene, Dermavant,
8. Langley RG, Tsai TF, Flavin S, Song M, Randazzo
Dermira, Janssen, Lilly, Novartis, Pfizer,
B, Wasfi Y, et al. Efficacy and safety of guselkumab
in patients with psoriasis who have an inadequate
Regeneron, and Sanofi; has received research
response to ustekinumab: results of the randomsupport from AbbVie, Bristol Meyers Squibb,
ized, double-blind, phase III NAVIGATE trial. Br J
Celgene, Dermira, Incyte, Janssen, Lilly, Merck,
Dermatol. 2018;178(1):114–23.
Novartis, Pfizer, and Regeneron Pharmaceuticals
9. Sofen H, Smith S, Matheson RT, Leonardi CL,
Calderon C, Brodmerkel C, et al. Guselkumab (an
Inc.; and has served as a paid speaker for AbbVie,
IL-23-specific mAb) demonstrates clinical and
Celgene, Janssen, Lilly, Novartis, Pfizer,
molecular response in patients with moderate-to-­
Regeneron Pharmaceuticals Inc., and Sanofi.
severe psoriasis. J Allergy Clin Immunol [Internet].
2014;133(4):1032–40. Available from: doi:https://doi.
org/10.1016/j.jaci.2014.01.025.
No Conflict of Interest
10. Gordon KB, Duffin KC, Bissonnette R, Prinz JC,
Deep Joshipura and Brooke Rothstein.
Wasfi Y, Li S, et al. A Phase 2 Trial of Guselkumab
versus Adalimumab for Plaque Psoriasis. N Engl J
Med. 2015;373(2):136–44.
11. Ohtsuki M, Kubo H, Morishima H, Goto R, Zheng
References
R, Nakagawa H. Guselkumab, an anti-interleukin-23
monoclonal antibody, for the treatment of moderate to
1. Al-Salama ZT, Scott LJ. Guselkumab: A Review
severe plaque-type psoriasis in Japanese patients: effiin Moderate to Severe Plaque Psoriasis. Am J Clin
cacy and safety results from a phase 3, randomized,
Dermatol [Internet]. 2018 Dec 22 [cited 2019 Aug
double-blind, placebo-controlled study. J Dermatol.
4];19(6):907–18. Available from: http://www.ncbi.
2018;
nlm.nih.gov/pubmed/30467781.
2. Janssen Biotech. Tremfya (Guselkumab)[package 12. Sofen H, Smith S, Matheson RT, Leonardi CL,
Calderon C, Brodmerkel C, et al. Guselkumab (an
insert]. US Food and Drug Administration website.
IL-23-specific mAb) demonstrates clinical and
https://www.accessdata.fda.gov/drugsatfda_docs/
molecular response in patients with moderate-to-­
label/2017/761061s000lbl.pdf. Revised 7/2017.
severe psoriasis. J Allergy Clin Immunol. 2014;
Accessed 06/2019.
3. Puig L. The role of IL 23 in the treatment of psoriasis. 13. Armstrong AW, Reich K, Foley P, Han C, Song M,
Shen YK, et al. Improvement in Patient-Reported
Expert Rev Clin Immunol. 2017;
Outcomes (Dermatology Life Quality Index
4. Zhuang Y, Calderon C, Marciniak SJ, Bouman-Thio
and the Psoriasis Symptoms and Signs Diary)
E, Szapary P, Yang TY, et al. First-in-human study
with Guselkumab in Moderate-to-Severe Plaque
to assess guselkumab (anti-IL-23 mAb) pharmacoPsoriasis: Results from the Phase III VOYAGE 1 and
kinetics/safety in healthy subjects and patients with
VOYAGE 2 Studies. Am J Clin Dermatol [Internet].
moderate-­to-severe psoriasis. Eur J Clin Pharmacol.
2019;20(1):155–64. Available from: doi:https://doi.
2016;
org/10.1007/s40257-018-0396-z.
5. Zhu Y, Marini JC, Song M, Randazzo B, Shen YK,
Li S, et al. Immunogenicity of Guselkumab Is Not 14. Griffiths C, Papp K, Song M, Randazzo B, Li S, Shen
Y, et al. Maintenance of response with guselkumab
Clinically Relevant in Patients with Moderate-to-­
for up to 3 years’ treatment in the phase 3 VOYAGE
Severe Plaque Psoriasis. J Invest Dermatol. 2019;
1 trial of patients with plaque psoriasis. In: Journal
6. Blauvelt A, Papp KA, Griffiths CEM, Randazzo
of the European Academy of Dermatology and
B, Wasfi Y, Shen YK, et al. Efficacy and safety of
Venereology [Internet]. 2019. p. 49–50. Available
guselkumab, an anti-interleukin-23 monoclonal antifrom: http://www.embase.com/search/results?subacti
body, compared with adalimumab for the continuous
on=viewrecord&from=export&id=L627805046%0A
treatment of patients with moderate to severe psohttp://dx.doi.org/10.1111/jdv.15514
riasis: Results from the phase III, double-blinded,
sis such as inflammatory bowel disease still needs
to be better elucidated. Additional long-term
safety data is needed to gather further information on the maintenance of therapeutic response
and rare adverse events that may be associated
with guselkumab use.
224
15. Foley P, Gordon K, Griffiths CEM, Wasfi Y, Randazzo
B, Song M, et al. Efficacy of guselkumab compared
with adalimumab and placebo for psoriasis in specific body regions a secondary analysis of 2 randomized clinical trials. JAMA Dermatol. 2018;154(6):
676–83.
16. Gordon KB, Blauvelt A, Foley P, Song M, Wasfi Y,
Randazzo B, et al. Efficacy of guselkumab in subpopulations of patients with moderate-to-severe plaque
psoriasis: a pooled analysis of the phase III VOYAGE
1 and VOYAGE 2 studies. Br J Dermatol. 2018;
17. Gordon KB, Armstrong AW, Foley P, Song M, Shen
Y-K, Li S, et al. Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-­
regulated IL-17 and IL-22 in psoriasis: VOYAGE 2
study. J Invest Dermatol. 2019;
18. Johnson J and. No Title [Internet]. 2018. Available
from: https://www.jnj.com/new-phase-3-data-demonstrate-superiority-of-tremfya-guselkumab-vs-cosentyx-secukinumab-in-delivering-pasi-90-responses-inthe-treatment-of-moderate-to-severe-plaque-psoriasis-at-week-48
19. Terui T, Kobayashi S, Okubo Y, Murakami M,
Zheng R, Morishima H, et al. Efficacy and Safety of
Guselkumab in Japanese Patients With Palmoplantar
Pustulosis. JAMA Dermatology [Internet]. 2019 Jul 3
[cited 2019 Aug 1]; Available from: http://www.ncbi.
nlm.nih.gov/pubmed/31268476
20. Reich K, Papp KA, Armstrong AW, Wasfi Y, Li S,
Shen YK, et al. Safety of guselkumab in patients
with moderate-to-severe psoriasis treated through
100 weeks: a pooled analysis from the randomized
VOYAGE 1 and VOYAGE 2 studies. Br J Dermatol.
2019;180(5):1039–49.
21. Kim SR, Kibbi N, Craiglow BG. Guselkumab for the
treatment of severe refractory psoriasis in a pediatric patient. JAAD Case Reports [Internet]. 2019 Jun
[cited 2019 Aug 4];5(6):552–4. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/31245518
22. Casseres RG, Kahn JS, Her MJ, Rosmarin
D. Guselkumab in the treatment of hidradenitis suppurativa: a retrospective chart review. J American
Academy Dermatology. 2019;
23. Bartos G, Cline A, Beroukhim K, Burrall BA,
Feldman SR. Current biological therapies for use
in HIV-positive patients with psoriasis: case report
D. Joshipura et al.
of gesulkumab used and review. Dermatol Online J.
2018;
24. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T,
Smith K, et al. IL-23 promotes tumour incidence and
growth. Nature. 2006;
25. Grossberg LB. A Case Report of Successful Treatment
of Crohn’s Disease and Psoriasis With Guselkumab.
Inflamm Bowel Dis [Internet]. 2019 Jun 18 [cited
2019 Aug 2];25(7):e84–e84. Available from: http://
www.ncbi.nlm.nih.gov/pubmed/30863855
26. Sandborn WJ, Gasink C, Gao L-L, Blank MA,
Johanns J, Guzzo C, et al. Ustekinumab Induction and
Maintenance Therapy in Refractory Crohn’s Disease.
N Engl J Med [Internet]. 2012 Oct 18 [cited 2019 Aug
1];367(16):1519–28. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/23075178
27. Feagan BG, Sandborn WJ, D’Haens G, Panés J,
Kaser A, Ferrante M, et al. Induction therapy with
the selective interleukin-23 inhibitor risankizumab in
patients with moderate-to-severe Crohn’s disease: a
randomised, double-blind, placebo-controlled phase
2 study. Lancet (London, England) [Internet]. 2017
Apr 29 [cited 2019 Aug 1];389(10080):1699–709.
Available from: https://linkinghub.elsevier.com/
retrieve/pii/S0140673617305706
28. Deodhar A, Gottlieb AB, Boehncke W-H, Dong B,
Wang Y, Zhuang Y, et al. Efficacy and safety of guselkumab in patients with active psoriatic arthritis: a
randomised, double-blind, placebo-controlled, phase
2 study. Lancet [Internet]. 2018 Jun 2 [cited 2019 Aug
2];391(10136):2213–24. Available from: http://www.
ncbi.nlm.nih.gov/pubmed/29893222
29. Schlapbach C, Hänni T, Yawalkar N, Hunger
RE. Expression of the IL-23/Th17 pathway in lesions
of hidradenitis suppurativa. J Am Acad Dermatol.
2011;
30. Kovacs M, Podda M. Guselkumab in the treatment of severe hidradenitis suppurativa. J Eur
Acad Dermatology Venereol. 2019;33(3):e140–1.
Available
from:
http://www.ncbi.nlm.nih.gov/
pubmed/30480844
31. Ferris LK, Ott E, Jiang J, Hong HCH, Li S, Han C,
et al. Efficacy and safety of guselkumab, administered
with a novel patient-controlled injector (one-press),
for moderate-to-severe psoriasis: results from the
phase 3 ORION study. J Dermatolog Treat. 2019;
17
Tidrakizumab
George Han
Abstract
Tildrakizumab is a monoclonal antibody targeting the p19 subunit unique to the cytokine
IL-23 that is FDA-approved in the treatment
of plaque psoriasis. IL-23 is a central regulatory cytokine in the pathogenesis of psoriasis.
Tildrakizumab was shown to have superior
efficacy in treating psoriasis as compared to
both placebo and an active comparator (etanercept) in two parallel pivotal phase III trials.
This biologic medication has demonstrated
efficacy, combined with strong evidence of
durability and an excellent safety profile.
Additionally, the fact that it is dosed every
12 weeks is an attractive feature to many
patients. Early results for treatment of psoriatic arthritis are promising, and treatment
seems to be consistent across patient weight
categories and previous treatment characteristics. Numerous nuances exist in the approach
to systemic therapy for psoriasis patients, and
tildrakizumab is able to navigate many comorbidities to deliver a reasonable first-line biologic medication for patients with psoriasis.
G. Han (*)
Icahn School of Medicine at Mount Sinai,
New York, NY, USA
e-mail: george.han@mountsinai.org
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_17
Key Learning Objectives
1. To understand the mechanism of action
of Tidrakizumab
2. To understand the appropriate use and
efficacy of the Tidrakizumab
3. To understand the safety issues of
Tidrakizumab
Introduction
Tildrakizumab (Tildrakizumab-asmn, SUN
Pharmaceuticals US, Cranbury, NJ) is a high-­
affinity IgG1/κ monoclonal antibody targeting
the p19 subunit of the cytokine IL-23. It represents the first biologic that was studied targeting IL-23 specifically, with phase II trials
starting in 2010 and phase III trials starting in
2012 [1]. Initially developed by Schering-Plough
(Kenilworth, NJ) and then Merck (Kenilworth,
NJ), the rights to market this medication were
bought by SUN Pharmaceuticals in 2014.
Subsequently, a licensing agreement was made
with Almirall (Barcelona, Spain) for marketing of the medication in Europe. Results from
phase III trials were reported in 2017, with active
comparator (Etanercept) and placebo controls.
It is FDA approved in the US for the treatment
of plaque psoriasis with studies currently under
way for treatment of psoriatic arthritis. The dos225
226
ing of this medication is an injection of 100 mg
at 0 weeks and 4 weeks, followed by injections
every 12 weeks. It is indicated in the US for
administration by a health care provider.
G. Han
agents (Mendelian susceptibility to mycobacterial disease) often caused by an autosomal recessive deficiency in IL-12. Furthermore, these
patients are susceptible to Candida and Klebsiella
infections [5]. With regards to tumor immunity, it
is becoming clear that there are numerous roles
Rationale of Targeting IL-23
of IL-12 in tumor immunity, with a role of
IL-12 in both promoting cytotoxic Natural Killer
IL-23 is a proinflammatory cytokine that func- (NK) cell function and in activating Interferon-­
tions via upregulation of the Th17 axis in inflam- gamma (IFN-γ) producing Th1 cells via the
mation, with downstream effects carried out STAT4 pathway [6–8]. Furthermore, IL-12 can
primarily via IL-17. Specifically, IL-23 induces effectively reprogram immune cells to act against
differentiation of naïve CD4+ T cells into patho- tumor cells in certain environments [9]. Thus,
genic Th17 cells, which then produces IL-17, there may be a role of IL-12 in protecting the host
IL-6, and TNF-α [2]. Prior to the study of til- against the emergence of spontaneous tumors
drakizumab, numerous medications had been [10] and it would be preferable to not block this
developed targeting the IL-12/IL-23 pathway in cytokine in this context. On the contrary, IL-23
psoriasis. Ustekinumab and briakinumab are has been proposed as a disease marker in cancer,
both monoclonal antibodies targeting the shared with numerous pro-tumor and metastasis funcp40 subunit of IL-12 and IL-23 [3]. While early tions that are appearing in varied malignancies
studies focusing on examining the role of the p40 such as breast cancer, hepatocellular carcinoma,
subunit seemed to show a role of this pathway in colorectal cancer, oral squamous cell carcinoma,
psoriasis, subsequently, it was determined that and non-small cell lung cancer [11–16], among
these medications are able to treat psoriasis pri- others [10]. Thus, it seems rather consistent that
marily by blocking IL-23. A study with human blocking this pro-tumor molecule (IL-23) should
skin biopsy samples showed that while the p40 not lead to any concerns about malignancy;
subunit (shared by IL-12 and IL-23) and the p19 indeed, utilization of anti-IL-23 treatment in
subunit (unique to IL-23) are elevated in lesional oncology has been proposed as a potential treatpsoriasis skin, the p35 subunit (unique to IL-12) ment in combination with other immunotherapies
is not. On the contrary, levels of all three subunits [17]. It should be noted that in long-term registry
are the same in non-lesional skin from psoriasis data, no evidence was found that blocking IL-12
patients. In normal skin, expression of all three and IL-23 with ustekinumab increased the risk
subunits are the same or lower than in non-­ for cancer [18].
lesional skin from psoriasis patients [4]. Taken
Previously, there was some concern that tartogether, these data were important in ­determining geting p40 (IL-12 and IL-23) was associated with
that the inflammation underlying psoriasis pri- the development of major adverse cardiovascular
marily hinges upon increased levels of IL-23 and events (MACE). One drug, briakinumab, was
has little reliance on IL-12.
withdrawn from clinical development due to the
Aside from the theoretical rationale that sup- emergence of multiple MACE during Phase II
ports targeting IL-23 rather than IL-12 in treating and III trials. While a statistically significant
psoriasis, there are specific considerations that increase in risk of MACE is under debate and
make targeting IL-23 much more attractive than multiple analyses have shown both risk and no
IL-12. In terms of immunosuppression, it appears risk in this regard [19–22], the data does seem to
that there are numerous functions of IL-12 in host support at least a trend towards MACE among
defense. It has been shown that IL-12 appears to these studies. On the contrary, there seems to be
be important in the immune response to no signal or trend towards MACE in any of the
Mycobacterium and Salmonella infections, with medications targeting IL-23 [22]. The mechaa condition that causes susceptibility to these nisms whereby blockade of these interleukins
17 Tidrakizumab
227
can result in a cardiac event are unclear, but what- III parallel trials across sites in North America,
ever minimal trend there seems to be with medi- Europe, Asia, and Australia (reSURFACE 1 and
cations targeting both IL-12 and IL-23 together reSURFACE 2) [29]. The study was conducted
seems to disappear with IL-23 blockade alone.
with two doses of tildrakizumab (100 mg q12wk
As compared to IL-17 blocking agents, one and 200 mg q12wk), which was likely a result
notable difference among these agents is with of the dose-ranging phase IIb studies showing a
regard to their roles in intestinal immunoregula- difference of about 10% in achievement of the
tion. IL-17 inhibition exacerbates colitis, likely primary endpoint (PASI75 achievement, both at
due to weakening intestinal epithelial barrier week 12 and week 16) [1]. While many medicafunction (subsequently allowing for microbial tions proceed with one tested dose in Phase III
penetration and increased inflammation) while trials, the sponsor likely thought that there was
IL-23 inhibition seems to promote an anti-­ enough of a benefit in the higher dose group to
inflammatory milieu in the gut [23]. While IL-17 proceed with testing it in larger phase III trials.
has been shown to exacerbate inflammatory bowel For one of the the Phase III trials (reSURFACE
disease (IBD) [24], IL-23 blockade appears to be 2), an active comparator group treated with etana promising candidate in treatment of Crohn’s dis- ercept in addition to the control group was also
ease [25]. Notably, the actual incidence of IBD in included.
large analyses of IL-17 inhibitors is low [26, 27],
Baseline characteristics of this trial were simibut it is a true, predictable result of the mechanism lar to most psoriasis trials [29]. The vast majority
of action of this class of medication.
of patients were white (65–92%, percentages
given as proportion of patients in each arm) and
male (65–72%). Average weight was close to 90
Pharmacokinetics/
Kg and average body surface area was slightly
over 30%. The mean PASI at baseline was
Pharmacodynamics
roughly 20. In reSURFACE 1, percent treated
Subcutaneous dosing of tildrakizumab results in previously with biologics was 23% across all
slow systemic clearance, limited volume of dis- groups whereas in reSURFACE 2, that number
tribution, and a long half-life in pharmacokinetic was between 12–13%.
studies [28]. After a single subcutaneous injecThe co-primary endpoints of reSURFACE 1
tion of tildrakizumab, a dose-related increase in and 2 were achievement of PASI 75 and PGA or 0
serum concentration was observed, peaking at or 1 with at least a 2-point reduction in PGA from
roughly 1 week and exhibiting a slow, linear baseline. Importantly, the primary endpoint outdecrease over time. The volume of distribution come measures were taken at week 12. At the
was fairly low and the half-life was roughly time of these trials, there were only three approved
23–25 days for the doses studied. Bioavailability injectable biologics for psoriasis: etanercept,
of tildrakizumab was estimated to approach 80% adalimumab, and ustekinumab. Likely due to the
[28]. There is no weight-based dosing for til- rate of efficacy for TNF-α inhibitors, the paradrakizumab; although multiple doses were stud- digm at the time was to measure primary endied in Phase III trials, there was not enough of a points at week 12, even for ustekinumab [30].
difference in efficacy between doses to allow for Additionally, in the Phase II trials of tildrakiapproval of the higher dose.
zumab, the rise in achievement of PASI 75
between weeks 12 and 16 was rather modest [1].
However, it has since become more clear that tarClinical Efficacy
geting IL-12/23 and specifically IL-23 as well,
leads to a somewhat slower rise towards peak effiThe efficacy of tildrakizumab in treating psoriasis cacy [31]. While tildrakizumab treatment was sigwas demonstrated in two large, multicenter, ran- nificantly better than placebo at week 12 in both
domized, double-blind placebo-controlled phase co-primary endpoints, the numbers were perhaps
G. Han
228
somewhat disappointing as they were found to be
only comparable to previously reported numbers
with ustekinumab. The percent achieving PASI 75
for tildrakizumab 200 mg was 62% and 66% for
reSURFACE 1 and 2, respectively; for tildrakizumab 100 mg, 64% and 61%; for etanercept
48% (reSURFACE 2 only); and for placebo, 6%
and 6%. The achievement of PGA 0 or 1, a somewhat more stringent criteria, for tildrakizumab
200 mg was 59% and 59% for reSURFACE 1 and
2, respectively; for tildrakizumab 100 mg, 58%
and 55%; for etanercept 48%; and for placebo,
7% and 4% [29]. Thus, it appeared from the primary endpoint outcomes that there was not much
of a difference between the two doses of tildrakizumab. Notably, the week 28 data was much better for tildrakizumab, with PASI 75 achieved by
79% of patients on tildrakizumab 200 mg and
77% of patients on tildrakizumab 100 mg. Clear
or minimal PGA was attained by 67% of tildrakizumab 200 mg treated patients and 63% of tildrakizumab 100 mg treated patients at week 28.
PASI 100 was achieved by 31% of patients on
tildrakizumab 200 mg and 22% of patients on tildrakizumab 100 mg. As IL-23 serves as more of a
regulatory cytokine in the pathogenesis of psoriasis than an effector molecule (such as IL-17), it is
perhaps not surprising that it takes longer for
these medications to reach peak efficacy, but it
should be noted that durability does seem to be a
strength of this drug (see below).
At this point, 3-year data has been presented
for tildrakizumab showing strong durability of
effect [32]. At week 148, 91.2% of the observed
cohort of responders (i.e. those who achieved
PASI75 and entered long-term extension) maintained PASI75. It should be noted that while NRI
data were presented (72.6% of responders maintained PASI75 response), the reporting of NRI
data at 3 years or longer is abnormal owing to the
likelihood that life events may necessitate someone’s withdrawal from a clinical trial. Other
reports have generally used as observed data or
other imputation methods for data points significantly longer than 100 weeks [33, 34].
Interestingly, over half of the NRI cohort (53.8%)
and over 2/3 of the observed population (67.6%)
achieved PASI90, implying that patients who
achieve PASI75 early on in treatment are more
likely than not to progress to a PASI90 response.
Psoriatic Arthritis
While psoriatic arthritis trials are ongoing for tildrakizumab and phase III trials have not been
completed at the time of writing, the Phase IIb
study of tildrakizumab for treating psoriatic
arthritis has been conducted and the results have
been reported. The results of this smaller study
are quite interesting and represent a departure
from the perceived weakness of the IL-23 inhibitor class, namely treating psoriatic arthritis. From
a conceptual standpoint, it has been shown that
there seems to be a different gene signature
between psoriatic skin and synovium—the former is IL-17 dominant, while the latter tends to
have a stronger TNF signature [35]. Furthermore,
a report of a different IL-23 inhibitor, risankizumab, revealed that not only were primary endpoints for treating ankylosing spondylitis (AS)
not met, there was no evidence of clinically
meaningful improvements compared to placebo
[36]. But the same does not seem to hold true for
psoriatic arthritis in general, where it is expected
that targeting IL-23 should offer efficacy in treating psoriatic arthritis. This was supported by a
Phase II trial of another IL-23 inhibitor, guselkumab, where 58% of patients achieved ACR20
at week 24 [37]. This result was similar to the
ACR20 response to adalimumab in the corresponding Phase III trial (ADEPT) [38].
However, when the psoriatic arthritis treatment
data for tildrakizumab were released, it was an
unexpected surprise. The ACR20 for tildrakizumab 100 mg (at the same dosing as for psoriasis, every 12 weeks) was reported to be 71.4%. In
fact, ACR50 for this dose was 45.5% and ACR70
was achieved in 22.1% of patients [39]. Of course,
these numbers have to be taken with a grain of salt
as they are Phase II trials with only about 80
patients in each group, but the numbers are strikingly higher than reported Phase II trial data of a
medication targeting the same pathway. It remains
to be seen how these different medications in the
same class end up distinguishing themselves, but
17 Tidrakizumab
efficacy in psoriatic arthritis could potentially be a
significant differentiator for tildrakizumab if the
results hold up in Phase III trials.
Safety/Adverse Events
From a safety standpoint, the effects of tildrakizumab do not seem to be associated with any
major safety concerns that stand out; in fact, the
specific safety data profile appears to be one of
the cleanest among all biologics. In the parallel
trials, the rates of adverse events (one or more)
were 42% and 49% for tildrakizumab 200 mg,
47% and 44% for tildrakizumab 100 mg, 48%
and 55% for placebo, and 54% for etanercept.
The rates of serious adverse reactions were low
across all groups; ranging from 1–3% for all
groups in the placebo-controlled period (with no
consistent trend observed). The most common
adverse events were nasopharyngitis and upper
respiratory infection. The percentages of patients
experiencing nasopharyngitis were 6% and 11%
for tildrakizumab 200 mg, 8% and 13% for tildrakizumab 100 mg, 5% and 8% for placebo, and
12% for etanercept. Respiratory tract infection
was only reported in reSURFACE 1 (likely an
issue with coding the adverse events) and this
was seen in 5% of patients on tildrakizumab
200 mg, 3% of patients on tildrakizumab 100 mg,
and 6% of patients on placebo. Importantly, in
part 2 of both trials, the rates of these infections
remained stably low. There were very low rates
and no signal for serious adverse events of interest, including severe infections, malignancies,
non-melanoma skin cancer, major adverse cardiovascular events, and drug-related hypersensitivity reactions. Overall, the rates of adverse
events with tildrakizumab are among the lowest
reported with any biologic and must be considered as a significant strength of the medication.
Immunogenicity
Immunogenicity is a possibility as with any biologic. The specific rates of anti-drug antibody
formation for tildrakizumab was about 6.5%
229
through 52–64 weeks, with about 2.5% of
patients developing treatment-emergent, neutralizing antibodies, which are generally associated
with reduced serum concentrations of the active
drug and thus modestly reduced efficacy [40].
This was found to be true in a sub-analysis of the
tildrakizumab trials, where treatment-emergent,
neutralizing antibodies were associated with a
modest decrease in PK of tildrakizumab and a
mean PASI reduction of about 10–15%. It should
be noted that comparatively, these are still low
rates of immunogenicity and neutralizing antibodies were not found to be associated with any
drug-related or serious adverse events [41].
Considerations in Treatment
Approach
When considering treatment options for psoriasis, there are numerous factors to consider. First,
there is of course efficacy. However, it should be
noted that the actual improvements in gross efficacy have started to cluster within a relatively
narrow range for the majority of patients. Thus,
other considerations may take a more prominent
role in the selection of an appropriate medication
for patients with psoriasis.
Speed of Onset
It should be noted that in general, the function of
IL-12/23 and IL-23 inhibitors is on the slower
side, especially as compared to IL-17 inhibitors.
Patients may drift upwards slowly with any class
of medication, but the rapid onset of action (i.e.
time to achieve 50% reduction in baseline PASI)
is the fastest for brodalumab, followed by ixekizumab and then secukinumab [42]. IL-23 inhibitors lag behind by a few weeks but the difference
is not on the order of months. Similarly, all biologics take a little more time to cross successive
PASI thresholds with plateauing of PASI 75 coming before that of PASI 90 and PASI 100 across
the board, even with IL-17 inhibitors. When considering an important life event or other extenuating circumstances, if one wishes to optimize for
G. Han
230
rapidity of onset of action, an IL-23 inhibitor
would likely yield to an IL-17 inhibitor.
Prior Treatment with Biologics
One useful consideration is to evaluate whether
patients who have previously been on other biologics will respond to a given treatment. For tildrakizumab, the percent achieving PASI 75 was
very similar whether or not a patient was on a
biologic previously. The number achieving PGA
0/1 was slightly lower in biologic-experienced
individuals (46.2% vs. placebo for tildrakizumab
100 mg) than for biologic-naïve patients (52.5%
vs. placebo for tildrakizumab 100 mg) [43].
Inflammatory Bowel Disease
For patients with concerns about inflammatory
bowel disease (either a personal history or a
strong family history), a clear choice in this realm
would be either a TNF-α inhibitor, an IL-12/23,
or an IL-23 inhibitor. The former two classes of
medications are approved for treatment of
Crohn’s disease/IBD while IL-23 inhibitors have
already reported promising Phase II data in the
treatment of IBD. Conversely, IL-17 inhibitors
have been found to exacerbate IBD, as previously
outlined [24].
Metabolic Syndrome
Given that metabolic syndrome is a common
comorbidity afflicting patients with psoriasis, it
should be noted that some reports dealing with
tildrakizumab treatment have specifically looked
at this subject. One report showed that patients
with metabolic syndrome in the reSURFACE trials had a higher incidence of cardiovascular disorders (50.6% for patients with metabolic
syndrome vs. 16.9% without) and psoriatic
arthritis (21.5% for patients with metabolic syndrome vs. 14.8% without). Patients with metabolic syndrome were also heavier on average,
with a mean weight at baseline of 106.9 Kg (vs.
82.9 Kg without metabolic syndrome). The
responses of both groups of patients (with metabolic syndrome and without), notwithstanding
the stark difference in body weight among other
factors, was very similar in all outcome measures
studied—PASI75, PASI90, PASI100, and mean
PASI improvement [44]. Further data are needed
about disease-specific modifying factors, as there
is a logical argument that reducing levels of pro-­
inflammatory cytokines in the bloodstream by
treating psoriasis with a biologic could reduce
atherosclerosis and cardiovascular risk, which
has been shown to hinge on similar cytokines and
specifically IL-23 [44].
Withdrawal and Retreatment
Tildrakizumab has been shown to have a relatively long duration of effect even after medication withdrawal, possibly due to the upstream/
regulatory function of IL-23 in psoriasis. In part
3 of the phase II trial, some patients were followed for 20 additional weeks off treatment after
the 52-week treatment period—less than 10%
relapsed in the tildrakizumab 100 mg group
(maximum PASI improvement reduced by 50%
or more) [1]. In a separate Phase III trial, 49% of
patients on tildrakizumab 100 mg treatment
maintained their PASI75 response 36 weeks after
cessation of treatment [45]—this is a different
measure and a higher bar than the previously
defined relapse metric. Average time to relapse
for tildrakizumab 100 mg treated patients was
226 days. In the same study, it was shown that
retreatment with tildrakizumab 100 mg for at
least 12 weeks was able to achieve PASI75 in
85.7% of patients.
Pregnancy
With regards to pregnancy, animal studies showed
no evidence of embryotoxicity or teratogenicity,
per the FDA label for tildrakizumab. The only
data available for human pregnancy thus far
comes from a total of 13 patients who became
pregnant in the clinical trials who were then
17 Tidrakizumab
removed from the study drug. Out of these
patients, all pregnancies carried to full term
resulted in normal live births and the rates of
spontaneous abortion were similar to the general
population (2 out of 13) [46]. Interestingly, given
the above duration of effect for tildrakizumab
where about half of patients maintain PASI75
response 36 weeks after discontinuation of treatment, it is likely that patients will continue
receiving efficacy throughout most of their pregnancy. Given that IgG is transferred across the
placenta only after week 13 of pregnancy, and
increases to peak levels in the third trimester
[47], there should be little concern in giving tildrakizumab to a woman of child-bearing age. If a
patient finds out she is pregnant and wishes to
stop the medication, it will be at least two half-­
lives of the medicine later that IgG can even be
transferred across the placenta given the half-life
of tildrakizumab.
Conclusions
Tildrakizumab is an effective treatment for
plaque psoriasis that appears to have an extremely
positive safety profile and good durability of
treatment response. It is unfortunate that while
this medication entered Phase III trials 2 years
before any other IL-23 inhibiting medication, it
was not the first to market and commercialization
of the drug was delayed. In the context of other
IL-23 targeted therapeutics, the efficacy is somewhat less when looking at PASI threshold attainment and clinical results may take somewhat
longer to peak, but it should be noted that on
average, improvements on this drug are still quite
remarkable given what our expectations from
biologics were even just a few years ago. The
safety profile of tildrakizumab is certainly a
strength of the medication, and allows for its confident usage in a wide array of patients. Further
positive attributes of tildrakizumab center around
its convenient dosing schedule and potential efficacy in psoriatic arthritis. It remains to be seen
whether this drug will find a notable position in
our treatment arsenal for psoriasis given the
crowded marketplace, but there is no reason that
231
one should not think of tildrakizumab as a reasonable first-line option in treating psoriasis
given its efficacy, safety, durability, and potential
to treat psoriatic arthritis.
References
1. Papp K, Thaci D, Reich K, Riedl E, Langley RG,
Krueger JG, Gottlieb AB, Nakagawa H, Bowman EP,
Mehta A, Li Q, Zhou Y, Shames R. Tildrakizumab
(MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. Br J Dermatol.
2015;173(4):930–9.
2. Iwakura Y, Ishigame H. The IL-23/IL-17 axis in
inflammation. J Clin Invest. 2006;116(5):1218–22.
3. Gandhi M, Alwawi E, Gordon KB. Anti-p40 antibodies ustekinumab and briakinumab: blockade of
interleukin-12 and interleukin-23 in the treatment
of psoriasis. Semin Cutan Med Surg. 2010;29(1):
48–52.
4. Chen X, Tan Z, Yue Q, Liu H, Liu Z, Li J. The expression of interleukin-23 (p19/p40) and interleukin-12
(p35/p40) in psoriasis skin. J Huazhong Univ Sci
Technolog Med Sci. 2006;26(6):750–2.
5. de Beaucoudrey L, Samarina A, Bustamante J, Cobat
A, Boisson-Dupuis S, Feinberg J, Al-Muhsen S,
Janniere L, Rose Y, de Suremain M, Kong XF, Filipe-­
Santos O, Chapgier A, Picard C, Fischer A, Dogu F,
Ikinciogullari A, Tanir G, Al-Hajjar S, Al-Jumaah
S, Frayha HH, AlSum Z, Al-Ajaji S, Alangari
A, Al-Ghonaium A, Adimi P, Mansouri D, Ben-­
Mustapha I, Yancoski J, Garty BZ, Rodriguez-Gallego
C, Caragol I, Kutukculer N, Kumararatne DS, Patel
S, Doffinger R, Exley A, Jeppsson O, Reichenbach J,
Nadal D, Boyko Y, Pietrucha B, Anderson S, Levin
M, Schandene L, Schepers K, Efira A, Mascart
F, Matsuoka M, Sakai T, Siegrist CA, Frecerova
K, Bluetters-Sawatzki R, Bernhoft J, Freihorst J,
Baumann U, Richter D, Haerynck F, De Baets F,
Novelli V, Lammas D, Vermylen C, Tuerlinckx D,
Nieuwhof C, Pac M, Haas WH, Muller-Fleckenstein
I, Fleckenstein B, Levy J, Raj R, Cohen AC, Lewis
DB, Holland SM, Yang KD, Wang X, Wang X, Jiang
L, Yang X, Zhu C, Xie Y, Lee PP, Chan KW, Chen TX,
Castro G, Natera I, Codoceo A, King A, Bezrodnik L,
Di Giovani D, Gaillard MI, de Moraes-Vasconcelos D,
Grumach AS, da Silva Duarte AJ, Aldana R, Espinosa-­
Rosales FJ, Bejaoui M, Bousfiha AA, Baghdadi JE,
Ozbek N, Aksu G, Keser M, Somer A, Hatipoglu N,
Aydogmus C, Asilsoy S, Camcioglu Y, Gulle S, Ozgur
TT, Ozen M, Oleastro M, Bernasconi A, Mamishi S,
Parvaneh N, Rosenzweig S, Barbouche R, Pedraza
S, Lau YL, Ehlayel MS, Fieschi C, Abel L, Sanal O,
Casanova JL. Revisiting human IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries.
Medicine (Baltimore). 2010;89(6):381–402.
18
Risankizumab
Erica B. Lee, Deeti J. Pithadia, Kelly A. Reynolds,
and Jashin J. Wu
Abstract
Risankizumab is a humanized IgG1 monoclonal antibody that targets the p19 subunit of
interleukin-23 (IL-23). It has demonstrated
substantial clinical efficacy in the treatment of
psoriasis. This chapter reviews the efficacy
and safety of risankizumab for the treatment
of psoriasis as evidenced by the clinical trials
to date. Four phase III trials have shown
risankizumab to be more effective than
ustekinumab and adalimumab in terms of
PASI and sPGA scores with similar safety
profiles to placebo. Thus far, no significant
safety concerns have emerged for this drug,
though further long-term studies will be critical in confirming this.
E. B. Lee
Department of Dermatology, University of Nebraska
Medical Center, Omaha, NE, USA
D. J. Pithadia
Department of Pediatrics, Massachusetts General
Hospital, Boston, MA, USA
K. A. Reynolds
Department of Internal Medicine, Kettering Hospital
Network, Kettering, OH, USA
e-mail: kpassabe@alumni.nd.edu
J. J. Wu (*)
Dermatology Research and Education Foundation,
Irvine, CA, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_18
Key Learning Objectives
1. To understand the mechanism of action
of Risankizumab
2. To understand the appropriate use and
efficacy of the Risankizumab
3. To understand the safety issues of
Risankizumab
Introduction
Interleukin-23 (IL-23) is a heterodimer of a p40 subunit shared by IL-12 and IL-23 and a p19 subunit
that is exclusive to IL-23 [1, 2]. Since its discovery
in 2000, it has been identified as a key inflammatory cytokine involved the pathogenesis of psoriasis [2, 3]. Ustekinumab, an IL-12/23 inhibitor, has
demonstrated effectiveness in treating psoriasis and
other autoimmune diseases [4–7]. However, more
recent evidence has shown that psoriatic skin lesions
have elevated levels of the IL-23 p40 and p19 subunits but normal levels of the IL-12 specific subunit,
p35 [8]. In a phase I study, Kopp et al. later confirmed that specific inhibition of IL-23 by tildrakizumab improves psoriatic symptoms [9]. Moreover,
molecular and histopathologic profiles of skin from
patients treated with an IL-23 inhibitor were shown
to have “excellent improvement” in global histopathologic scores at significantly higher rates than
patients treated with ustekinumab [10].
235
E. B. Lee et al.
236
Risankizumab (AbbVie Pharmaceuticals, Inc.,
Chicago, IL) is a humanized IgG1 monoclonal
antibody that specifically targets and inhibits the
p19 subunit of interleukin (IL)-23 [11]. It is the
third IL-23 inhibitor to be approved for the treatment of moderate-to-severe plaque psoriasis (following guselkumab and tildrakizumab) [12]. It
is also being investigated for use in Crohn’s disease, ankylosing spondylitis, atopic dermatitis,
ulcerative colitis, asthma, and hidradenitis suppurativa [13–20].
Pharmacology
A phase I, single-rising-dose, placebo-controlled
trial of patients with moderate-to-severe plaque
psoriasis investigated the safety, efficacy, pharmacokinetics, and biomarker results of risankizumab [21]. Eighteen patients received a single
intravenous (IV) dose of 0.01, 0.05, 0.25, 1, 3,
or 5 mg/kg and 13 patients received a single
dose of 0.24 or 1 mg/kg subcutaneously. In this
study, risankizumab showed linear pharmacokinetics with mean clearance of 0.33 L/day and a
mean terminal phase volume of distribution of
10.8 L. Risankizumab’s half-life ranged between
20 and 28 days. Maximal exposure ranged from
4 to 10 days in patients receiving risankizumab
subcutaneously. Bioavailability was 59% for
both subcutaneous and IV administration.
These findings were confirmed by phase I and
II trials in subjects with psoriasis and Crohn’s disease [22]. Based on the results of these analyses,
clearance was estimated to be 0.35 L/day. Steadystate volume of distribution was estimated to be
11.7 L, and terminal-phase elimination half-life
was calculated as 27 days. In patients receiving
risankizumab subcutaneously, bioavailability was
72%. It was also found that higher body weight
may have modest effect on risankizumab levels,
particularly in patients greater than 100 kg.
Upon incorporation of data from phase III
clinical trials, clearance was found to be relatively similar to previous estimates at 0.31 L/
day [23]. Calculated steady-state volume of distribution and terminal-phase elimination halflife were also consistent at 11.2 L and 28 days,
respectively. Bioavailability when given subcutaneously was markedly higher than previous findings at 89%. Steady-state plasma exposure was
attained by week 16 of dosing.
Dosing and Monitoring
The standard dosing of risankizumab is 150 mg
(two 75 mg injections) administered subcutaneously at week 0, week 4, then every 12 weeks.
Prescribing information recommends that all
patients undergo evaluation for tuberculosis
infection prior to beginning risankizumab [24].
The guidelines for treatment with biologics published by the American Academy of Dermatology
(AAD) and the National Psoriasis Foundation
(NPF) also suggest that patients be screened with
a complete blood count, complete metabolic profile, serologic tests for tuberculosis, hepatitis B
and C, and possibly HIV testing at the discretion
of the prescriber [25].
With regard to ongoing monitoring, the
AAD/NPF guidelines suggest yearly tuberculosis screening in high-risk patients (patients in
contact with individuals with active TB and in
patients with an underlying medical condition).
All other patients may be screened annually at
the discretion of the provider. Patients should
also have regular follow-up visits with their dermatologists, which should include screening for
nonmelanoma skin cancer, hepatitis B and C,
adverse effects, and infections [25].
Clinical Efficacy
Phase I and II trials have demonstrated the efficacy of risankizumab in treating patients with
moderate-to-severe psoriasis. In the previously
mentioned phase I trial, 87% of patients treated
with a single dose of risankizumab achieved at
least a 75% decrease in the Psoriasis Area and
Severity Index (PASI), with 58 and 16% achieving PASI 90 and PASI 100, respectively, by week
12 [21]. The phase II trial directly compared
risankizumab to ustekinumab in 166 patients randomized to receive either risankizumab 18, 90,
18 Risankizumab
or 180 mg (weeks 0, 4, and 16) or ustekinumab
45 or 90 mg (based on body weight, weeks 0,
4, and 16) [11]. At week 12, the proportion of
patients achieving PASI 90 was 77% in those
treated with risankizumab, compared to 40% of
ustekinumab patients (P < 0.001). Moreover,
98% of the patients in the 90-mg risankizumab
group achieved PASI 75, with 80% of patients
reaching this endpoint as early as week 8.
Four phase III trials have formally evaluated the safety and efficacy of risankizumab:
UltIMMa-1, UltIMMa-2, IMMvent, and
IMMhance. UltIMMa-1 and UltIMMa-2 were
replicate, randomized, double-blind, placebo- and
active-comparator-controlled trials [26]. Patients
were randomized to receive either 150 mg risankizumab (week 0, 4, then every 12 weeks), 45 or
90 mg ustekinumab (based on weight per label),
or placebo for the first 16 weeks of the study. From
weeks 16 to 52, patients initially treated with
placebo received risankizumab, while all others
maintained their original treatment. Co-primary
endpoints included the percentage of patients
achieving PASI 90 and a static Physician’s Global
Assessment (sPGA) of 0 or 1 at week 16.
In UltiMMa-1, risankizumab outperformed
both placebo and ustekinumab in terms of the primary endpoints. PASI 90 was achieved by 229 of
304 patients receiving risankizumab (75.3%) compared to 5 of 102 (4.9%) receiving placebo and 42
of 100 (42.0%) treated with ustekinumab at week
16 (P < 0.0001 vs. placebo and ustekinumab). By
the first measured time point (week 4), the proportion of patients on risankizumab attaining PASI 90
was significantly higher than those treated with
placebo, and by week 8, significantly higher than
ustekinumab (P = 0.0001). Findings were similar in
terms of sPGA scores, with 87.8% of patients reaching sPGA 0 or 1 versus 7.8 and 79.9% of patients
receiving placebo and ustekinumab, respectively
(P < 0.0001). Moreover, 35.9% of patients receiving risankizumab achieved PASI 100, or complete
clearance of psoriatic lesions, by week 16, compared to 12% of patients receiving ustekinumab
and 0% receiving placebo. At the end of the study
period, 81.9% of patients on continuous risankizumab and 78.4% of patients who were switched
from placebo at week 16 achieved PASI 90.
237
The results of UltiMMa-2 also demonstrated
superior efficacy of risankizumab compared to
placebo and ustekinumab. At week 16, 74.8%
(220 of 294) of patients in the risankizumab
group achieved PASI 90, versus 2.0% (2 of
98) and 47.5% (47 of 99) in the placebo and
ustekinumab groups, respectively (P < 0.0001 vs.
both placebo and ustekinumab). In addition, an
sPGA 0/1 score was attained by 83.7% of risankizumab patients, 5.1% of placebo patients, and
61.6% of ustekinumab patients (P < 0.0001 vs.
placebo and ustekinumab). In this trial, 50.7% of
patients treated with risankizumab experienced
complete clearance of psoriatic lesions at week
16; this increased to 59.5% in patients on continuous risankizumab by week 52.
The IMMvent trial was a double-blind, active-­
comparator trial that assessed the safety and
efficacy of risankizumab compared to the TNF
inhibitor adalimumab [27]. In the first phase of
the trial, patients were randomly assigned to therapy with either risankizumab 150 mg (subcutaneous injection at weeks 0, 4, then every 12 weeks)
or adalimumab (80 mg at week 0, 40 mg at week
1, then 40 mg every other week thereafter).
During weeks 16–52, those who were originally
assigned to adalimumab were regrouped based
on their response at 16 weeks: those with less
than PASI 50 response switched to risankizumab,
those with PASI 90 remained on adalimumab,
and those with response between PASI 50 and
PASI 90 were re-randomized to either initiate
risankizumab or continue adalimumab. Patients
originally assigned to risankizumab continued
their treatment with dosing every 12 weeks.
Although the data has not yet been formally published, it has been reported that risankizumab
performs significantly better than adalimumab
both in terms of the primary endpoints at week 16
(PASI 90 and sPGA 0/1), and the secondary endpoint, PASI 100 at week 44 [27]. Of 301 patients
in the risankizumab group, 72% achieved PASI
90, compared to 47% of 304 patients in the adalimumab group at week 16. Eighty-four percent of
risankizumab patients attained sPGA 0/1 at this
time point, versus 60% of adalimumab patients.
In addition, of those who switched to risankizumab at week 16, 40% achieved PASI 100 at
238
week 44. Preliminary results were not reported
for patients who had been on risankizumab for
duration of the entire trial.
The fourth phase III clinical trial, IMMhance,
was a placebo-controlled study comparing the
safety and efficacy of continuous treatment and
randomized withdrawal of risankizumab over
the course of 104 weeks [28, 29]. In the initial phase, subjects were randomized to receive
either risankizumab 150 mg or placebo for the
first 28 weeks. The primary endpoints were PASI
90 and sPGA 0/1. In the second phase, risankizumab patients who achieved sPGA 0/1 were
re-­randomized to continue risankizumab (maintenance) or placebo (withdrawal). Starting at
week 32, any patient who experienced a relapse,
defined as sPGA score of 3 or greater, was reinitiated on risankizumab (injection given immediately, 4 weeks later, then every 12 weeks). The
primary endpoint for the second phase of the
study was sPGA 0/1 at week 52. At week 16, 73%
of patients assigned to risankizumab achieved
PASI 90, and 84% attained sPGA 0/1, compared
2 and 7%, respectively, in the placebo group. At
week 52, the proportion of patients in the continuous risankizumab group maintaining sPGA 0/1
was 87%, versus 71% in the withdrawal group
(P < 0.001). These findings suggest that like
other biologics, the efficacy of risankizumab is
maximized with continuous treatment rather than
periods of discontinuation and re-initiation.
Safety
As risankizumab is one of the newest biologics
to be approved, safety data is limited to what
has been reported in clinical trials. Adverse
events (AEs) were reported in 65% (20 of 31) of
patients followed for 24 weeks after a single dose
of risankizumab in the phase I trial, though severity of adverse events did not appear to correlate
with the dose received [21]. The most common
adverse events reported were mild-to-moderate
upper respiratory tract infections (10%), mild
nasopharyngitis (13%), and mild-to-moderate
headache (10%). Four serious AEs (SAEs) were
reported concurrently with risankizumab ther-
E. B. Lee et al.
apy. These included alcoholic pancreatitis, ischemic thalamic stroke, transient ischemic attack,
and polymyositis; investigators considered each
of these independent of the study medication.
Injection-site reactions were reported in 2 of 24
patients receiving risankizumab intravenously,
while no reactions were reported in the subcutaneous administration group.
The UltIMMa phase III trials demonstrated
similar frequency of AEs among individuals treated with risankizumab and those treated
with ustekinumab [26]. At the end of week
16 in UltIMMa-1, 49.7% of patients receiving
risankizumab and 50.0% of patients receiving
ustekinumab reported adverse events. Seven
risankizumab patients reported SAEs in this
time period, including one serious infection
and one squamous cell carcinoma. Findings
were similar in UltIMMa-2; 45.6 and 53.5% of
patients reported any AE in the risankizumab
and ustekinumab groups, respectively, by the
end of week 16. Six SAEs were reported among
risankizumab-­
treated patients, including three
serious infections and one basal cell carcinoma.
Across both trials, the most commonly reported
adverse events were upper respiratory infection,
psoriasis, and diarrhea. No tuberculosis, opportunistic infections, major adverse cardiovascular
events (MACEs) or serious hypersensitivity reactions were reported.
Overall rates of AEs per patient-years
(PY) across the entire 52-week durations of
UltIMMa-1 and UltIMMa-2 were 245.6 and
281.0 for risankizumab and ustekinumab, respectively [27]. Serious AEs occurred at a rate of 9.8
per 100 PY on risankizumab, compared to 1.9
per 100 PY on ustekinumab. Of these, serious
infections occurred slightly less frequently in the
risankizumab group (1.6 per 100 PY vs. 2.5 per
100 PY with ustekinumab), though MACE (0.5
per 100 PY vs. 0.0 per 100 PY), malignancy of
any kind (1.5 per 100 PY vs. 0.5 per 100 PY),
and death (0.3 per 100 PY vs. 0.0 per 100 PY)
occurred with higher frequency in patients on
risankizumab. One risankizumab patient died
from sudden cardiac arrest 101 days after the
last dose of risankizumab, and a second died
of an unknown cause 161 days after the last
18 Risankizumab
dose. Moreover, an additional risankizumabtreated patient in the IMMvent trial died of an
acute myocardial infarction on study day 73.
The IMMhance trial also reported death of one
patient on risankizumab; this occurred on study
day 263 and was ruled to be due to a MACE [29].
All of these patients had cardiovascular risk factors prior to initiation of the drug. It is important to consider that the sample sizes of the trials
conducted so far are still relatively small; further
research and larger population sizes are needed to
determine whether risankizumab may have any
serious long-term adverse effects.
Pooled data from all phase III clinical trials found that 24% (263 of 1079) of patients
treated with risankizumab were positive for
anti-­risankizumab antibodies by week 52 [24].
Of these, about 57% (14% of all risankizumab-­
treated patients) were deemed to have neutralizing antibodies. However, higher antibody levels
were associated with lower risankizumab concentrations and reduced clinical efficacy in only
1% of patients.
Pregnancy and Lactation
Available data regarding the safety of use in
pregnancy and lactation is limited to studies
in cynomolgus monkeys [24]. It is known that
risankizumab may be transmitted from mother to
fetus or infant, as human IgG is able to cross the
placenta and is present in breastmilk. At doses
that are 20 times the maximum recommended
human dose (2.5 mg/kg based on administration
of a 150 mg dose to a 60 kg individual), increased
fetal or infant loss was found in pregnant monkeys. However, no effects on functional or immunological development related to risankizumab
were observed in infant monkeys from birth
through 6 months.
Conclusion
The elucidation of IL-23 as an important cytokine in the pathogenesis of psoriasis has led to
great advances in the development of effective
239
biologic therapies. The advent of IL-23 inhibitors has provided psoriasis patients with novel
options with exceptional clinical efficacy seen in
the phase III clinical trials. However, it is important to consider the paucity of long-term efficacy
and safety data. Further studies are undoubtedly
necessary to specify the role of IL-23 inhibitors in
the treatment of psoriasis.Conflicts of InterestDr.
Wu is an investigator for AbbVie, Amgen, Eli
Lilly, Janssen, Novartis; a consultant for AbbVie,
Almirall, Amgen, Bristol-Myers Squibb, Celgene,
Dermira, Dr. Reddy’s Laboratories, Eli Lilly,
Janssen, LEO Pharma, Novartis, Promius Pharma,
Regeneron, Sun Pharmaceutical, and UCB,
Valeant Pharmaceuticals North America LLC;
and a speaker for AbbVie, Celgene, Novartis,
Regeneron, Sanofi Genzyme, Sun Pharmaceutical,
UCB, Valeant Pharmaceuticals North America
LLC. The rest of the authors have no conflicts to
disclose.
References
1. Oppmann B, Lesley R, Blom B, et al. Novel p19
protein engages IL-12p40 to form a cytokine, IL-23,
with biological activities similar as well as distinct
from IL-12. Immunity. 2000;13:715–25. https://doi.
org/10.1016/S1074-7613(00)00070-4.
2. Girolomoni G, Strohal R, Puig L, et al. The role
of IL-23 and the IL-23/TH 17 immune axis in the
pathogenesis and treatment of psoriasis. J Eur Acad
Dermatol Venereol. 2017;31(10):1616–26. https://doi.
org/10.1111/jdv.14433.
3. Chan JR, Blumenschein W, Murphy E, et al.
IL-23 stimulates epidermal hyperplasia via TNF
and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis. J Exp Med.
2006;203(12):2577–87. https://doi.org/10.1084/jem.
20060244.
4. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy
and safety of ustekinumab, a human interleukin-12/23
monoclonal antibody, in patients with psoriasis:
76-week results from a randomised, double-blind,
placebo-controlled trial (PHOENIX 1). Lancet.
2008;371(9625):1665–74.
https://doi.org/10.1016/
S0140-6736(08)60725-4.
5. Papp KA, Langley RG, Lebwohl M, et al. Efficacy
and safety of ustekinumab, a human interleukin-12/23
monoclonal antibody, in patients with psoriasis:
52-week results from a randomised, double-blind,
placebo-controlled trial (PHOENIX 2). Lancet.
2008;371(9625):1675–84.
https://doi.org/10.1016/
S0140-6736(08)60726-6.
Secukinumab for the Treatment
of Inflammatory Skin and Joint
Disease
19
Jason E. Hawkes and Avishan Vishi Hawkes
Abstract
and rheumatology. While the exact roles of
interleukin-17 in the development of inflammatory diseases is not entirely clear, ongoing
research and clinical studies are expanding
our knowledge base and leading to the development of new treatments that can improve
clinical outcomes for patients affected by
these conditions.
Psoriasis is a chronic inflammatory skin condition characterized by thick, erythematous,
scaly plaques commonly found on the extensor surfaces, scalp, and trunk. While the etiology of this skin condition has not been fully
elucidated, research has unequivocally shown
that psoriasis represents a bona fide T cell-­
mediated disease that involves the skin, joints,
and a myriad of other organs/tissues. The
Abbreviations
recent discovery of a set of pathogenic T cells
that produce high levels of interleukin-17 in
ACR 20
American College of Rheumatolresponse to interleukin-23 led to a major paraogy 20 score
digm shift in the pathogenic model for this
AS
Ankylosing spondylitis
condition resulting in numerous novel targeted
ASAS 20
Assessment of Spondyloarthritis
immune therapies. The robust phase 3 clinical
International Society 20 (ASAS
trial program for anti-interleukin-17A via
20) response
secukinumab (sold under the brand
axSpA
Axial spondyloarthritis
Cosentyx®) for the treatment of moderate-to-­
DLQI
Dermatology Life Quality Index
severe plaque psoriasis, psoriatic arthritis, and
FDA
US Food and Drug Administration
ankylosing spondylitis provides a solid founIBD
Inflammatory bowel disease
dation supporting the high clinical efficacy
Ig
Immunoglobulin
and safety of this medication in dermatology
IL-17
Interleukin-17
IL-23
Interleukin-23
NAPSI
NAil Psoriasis Severity Index
J. E. Hawkes (*)
nr-axSpA
Nonradiographic axSpA
Department of Dermatology, University of California
PASI
Psoriasis Area and Severity Index
Davis and PCN-Rocklin, Sacramento, CA, USA
e-mail: jehawkes@ucdavis.edu
PK
Pharmacokinetic
PPP
Palmoplantar psoriasis
A. V. Hawkes
Regeneron Pharmaceuticals, Inc.,
ppPASI
Palmoplantar Psoriasis Area and
Tarrytown, NY, USA
Severity Index
e-mail: Vishi.Hawkes@regeneron.com
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_19
243
J. E. Hawkes and A. V. Hawkes
244
PsA
PSSI
TNF
Psoriatic arthritis
Psoriasis Scalp Severity Index
Tumor necrosis factor
selective blockade of IL-17A and IL-23p19. This
book chapter will focus on secukinumab, the first
FDA-approved monoclonal antibody to selectively target IL-17A for the treatment of psoriatic
disease.
Key Learning Objectives
1. To understand the mechanism of action
of Secukinumab
2. To understand the appropriate use and
efficacy of the Secukinumab
3. To understand the safety issues of
Secukinumab
Secukinumab: Background
and Pivotal Clinical Trial Data
The rapid onset, clinical efficacy, and safety
profile of secukinumab underscores the importance of the IL-23/IL-17 signaling pathway in
the pathogenesis of psoriasis and inflammatory
joint diseases. Originally developed in 1996
Introduction
from HuMab® mice (Medarex, Inc.) using a portion of the human immunoglobulin repertoire,
Psoriasis is a chronic, inflammatory skin dis- secukinumab (previously known as AIN457) is
ease that is estimated to affect approximately a fully human immunoglobulin (Ig)G1/κ mono3% of the US population [1]. Plaque psoriasis, clonal antibody that was subsequently tested
the most common disease subtype, is typified in clinical trials by Novartis Pharmaceuticals
by well-­
demarcated, scaly, thickened plaques Corporation for the treatment of psoriasis,
on the scalp, trunk, and extensor surfaces of the rheumatoid arthritis, and uveitis [4]. The FDA
extremities. Inflammatory involvement of the approved secukinumab for the treatment of
joints, known as psoriatic arthritis (PsA), occurs moderate-­
to-severe plaque psoriasis in adults
in approximately one-third of patients with pre-­ on January 21, 2015. Secukinumab is currently
existing skin disease or can be the presenting sold under the trade name Cosentyx® and selecsymptoms of psoriasis. Other less common pso- tively targets the IL-17A isoform. It was the firstriasis variants include erythrodermic, pustular, in-­
class FDA-approved monoclonal antibody
palmoplantar, guttate, and inverse subtypes.
that directly inhibits the IL-17 immune axis [5].
The pathogenesis of psoriasis is a complex, Secukinumab was subsequently approved for the
T-cell mediated skin and joint disease primar- treatment of ankylosing spondylitis (AS) and PsA
ily driven by upregulation of the interleukin-23 in adults on January 15, 2016. Below is a sum(IL-­23)/IL-17 signaling pathway [2, 3]. While mary of pivotal clinical trials for secukinumab
the exact cause of psoriasis is still unknown, for each approved clinical indication.
the onset of disease is clearly modified by several factors including psoriasis-associated genes
or susceptibility loci, environmental exposures, Plaque Psoriasis
diet, medications, and infections. In the last two
decades, science and clinical trials have rapidly For plaque psoriasis, secukinumab is adminexpanded our knowledge of psoriatic disease, istered subcutaneously with a loading dose of
leading to the development and US Food and 300 mg (two 150 mg injections) at weeks 0, 1,
Drug Administration (FDA) approval of a broad 2, 3, and 4, then monthly thereafter. The 150 mg
array of topicals, oral immunosuppressants, and dose at the same dosing interval is available and
injectable immunotherapies. This therapeutic may be sufficient for some patients. Key phase
armamentarium includes 11 monoclonal anti- 3 clinical trials provide evidence demonstrating
bodies (or biologics) whose targets range from the efficacy of secukinumab in the treatment of
inhibition of tumor necrosis factor (TNF) to moderate-­to-severe plaque psoriasis: ERASURE,
19
Secukinumab for the Treatment of Inflammatory Skin and Joint Disease
FIXTURE, and CLEAR trials. Additional, subsequent phase 3 trials built upon and bolster the
clinical data obtained from these three major
trials.
ERASURE was a double-blind, 52-week,
placebo-­
controlled trial with 738 patients
enrolled into secukinumab (300 or 150 mg
weekly for 5 weeks, then monthly) versus placebo [6]. 75% improvement in the Psoriasis Area
and Severity Index (PASI 75) for patients in the
secukinumab treatment groups (300 or 150 mg)
were 82 and 72%, respectively. Less than 5% of
patients achieved a PASI 75 in the placebo arm.
The FIXTURE trial was also a double-blind,
52-week, placebo-controlled with 1306 patients
randomized to treatment with secukinumab (300
and 150 mg as above) or etanercept (50 mg twice
weekly for 12 weeks, then weekly) versus placebo [6]. In this trial, a PASI 75 was achieved
in 77 and 67% of patients by week 12 in the
300 and 150 mg treatment arms, respectively.
In comparison, only 44% of patients achieved a
PASI 75 with etanercept versus 5% in the placebo treatment arm. Importantly, a pooled analysis of the data from ERASURE and FIXTURE
also showed ~95% of patients who had achieved
a PASI 75 in the core clinical trials were able
to achieve this same response by 12 weeks following secukinumab treatment interruption
(data presented at the 2017 American Academy
of Dermatology Annual Meeting in Orlando,
Florida).
The CLEAR study was a subsequent
52-week, double-blind, randomized controlled
trial that enrolled 676 patients to treatment with
secukinumab (300 mg weekly for 5 weeks, then
monthly) versus ustekinumab (45 or 90 mg at
weeks 0, 4, then every 12 weeks based on body
weight) [7]. Due to the high efficacy shown for
both treatments from previous studies, a more
stringent primary study endpoint of PASI 90
instead of PASI 75 was used in the ERASURE
and FIXTURE studies. The benchmark of PASI
90 as a primary study endpoint would continue to
be used in subsequent studies for newer, highly
effective biologic agents tested for the treatment
of psoriasis. At week 16, 79% of psoriasis patients
achieved a PASI 90 in the secukinumab group
245
compared to only 58% from the ustekinumab
group. The distinct superiority of secukinumab
compared to ustekinumab was still evident following 1 year of treatment [8], and secukinumab
was strongly associated with a significantly
higher Dermatology Life Quality Index. The
SCULPTURE trial reported a similar, sustained
clinical efficacy and safety for secukinumab
through 5 years [9]. Finally, the JUNCTURE [10]
and FEATURE [11] trials also demonstrated the
efficacy and safety of secukinumab administered
for auto-injector/pen and pre-filled syringes, and
clinical results were comparable with previous
studies.
ifficult to Treat Psoriasis Subtypes:
D
Palmoplantar, Nail, and Scalp
Psoriasis
Most psoriasis clinical trials to date have been
designed for plaque psoriasis or PsA, excluding
less common disease subtypes and patients with
disease that predominantly involves the scalp,
palmoplantar, intertriginous, or genital skin.
Scalp psoriasis, palmoplantar psoriasis (PPP),
and nail abnormalities have historically been
classified as more difficult to treat psoriasis areas.
The exact reasons for the patterned expression or
recalcitrant nature of disease in these specific skin
areas is not currently known. However, disproportionate environmental triggers (e.g. increased
trauma) and/or differences in resident immune
cells in these areas of skin represent a possible
explanation for these observations. Secukinumab
was one of the first psoriasis biologics evaluated
in trials specifically designed for patients with
these difficult to treat subtypes in the GESTURE,
TRANSFIGURE, and scalp psoriasis trials.
GESTURE was a phase 3, randomized,
double-­
blind, placebo-controlled, multicenter,
trial conducted across 15 countries and consisted
of 132 weeks of treatment for PPP patients [12].
205 subjects were randomized to secukinumab
300 or 150 mg versus placebo. The primary endpoint was Palmoplantar Investigator’s Global
Assessment (ppIGA) 0 (clear) or 1 (almost clear/
minimal) after 16 weeks of treatment. At week
J. E. Hawkes and A. V. Hawkes
246
16, 33 and 22% of patients achieved clear or
almost clear in the 300 and 150 mg treatments
groups, respectively, compared to only 1.5% in
the placebo treatment arm. This clinical response
was accompanied by significant reductions in
Palmoplantar Psoriasis Area and Severity Index
(ppPASI) and higher Dermatology Life Quality
Index (DLQI) 0/1 responses. Continued clinical improvement and a sustained efficacy was
observed in moderate-to-severe PPP patients
on continuous secukinumab treatment for up to
2.5 years [13].
In a very similar design as the GESTURE
trial, TRANSFIGURE was conducted across
39 study locations and consisted of 132 weeks
of secukinumab treatment for psoriatic nail
involvement [14]. The primary study endpoint
was improvement in the NAil Psoriasis Severity
Index (NAPSI) after 16 weeks of secukinumab
treatment. The primary endpoint was met demonstrating mean nail improvement in 73 and
64% of patients treated with secukinumab 300
and 150 mg, respectively. Improved NAPSI
scores were sustained with continuous treatment
over 2.5 years and was associated with multiple
improved patient reported outcomes and Quality
of Life indices.
Finally, secukinumab was studied for the
treatment of scalp psoriasis in a phase 3, double-­
blind, randomized trial of 102 psoriasis patients
across 17 study locations [15]. In this 24-week
study, patients were randomized to secukinumab
300 mg at weeks 0, 1, 2, 3, and 4 followed by
monthly injections for 20 weeks versus placebo.
The primary study measure was 90% improvement of Psoriasis Scalp Severity Index (PSSI
90) score from baseline to week 12. The proportion of patients achieving a PSSI 90 response at
week 12 was 53% for the secukinumab 300 mg
treatment group compared to only 2% of
patients receiving placebo. More than one-third
of patients receiving secukinumab achieved
complete clearance of the scalp at week 12,
­
whereas 0% of patients receiving placebo had
complete scalp clearance.
Psoriatic Arthritis
For PsA patients with coexistent skin disease,
secukinumab is dosed and administered as above
for moderate-to-severe plaque psoriasis. For PsA
with no skin disease, 150 mg of secukinumab can
be administered with a loading dose (150 mg at
weeks 0, 1, 2, 3, and 4, then monthly) or without a
loading dosage (150 mg every 4 weeks). 300 mg
dosing should be considered for PsA patients
with persistent or recalcitrant clinical disease and
symptoms despite receiving the 150 mg dosing
of secukinumab for an adequate period of time to
allow symptoms to resolve (usually 3–4 months).
Two initial phase 3 clinical trials (FUTURE 1
and 2) evaluated the efficacy of secukinumab for
the treatment of PsA. FUTURE 1 was a 52-week,
double-blind, placebo-controlled trial that randomized 606 patients with PsA to treatment with
secukinumab (10 mg/kg dose at weeks 0, 2, and 4,
then 150 or 75 mg subcutaneously every 4 weeks)
versus placebo [16]. Approximately 50% of
patients achieved at least a 20% improvement in
the American College of Rheumatology 20 score
(ACR 20) for both treatment arms compared to
only 17% in the placebo arm. This response was
observed and sustained through 1 year after initiation of secukinumab treatment. FUTURE 2
was a 4-year study that enrolled and randomized
397 PsA to secukinumab (300, 150, or 75 mg
monthly after weekly injections at weeks 0, 1,
2, 3, and 4) versus placebo [17]. After 24 weeks
of secukinumab treatment, 54% (300 mg), 51%
(150 mg), and 29% (75 mg) of patients treated with
secukinumab achieved an ACR 20 versus 15% of
patients in the placebo arm. At week 128, patients
with inadequate response to 150 or 75 mg dosing
were escalated to 300 mg based on the judgment
of the trial investigators. The ACR 20 and ACR 50
response rates were maintained around 70–75%
and 40–50%, respectively, between weeks 26
through 208. PASI 75/90 scores were slightly
lower for patients with PsA compared to plaque
psoriasis, but similar to those observed in the pivotal phase 3 trials for plaque psoriasis.
19
Secukinumab for the Treatment of Inflammatory Skin and Joint Disease
FUTURE 5 was another randomized, double-­
blind, placebo-controlled clinical trial and the
largest ever conducted for PsA patients receiving
treatment with any biologic [18]. In this study, 996
patients were randomized to 52 weeks of treatment in four different groups: secukinumab 300
or 150 mg monthly after loading doses at weeks
0, 1, 2, 3, and 4; secukinumab 150 mg monthly
with no loading dose; or placebo. The primary
endpoint was ACR 20 response at week 16 and
was achieved in 63, 56, and 60% of patients in the
secukinumab 300 mg + loading, 150 mg + loading, and 150 mg with no loading treatments
groups, respectively. 27% of patients receiving
placebo achieved an ACR 20 response at week
16. The ACR 20 response was sustained through
week 52 in all treatments arms with superiority
observed in the secukinumab 300 mg + loading
dose group. Importantly, the study also evaluated
multiple secondary endpoints including radiographic progression of joint disease at week 52,
complete response of enthesitis, and complete
response of dactylitis, which were achieved in
roughly half of patients for all treatment groups.
To date, most clinical trials have not discriminated between subtypes of PsA (e.g. axial PsA).
This may be due in part to our evolving understanding and terminology around inflammatory
arthropathies. Regardless, knowing whether these
subtypes have differential responses to specific
treatments is an important question to address.
Novartis will attempt to address this via an ongoing phase 3b clinical trial (ClinicalTrials.gov
Identifier: NCT02721966) evaluating the safety
and efficacy of secukinumab 150 or 300 mg in
the treatment of axial PsA patients who have
failed at least 2 non-steroidal anti-­inflammatory
drugs for at least 1 month. ASAS 20 response
with secukinumab 300 mg versus placebo at
Week 12 is the listed primary study end point of
this trial. This and other studies designed to tease
out PsA subtypes prior to the trial design will
be of interest to clinicians treating this group of
patients with complex disease.
247
Ankylosing Spondylitis
Axial spondyloarthritis (axSpA) is an inflammatory, spinal arthritis which can be severely
disabling for patients due to chronic back pain
that often manifests before the age of 45. Patients
with axSpA are characterized as having either AS
(also known as radiographic axSpA) or nonradiographic axSpA (nr-axSpA). This condition is also
associated with psoriasis and shares overlapping
clinical features with PsA, such as sacroiliitis,
synovitis, enthesitis, dactylitis, and the HLAB27 gene [19, 20]. It is not surprising, therefore,
that a significant proportion of patients with AS
and PsA respond to treatment with secukinumab.
Secukinumab for the treatment of AS is administered as 150 mg with or without a loading dose:
150 mg every 4 weeks or 150 mg at weeks 0, 1, 2,
3, and 4 followed by monthly injections.
The efficacy of secukinumab for the treatment
of active AS was studied in four pivotal phase 3,
double-blind, randomized, placebo-controlled
trials: MEASURE 1-4. MEASURE 1 enrolled
and randomized 371 AS patients for treatment
with intravenous secukinumab (10 mg/kg dose)
at weeks 0, 2, and 4 followed by 150 or 75 mg
every 4 weeks versus placebo [21]. The primary
endpoint for MEASURE 1 and 2 was the proportion of patients with at least 20% improvement in
the Assessment of Spondyloarthritis International
Society (ASAS 20) response criteria at week 16.
At week 16, ASAS 20 response rates were 61 and
60% for the 150 and 75 mg doses, respectively,
compared to only 29% in the placebo group. In
MEASURE 2, a total of 219 AS patients were
enrolled and randomized to treatment for 3 years
with subcutaneous secukinumab (150 or 75 mg)
at weeks 0, 1, 2, 3, and 4 followed by monthly
injections versus placebo [21]. Patients in the
placebo group were then randomly switched to
subcutaneous secukinumab (150 or 75 mg) at
week 16. ASAS 20 response rates at week 16
were 61 and 41% for subcutaneous secukinumab
(150 and 75 mg), respectively, compared to only
248
28% of patients in the placebo group. ASAS 40
response rates at week 16 for the 150 mg treatment group were 36% and gradually improved
to 49% through week 52. It is important to note
that significant improvement in AS symptoms
were observed for patients treated with 150 mg
of secukinumab in all dosing groups, whereas
75 mg of secukinumab was only significant with
a higher loading dose.
MEASURE 3 was a 52-week trial that evaluated the safety and efficacy of subcutaneous
secukinumab 300 and 150 mg monthly maintenance dosing for AS following intravenous
loading (10 mg/kg at weeks 0, 2, and 4) versus
placebo [22]. 61 and 58% of patients achieved
the ASAS 20 response rate target at week 16
for the 300 and 150 mg treatment arms, respectively, compared to 36.8% in the placebo group.
As with prior studies, improvements in clinical disease were maintained from week 16
through week 52. The clinical improvements and
ASAS20 response rates observed in MEASURE
3 were essentially reproduced in MEASURE 4
[23], which evaluated the efficacy and safety of
secukinumab 150 mg via a self-administered prefilled syringe (with or without a loading regimen)
in AS patients for 104 weeks. However, due to
a high placebo response rate, the results in the
study were not statistically significant.
Pharmacologic Properties
and Safety
J. E. Hawkes and A. V. Hawkes
erties for this medication have been established
across three major multiple clinical indications
and in a highly diverse demographic of patients.
Secukinumab has also been used safely in
plaque psoriasis, PsA, and AS patients for more
than 5 years. Therefore, the above referenced phase
3 clinical trials have provided a robust data set that
establishes the high efficacy and excellent safety
of secukinumab across multiple indications. The
adverse events reported in clinical trials for these
three indications have been remarkably similar
and are summarized in Table 19.1. The most commonly reported adverse events in approximately
10% of patients was headache and nasopharyngitis or upper respiratory infections. Less common
adverse events included non-serious infections or
infestations, diarrhea, arthralgias, mucocutaneous
candidiasis, hypertension, and hypercholesterolemia. Rare adverse events (occurring in less than
1% of patients) included transient neutropenia,
major adverse cardiac event, inflammatory bowel
disease (IBD), serious infections, uveitis, and
malignancy or unspecific tumor formation.
Mucocutaneous candidiasis and IBD are
two particular adverse events of interest for this
particular class of medication. The development of candida and other viral infections as a
result of IL-17 inhibition reflects the importance
Table 19.1 Summary of adverse events for secukinumab
observed in phase 3 clinical trials for the treatment of
plaque psoriasis, psoriatic arthritis (PsA), and ankylosing
spondylitis (AS)
Common Adverse Events: >10% of patients
• Nasopharyngitis or upper respiratory infections
The pharmacologic and biochemical properties • Headache
of secukinumab and its mode of administration Less Common Adverse Events: 9–1% of patients
determine its observed clinical efficacy and safety • Diarrhea
in treated patients. As a human IgG1-based anti- • Mucocutaneous candidiasis
body targeting IL-17A, secukinumab shares the • Non-serious infection/infestation
• Hypertension
stability and long half-life of other IgG1 antibod- • Hypercholesterolemia
ies in humans [24]. These properties, as well as • Arthralgias
its abundance in the human body, were factors Rare Adverse Events: <1% of patients
that certainly influenced the decision underlying • Inflammatory bowel disease
the design of secukinumab. The pharmacokinetic • Serious infections
• Injection site reactions
(PK) properties of secukinumab have also been • Major adverse cardiac event
established with a known half-life of ~25 days, • Uveitis
high absolute bioavailability, and no dose-­ • Neutropenia
dependent clearance [25]. The favorable PK prop- • Malignancy or unspecified tumors
19
Secukinumab for the Treatment of Inflammatory Skin and Joint Disease
of this specific cytokine in providing humans
and the skin with protection against this infection. Humans with inborn errors of IL-17RA or
IL-17F are also associated with recurrent candida
infections, upper respiratory infections, and mild
skin infections that provides a natural experiment
in human nature that reflects complete blockade
of IL-17 signaling in the skin [26].
The potential association between IL-17
blockade with secukinumab and the subsequent
development of IBD is complicated for several
reasons. First, the families and individuals with
inborn errors in IL-17 signaling (i.e. no production of IL-17 in the body) do not go on to develop
any major sequela, such as IBD or malignancy.
This observation argues against the suggested link
between suppression of IL-17 by secukinumab and
the development of IBD. Second, secukinumab
and brodalumab (an IL-17 receptor inhibitor)
were tested for clinical efficacy in patients with
IBD and no prior history of psoriatic disease.
Some of the patients in these trials reported worsening of their gastrointestinal symptoms [27, 28].
This has led some clinicians to exercise caution
with IL-17 inhibitors when treating patients with
IBD and a concomitant inflammatory condition,
such as psoriasis or PsA. However, patients with
psoriatic disease already have an increased risk
for developing IBD compared to the general population, which suggests a potential genetic rather
than treatment-­associated link [29]. Attempts to
prove a causative association between IL-17 inhibition and the development of new-onset IBD
in humans or mice are ongoing, but have thus
far been inconclusive. Understanding the role of
IL-17 in the mucosa and gastrointestinal system
are critically important as we are just beginning to
understand the role of the IL-23/IL-17 signaling
in tissues beyond the skin.
uture Direction of IL-17 Blockade
F
for Chronic Inflammatory
Conditions
The development of secukinumab and other
IL-17 inhibitors (e.g. ixekizumab, brodalumab,
and bimekizumab) have transformed the way
249
psoriasis is treated. Nevertheless, patients
with psoriatic disease who are unresponsive to
secukinumab or other agents in this drug class
underscore the complexity of this disease, especially since many of these patients are responsive
to broader-acting agents such as TNF inhibitors, methotrexate, or cyclosporine. The rapid
progress in the treatment of skin manifestations
of psoriasis with IL-17 antagonists compared to
first- and second-generation biologic treatments
(TNF inhibitors or ustekinumab) is astonishing
in comparison to the minimal progress we have
made in the treatment of inflammatory arthropathies with these same agents. A side-by-side comparison of the PASI and ACR scores from phase
3 clinical trials for biologics used for psoriasis
accentuates the treatment gap for the treatment
of skin versus joint disease [2]. This has raised
some experts in the field to suggest a future treatment strategy that includes the concomitant use
of IL-17 inhibitors with a TNF inhibitor or the
use or novel molecules that simultaneously target
two cytokines (e.g. TNF and IL-17A) via bispecific antibodies [30].
Recent phase 2 clinical data in plaque psoriasis for bimekizumab, which targets both IL-17A
and IL-17F, is very encouraging and provides an
excellent proof of concept for this novel therapeutic strategy [31]. Additional data about the
testing of bispecific antibodies is also available for review [32, 33]. The anticipated high
cost and/or increased adverse events associated
with two simultaneously administered biologics
are the most likely deterrents for this treatment
approach. Preclinical or early phase 1 clinical
trial data for bispecific antibodies in the treatment of inflammatory conditions are just starting
to emerge. As technology continues to advance,
the promise of dual cytokine inhibition for the
treatment of chronic inflammatory diseases is
strong and worth ongoing investigative efforts.
The continued development of novel bispecific
molecules in conjunction with translational
research projects that investigate the role of IL-17
on the immune cells unique to specific tissues
will help advance our ability to better manage
these complex inflammatory conditions. The role
of secukinumab and other IL-17 antagonists for
250
the treatment of neutrophilic dermatosis, such as
pyoderma gangrenosum or Sweet syndrome, will
also be of interest given the role of this cytokine
on the upregulation of molecules that enhance the
recruitment of neutrophils into the skin.
Conclusion
The central role for the IL-23/IL-17 signaling
pathway in psoriasis and associated inflammatory joint diseases has broadened our understanding of the dysregulated immune events driving
chronic inflammatory conditions and has led to
the development of highly effective, targeted
biologic therapies. As a first-in-class inhibitor of
IL-17A, secukinumab has proven to be a rapid
acting, robust, sustainable, and safe treatment
for psoriasis, PsA, and AS. For this reason, it has
become a first-line therapy for many patients,
especially those with comorbidities or reservations about initiating treatment with traditional
systemic immunosuppressants. Clinical trials
specifically designed to investigate the efficacy
and safety of secukinumab for the treatment of
difficult to treat disease, such as PPP, nail disease,
and scalp psoriasis, is unprecedented in the field
and gives clinicians additional empiric evidence
to make more informed clinical decisions for the
treatment of psoriatic disease and AS.
Acknowledgements None.
Conflict of Interest JEH currently serves on the medical
board of the National Psoriasis Foundation and has been a
consultant for AbbVie, Janssen, LearnSkin, Novartis,
Pfizer, Regeneron-Sanofi, VisualDx, and UpToDate. AVH
is a current employee of Regeneron Pharmaceuticals, Inc.
and receives stock in the company as part of her
employment.
References
1. Rachakonda TD, Schupp CW, Armstrong
AW. Psoriasis prevalence among adults in the United
States. J Am Acad Dermatol. 2014;70(3):512–6.
https://doi.org/10.1016/j.jaad.2013.11.013.
2. Hawkes JE, Yan BY, Chan TC, Krueger JG. Discovery
of the IL-23/IL-17 signaling pathway and the treat-
J. E. Hawkes and A. V. Hawkes
ment of psoriasis. J Immunol. 2018;201(6):1605–13.
https://doi.org/10.4049/jimmunol.1800013.
3. Martin DA, Towne JE, Kricorian G, Klekotka P,
Gudjonsson JE, Krueger JG, et al. The emerging role of
IL-17 in the pathogenesis of psoriasis: preclinical and
clinical findings. J Invest Dermatol. 2013;133(1):17–
26. https://doi.org/10.1038/jid.2012.194.
4. Fishwild DM, O’Donnell SL, Bengoechea T,
Hudson DV, Harding F, Bernhard SL, et al. High-­
avidity human IgG kappa monoclonal antibodies
from a novel strain of minilocus transgenic mice.
Nat Biotechnol. 1996;14(7):845–51. https://doi.
org/10.1038/nbt0796-845.
5. Hueber W, Patel DD, Dryja T, Wright AM, Koroleva I,
Bruin G, et al. Effects of AIN457, a fully human antibody
to interleukin-17A, on psoriasis, rheumatoid arthritis,
and uveitis. Sci Transl Med. 2010;2(52):52ra72. https://
doi.org/10.1126/scitranslmed.3001107.
6. Langley RG, Elewski BE, Lebwohl M, Reich K,
Griffiths CE, Papp K, et al. Secukinumab in plaque
psoriasis—results of two phase 3 trials. N Engl J
Med. 2014;371(4):326–38. https://doi.org/10.1056/
NEJMoa1314258.
7. Thaci D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F,
Kingo K, et al. Secukinumab is superior to ustekinumab
in clearing skin of subjects with moderate to severe
plaque psoriasis: CLEAR, a randomized controlled
trial. J Am Acad Dermatol. 2015;73(3):400–9. https://
doi.org/10.1016/j.jaad.2015.05.013.
8. Blauvelt A, Reich K, Tsai TF, Tyring S, Vanaclocha F,
Kingo K, et al. Secukinumab is superior to ustekinumab
in clearing skin of subjects with moderate-­to-severe
plaque psoriasis up to 1 year: results from the CLEAR
study. J Am Acad Dermatol. 2017;76(1):60–9. e9.
https://doi.org/10.1016/j.jaad.2016.08.008.
9. Bissonnette R, Luger T, Thaci D, Toth D, Lacombe
A, Xia S, et al. Secukinumab demonstrates high
sustained efficacy and a favourable safety profile in
patients with moderate-to-severe psoriasis through 5
years of treatment (SCULPTURE Extension Study).
J Eur Acad Dermatol Venereol. 2018;32(9):1507–14.
https://doi.org/10.1111/jdv.14878.
10. Paul C, Lacour JP, Tedremets L, Kreutzer K, Jazayeri
S, Adams S, et al. Efficacy, safety and usability of
secukinumab administration by autoinjector/pen in
psoriasis: a randomized, controlled trial (JUNCTURE).
J Eur Acad Dermatol Venereol. 2015;29(6):1082–90.
https://doi.org/10.1111/jdv.12751.
11. Blauvelt A, Prinz JC, Gottlieb AB, Kingo K, Sofen H,
Ruer-Mulard M, et al. Secukinumab administration
by pre-filled syringe: efficacy, safety and usability
results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol. 2015;172(2):484–93.
https://doi.org/10.1111/bjd.13348.
12. Gottlieb A, Sullivan J, van Doorn M, Kubanov A,
You R, Parneix A, et al. Secukinumab shows significant efficacy in palmoplantar psoriasis: results
from GESTURE, a randomized controlled trial. J
Am Acad Dermatol. 2017;76(1):70–80. https://doi.
org/10.1016/j.jaad.2016.07.058.
20
Ixekizumab
Caitriona Ryan and Roisin O’Connor
Abstract
Ixekizumab is a fully human monoclonal antibody that selectively targets IL-17A which has
shown to be highly effective in the treatment
of psoriasis and psoriatic arthritis. This chapter reviews the efficacy and safety profile of
ixekizumab for the treatment of psoriasis
based on clinical studies to date. Studies demonstrate that ixekizumab is highly effective in
the treatment of moderate-to-severe psoriasis
and the majority of patients achieve high
clearance rates. Uncommon adverse events
reported during ixekizumab therapy, included
neutropenia, candida infections, and inflammatory bowel disease, however long-term
safety data beyond 5 years is not yet
available.
C. Ryan (*)
Institute of Dermatologists Ireland, Dublin, Ireland
Charles Institute of Dermatology, University College
Dublin, Dublin, Ireland
e-mail: cryanoffice@instituteofdermatologists.ie
R. O’Connor
Department of Dermatology, Children’s Health
Ireland (CHI) at Crumlin, Dublin, Ireland
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_20
Key Learning Objectives
1. To understand the mechanism of action
of Ixekizumab
2. To understand the appropriate use and
efficacy of the Ixekizumab
3. To understand the safety issues of
Ixekizumab
Introduction
Ixekizumab (Taltz, Eli. Lilly) is a humanised
IgG4 monoclonal antibody that selectively binds
to IL-17A and inhibits its interaction with the
IL-17 receptor [1, 2]. It has been consistently
shown to be effective in the treatment of
moderate-­to-severe psoriasis [3]. Ixekizumab has
been approved in adults for the treatment of
moderate-­
to-severe plaque psoriasis and also
psoriatic arthritis [4].
Ixekizumab is composed of two light chain
polypeptides of 219 amino acids each, and two
heavy chain polypeptides of 445 amino acids
each [5]. Ixekizumab selectively blocks IL-17A
which is a member of the IL-17 family of cytokines along with IL-17B, IL-17C, IL-17D,
IL-17E and IL-17F [1]. Il-17A is produced by
CD4+ T-cells called Th17 cells which represent
a subset of CD4+ helper lymphocytes [6]. The
family of IL-17 homodimeric proteins differ in
253
C. Ryan and R. O’Connor
254
amino acid sequence and consequently in spatial structure [1]. Ixekizumab binds specifically
to IL-17A [1]. The active form of IL-17A occurs
as a homodimer (A/A) or a heterodimer (A/F)
with IL-17F [1]. The physiological response to
IL-17A involves the release of cytokines and
chemokines which are responsible for recruiting
and activating neutrophils and memory T-cells
to the site of inflammation, and maintaining a
pro-­inflammatory state [1]. Il-17A has a key role
in chronic inflammation and autoimmunity [1].
Current data suggests that IL-17A has three main
functions including host defence, neutrophil
homeostasis, and chronic pathogenic inflammation [1, 7, 8].
The discovery of IL-17, which plays a critical role in the development of psoriasis, has
opened many new treatment options. The class
of IL-17 inhibitors includes secukinumab, ixekizumab, brodalumab, bimekizumab, netakimab
and M1095 [9].
Pharmacodynamics
Ixekizumab targets the IL-17 cytokine pathway
which plays a key role in the pathogenesis of psoriasis. Phase 1 data based on psoriatic skin biopsies demonstrate a dose-dependent reduction of
epidermal thickness, a reduction in proliferating
keratinocytes, T cells, dendritic cells and reductions in inflammatory markers including
C-reactive protein from baseline to day 43 [9, 10].
Pharmacokinetics
Mean peak concentrations occur between 4 and
7 days following the administration of one subcutaneous dose of ixekizumab in patients with psoriasis, with doses ranging from 5 to 160 mg [10].
Analyses suggest the average bioavailability of
ixekizumab following subcutaneous injection is
54–0%. After the 160 mg starting dose, the mean
(SD) maximum plasma concentration (Cmax) of
ixekizumab is 19.9 (8.15) μg/ml. Steady state is
achieved by week 8 following the initial starting
dose of 160 mg and the 80 mg Q2W dosing sched-
ule. Estimated mean (SD) of Cmax,ss is 21.5 (9.16)
μg/ml, and Ctrough,ss is 5.23 (3.19) μg/ml. After
swapping from the 80 mg Q2W dosing schedule
to the 80 mg Q4W dosing regimen at Week 12,
steady state is reached after approximately
10 weeks. Estimated mean (SD) of Cmax,ss, is 14.6
(6.04) μg/ml and Ctrough,ss is 1.87 (1.30) μg/ml [10].
Clinical Efficacy
Three pivotal phase III trials, UNCOVER-1,
UNCOVER-2 and UNCOVER-3 have evaluated
the efficacy and safety of various dosing regimens of ixekizumab compared to placebo in
patients with moderate to severe psoriasis [3].
UNCOVER-2 and UNCOVER-3 trials also compared ixekizumab to etanercept [11].
In UNCOVER-1 1296 patients were randomly
assigned in a 1:1:1 ratio to receive 80 mg ixekizumab every 2 weeks (Q2W), 80 mg ixekizumab
every 4 weeks (Q4W), or placebo. Patients
assigned to the ixekizumab cohort received
160 mg starting dose followed by 80 mg Q2W or
Q4W. The co-primary endpoints were Psoriasis
Area and Severity Index (PASI) 75 and static
Physician Global Assessment (sPGA) 0 or 1 at
week 12. Patients who responded to ixekizumab
treatment at 12 weeks (sPGA 0-1) were re-­
randomised to receive placebo, ixekizumab
80 mg Q4W, or ixekizumab 80 mg every
12 weeks with 48 weeks of follow up [3, 12].
By week 12, a significant superior response
was reported to both ixekizumab regimens compared to placebo. The percentage of patients
achieving PASI 75 was 89.1 and 82.6% for ixekizumab Q2W and Q4W compared to 3.9% in the
placebo group (p < 0.001 compared to placebo)
[12]. 81.8% achieved an sPGA of 0 or 1 with
ixekizumab Q2W and 76.4% with ixekizumab
Q4W compared to 3.2% in the placebo group
(P < 0.001) [12]. Of the patients in the 2-week
dosing cohort, 70.9% had a PASI 90 response,
and 35.3% had a PASI 100 response at week 12
[12]. UNCOVER-1 demonstrated that this
response was sustained through 60 weeks.
72.9% of ixekizumab-treated responders
maintained sPGA of 0 or 1, 77.7% maintained or
20
Ixekizumab
achieved PASI 75, and 52% maintained or
achieved PASI 100 [11, 12].
In UNCOVER-2, 1224 patients were randomly assigned in a 2:2:2:1 ratio to receive 80 mg
ixekizumab Q2W, 80 mg ixekizumab Q4W, etanercept 50 mg twice weekly or placebo [12]. The
UNCOVER-1 and UNCOVER-2 trials shared
similar induction designs. Patients in the ixekizumab groups received 160 mg starting dose followed by 80 mg Q2W or Q4W. At 12 weeks, the
study showed ixekizumab was statistically superior compared to placebo [12]. The percentage of
patients achieving PASI 75 was 89.7 and 77.5%
for ixekizumab Q2W and Q4W respectively,
compared to 2.4% in the placebo group
(P < 0.0001) [12]. 83.2% of the Q2W group and
72.9% of the Q4W group achieved sPGA of 0 or
1, compared to 2.4% in the placebo group
(P < 0.0001 compared to placebo) [12]. Both dosing schedules of ixekizumab were superior to
placebo in achieving PASI 90, PASI 100, and
improvement in DLQI score (P < 0.0001 compared to placebo) [12]. Ixekizumab 80 mg Q2W
and Q4W regimens were also more efficacious in
terms of number of patients reaching PASI 75
and sPGA 0 or 1 at week 12 when compared to
etanercept (P < 0.001) [11, 12].
In UNCOVER-3 1346 patients were randomly
assigned in a 2:2:2:1 ratio to receive 80 mg ixekizumab Q2W, 80 mg ixekizumab Q4W, etanercept
50 mg twice weekly, or placebo [12].
Patients in the ixekizumab groups received
160 mg starting dose followed by 80 mg dosing
Q2W or Q4W [12]. UNCOVER-3 showed statistically better results for ixekizumab 80 mg Q2W
and ixekizumab 80 mg Q4W than placebo [12].
87.3% of the Q2W group and 84.2% of the Q4W
group achieved PASI 75, compared to 7.3% in
the placebo group (P < 0.0001) [12]. 80.5% of the
Q2W and 75.4% of the Q4W group achieved an
sPGA of 0 or 1, compared to 6.7% in the placebo
group (P < 0.0001) [12]. Both ixekizumab dosing
regimens were superior to placebo in achieving
PASI 90, PASI 100 and improvements in DLQI
(p < 0.0001) [11, 12].
Significantly more patients who had an itch
numeric rating scale (NRS) score of 4 or more
at baseline experienced an improvement of
255
4 or more points in both ixekizumab-treated
groups compared to placebo and etanercept.
Improvements were reported as early as week 1
for each ixekizumab dose versus placebo or etanercept (p < 0.0001) [11].
Pooled data from 2570 patients in
UNCOVER-2 and UNCOVER-3 trials showed
that ixekizumab treated patients achieved more
rapid improvements both in health-related quality of life (HRQol) and itch compared to those
receiving etanercept or placebo [2].
Ixekizumab-treated patients (both dosing
groups) achieved the minimally clinical important difference (MCID) for the dermatology life
quality index (DLQI) and itch numeric rating
scale (NRS) scores at 2.1 weeks, while the
median times for MCID in etanercept-treated
patients were 4 weeks for DLQI and 8.1 weeks
for NRS. The majority of patients in the placebo
group did not achieve the MCID during the
12-week induction period [2].
Bodyweight
Pooled data from three Phase 3 studies
(UNCOVER-1, UNOCVER-2, UNCOVER-3)
were used to evaluate the effect of bodyweight on
the efficacy of ixekizumab treatment in patients
with moderate-to-severe psoriasis [13]. 3855
patients were included in the analysis and patients
were stratified into three bodyweight groups
(<80 kg, 80 to <100 kg, ≥100 kg) [13]. A higher
proportion of patients across all body weight
groups treated with ixekizumab achieved PASI
75, PASI 90, or PASI 100 at week 12 compared to
placebo or etanercept [13]. There was no significant difference in PASI 75 response rates across
the different bodyweight groups [13].
Psoriatic Arthritis
Two phase III clinical trials, SPIRIT-P1 and
SPIRIT-P2, demonstrated the superiority of
ixekizumab (80 mg Q2W and Q4W) over placebo in moderate-to-severe psoriatic arthritis
(PsA) in patients who failed treatment with either
256
C. Ryan and R. O’Connor
NSAIDs, conventional disease-modifying anti-­ twice weekly), or 80 mg ixekizumab Q2W or
rheumatic drugs (csDMARDs), or tumour necro- Q4W after a starting dose of 160 mg [17]. At
sis factor-α inhibitors (TNFi) for multiple joint week 12, all ixekizumab-treated patients were
and cutaneous indices [14].
assigned to open-label to receive ixekizumab
In SPIRIT-P1, 417 patients naive to biologic Q4W through to week 60 [17]. At week 12, the
therapy with active psoriatic arthritis PsA were placebo group received a 160 mg starting dose
randomised to receive subcutaneous injections of of ixekizumab, followed by IXE Q4W thereafplacebo, adalimumab 40 mg once every 2 weeks, ter [17]. A week 12, the etanercept group
ixekizumab 80 mg Q2W, or ixekizumab 80 mg received placebo washout, then IXE Q4W at
Q4W [15]. Both ixekizumab dosing regimens week 16 and thereafter [17].
included a 160-mg starting dose. The primary
Of 1346 patients in this study, 796 had fingerendpoint was an American College of nail psoriasis at baseline and were included in
Rheumatology (ACR) 20 response at week 24 this subgroup analysis [17]. The Nail Psoriasis
compared to placebo [15]. More patients achieved Severity Index (NAPSI) was the assessment tool
an ACR20 response with ixekizumab Q2W used to evaluate the severity of fingernail psoria(62.1%) and ixekizumab Q4W (57.9%) than pla- sis. A modified version of NAPSI was used and
cebo (30.2%) (p ≤ 0.001) [15]. Significantly less toenail involvement was not assessed [17]. Each
disease activity and functional disability was fingernail was divided into four quadrants and
reported with both ixekizumab Q2W and Q4W NAPSI was used to assign a score to each nail for
when compared to placebo at week 12 and 24 nail bed and nail matrix psoriasis [17]. The total
[15]. Significantly less progression of structural NAPSI fingernail score ranged from 0 (no nail
damage was reported at week 24 (p ≤ 0.01) with psoriasis) to 80 (severe nail psoriasis) [17].
ixekizumab treatment [15]. Ixekizumab was also
Ixekizumab showed significant improvement
superior in achieving PASI 75, 90 and 100 com- in fingernail psoriasis with promising results evipared to placebo in this study (p ≤ 0.001) [15].
dent as early as week 2, with greater NAPSI
363 patients with psoriatic arthritis for a min- improvement in the ixekizumab Q4W (5.1%)
imum of 6 months who had an incomplete arm of the study compared to etanercept (−7.9%,
response to, or were intolerant of, tumour necro- p = 0.024) [18]. By week 12, both ixekizumab
sis factor inhibitors were recruited to SPIRIT-P2 groups exhibited greater NAPSI improvements
[16]. 363 patients were randomly assigned from baseline in contrast to placebo and etaner(1:1:1) to receive 80 mg of ixekizumab Q2W or cept [17].This effect was maintained through
Q4W after 160 mg starting dose, or placebo [16]. 60 weeks of treatment [17].
The primary endpoint was ACR-20 response at
Patients that were switched to ixekizumab
week 24 [16]. The percentage of patients who from placebo or etanercept at week 12 or 16
achieved ACR-20 response by week 24 was 53 respectively, demonstrated comparable improveand 48% for ixekizumab Q4W and Q2W, respec- ments to patients who received continuous ixekitively, compared to 20% of placebo-treated zumab treatment [17]. A higher proportion of
patients [16].
patients in the ixekizumab Q4W (19.7%) and
Q2W (17.5%) group achieved complete resolution of fingernail psoriasis compared to placebo
Nail Psoriasis
(4.3%) or etanercept (10.2%) at week 12 [17].
Irrespective of the initial stratification, more than
Subgroup analysis in UNCOVER-3 evaluated 50% of patients achieved complete resolution by
the efficacy of ixekizumab compared to placebo week 60 IXE Q4W treatment [17]. Complete
or etanercept in patients with baseline finger- resolution rates in this study are significantly
nail psoriasis [17]. Patients were randomized higher when compared to reports of clearance
1:2:2:2 to receive placebo, etanercept (50 mg rates with other biologics [17, 19–21].
20
Ixekizumab
Scalp
The scalp is very often affected in psoriasis and is
a particularly challenging area to treat [22]. There
is limited information available on the efficacy of
biologic therapy for scalp psoriasis [22]. A subgroup analysis was performed in a subset of
patients with scalp psoriasis from UNCOVER-1,
UNCOVER-2 and UNCOVER-3 trials to evaluate
the efficacy of ixekizumab over 60 weeks [22].
The Psoriasis Scalp Severity Index (PSSI) was
the assessment tool used to evaluate the severity
of scalp psoriasis. PSSI is calculated as the sum
of results for erythema, induration and desquamation multiplied by a score for the degree of
scalp involvement [22].
Among patients with scalp psoriasis at baseline, (PSSI) 75, 90 and 100 were achieved at week
12 in a higher proportion of patients treated with
ixekizumab Q2W (89.9, 81.7 and 74.6%) or Q4W
(83.6, 75.6 and 68.9%) compared to placebo (12.7,
7.6 and 6.7%) or etanercept (67.6, 55.5 and 48.1%)
[22]. These responses were sustained through
week 60 of the maintenance (UNCOVER-1
and UNCOVER-2) and LTE arm of the study in
patients who remained on ixekizumab Q4W [22].
Improvements occurred in patients with baseline scalp psoriasis in the UNCOVER-3 trial. The
median time to PSSI 75, 90 and 100 were 2.1, 4.1
and 4.3 weeks, respectively in the ixekizumab
Q2W group compared to 8.1, 8.3 and 12 weeks,
respectively in etanercept group [22].
Palmoplantar Psoriasis
Palmoplantar psoriasis is not only associated with
considerable discomfort, and pain it also affects
dexterity and mobility with significant quality of
life implications [23–26]. Using pooled data from
UNCOVER-1, UNCOVER-2 and UNCOVER-3
trials, the efficacy of ixekizumab was evaluated in
a subpopulation of patients with moderate-tosevere plaque psoriasis and moderate-­
to-severe
non pustular palmoplantar involvement [26].
The Palmoplantar Psoriasis Area and Severity
Index (PPASI) was used to assess the severity of
257
psoriasis on the palms and soles. PPASI is calculated
as the sum of results for erythema, induration and
desquamation multiplied by a score for the degree of
palm and sole involvement (range 0–72) [26].
28.3% of patients from UNCOVER-1,
UNCOVER-2 and UNCOVER-3 had evidence of
palmoplantar psoriasis at baseline (PPASI ≥ 0).
Of these, 9.1% of patients had moderate-to-­
severe palmoplantar psoriasis at baseline
(PPASI ≥ 8) [26]. Among patients with palmoplantar psoriasis, 85.9, 73.9 and 48.9% treated
with ixekizumab Q4W and 79.8, 69.3 and 51.8%
treated with ixekizumab Q2W achieved PPASI
50, 75 and 100 respectively, at week 12, which is
significantly more than placebo (32.9, 18.8 and
8.2%; p < 0.001) and etanercept (67.8, 44.1, and
32.2%; p < 0.05) [26].This response was maintained or improved in patients continuing on
ixekizumab Q4W through week 60 [26].
Genital Psoriasis
Genital psoriasis is a common, distressing and
difficult-to-treat form of plaque psoriasis with a
detrimental impact on quality of life and psychosexual functioning [27].
Ixora-Q was a phase IIIb, randomised, double-­
blind, placebo-controlled trial which appraised
the efficacy of ixekizumab in patients with
moderate-­to-severe genital psoriasis with ≥1%
body surface area involved [27]. The static
Physician’s Global Assessment of Genitalia
(sPGA-G) was developed to assess the severity of
genital psoriasis [27]. 149 patients with moderate-­
to-­severe genital psoriasis (sPGA-G) score ≥ 3),
with BSA ≥ 1% were randomised 1:1 to receive
placebo or ixekizumab (160 mg at week 0, then
80 mg every 2 weeks) [27]. The primary endpoint
was to establish if ixekizumab was superior to
placebo at week 12. This was measured by the
percentage of patients achieving 0 or 1 (clear or
minimal) on the sPGA-G [27].
At week 12, 73% of patients in the ixekizumab
group achieved clear or almost clear genital skin
(sPGA-G 0 or 1) compared to 8% in the placebo
group. Fifty-six percent of patients achieved com-
C. Ryan and R. O’Connor
258
plete clearance of genital psoriasis compared to
placebo 5% (p < 0.001) [27]. In keeping with previous clinical studies of ixekizumab, 73% of patients
achieved an overall sPGA 0 or 1 compared to placebo (3%, p < 0.001) [27]. Significant clinical
improvement was reported as early as week 1 for
sPGA-G 0 or 1, sPGA-G 0 and overall sPGA 0 or
1, and as early as week 4 for overall sPGA 0 [27].
Ixekizumab resulted in significant improvements in genital itch and HRQoL. 60% of patients
treated with ixekizumab achieved a clinically
meaningful (≥3-point) improvement from baseline in the genital itch numeric rating scale (NRS)
compared to placebo (8%) at week 12 [27].
Almost 80% of patients treated with ixekizumab reported that the frequency of sexual
activity was rarely affected by genital psoriasis
by week 12 of treatment and significant improvement was already observed within the first week
of treatment. Additionally, 45% of patients receiving ixekizumab reported no clinically significant
impact on HRQoL at week 12 [27]. There are
limited number of published open-label studies
that have investigated the efficacy of therapeutic
interventions for genital psoriasis [28–30].
Body Regions
Pooled data from 3 trials (UNCOVER-1,
UNCOVER-2, UNCOVER-3) through week 12
was used to assess the efficacy of ixekizumab on
moderate-to-severe psoriasis affecting various
body sites (head/neck, arms, trunk, legs) [18].
Ixekizumab Q2W was associated with significantly greater mean percent improvements in
PASI from baseline compared to placebo for each
body region. Improvements increased through
week 12 with the highest on the trunk (92.8%),
followed by the head/neck (91.4%), arms (89.9%)
and legs (88.7%) (p < 0.001 vs. placebo) [18].
Erythrodermic and Pustular
Psoriasis
A phase 3, multicentre, single-arm, open-label,
long-term study was carried out to evaluate the
long term efficacy and safety of ixekizumab in
Japanese patients with plaque psoriasis (n = 78),
erythrodermic psoriasis (n = 8) and generalized
pustular psoriasis (n = 5) [31]. 160 mg of ixekizumab was administered at week 0, followed by
80 mg every 2 weeks from weeks 2 to 12, and
every 4 weeks from weeks 16 to 52 [31]. At week
52, PASI 75, PASI 90 and PASI 100 was achieved
in 92.3, 80.8 and 48.7% of patients [31]. Patients
with erythrodermic psoriasis or generalised pustular psoriasis responded favourably to ixekizumab therapy and 75 and 60% of patients
achieved a sPGA 0 or 1 at week 52 [31].
Improvements in PASI, PSSI, DLQI and itch
NRS were reported at week 12 and maintained
through week 52 [31].
Adverse Effects
Comprehensive ixekizumab safety data comes
from the cumulative safety analysis covering up
to 319 weeks of ixekizumab exposure combined
from 11 controlled and uncontrolled ixekizumab
studies on psoriasis, including three Phase 3 studies (UNCOVER-1, -2, and -3) [32]. Ixekizumab
exhibited an acceptable safety profile and no
novel safety findings compared to previous
reports [3, 11, 32, 33].
5689 patients treated with ixekizumab from
11 studies were included in the analysis, which
accounted for 12 061.5 PY of exposure [32].
Treatment-emergent adverse events (TEAE)
were reported by 83.9% of patients. 71% of
patients reported mild-to-moderate TEAEs and
12.9% reported severe TEAEs [32]. A TEAE was
an event that first occurred or increased in severity after baseline, on or prior to the final day,
within the treatment time [32]. The most commonly (>6%) reported TEAE after 12 061.5 PY
of ixekizumab therapy was: nasopharyngitis
(22.9%), upper respiratory tract infection
(13.5%), injection-site reaction (9.5%), headaches (7.8%) and arthralgia (7.1%) [32]. These
results are similar to those previously reported
with 6480 PY exposure [33]. Serious adverse
events AEs were reported in 11.8% of patients
and death occurred in 0.4% of patients (cardiac
disorder (n = 11), neoplasm (n = 2), unknown
cause (n = 5), respiratory failure (n = 2), severe
20
Ixekizumab
cerebrovascular event (n = 1), severe dementia
(n = 1) and injury (n = 1) [32].
6.7% of patients reported TEAEs resulting in
discontinuation from the study. There was no
cases of confirmed tuberculosis (TB) or reactivation. However, 0.5 and 0.2% of patients reported
a positive Mycobacterium tuberculosis complex
test and a positive tuberculin test. These were the
most commonly reported AE that lead to discontinuation from the study [32].
Research suggests a high rate of false-positive
TB test results are commonly found in populations with a low risk of Mycobacterium tuberculosis infection which reflects the cohorts in these
studies [34–36].
While there were no serious injection-site
reactions reported, 0.2% of patients discontinued
the study due to injection site reaction [36].
Adverse Events of Special Interest
Ixekizumab exposure over 156 weeks showed
no increase in incidence rates (IR) of adverse
events of special interest (AESI) [32]. Infections,
injection site reactions and allergic reactions/
hypersensitivities were the most commonly
reported AESI [32]. Contact dermatitis, eczema,
urticaria, dermatitis, rash and allergic rhinitis
were the most common allergic events. Most of
the injection-­site reactions were mild or moderate [32].
Infections
In keeping with published literature to date infections are the most frequently AEs associated
ixekizumab therapy [11, 33]. 60.8% of patients
reported an infection while on ixekizumab therapy, however 25.4% were mild and 32.4% were
moderate [32]. Only 3% were reported as severe
infections [32]. Nasopharyngitis (22.9%), upper
respiratory tract infection (13.5%), bronchitis
(5.2%) and sinusitis (5.4%) are among the most
commonly reported infections [32]. Serious
infections were reported in 2.6% of patients,
however none of these resulted in death [32].
Cellulitis was the most frequently reported seri-
259
ous infection affecting 0.5% of ixekizumab
treated patients [32]. In keeping with IL-17A
blockade and its role in mucosal immunity,
mucocutaneous candidiasis was the most commonly observed opportunistic infection. This
integrated analysis of 11 clinical studies showed
no reports of endemic mycoses, systemic candidiasis, invasive aspergillus or other invasive fungal infections [32].
IBD
Research has shown that the prevalence of
Crohn’s disease and ulcerative colitis is
increased in patients with psoriasis [37–40].
Pooled data from seven ixekizumab psoriasis
trials reported that the incidence of Crohn’s disease and ulcerative colitis cases were uncommon (<1%) in ixekizumab treated patients [41].
The results are similar with those observed in
the analysis of combined data of 11 ixekizumab
psoriasis trials. Following 3 years of ixekizumab
treatment the IRs of Crohn’s disease and ulcerative colitis were 0.0 and 0.1 per 100 PYs,
respectively [32].
Malignancy
Based on the combined data of 11 ixekizumab
psoriasis trials, ixekizumab exposure up to
156 weeks was not associated with in increased
risk malignancy [32].
Depression
Depression is common in patients with psoriasis. The efficacy of ixekizumab was evaluated in patients with moderate-to-severe plaque
psoriasis and moderately severe depressive
symptoms [42]. Data were pooled from 3 randomised, double-­
blind, controlled phase 3 trials. Depressive symptoms and inflammation
were evaluated at baseline and week 12 using
a self-report questionnaire to quantify depressive symptoms (QIDS-SR16) and by measuring
serum C-reactive protein (hs CRP) [42]. A sub-
260
group analysis was performed on patients with
at least moderately severe depressive symptoms
at baseline (QIDS-SR16 total score ≥ 11) [42].
The comorbid depressive symptom group was
defined as patients who had a (QID-SR16) total
score ≥ 11 at baseline [42]. Comorbid patients
treated with ixekizumab Q2W and Q4W reported
better responses in their QIDS-SR16 total score
(−7.1 and −6.1) compared to placebo (−3.4;
p < 0.001) [42]. Ixekizumab Q2W and Q4W
was associated with higher rates of remission of
depressive symptoms (45.2%, 33.6%) compared
with placebo (17.8%; p ≤ 0.01) [42]. Ixekizumab
treated patients was also associated with notable
reductions in hs CRP and PASI compared to placebo [42].
Summary
Ixekizumab selectively blocks IL-17A which
is a member of the IL-17 family of cytokines. Numerous clinical trials (UNCOVER-1,
UNCOVER-2, UNCOVER-3, and others) have
shown Ixekizumab to be efficacious in treating psoriasis and psoriatic arthritis. Research
has also shown ixekizumab to be well tolerated
with a safety profile similar to others in the class.
Recently published 5-year safety data, shows
no new or unexpected safety concerns have
emerged. However concern remains regarding
the long-­term side effects of anti-IL17 agents
until more long term data is available. The ongoing collection of data in registries will be important to allow for comprehensive safety data.
References
1. Liu L, Lu J, Allan BW, Tang Y, Tetreault J, Chow CK,
et al. Generation and characterization of ixekizumab,
a humanized monoclonal antibody that neutralizes
interleukin-17A. J Inflamm Res. 2016;9:39–50.
2. Leonardi CL, Blauvelt A, Sofen HL, Gooderham M,
Augustin M, Burge R, et al. Rapid improvements
in health-related quality of life and itch with ixekizumab treatment in randomized phase 3 trials: results
from UNCOVER-2 and UNCOVER-3. J Eur Acad
Dermatol Venereol. 2017;31(9):1483–90.
C. Ryan and R. O’Connor
3. Gordon KB, Blauvelt A, Papp KA, Langley RG,
Luger T, Ohtsuki M, et al. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl
J Med. 2016;375(4):345–56.
4. Blegvad C, Skov L, Zachariae C. Ixekizumab for
the treatment of psoriasis: an update on new data
since first approval. Expert Rev Clin Immunol.
2019;15(2):111–21.
5. https://www.accessdata.fda.gov/drugsatfda_docs/
label/2018/125521s009lbl.pdf
6. Miossec P, Korn T, Kuchroo VK. Interleukin-17
and type 17 helper T cells. N Engl J Med.
2009;361(9):888–98.
7. Stark MA, Huo Y, Burcin TL, Morris MA, Olson TS,
Ley K. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity.
2005;22(3):285–94.
8. Cua DJ, Tato CM. Innate IL-17-producing cells: the
sentinels of the immune system. Nat Rev Immunol.
2010;10(7):479–89.
9. Gisondi P, Geat D, Pizzolato M, Girolomoni G. State
of the art and pharmacological pipeline of biologics
for chronic plaque psoriasis. Curr Opin Pharmacol.
2019;46:90–9.
10. http://www.medicines.org.uk/emc/product/7233/
smpc
11. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof
P, Paul C, Menter A, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-­
severe psoriasis (UNCOVER-2 and UNCOVER-3):
results from two phase 3 randomised trials. Lancet.
2015;386(9993):541–51.
12. Farahnik B, Beroukhim K, Zhu TH, Abrouk M,
Nakamura M, Singh R, et al. Ixekizumab for the
treatment of psoriasis: a review of phase III trials.
Dermatol Ther. 2016;6(1):25–37.
13. Reich K, Puig L, Mallbris L, Zhang L, Osuntokun
O, Leonardi C. The effect of bodyweight on the
efficacy and safety of ixekizumab: results from an
integrated database of three randomised, controlled
phase 3 studies of patients with moderate-to-severe
plaque psoriasis. J Eur Acad Dermatol Venereol.
2017;31(7):1196–207.
14. O’Rielly DD, Rahman P. A review of ixekizumab in
the treatment of psoriatic arthritis. Expert Rev Clin
Immunol. 2018;14(12):993–1002.
15. Mease PJ, van der Heijde D, Ritchlin CT, Okada M,
Cuchacovich RS, Shuler CL, et al. Ixekizumab, an
interleukin-17A specific monoclonal antibody, for
the treatment of biologic-naive patients with active
psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active
(adalimumab)-controlled period of the phase III trial
SPIRIT-P1. Ann Rheum Dis. 2017;76(1):79–87.
16. Nash P, Kirkham B, Okada M, Rahman P, Combe B,
Burmester GR, et al. Ixekizumab for the treatment
of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors:
results from the 24-week randomised, double-blind,
21
Brodalumab
Annika S. Silfvast-Kaiser, Dario Kivelevitch,
So Yeon Paek, and Alan Menter
Abstract
Key Learning Objectives
Brodalumab is a recombinant, fully human
1. To understand the mechanism of action
monoclonal receptor IgG2 antibody approved
of brodalumab
for the treatment of moderate-to-severe plaque
2. To understand the appropriate use and
psoriasis. It inhibits the IL-17 receptor A
efficacy of brodalumab
(IL-17RA), differing from other biologics in
3. To understand the safety issues of
the IL-17 class which target the IL-17A cytobrodalumab
kine itself. It is a highly effective medication,
with a rapid onset of action. Its superiority to
placebo and to ustekinumab has been shown
in clinical trials, reducing both the severity
Introduction
and the extent of psoriasis, with efficacy
­sustained up to 52 weeks. It has also shown
Psoriasis affects approximately 2–3% of the
superiority to placebo in patients with diffiworldwide population [1]. It is characterized by
cult-to-treat nail and scalp psoriasis and early
an extensive inflammatory infiltrate in the derevidence of efficacy in patients with psoriatic
mis with excessive growth of the epidermal skin
arthritis. Brodalumab is generally well-­
layer, presenting as well-demarcated, erythematolerated with a safety profile similar to that of
tous plaques with overlying silvery scale [2]. In
other biologics, with the addition of a label
addition to skin manifestations, 30–35% of psowarning relating to suicidal ideation. Herein,
riasis patients are affected by psoriatic arthritis
we review the data behind the use of broda(PsA), usually presenting 10–15 years after the
lumab for the treatment of psoriasis and psorionset of skin lesions [3]. Psoriasis is now largely
atic arthritis.
considered a systemic disease which can affect a
multitude of organ systems including the cardiovascular system in addition to psychosocial
health issues. Psoriasis is thought to result from
initial antigenic or environmental stimuli in
combination with predisposing genetic factors
A. S. Silfvast-Kaiser · D. Kivelevitch · S. Y. Paek
and dysregulation of the innate and adaptive
A. Menter (*)
Division of Dermatology, Baylor Scott & White,
immune systems [4]. These antigenic stimuli
Dallas, TX, USA
activate native immune cells including T-helper
e-mail: annikask@utexas.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_21
263
A. S. Silfvast-Kaiser et al.
264
cells (Th1 and Th17), dendritic cells, and keratinocytes which then produce multiple pro-inflammatory cytokines including tumor necrosis
factor (TNF)-alpha, interferon-alpha, IL-12,
IL-17, and IL-23 [5, 6]. A complex interplay
between immune cells and proinflammatory
cytokines exists in this T-cell mediated chronic
inflammatory skin disease. Ultimately, the cytokines released by Th1 and Th17 cells result in
the characteristic inflammatory environment
seen in psoriasis. Among others, Th17 cells
release the full spectrum of cytokines IL-17A
through IL-17F. IL-17A is the most influential,
having been established as a factor in the development of psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease
[7]. IL-17 is involved in neutrophil chemotaxis
and stimulates fibroblast production of vascular
endothelial growth factor, leading to endothelial
cell proliferation and angiogenesis [8]. IL-17A
also plays a role in the innate immune defense
against fungal and bacterial pathogens [9].
Role of IL-17 in Psoriasis
IL-17 and its related cytokines play an important
role in the immunopathogenesis of psoriasis [10–
12]. This family of cytokines (IL-17A, IL-17B,
IL-17C, IL-17D, IL-17E [IL-25], and IL-17F)
has been shown to induce expression of psoriatic
pro-inflammatory molecules in keratinocytes [9,
13]. IL-17 receptors are found on the surface of
keratinocyte cells and promote signaling within
the cell by receiving IL-17 cytokines. Elevated
IL-17A, 17C, and 17F messenger RNA (mRNA)
have been shown in the serum and plaques of
psoriasis patients [14–16]. The success of IL-17
and IL-23 biologic targeting agents in the treatment of psoriasis has established the IL-17 cytokines as key players in psoriasis disease
development [16, 17]. As our understanding of
psoriasis continues to develop, an increasing
number of systemic biologic agents that target
these cytokines have been developed and are
available to patients. Brodalumab is one such
agent, targeting the IL-17 cytokines via blockage
of the IL-17 receptor A.
Brodalumab
Brodalumab (Siliq™, Ortho-Dermatologics,
United States; Kyntheum®, Leo Pharma, Europe)
is a fully human IgG2 monoclonal antibody that
differs from other anti-IL-17 agents (secukinumab
and ixekizumab) by binding the subunit A of the
IL-17 receptor rather than the IL-17 cytokine
itself [18] (Fig. 21.1). By blocking IL-17RA,
brodalumab manages to inhibit the downstream
inflammatory activity of several interleukins
(IL-17A, IL-17C, IL-17F, IL-17E [IL-25], as
well as the IL17A/F heterodimer, preventing psoriatic inflammation [19, 20]. Brodalumab is the
only biologic currently approved for the treatment of psoriasis with activity against IL-17C, a
cytokine critical in the development of psoriasis,
and the most abundant IL-17 cytokine found in
psoriatic lesional skin [21–28]. Brodalumab was
approved in February 2017 for the treatment of
moderate-to-severe plaque psoriasis. Its superiority to placebo as well as to ustekinumab has been
shown at 12 weeks for both PASI 75 and PASI 90
[29, 30]. It is not currently approved for the treatment of psoriatic arthritis, but is under investigation in clinical trials for this indication.
osing, Storage, Administration,
D
and Pharmacokinetics
Brodalumab is a subcutaneous, self-injectable
medication dosed initially as one 210 mg/1.5 mL
prefilled syringe at weeks 0, 1, and 2, and subsequently every 2 weeks [28, 31]. Storage of the
syringe should occur at 2–8 °C or can be stored at
room temperature (for up to 2 weeks, then it
should be discarded). No re-refrigeration should
occur. The medication should be allowed to reach
room temperature for approximately 30 minutes,
if the syringe has been refrigerated before injection [32]. If no or inadequate improvement is
seen at 16 weeks, discontinuation of brodalumab
should be considered as the likelihood of reaching greater disease improvement after this time
point is unlikely [32].
Brodalumab reached maximum plasma concentration 2–4 days after one brodalumab 210 mg
21
Brodalumab
Fig. 21.1 Mechanism
of action of brodalumab.
The heterodimeric
IL-17RA is blocked by
brodalumab, decreasing
the downstream release
of psoriasis-related
inflammatory cytokines
265
Th17 cell
IL-17A - IL-17F
IL-17F
IL-17A
Brodalumab
IL-17RA
Brodalumab
subcutaneous dose, with steady-state achieved
after 10–12 weeks. After 20 weeks of administration the estimated accumulation ratio was 2.5-­
fold [33]. After subcutaneous injection, the
estimated bioavailability was 57.6% [34]. The
estimated half-life of brodalumab is 10.9 days
[33]. Age, sex and race had no effect on the pharmacokinetics of brodalumab. The effect of renal
or hepatic impairment on its pharmacokinetics
has not been studied. Hepatic impairment and
renal elimination are not expected to be clinically
relevant as brodalumab is mainly eliminated via
catabolism [33]. Although the area under the
serum concentration-time curve at steady state
was predicted to be two-fold higher in patients
weighing less than 75 kg, no dosage adjustments
for body weight are recommended [33].
Clinical Efficacy in Plaque Psoriasis
Overall, brodalumab has shown similar efficacy
to the other two IL-17 inhibitors. It exhibits an
Target cell
Brodalumab
early response (seen as early as 4 weeks), maintenance of response (up to 52 weeks), as well as no
loss of efficacy in patients with prior biologic
exposure.
The most common methods for clinical assessment in psoriasis clinical trials are the Psoriasis
Assessment and Severity Index (PASI) and the
Physicians Global Assessment (PGA). The PASI
score is based on the quality of psoriatic lesions
(i.e. erythema, induration, and scale) weighted by
body surface area, on a scale of 0–72, with higher
scores indicating more severe disease. Trial endpoints commonly assess the percentage of
patients who achieve a certain reduction in PASI
score compared to baseline (i.e. a 75% reduction
in PASI score is termed PASI 75 with a 90%
reduction termed as PASI 90). The PGA score is
graded on a scale of 0–5 with 0 representing
“clear” and 5 representing “severe” disease
involvement.
Brodalumab is indicated for the treatment of
moderate-to-severe plaque psoriasis in adult
patients who are candidates for systemic therapy
266
or phototherapy, having either had inadequate
response to, or lost response to, other systemic
therapies [28]. Below, we discuss the results of
the phase I, II, and III clinical trials that led to
brodalumab’s eventual approval.
A. S. Silfvast-Kaiser et al.
safety profiles of both the brodalumab and placebo cohorts were similar. Two patients (one
from the 350 mg cohort and another from the
700 mg cohort) receiving brodalumab exhibited
formation of non-neutralizing antibodies.
Another phase I clinical trial in Japan evaluPhase I Clinical Trials
ated the safety, tolerability, pharmacokinetics,
Brodalumab’s safety and efficacy was initially and pharmacodynamics of brodalumab in 40
investigated in a double-blind, randomized, healthy volunteers and in 8 subjects with
placebo-­controlled, ascending single-dose trial of moderate-­to-severe psoriasis [37]. Subjects with
25 healthy controls and patients with moderate-­ psoriasis had to meet inclusion criteria of
to-­
severe psoriasis with a Psoriasis Area and PASI ≥ 10, BSA ≥ 10%, and have undergone at
Severity Index (PASI) score ≥ 10 and Body least one previous phototherapy or systemic therSurface Area (BSA) ≥ 10%. Patients were fol- apy. In the healthy group, 8 subjects were ranlowed for 85 days with 20 of 25 patients receiv- domized in a 2:6 ratio to receive either placebo or
ing a single dose of brodalumab (4 patients a single dose of brodalumab at 70 mg, 140 mg,
received 140 mg subcutaneously (SC), 8 received 210 mg, or 420 mg SC or 210 mg IV. Psoriasis
350 mg SC, and 8 received 700 mg intravenously patients either received one dose of 140 mg SC
(IV)). The 5 other patients received placebo. The brodalumab or 350 mg SC. Rapid, dose-­
majority of patients were men (76%) with a dependent improvement was seen in all psoriasis
median age of 43 years and mean baseline PASI patients receiving brodalumab treatment. All 7
score of 14.1 [35, 36]. Rapid, dose-dependent patients in the 350 mg cohort reached PASI 50; 6
improvement in both PASI and static Physician of these patients achieved PASI ≥ 75; 3 of 6
Global Assessment (sPGA) scores within patients in the 140 mg cohort also achieved
2 weeks of dosing with either 350 mg SC or PASI ≥ 75. Safety profiles were similar between
700 mg IV brodalumab was seen. Two of four both the healthy patients and those with psoriasis.
patients who received 140 mg SC achieved PASI Injection site erythema was the most commonly
50. All patients on 700 mg IV achieved PASI 50 reported AE for both placebo and brodalumab.
by 4 weeks, with all but one achieving PASI 75 or Brodalumab antibodies were not detected in any
greater by week 6. Three patients achieved PASI group up to 9 weeks.
90 by week 6. Six of eight patients who received
350 mg SC achieved PASI 50 and 3 of 8 patients Phase II Clinical Trials
receiving the same dose reached PASI 75. None A total of 188 patients with moderate-to-severe
of the 5 patients receiving placebo achieved PASI psoriasis with BSA ≥ 10% and PASI ≥ 12 were
50 [35].
enrolled and completed a phase II, randomized,
Lesional and non-lesional skin biopsies were double-blind, placebo-controlled, dose-ranging
performed on all subjects prior to treatment and study to evaluate the short term efficacy and
then twice after dosing. The patients in the two safety of brodalumab. Sixty-six percent of the
highest dose cohorts (300 and 700 mg) showed patients were male with a mean age of 43, and a
significant reductions in epidermal thickness, mean PASI and BSA of 19 and 24%, respectively
keratin 16, and Ki67-expresssing cells (as early [18]. Patients were randomly assigned to one of
as week 1 after dosing of the two highest doses), five treatment groups (70 mg, 140 mg, or 210 mg
along with lesional IL-17A, F and C mRNA lev- SC on day 1, week 1, 2, 4, 6, 8, and 10; or 280 mg
els which returned to non-lesional levels over SC at day 1, week 4, and week 8; or placebo).
6 weeks [20, 35]. The most common adverse The percentage of improvement in PASI score at
events (AEs) experienced by those receiving bro- week 12 compared to baseline was the primary
dalumab were headache, gastroenteritis, and the endpoint. Secondary endpoints were attaining
Koebner phenomenon at the biopsy site. The PASI 50, 75, 90, 100, as well as BSA and sPGA
21
Brodalumab
scores at week 12. Compared to placebo, all brodalumab groups achieved significantly greater
mean PASI improvement at week 12 (p < 0.001),
with the earliest clinical improvement seen at
week 2. In the various brodalumab dosing arms
receiving 70, 140, 210, or 280 mg the mean PASI
improvement was 45, 85.9, 86.3, and 76% respectively. The placebo arm had 16% mean PASI
improvement. At week 12, PASI 75 or greater
was achieved by 77% in the 140 mg brodalumab
group and 82% in the 210 mg brodalumab group.
In these two groups, PASI 90 or greater was seen
in 72 and 75%, respectively. 38.3% of patients in
the 140 mg arm and 80% of patients in the
210 mg arm reached PASI 100. A sub-analysis of
this phase II data also showed that patients
achieved clinical improvement and similar rates
of AEs irrespective of whether self-reported psoriatic arthritis was present or not [38].
Compared to placebo, the brodalumab groups
also showed significantly greater improvements
in BSA, sPGA, Dermatology Quality of Life
Index (DLQI) and SF-36 at week 12 [18].
Inflammatory markers and epidermal thickness
also significantly improved in the brodalumab
groups compared to placebo. The most commonly reported AEs in the brodalumab group
were nasopharyngitis, upper respiratory i­ nfection,
arthralgia, and injection site erythema. Three
serious adverse events occurred with brodalumab: renal colic and two cases of grade 3
asymptomatic neutropenia (resolving after brodalumab withdrawal). Secondary analyses have
also shown that at week 12, the brodalumab treatment groups demonstrated significant improvement in patient reported outcome measures
including DLQI and Psoriasis Symptom
Inventory (PSI) compared to placebo. Patients
with prior biologic exposure and those naïve to
prior biologic therapies showed no difference in
the mean improvements in PASI scores [18, 38].
A 5-year open-label extension of this phase II
trial enrolled 181 of the original 198 patients to
evaluate the long-term safety and efficacy of brodalumab 210 mg every 2 weeks [39]. At 52 weeks, a
dose reduction to 140 mg for patients ≤100 kg
(n = 119) was implemented. Patients with inadequate response to this lower dose were then allowed
267
to increase their dose back to 210 mg (n = 19).
Ninety percent of patients achieved sPGA 0/1
(clear to almost clear) at 12 weeks, 85% at
48 weeks, 76% at 96 weeks, and 72% at 144 weeks.
At weeks 12 and 48, the mean BSA improvement
from the baseline BSA of the parent study was 95
and 96%, respectively. The most frequently
reported AEs occurring during open-­label extension were mild to moderate in severity and included
nasopharyngitis, upper respiratory tract infection,
arthralgia, back pain, and influenza. 14 patients
reported AEs of grade 3 (severe) or greater and 9%
of patients reported SAEs including cholecystitis,
constipation (likely related), pyelonephritis, and
benign parathyroid tumor. One death occurred due
to rupture of an aortic aneurysm [38, 39].
In Japan, a phase II study randomized 151
moderate-to-severe plaque psoriasis patients to
doses of 70, 140, 210 mg, or placebo at day 1,
weeks 1, 2, 4, 6, 8 and 10 [40]. Efficacy and
safety outcomes were similar to the phase II trial
discussed above with the most common AEs in
brodalumab patients being nasopharyngitis, diarrhea, upper respiratory tract inflammation, and
folliculitis. At week 12, the mean improvement in
PASI scores for the 70 mg, 140 mg, 210 mg, and
placebo arms were 37.7, 82.2, 96.8, and 9.4%,
respectively. PASI 75 was achieved at week 12 by
26, 78, and 95% of patients in the 70, 140, and
210 mg groups, respectively. PASI 90 or greater
and PASI 100 was achieved by 15, 65, 92% and
2.6, 35, and 59% of these patients, respectively.
DLQI scores of 0 or 1 were also significantly
more common in patients in the 140 mg and
210 mg groups at week 12 (54.1 and 56.8%)
compared to those on placebo (8.8%). Long-term
brodalumab treatment also showed sustained
clinical response and favorable safety profile in
an open-label extension (OLE) of this study [41].
133 of 145 patients (92%) completed the study
with 94.4, 87.5, and 55.6% of patients in the
210 mg cohort achieving PASI 75, 90, and 100 by
week 52 and 78.1, 71.2, and 43.8% of patients in
the 140 mg group achieving PASI 75, 90, and
100, respectively. Nasopharyngitis (35.2%),
upper respiratory tract inflammation (10.3%),
and contact dermatitis (9.7%) were the most
commonly reported AEs.
A. S. Silfvast-Kaiser et al.
268
hase III Clinical Trials
P
or almost clear. Between 37 and 44% of patients
Three phase III clinical trials (AMAGINE-1, in all AMAGINE trials achieved a PASI 100
AMAGINE-2, and AMAGINE-3) have been response by week 12 and approximately 70% of
completed to assess the efficacy, safety, and patients achieved PASI 90 by week 12.81% of
withdrawal-­
retreatment effect of brodalumab patients who had failed prior biologic therapy
versus placebo in moderate-to-severe plaque pso- were able to attain PASI 75 response with 32% of
riasis. AMAGINE-1 compared brodalumab only them achieving PASI 100. Of the PASI 100
to placebo. AMAGINE-2 and AMAGINE-3 com- responders from week 12 in the AMAGINE 2 and
pared brodalumab’s efficacy and safety to that of 3 trials, 72% maintained PASI 100 response at
ustekinumab in addition to placebo. Both of these week 52.
studies were multicenter, randomized, double-­
blind, placebo-controlled, active comparator-­ AMAGINE-1
controlled, parallel group trials with a 12-week In AMAGINE-1, 661 patients with moderate-to-­
induction period, followed by maintenance with severe psoriasis were followed through a 12-week
brodalumab up to week 52 (Table 21.1) [29, 30]. induction phase and then a withdrawal and treatAll phase III studies required a diagnosis of ment phase through 52 weeks [29]. Ninety six
plaque psoriasis for ≥6 months, BSA ≥ 10%, percent of patients completed the induction phase
PASI ≥ 12 and sPGA ≥ 3. The primary endpoint and 84.4% of patients continued through treatfor all three AMAGINE trials was PASI 75 and ment withdrawal and re-treatment through week
sPGA 0/1 at week 12 as compared to placebo. 52. During the induction phase, patients received
For AMAGINE-2 and AMAGINE-3, PASI 100 either brodalumab 140 mg, 210 mg, or placebo,
for brodalumab versus ustekinumab was also a every 2 weeks for 12 weeks. After 12 weeks,
primary endpoint. Between 76 and 80% of patients with sPGA score of 0/1 were re-­
patients in all three trials achieved sPGA of clear randomized to either continue with their current
Table 21.1 Brodalumab phase III clinical trial outcomes [29, 30]
Phase III trial
AMAGINE-1
(n = 661)
AMAGINE-2
(n = 1831)
AMAGINE-3
(n = 1881)
Brodalumab
Study arms
Placebo
Brodalumab
140 mg
Brodalumab
210 mg
Placebo
Ustekinumab
Brodalumab
140 mg
Brodalumab
210 mg
Placebo
Ustekinumab
Brodalumab
140 mg
Brodalumab
210 mg
Phase III trial results
Week 12
Primary & Secondary
Outcomes (PASI
75/90/100)
2.7/0.9/0.5%
60.3a/42.5 a/23.3a%
83.3a/70.3a/41.9a%
Week 12
sPGA 0/1 & sPGA 0
Week 52 Outcomes
(PASI 75/90/100)
1.4 & 0.5%
53.9 & 23.3%
75.7 & 41.9%
–
–/66.7/43.9%
–/78.3/67.5%
8.1/1.9/0.6%
70/47/21.7%
66.6a,b/49a,b/25.7a,b%
86.3a,b/69.9a,c/44.4a,c%
3.9 & 0.6%
61 & 21.7%
58 & 25.7%
78.6 & 44.8%
–
–
–
80/75/56%
6/2.9/0.3%
69.3/47.9/18.5%
69.2a,b/52a,b/27a,c%
85.1a,c/68.9a,c/36.7a,c%
4.1 & 0.3%
57.2 & 18.5%
59.9 & 27%
79.6 & 36.7%
–
–
–
80/73/53%
p < 0.001 for the comparison with placebo
p > 0.05 for the comparison with ustekinumab
c
p < 0.01 for the comparison with ustekinumab
a
b
21
Brodalumab
treatment or to switch to placebo. Patients who
experienced disease return with sPGA ≥ 3 after
re-randomization to placebo were then re-started
on their induction dose of brodalumab up to week
52. If patients had originally been randomized to
the placebo group, or if they had sPGA ≥ 1 after
week 12, they were started on brodalumab
210 mg every 2 weeks.
By week 12, PASI 75 was achieved by 83.3%
of the brodalumab 210 mg group, 60.3% of brodalumab 140 mg group, and in 2.7% of those
receiving placebo [29]. In the 210 and 140 mg
brodalumab arms, PASI 90 response was seen in
70.3 and 42.5% of patients respectively, compared to 0.9% in the placebo group. 41.9 and
23.3% of patients in the 210 and 140 mg arms
achieved PASI 100 respectively, compared to
0.5% in the placebo group [29, 38, 42]. These
significant differences in clinical response were
sustained until week 52. sPGA scores of 0/1 were
achieved by 75.7 and 53.9% of patients on brodalumab 210 mg and 140 mg, respectively, compared to placebo at 1.4%. Significant
improvements on the Psoriasis Symptom
Inventory (PSI) (which evaluates 8 psoriasis
signs and symptoms; see Table 21.2) were also
seen compared to placebo [43, 44].
Those who lost control of their psoriasis with
withdrawal of brodalumab were able to recover
their previous treatment sPGA score within
12 weeks of resuming therapy with brodalumab
[45]. One hundred percent improvement in the
Psoriasis Scalp Severity Index (PSSI) was
achieved by 63.4 and 41% of patients in the
140 mg and 210 mg brodalumab groups, as comTable 21.2 Psoriasis symptom inventory items [44]
Psoriasis Symptom Inventory (PSI)a,b
• Itch
• Redness
• Scaling
• Burning
• Stinging
• Cracking
• Flaking
• Pain
Each item is scored on a scale of 0 (not at all severe) to 4
(very severe), with a total score from 0 to 32
b
Response of PSI is defined as attaining a total score of ≤8
a
269
pared to 3.2% in the placebo group [46]. At week
12, the most frequently reported adverse events
in the brodalumab cohorts were nasopharyngitis,
upper respiratory tract infection, and headache.
SAEs while on brodalumab 210 mg, 140 mg, and
placebo occurred in 1.8, 2.7, and 1.4% of patients,
respectively.
The impact of brodalumab treatment on quality of life outcomes was also investigated in
AMAGINE-1. At 12 weeks, in those receiving
brodalumab, a significant proportion of patients
reported PSI of 0, DLQI of 0, and satisfaction
with treatment compared to placebo patients.
Health-related quality-of-life measures also
showed significantly greater improvement in
patients treated with brodalumab compared with
placebo. Over 60% of patients with moderate and
severe anxiety or depression at baseline exhibited
improvement to mild, moderate, or normal severity by week 12 on brodalumab [29].
In addition, psoriasis biomarkers such as
mRNA expression of IL-17 cytokines, IL-23, and
cell counts of epidermal Ki-67, dermal CD3, epidermal CD3, dermal CD8, and epidermal CD8,
were all significantly reduced in psoriatic lesional
skin at 12 and 52 weeks, compared to baseline in
the patients treated with brodalumab [3].
AMAGINE-2 and AMAGINE-3
AMAGINE-2 and AMAGINE-3 were both large,
double-blind, placebo-controlled, multinational
studies in moderate-to-severe plaque psoriasis
with identical designs [30]. The efficacy and
safety of brodalumab 140 and 210 mg every
2 weeks was evaluated in comparison to both
ustekinumab and placebo (in a 2:2:1:1 ratio).
Ustekinumab is a human monoclonal antibody
which acts against the p40 subunit common to
IL-12 and IL-23. Ustekinumab works upstream
compared to brodalumab which works by driving
downstream signaling. Ustekinumab was
approved for the treatment of moderate-to-severe
plaque psoriasis in 2009 and for PsA in 2013.
During the first 12 weeks the treatment arms of
both AMAGINE-2 and -3 included: 140 or
210 mg brodalumab every 2 weeks; ustekinumab
(45 mg if ≤100 kg, 90 mg if >100 kg), on day 1
and week 4; or placebo. Patients who were
270
receiving brodalumab were randomly reassigned
to 1 of 4 maintenance schedules: 140 mg or
210 mg every 2 weeks, 140 mg every 4 weeks, or
140 mg every 8 weeks after the initial 12-week
period. Those who were assigned to the
ustekinumab arm from the beginning continued
receiving ustekinumab every 12 weeks. Those
who commenced on placebo were switched to
brodalumab 210 mg every 2 weeks. After week
52 and completion of the maintenance phase,
patients who were still continuing to receive
ustekinumab were eligible to switch to brodalumab 210 mg every 2 weeks as part of the OLE.
Two co-primary endpoints assessed the efficacy of both brodalumab arms in both studies
compared to placebo: the percentage of patients
who reached PASI 75 and sPGA 0/1 at week 12.
The efficacy of 210 mg brodalumab was also
compared to ustekinumab in both studies with
PASI 100 as the primary endpoint at 12 weeks.
Both AMAGINE-2 and -3 showed superiority of
210 mg brodalumab over ustekinumab and placebo. However, the patients in the brodalumab
140 mg arm had response rates significantly superior to ustekinumab only in AMAGINE-3 [30].
A pooled analysis of both trials showed similar efficacy of brodalumab in patients with prior
biologic exposure, as well as those who were
naïve. Non-neutralizing antibodies against brodalumab were found in AMAGINE-2 and
AMAGINE-3 (in 1.8 and 2.3% of patients,
respectively). No loss of efficacy or adverse
events were associated with these antibodies.
Neutralizing antibodies were not found in any
patients [30].
The most common AEs included nasopharyngitis, upper respiratory tract infection, headache,
and arthralgia, with the proportion of patients on
brodalumab or ustekinumab reporting at least
one AE greater than that of placebo patients.
Transient, reversible, mostly mild cases of neutropenia also occurred more frequently in the
brodalumab and ustekinumab groups as compared to placebo, but were not associated with
serious infections. No clinically apparent differences were seen in the types of serious AEs
among the study groups. Consistent with the role
that IL-17A plays in mucocutaneous host
A. S. Silfvast-Kaiser et al.
defense, Candida infections occurred more commonly with brodalumab (1.2%) than with
ustekinumab (0.5%) or placebo (0.5%) in the
induction phase [47–49].
Over the 52-week trial periods, 6 deaths
occurred in both the brodalumab and ustekinumab
groups due to: stroke (1), cardiac arrest (3), pancreatic carcinoma (1), and accidental death after
motor vehicle collision (1). In AMAGINE-2, one
patient committed suicide 19 days after the last
dose of brodalumab 210 mg. After the completion of the studies, an additional 3 deaths
occurred: one due to suicide, another from hemophagocytic histiocytosis syndrome, and the third
from cardiomyopathy. One additional suicide
occurred during the OLE, after week 52 [30].
A pooled secondary data analysis of
AMAGINE-1, -2, and -3, compared patients who
achieved PASI 100 or sPGA 0 to those who
achieved PASI 75 to <100 or an sPGA of 1, in
order to evaluate the clinical meaningfulness of
complete skin clearance based on PSI scores and
DLQI. When comparing PASI groups, a significantly greater proportion of patients achieving
PASI 100 reported a PSI score of 0 (45%) compared to those achieving PASI 75 to <100 (8%).
A similarly significant trend was seen in these
two groups as related to DLQI scores of 0/1 (80%
of PASI 100 and 55% of PASI 75 to <100
patients). When comparisons were based on
sPGA 0/1, similar results were also seen [50].
AMAGINE-2
In AMAGINE-2, brodalumab was superior to
ustekinumab in achieving PASI 100 at both the
140 mg and 210 mg doses at week 12, but only significantly superior with the 210 mg group.
Response rates for PASI 75/90/100 in the brodalumab 140 mg, brodalumab 210 mg, and
ustekinumab groups were 67%/49.0%/25.7%,
86%/69.9%/44.4%, and 70%/47.0%/21.7%,
respectively. Placebo response rates for PASI
75/90/100 were: 8.1%/1.9%/0.6%, respectively
[30]. Rates of sPGA scores of 0/1 were also significantly higher with both doses of brodalumab (58
and 79%) as compared to placebo (4%). The most
common AEs were the common cold, upper respiratory tract infection, headache, and joint pain [51].
21
Brodalumab
AMAGINE-3
In AMAGINE-3, brodalumab was also shown to be
superior to ustekinumab and placebo with a primary endpoint of PASI 100. Week 12 response
rates for PASI 75/90/100 in the brodalumab 140 mg
and 210 mg arms were: 69%/52.0%/27.0% and
85%/68.9%/36.7%, respectively. Ustekinumab and
placebo exhibited response rates of PASI 75/90/100
at 69%/47.9%/18.5% and 6%/2.9%/0.3%, respectively [30]. The secondary endpoints of PSI, PASI
100 and sPGA at week 12 were greater for brodalumab compared to ustekinumab and placebo;
however, statistically significant results were not
achieved against ustekinumab. Rates of sPGA
scores of 0/1 were significantly higher with both
doses of brodalumab (60 and 80%) when compared to placebo (4%) [30]. The most commonly
reported AEs in the brodalumab groups were nasopharyngitis, upper respiratory tract infection,
arthralgia, and headache [52].
At 52 weeks, PASI 75/90/100 was achieved by
80%/73%/53% of patients on 210 mg brodalumab, respectively, outperforming both the
ustekinumab (69%/57%/19%) and placebo
cohorts [42]. Significant clinical efficacy of brodalumab was maintained through 120 weeks in
an OLE study [53]. A systematic review of the
long-term efficacy of brodalumab compared to
other novel biologic agents for psoriasis concluded that brodalumab showed superiority compared to secukinumab, ustekinumab, and
etanercept in sustaining PASI response as well as
52-week complete clearance [54].
The majority of patients rescued with brodalumab after initial ustekinumab treatment achieved
PASI 75 and sPGA 0/1 responses by week 12 [30].
By week 52, a significant number of these patients
had also achieved PASI 100. Brodalumab showed
greater effectiveness when compared to
ustekinumab in non-naïve biologic patients, with
40% of brodalumab patients achieving PASI 100
compared to 17% of those on ustekinumab.
Brodalumab exhibited more rapid onset of action
as well, achieving PASI 75 at a median of
4.2 weeks versus 9.4 weeks with ustekinumab.
271
Clinical Efficacy in Psoriatic Arthritis
Brodalumab has also been investigated as a
potential treatment for psoriatic arthritis.
Although early results from PsA trials showed
some promise, further investigations are needed
to evaluate its potential to benefit patients with
PsA, as brodalumab does not yet carry an indication for the treatment of PsA. A phase II randomized, placebo-controlled trial showed that
approximately 40% of 159 patients treated with
brodalumab 140 or 280 mg every 2 weeks were
able to achieve ACR20 (American College of
Rheumatology response criteria) compared to
18% of placebo patients at week 12. At week 12,
rates of ACR50 for brodalumab versus placebo
were 14 and 4%, respectively. By 24 weeks,
51% patients in the 140 mg group and 64% in
the 280 mg group achieved ACR20 response
versus 44% for those who switched from placebo to open-label brodalumab. Response was
sustained through week 52 [55]. It is important
to recognize that in clinical trials for PsA, up to
50% of patients are maintained on their preexisting systemic therapies when commencing a
biologic clinical trial. The most commonly
reported AEs were similar to those of the plaque
psoriasis trials. Rates of serious adverse events
were similar as well (3 vs. 2% in brodalumab vs.
placebo groups, respectively). No statistical difference in response was seen in non-naïve biologic patients [32].
In a Japanese phase II trial for moderate-to-­
severe plaque psoriasis, 20% improvement in
ACR20 was seen in patients receiving brodalumab 70 mg (1 patient), 140 mg (2 patients), and
210 mg (4 patients) and none receiving placebo
[40]. At week 52, 75% of the patients with PsA in
the 210 mg group achieved ACR20 compared to
38% in the 140 mg group [41].
Brodalumab completed phase 3 testing for
psoriatic arthritis in 2017 (AMVISION-2).
Results have not been published. One phase 3
trial (AMVISION-1) was terminated in 2015,
with a cited reason of “sponsor decision.”
272
linical Efficacy in Difficult-to-Treat
C
Psoriasis
Subgroup analyses in psoriasis patients treated
with brodalumab with nail and scalp involvement
(both considered difficult-to-treat areas) showed
improvement in nail psoriasis severity index
(NAPSI) score as well as psoriasis scalp severity
index (PSSI) from a baseline score of ≥6, and
≥15 with scalp surface area involvement of
≥30%, respectively. In patients with either of
these two subtypes of psoriasis, significant
improvements from baseline to week 12 were
seen in both NAPSI and PSSI scores (p < 0.001).
For the brodalumab 140 mg and 210 mg groups,
37.5 and 46.3% improvement of NAPSI was
shown, respectively, compared to 11.6% for placebo patients at week 12. Of 661 patients enrolled
in the AMAGINE-1 study, 9.5, 61.8, and 89% of
the placebo, brodalumab 140 mg, and 210 mg
groups, achieved PSSI 75 response at the end of
the 12-week induction phase, respectively. PSSI
90 and 100 responses of 4.2%, 52.4%, 76.8% and
3.2%, 41%, and 63.4%, were seen in the same
treatment groups, respectively. Significant
improvement in both brodalumab groups was
seen as early as week 2 and maintained until
week 12 [46, 56].
Palmoplantar pustular psoriasis (PPPP), also
known as palmoplantar pustulosis (PPP), is a
form of psoriasis characterized by sterile yellow
pustules of the palms and/or soles, sometimes in
addition to the characteristic indurated, erythematous, scaly lesions of plaque psoriasis. Largely
because of the location of involvement, this condition can be extremely debilitating due to pain
and disease-related functional limitation. Recent
studies have shown that the IL-17 cytokine plays
an important role in the pustular forms of psoriasis, with detectable levels of IL-17A, -C, and -F
in palmoplantar pustular lesions [57–59]. There
are limited data available regarding the effectiveness of biologic treatment for this psoriatic variant. The few case reports regarding PPPP/PPP
patients treated with brodalumab show inconsistent results. Formal clinical trials need to be performed to determine whether brodalumab could
A. S. Silfvast-Kaiser et al.
be an effective therapeutic option for pustular
forms of psoriasis [60, 61].
Improvements in Quality of Life
Health-related quality of life assessed by the
Psoriasis Symptom Inventory (PSI) and the
Dermatology Life Quality Index (DLQI) in all
clinical trials with brodalumab exhibited significantly higher numbers of patients with improvement on both doses of brodalumab compared to
placebo [29, 30]. At week 12 of a pooled analysis
of AMAGINE-1, -2, and -3, significantly more
brodalumab patients in the 210 mg every 2 weeks
group had a DLQI score of 0/1 versus those on
placebo (59 vs. 6% respectively, p < 0.001) [62].
A majority of patients (68–84%) receiving brodalumab also reported that psoriasis had no
impact on their daily activities, leisure activities,
personal relationships, and work/school as a
result of their treatment [62]. In AMAGINE-2
and -3, brodalumab also improved productivity
loss as indicated by the self-reported Work
Limitations Questionnaire [63]. Depression and
anxiety as assessed by the Hospital Anxiety and
Depression Scale (HADS) were also improved.
Among those patients with baseline moderate
and severe anxiety or depression (n = 139), a
majority improved to normal, mild, or moderate
at week 12 [64].
Safety and Tolerability
Common Adverse Events
The most common adverse events relating to brodalumab therapy, reported through week 120 of
an open label extension (OLE) study in patients
receiving treatment with brodalumab can be
found in Table 21.3 [32].
Most adverse events regarding brodalumab
are related to its potential to increase the risk of
infection due to its role as an immune modulator.
Similar to other IL-17 inhibitors, brodalumab has
demonstrated a small increased risk of neutrope-
21
Brodalumab
Table 21.3 Most commonly reported adverse events of
brodalumab through week 120 of open-label extension
Most common adverse events with brodalumab
therapy through 120 weeks
• Nasopharyngitis (27%)
• Upper respiratory tract infections (20%)
• Arthralgia (16%)
• Back pain (11%)
• Gastroenteritis (10%)
• Influenza (9%)
• Oropharyngeal pain (9%)
• Sinusitis (9%)
nia and Candida infections, as well as potential
exacerbation of inflammatory bowel disease [6,
32, 33]. In addition to the most common adverse
events (seen in Table 21.2), mild to moderate oral
candidiasis, injection site reactions, and serious
adverse events occurred in 3, 8, and 15% of
patients, respectively. Transient grade 2 absolute
neutrophil abnormalities were seen in 2% of
patients. All resolved on their own without treatment modification. Several cases of grade 3 neutropenias were also reported [32]. SAEs
throughout the entirety of the study occurred at a
rate of 8.3 in subjects treated with brodalumab,
and at a rate of 13 with those on ustekinumab.
Within AMAGINE-2 and AMAGINE-3 the rates
were 7.9 and 4.0, respectively.
Patients should be counseled to seek medical
care should signs or symptoms of infection occur
while on biologic therapies, including brodalumab.
Inflammatory Bowel Disease
There is a known association between psoriasis
and inflammatory bowel disease (IBD). Patients
with Crohn’s disease and ulcerative colitis (UC)
have shown higher prevalence rates of psoriasis.
Similarly, psoriasis patients have also shown
higher rates of IBD. Crohn’s disease is genetically linked to psoriasis [28].
Brodalumab is contraindicated in patients
with Crohn’s disease [28]. Clinical trials for brodalumab excluded patients with an established
diagnosis of IBD as potential risk of exacerbation
had already been observed in patients in the
ixekizumab and secukinumab trials. The inci-
273
dence of new-onset Crohn’s disease in clinical
trials with brodalumab was approximately less
than 1:1000, with one patient on treatment with
brodalumab experiencing new-onset Crohn’s disease during the maintenance phase. In general,
providers should use caution when considering
the use of IL-17 inhibitors in patients with IBD
[28, 30, 56].
Serious Infections
In the pivotal phase 3 clinical trials, serious infections and fungal infections were observed at a
higher rate in patients on brodalumab as compared to placebo [30]. One patient had to discontinue therapy due to cryptococcal meningitis [31].
Immunizations
The use of live vaccines in patients on brodalumab should be avoided [28]. If necessary, treatment may be interrupted for administration [65].
Pregnancy
No specific contraindication exists for the use of
brodalumab in pregnancy. However, risks and
benefits should be carefully assessed prior to initiation of therapy as efficacy and safety of brodalumab use in pregnancy has not been investigated.
It is unknown whether brodalumab is excreted in
human milk.
Elderly
Brodalumab has not been associated with higher
rates of adverse reactions in the elderly [66].
Suicidal Behavior
During the phase III brodalumab clinical trials, 4
completed suicides (one case was ruled as indeterminate) were seen. These all occurred after the
274
A. S. Silfvast-Kaiser et al.
first 12 weeks of the trials (after the placebo-­ Table 21.4 Screening guidelines prior to initiation of
controlled portion), with 3 of 4 suicides occur- therapy with brodalumab
ring in patients who had previously attained PASI Screening guidelines for brodalumab initiation
100 on brodalumab. All patients who completed – Complete blood count
– Comprehensive metabolic panel
suicide had underlying psychiatric disorders or – Hepatitis B/C
stressors and had received brodalumab therapy at – HIV
210 mg every 2 weeks; however, none of the sui- – TB
cides occurred during active treatment with bro- – Personal or family history of IBD or
symptomatology consistent with IBD
dalumab [67]. The suicides occurred 58, 27, and – Psychiatric history
19 days after each subject’s last dose [16, 68].
The FDA concluded there was no established
drug-related risk of suicide or suicidal ideation; Contraindications and Cautions
they also found no causal or temporal relationship. Although a causal or temporal relationship Brodalumab is contraindicated in patients with
is lacking, brodalumab carries a black box warn- Crohn’s disease due to observed worsening. It
ing for increased risk of suicidal ideation and should be used with caution in patients with
behavior [69, 70]. As a result, it is only available IBD. Careful attention should also be paid to
to registered providers to prescribe through the patients who present with chronic or recurrent
Siliq® Risk Evaluation and Mitigation Strategy infections. Should a patient experience a non-­
(REMS) Program which requires providers to be resolving active infection, the medication should
certified with the program in addition to having be discontinued.
patients sign an agreement and receive a pocket-­
size guide explaining suicidal behavior and what
behaviors would warrant immediate medical Initiation of Therapy
evaluation [32, 68].
Oftentimes, the burden of psoriasis extends In addition to screening for any of the above conpast the skin’s surface. This includes significant traindications, most providers recommend estabeffects on patient quality of life and disease-­ lishing baseline health before initiating therapy
related morbidity. Studies have shown that with biologics, including brodalumab. In general,
patients with psoriasis are overall more prone to a patient’s health history, existence of comorbidiexperience psychological burden and to attempt ties, and baseline status prior to the initiation of
suicide than patients without psoriasis [71–74]. biologic therapies such as IL-17 agents should be
Patients with psoriasis experience higher rates of established by performing a thorough history and
depression, anxiety, self-harm, and suicidality physical, along with the appropriate laboratory
compared
to
the
general
population. assessments (Table 21.4). This includes recomUnsurprisingly then, most of the patients who mended tuberculosis (TB) testing [32].
completed suicide during the brodalumab clinical
trials had a history of predisposing risk factors
such as depression and/or suicidal behavior [67]. Conclusion
Prior to prescribing brodalumab, providers
should weigh the risks and benefits of therapy with Psoriasis is a complex and debilitating disease
brodalumab in patients with a history of depres- which can impact both the physical and emosion, suicidal ideation, and/or behavior. Patients tional health of a patient. The scope of psoriasis
and their caregivers should also be instructed to treatments has widened considerably within the
seek medical attention immediately should the last decade. As the understanding of psoriasis and
patient begin experiencing worsening or new its pathogenesis deepens, psoriasis therapies are
depression, manifestations of suicidal ideation or becoming increasingly more effective and spebehavior, or other significant mood changes.
cific. For many years, PASI 50 and later PASI 75,
21
Brodalumab
were used as the standard end point in clinical
trials for the evaluation of treatment efficacy.
With newer biologic agents such as brodalumab,
PASI 90 and PASI 100 are increasingly becoming
the new standard as these are now realistic,
achievable endpoints [18, 37, 75]. Brodalumab’s
efficacy, rapid onset of action, and role in
difficult-­to-treat psoriasis help distinguish it from
other biologic agents [76]. Instead of blocking
the individual IL-17 cytokines, brodalumab
blocks the IL-17 receptor, which appears to yield
additional clinical benefits for cutaneous disease.
Its rapidity of action and its efficacy speak to the
important role of the IL-17 receptor A in driving
downstream signaling in keratinocytes, causing
the expression of the pro-inflammatory molecules that contribute to psoriasis [24, 77, 78].
Further clinical trials regarding progression of
joint disease and destruction in patients treated
with brodalumab are needed as the efficacy
results for psoriatic arthritis are less striking [38].
Despite its boxed label warning regarding suicidality, providers should consider brodalumab a
realistic treatment option, especially for those
who have experienced failure of other treatment
options, or for those with a significant inflammatory flare of their psoriasis. Evaluation of the possible association of brodalumab with suicidality
have failed to identify a link [69, 70]. It is important to remember that psoriasis patients overall
are known to carry a significantly greater psychological burden (including higher incidences of
both suicidal ideation and completed suicides)
compared to patients without psoriasis [71–74].
Depression and anxiety symptoms have been
shown to improve with treatment by biologics in
these patients, including with treatment by brodalumab [79]. Compared to placebo and
ustekinumab, brodalumab has shown significant
superiority, with mean time to PASI 75 response
nearly twice as rapid for brodalumab patients
(210 mg every 2 weeks) compared to those
treated with ustekinumab [80]. By targeting the
Th17 inflammatory pathway which is specific
and critical to the development of psoriatic
plaques, IL-17 inhibitors, including brodalumab,
have shown the potential to enhance and shorten
275
the duration to clinical improvement compared to
other biologic agents available for the treatment
of psoriasis. The efficacy and rapidity of improvement with brodalumab treatment speaks volumes
regarding the exciting future of biologics for
moderate-to-severe psoriasis.
References
1. Takeshita J, Gelfand JM, Li P, et al. Psoriasis in the US
Medicare population: prevalence, treatment, and factors associated with biologic use. J Invest Dermatol.
2015;135:2955–63.
2. Ouyang W. Distinct roles of IL-22 in human psoriasis
and inflammatory bowel disease. Cytokine Growth
Factor Rev. 2010;21(6):435–41.
3. Roostaeyan O, Kivelevitch D, Menter A. A review article
on brodalumab in the treatment of moderate-­to-­severe
plaque psoriasis. Immunotherapy. 2017;9(12):963–78.
4. Hugh JM, Weinberg JM. Update on the pathophysiology of psoriasis. Cutis. 2018;102(5S):6–12.
5. Cai Y, Fleming C, Yan J. New insights of T cells in
the pathogenesis of psoriasis. Cell Mol Immunol.
2012;9(4):302–9.
6. Roman M, Chiu M. Spotlight on brodalumab in the
treatment of moderate-to-severe plaque psoriasis:
design, development, and potential place in therapy.
Drug Des Devel Ther. 2017;11:2065–75.
7. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional
specialization of the IL-17 family members.
Immunity. 2011;34(2):149–62.
8. Numaski M, Fukushi J, Ono M, et al. Interleukin-17
promotes angiogenesis and tumor growth. Blood.
2003;101(7):2620–7.
9. Lynde CW, Poulin Y, Vender R, Bourcier M, Khalil
S. Interleukin 17A: toward a new understanding
of psoriasis pathogenesis. J Am Acad Dermatol.
2014;71(1):141–50.
10. Elder JT. Genome-wide association scan yields new
insights into the immunopathogenesis of psoriasis.
Genes Immun. 2009;10:201–9.
11. Ellinghaus E, Ellinghaus D, Stuart PE, et al. Genome-­
wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. Nat Genet. 2010;42:991–5.
12. Georgescu SR, Tampa M, Caruntu C, Sarbu MI, et al.
Advances in understanding the immunological pathways in psoriasis. Int J Mol Sci. 2019;20(3):739.
13. Patel D, Kuchroo VK. Th17 cell pathway in human
immunity: lessons from genetics and therapeutic
interventions. Immunity. 2015;43(6):1040–51.
14. Li J, Li D, Tan Z. The expression of interleukin-17,
interferon-gamma, and macrophage inflammatory
protein-3 alpha mRNA in patients with psoriasis
vulgaris. J Huazhnog Univ Sci Technolog Med Sci.
2004;24:294–6.
Biosimilars for Psoriasis
22
Sarah Lonowski, Nirali Patel, Nika Cyrus,
and Paul S. Yamauchi
Abstract
Biologics have revolutionized the treatment of
numerous conditions. While the therapeutic
benefit of biologics has been dramatic, the
development of these agents has been accompanied by significant increases in healthcare
costs. Recently there has been growing interest in the development of biosimilar agents,
which have the potential to decrease costs and
improve access to this powerful class of medications. In this chapter, we discuss the legisla-
S. Lonowski
Department of Medicine, Division of Dermatology,
David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA
e-mail: slonowski@mednet.ucla.edu
N. Patel
David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA
e-mail: niralipatel@mednet.ucla.edu
N. Cyrus
Division of Dermatology, Kaiser Permanente Orange
County, Irvine, CA, USA
P. S. Yamauchi (*)
Department of Medicine, Division of Dermatology,
David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA
David Geffen School of Medicine, University of
California Los Angeles, Los Angeles, CA, USA
Dermatology Institute & Skin Care Center, Inc.,
Clinical Science Institute, Santa Monica, CA, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_22
tive, regulatory, and scientific framework for
the development and approval of biosimilars.
We also review the current state of the biosimilars market as it relates to psoriasis, and
examine current barriers to widespread utilization of biosimilar agents in clinical
practice.
Key Learning Objectives
1. To understand the development pathway for biosimilars
2. To understand the approval process for
biosimilars
3. To review the use of biosimilars for
process
Background
Biologics are highly complex pharmaceutical agents isolated or synthesized from natural
sources. These may take the form of antibodies,
recombinant proteins, vaccines, blood, and plasma
products [1–3]. Biologics are distinguished from
chemically-synthesized drugs by their much larger
size (100–1000×) and complex molecular structures [4]. Biologics have revolutionized the treatment of numerous dermatologic diseases, chronic
inflammatory diseases, and certain malignancies.
Biologics are the fastest-­growing segment of the
279
S. Lonowski et al.
280
Table 22.1 Available patent expiration dates for psoriasis biologics in the US and EU [2, 6]
Brand name
Humira
Remicade
Stelara
Cimzia
Enbrel
Cosentyx
Taltz
Generic name
Adalimumab
Infliximab
Ustekinumab
Certolizumab
Etanercept
Secukinumab
Ixekizumab
Expiration year (US)
2016
2018
2023
2024
2028
2028
2036
pharmaceutical industry, accounting for 22% of
the drugs approved by the United States Food
and Drug Administration (FDA) between 2008
and 2017 [5]. Within the field of dermatology, the
wave of biologics has undoubtedly had the greatest impact on the treatment of psoriasis, with 11
biologic agents currently FDA-approved for this
indication and 5 new agents since 2017.
As many biologics reach the end of their
patent protection (Table 22.1), there has been
growing interest in the development of biosimilar agents [7]. Biosimilars are reproductions of
biologics which are highly similar to the original
biologic agent (called the reference product) in
terms of structure, mechanism of action, safety,
and efficacy and must be given in the same form
and dosage as the reference product [2, 8–10].
The FDA defines a biosimilar as a biologic product that is “highly similar to a US licensed reference biological product notwithstanding minor
differences in clinically inactive components,
and for which there are no clinically meaningful differences between the biological product
and the reference product in terms of the safety,
purity, and potency of the product” [11]. The
European Medicines Agency (EMA) defines a
biosimilar as “a biological medicinal product that
contains a version of the active substance of an
already authorized original biological medicinal
product” [10].
While the therapeutic benefit of biologics has
been dramatic, the development of these complex agents has been accompanied by significant
increases in healthcare costs. Biologics are expensive, with an average cost of $10,000–30,000 per
year [12]. Biologics accounted for nearly a quarter (24%) of worldwide pharmaceutical spending
in 2015 and 40% of drug spending in the United
Expiration year (EU)
2018
2015
2024
2021
2015
2030
Unavailable
States (US) in 2017 [3]. Tumor necrosis factoralpha inhibitors adalimumab, etanercept, and infliximab were 3 of the top 5 most expensive drugs
in terms of overall expenditures in 2016 [13]. The
economic burden of psoriasis alone in the US is
substantial, with estimates ranging from $35.2 to
$112 billion [14, 15].
The Biologics Price Competition and
Innovation Act (BCPI) of 2009 was approved as
part of the Patient Protection and Affordable Care
Act and provided a legislative framework for an
abbreviated process for the approval of biosimilars. The stated goal of the BPCI was to improve
patient access to biologic therapies by decreasing
costs [2]. In addition to lowering drug development costs, the BCPI was expected to lead to
increased competition among manufacturers [16].
The BPCI enabled the FDA to approve biosimilar
medications following a review of the “totality of
evidence” from extensive analytical, nonclinical,
and clinical studies for these agents [4, 11, 17].
The first biosimilar agent was not approved in
the US until 2015, however the speed of development has increased dramatically in the past few
years. As of June 27, 2019 there are 21 biosimilars approved by the FDA, though not all of these
are commercially available [18]. The potential
for future growth is substantial, with over 1000
agents currently in the biosimilar pipeline [19].
The global biosimilars market size is expected to
reach a value of USD $61.47 billion by 2025 [20].
Generics Versus Biosimilars
While conceptually similar to generic small molecule medications, biosimilars differ from generics in several important ways. Generic drugs are,
22
Biosimilars for Psoriasis
by definition, identical to their brand name equivalents, whereas biosimilars are not exact copies
of their reference products [17]. Biosimilars
are much larger products and have complex,
dynamic structures that are highly vulnerable to
alterations in the manufacturing process. Even
slight changes in temperature, purification, and
storage can lead to chemical modifications, such
as misfolding or glycosylation, which affect the
ultimate form and potentially the functionality
of the drug [3, 17, 21]. For this reason, biologics cannot be exactly reproduced. Biosimilars are
therefore considered “unique but related” to their
reference product [22]. It is important to note that
manufacturing of reference biologic products is
also intricate, and changes in manufacturing processes, handling, and storage have the potential
to cause slight modifications in the end-product,
a phenomenon known as batch variability [23].
Biosimilars take longer and are more expensive to produce than generics. Biosimilars take on
average 5–10 years and cost $100–250 million to
develop, compared with 2 years and $1–10 million for most generics [3]. Another important
distinction between generics and biosimilars
is the potential for immunogenicity. Biologics,
and therefore biosimilars, have the potential to
elicit an immune response resulting in the production of anti-drug antibodies. Therefore, the
development of biosimilars requires a thorough
assessment of immunogenic potential and immunologic adverse events, which is not required for
generic agents [24].
Naming of Biosimilars
In January 2017 the FDA released guidelines
which require a four-letter suffix to be appended
to the original nonproprietary biologic name. For
instance, Amjevita, a biosimilar to adalimumab,
is designated as adalimumab-atto. The stated
purpose of the guideline is to prevent confusion
between products and to facilitate ongoing pharmacovigilance monitoring [25].
FDA requires that biosimilar package inserts
contain the same information as the reference
biologic regarding safety and efficacy, in a man-
281
ner similar to the labeling of generic medications [2]. Notably, these labels may not include
information on clinical data demonstrating no
clinically meaningful differences between the
biosimilar and its reference product [2, 17].
Development of Biosimilars
The process of biosimilar development centers
on reproduction of the essential aspects of the
reference product following a thorough examination of its structure and function. Biosimilar
manufacturers must first study the reference
product based on publicly available information,
then use “reverse engineering” to independently
design a process that will reproduce a highly
similar biological agent [3, 4]. Because of the
large and dynamic structure of these agents, the
goal of this undertaking is not to create an exact
copy of the originator biologic, but to create a
bioequivalent product, with only minor variations in clinically insignificant components of
the structure. Initially, detailed characterization
studies are performed in order to identify the
critical quality attributes (CQAs) of the reference biologic agent [11]. These CQAs determine
the biologic function and therefore the resulting
clinical effect [11]. Once a biosimilar manufacturer has produced a product that is highly similar to the reference product in terms of structure,
mechanism of action, and CQAs, the product can
undergo approval through appropriate regulatory
bodies.
Approval Process
The approval process for biosimilars focuses on
establishing biosimilarity between the proposed
product and the reference biologic agent rather
than demonstrating independent safety and efficacy, as is the case for most novel pharmaceutical
agents. The manufacturer of the biosimilar product submits comparative data to the reference
agent, which is subsequently analyzed by the
regulatory bodies to determine whether the proposed product will be approved as a biosimilar.
S. Lonowski et al.
282
Characterization
studies
Nonclinical
studies
(Animal)
Clinical
pharmacologic
studies
• Analysis of structure
and function
• Animal PK, PD, and
toxicity profile
• Pharmacokinetic (PK)
assays
• Pharmacodynamic
(PD) assays
• Immunogenicity
assessment
Comparative
clinical study
• Confirmatory safety
and efficacy studies
• Phase III clinical trial
for at least one
specific indication
Fig. 22.1 Totality of evidence approach in approval of biosimilars by regulatory agencies
The FDA has an abbreviated pathway for the
approval of biosimilars which was established
through the BCPI in 2009 [26]. Initially, manufacturers submit a biologics license application.
In this 351(k) application, the biosimilar is tested
across an array of different analytical assays,
which must demonstrate by standard criteria that
the activity of the new product is equivalent to
the original agent, utilizes the same mechanism
of action for the proposed condition(s) of use,
and has the same route of administration, dosage
form, and strength [26]. In addition, they must
present data showing absence of clinically meaningful differences.
The approval of biosimilars through the
FDA and the EMA uses a “totality of evidence”
approach. This involves a stepwise investigational
process which includes analytical studies, animal studies, clinical pharmacokinetic (PK) and
pharmacodynamic (PD) studies, i­mmunogenicity
assessments, and, in some cases, additional clinical
studies (Fig. 22.1) [11].
Analysis of Structure and Function
First, comparative analytical characterization of
the structure and function of the biosimilar is
performed in order to demonstrate that the biological product is “highly similar” to the reference agent. Structural analyses ensure that the
biosimilar encodes the same primary amino acid
sequence as the original biologic agent [1]. The
primary structure of the protein, its arrangement,
size variants, level of glycosylation, and molecular charge are evaluated to characterize the quality
attributes of the proposed biosimilar and to ­identify
any potential differences that could impact clinical performance [27]. Minor differences in areas
of the compound that are not clinically active,
such as N- or C- terminal truncations, are
acceptable [1].
Next, functional assays are performed to assess
the pharmacologic activity of the biosimilar. In
vitro functional assays must demonstrate similarity between the biosimilar and the reference
product in terms of mechanism of action, receptor
binding, effector cell response, chemokine production, cytotoxicity, and other measures [8]. In
other words, these studies must prove the biosimilar replicates the effect of the originator product.
Nonclinical (Animal) Studies
In vivo (i.e. animal) studies are not required for
biosimilar approval, but may be undertaken in
some instances. Animal studies can provide more
data in support of biosimilarity; in particular,
animal toxicity studies may be utilized to demonstrate a similar safety profile compared to the
reference product. Animal studies may be considered unnecessary if available structural and
functional data already strongly support a high
degree of similarity between the biosimilar and
the originator biologic [2].
Clinical Studies
After completion of the analytical/functional and
nonclinical studies, clinical pharmacologic studies
are designed as the ultimate comparative assessment to establish bioequivalence. These studies
22
Biosimilars for Psoriasis
are typically conducted in healthy subjects, and
must be statistically powered to determine differences between the biosimilar agent and the reference product. The purpose of pharmacokinetic
(PK) assays is to determine how the human body
affects the drug in terms of absorption, distribution,
metabolism, and elimination [7]. Phase I human
PK studies are required for all biosimilar candidates, and must demonstrate pharmacologic bioequivalence in certain parameters such as serum
concentration of drug over time [17]. Human
pharmacodynamic (PD) studies are not always
required, but may be conducted to supplement
PK data. For a human or humanized monoclonal
antibody drug it can be difficult to determine how
much of the drug is present in the serum at any
given time. Through an assessment of the PK and
PD data available for the biosimilar and the reference product, exposure response profiles can be
compared.
Clinical immunogenicity assessments are also
undertaken to evaluate for any differences in
the incidence and severity of immune responses
between the reference product and the biosimilar.
Such studies are important because alterations
in immune response elicited by the biosimilar
agent may promote the development of anti-drug
antibodies and/or lead to acute clinical responses
such as anaphylaxis [11, 17]. At least one clinical study comparing the immunogenicity of the
proposed biosimilar to the reference product
is required by the FDA [11]. The formation of
anti-­drug antibodies is compared through titer
changes, time to development of antibodies, and
impact on pharmacokinetics [27].
Following PK, PD, and immunogenicity studies, biosimilar candidates must undergo at least
one phase III clinical trial for a specific indication
per FDA guidelines. Typically designed as an
equivalence trial, the objective is not to establish
efficacy of the biosimilar agent per se but rather
to demonstrate non-inferiority to its reference
product in terms of efficacy and safety [2, 11].
The biosimilar sponsor may choose which indication is tested.
Importantly, biosimilar agents may eventually
be approved for non-tested indications based on
the concept of extrapolation. Extrapolation refers
283
to the approval of a given biosimilar medication for additional clinical indications, outside
of those tested in a clinical trial. According to
the FDA, this is allowable if there is “sufficient
scientific justification for extrapolating clinical
data to support a determination of biosimilarity
for each condition of use for which licensure is
sought” [11]. For example the biosimilar Inflectra
(infliximab-dyyb) underwent clinical trials in
patients with rheumatoid arthritis and ankylosing
spondylitis, but has now been FDA-approved for
all the same indications as the reference product,
including plaque psoriasis and psoriatic arthritis
[28, 29]. In fact, all infliximab and some adalimumab and etanercept biosimilars were approved
for psoriasis via extrapolation [4].
Manufacturers must provide justification
for extrapolation via explanation of the drug’s
mechanism of action, pharmacokinetics, biodistribution, and immunogenicity [24]. Biosimilars
may not be approved for indications that are protected by regulatory exclusivity, such as adalimumab’s exclusive indication for adults with
moderate to severe hidradenitis suppurativa [2,
24]. Extrapolation decreases biosimilar development costs by decreasing the extent of clinical
trials that must be performed. However, the lack
of clear clinical trial data may be a point of hesitation for some clinicians considering prescribing
biosimilars for extrapolated indications.
Pharmacovigilance Studies
The clinical studies required for FDA approval
are of limited duration and are conducted in a
limited population, and therefore may not identify all potential adverse effects. Post-approval
safety monitoring is recommended by the WHO,
FDA, and the EMA, but the specific requirements for this monitoring varies by agency [4].
The EMA requires pharmacovigilance plans
as part of the initial biosimilar approval process, however the FDA does not [30]. The FDA
instead recommends that manufacturers “consult
with appropriate FDA divisions to discuss the
sponsor’s proposed approach to post-marketing
safety monitoring” on a case-by-case basis [11].
S. Lonowski et al.
284
In response to concerns regarding lack of safety
data, the International Psoriasis Council has
suggested the establishment of registries of all
patients treated with biosimilars to enable monitoring of adverse treatment events over time [25].
biosimilar does not have any impact on safety,
immunogenicity, or effectiveness.
A biosimilar with an interchangeable designation may be substituted for an originator biologic
without active intervention (such as a change in
prescription) by a prescribing provider, though
individual state substitution laws will impact this
practice [33]. In some states, a product that is
designated as interchangeable may be exchanged
for the reference product by a pharmacist without
notifying the ordering physician [33]. The NPF
has issued a position statement on interchangeable biosimilar substitution, detailing the minimum requirements that should be met in order
for biosimilar substitution to occur [34].
At the time of this publication there are no
FDA-approved interchangeable biosimilars in
the US. This may not be true for long, however.
Boehringer Ingelheim is currently pursuing an
interchangeability designation for BI 695501, its
adalimumab biosimilar [35]. It is likely that other
pharmaceutical companies will follow suit in the
coming months and years as the market continues
to grow and additional agents obtain regulatory
approval (Fig. 22.2).
Interchangeability
Biosimilars can obtain a special classification as
an “interchangeable biosimilar” through an additional approval process by the FDA, which was
finalized in May 2019 [31]. Interchangeability is
a specific designation given to biosimilars that are
expected to achieve the same clinical outcome as
the biologic product in any given patient, without any change in the safety or efficacy profile
between the new product and original agent [32].
The approval process for these agents requires
additional information from the manufacturer
to ensure that the biologic agent can be effectively deemed interchangeable. Importantly, the
application for interchangeability must include
“switching studies,” which demonstrate that
switching between the reference product and the
Biologic manufacturer
Payment for
product
Payment for
product
Drug wholesaler
Dispensing pharmacy
Drug
ent
m
burse
Formulary
rebate
r
Presc
reim
iption
Payer reimbursement
Pharmacy benefits
manager (PBM)
Drug
Payer/
Health Plan
Insurance premiums
% Pass through of rebate
Legend
Payments andProduct
cash flow
Premium payment
Patient
Employer
Fig. 22.2 US Pharmaceutical Distribution and Reimbursement System (for self-administered drugs)—simple
version [36]
22
Biosimilars for Psoriasis
285
Of note, several interchangeable biosimilars
have been approved outside the US. Other countries have been studying the interchangeability
of biosimilars in their respective markets. The
NOR-SWITCH study was a randomized controlled study initiated by the Norwegian government to study the safety and viability of switching
and interchanging infliximab and its biosimilar
agents in several diseases including psoriasis,
RA, spondyloarthritis, psoriatic arthritis, ulcerative colitis, and Crohn’s disease [37]. The study
found that there were no differences or clinical worsening in any of these conditions when
patients were switched between original products
and their biosimilars. They also found no difference in the development of anti-drug antibodies [37]. Additional studies regarding multiple
switch designs, including VOLTAIRE-X, will
provide additional information about the effect
of switching between biosimilars and innovator
products [38].
Biosimilars in Dermatology
Current FDA-approved biosimilars for the treatment of moderate to severe psoriasis are shown
in Table 22.2. Amjevita (adalimumab-atto),
Cyltezo (adalimumab-adbm), and Hyrimoz
(adalimumab-­adaz) are biosimilar medicines to
Table 22.2 Currently approved biosimilars for psoriasis
[18]
Brand
name
Erelzi
Eticovo
Amjevita
Cyltezo
Hyrimoz
Inflectra
Renflexis
Ixifi
Generic name
Etanercept-­szzs
Etanercept-­ykro
Adalimumab-­
atto
Adalimumab-­
adbm
Adalimumab-­
adaz
Infliximab-­dyyb
Infliximab-­abda
Infliximab-­qbtx
Phase III
trial for
FDA
approval date psoriasis
August
Yes
2016
April 2019
No
September
Yes
2016
August
No
2017
October
Yes
2018
April 2016
No
April 2017
No
No
December
2017
adalimumab. Erelzi (etanercept-szzs) and Eticovo
(Etanercept-­
ykro) are biosimilar medicines to
etanercept. Inflectra (infliximab-dyyb), Renflexis
(infliximab-­abda), and Ixifi (infliximab-qbtx) are
biosimilar medicines to infliximab. While these
biologic agents have all been approved for use
in patients with moderate to severe psoriasis,
only three (Amjevita, Erelzi, and Hyrimoz) have
undergone clinical trials specifically for the indication of psoriasis [4]. The remaining biosimilars
were approved via extrapolation.
There are several other biosimilars in phase
III clinical trials for the treatment of moderate
to severe plaque psoriasis. These include BCD457, CHS-1420, GP2017, M923, MSB11022,
and Myl-1401A, which are all biosimilars of
adalimumab. Biosimilars of etanercept ONS3010 and CHS-0214 are also undergoing clinical
trials for psoriasis [4]. There are also several biosimilars currently being studied for rheumatoid
arthritis that may be approved for psoriasis via
extrapolation if approved by the regulatory agencies their respective countries. These include
FKB327 and LBALM (adalimumab biosimilars), PF-06410293 and LBEC0101 (etanercept biosimilars), and ABP 710, BCD-055, and
N1-071 (infliximab biosimilars), all currently in
phase III clinical trials [4].
Data regarding biosimilar use among dermatologists in the United States is limited, due to
multiple factors including limited access to biosimilars in the current market and prescriber unfamiliarity with these medications [38]. Biosimilars
are more widely used in Europe resulting in
accumulation of significant data supporting the
use of biosimilars for psoriasis. A 10-year study
from Danish registries, for example, found no
significant differences in safety or drug survival
between reference and biosimilar versions of
etanercept and infliximab [39]. In some European
countries, national legislation has influenced the
use of biosimilars as part of efforts to decrease
costs and increase the availability of these drugs.
In May 2015, for instance, Denmark instituted
a national policy that patients should be started
on or switched to the cheapest version of a given
biologic (i.e. the biosimilar version) [39].
S. Lonowski et al.
286
Economic Advantage of Biosimilars
In general, cost savings with biosimilars are less
than those seen with generic small molecule
agents. While cost reductions associated with
small molecule generics can be 80% or higher,
estimated biosimilar acquisition cost savings in
the US have ranged from 10 to 40% [5, 40–43].
According to a 2017 estimate, the average cost for
an 8-week supply of an infliximab biosimilar was
18% less than its reference product [5]. Outside
the US, cost savings on biosimilars are variable,
ranging from as high as 70% in Norway (due to
discounted government pricing) to 30% in India
[25]. Europe has approved 23 biosimilars, with an
average price reduction of 20–30% [40].
While estimated US cost savings may seem
modest, they remain significant when viewed in
the context of the overall market size for biologic
agents. In 2014, the Rand Corporation estimated
a direct cost savings potential of $44.2 billion
between 2014 and 2024, accounting for about
4% of total biologic spending over that period
[17, 44]. As the biosimilar market expands, competition grows, and regulatory changes allow for
streamlining of the developmental process for
biosimilars, greater cost decreases may be seen.
arriers to Use and Future
B
Directions
Despite the passage of the BCPI nearly a decade
ago, market uptake of biosimilars in the US has
been slow. Reports from 2017 indicated that less
than 10% of total biologic spending ($11.5 billion) was subject to competition from biosimilars [45]. There are several factors at play which
­continue to limit access to and acceptance of biosimilars, some of which will be reviewed here.
atent Disputes and Extended
P
Patents for Branded Drugs
As of July 2019, 20 biosimilars have received
FDA approval but only 7 are commercially
­available [46]. Most have been withheld from the
market due to ongoing patent disputes between
the reference product manufacturer and the biosimilar manufacturer [12]. Additionally, while
many original drug patents for biologics are
approaching their expiration dates, some have
additional patents related to manufacturing processes which provide ongoing protection; for
example two additional patents for etanercept
(Enbrel) can extend patent protection until 2029
[3, 21]. In many instances, patent litigation has
had the effect of postponing market entry for
biosimilar products. Recent litigation settlements
involving Amgen and Sandoz, for instance, have
resulted in delayed introduction of adalimumab
biosimilars until 2023 [5].
Prescriber Considerations
Physician awareness and comfort level with prescribing biosimilars is another barrier to widespread use of these medications. Incomplete
understanding of what biosimilars are, apprehension about the significance of “minor differences”
between reference products and biosimilars, and
lack of long-term safety data are factors that may
limit physician willingness to prescribe biosimilars. According to a recent online survey of US
dermatologists, only 25% stated they “will definitely or are highly likely to prescribe biosimilars” [47]. Frequently cited concerns included
safety (66%), efficacy (71%), immunogenicity (63%) and the potential for patients to be
switched from a biologic to a biosimilar without
clinician awareness [47]. Since no biosimilars
have yet been given an interchangeable designation in the US, some clinicians remain wary of
the potential for adverse immunologic effects if
patients switch between originator biologics and
biosimilars. It is worthy of note, however, that
switching studies completed to date suggest that
immunologic risk is low [5, 48] (Fig. 22.3).
Prescriber acceptance of biosimilars hinges on
knowledge and comfort level with these agents.
A 2017 cross-sectional survey of dermatologists
found that physicians who were “fairly to very
22
Biosimilars for Psoriasis
287
familiar” with biosimilars were more comfortable prescribing biosimilars for psoriasis, even
if they had not been clinically studied for this
­indication [49].
Patient Factors
While the economic benefits of biosimilars are
easy to appreciate from a systems level perspective, this benefit may not be immediately apparent to the end user, i.e. the patient. The decreased
acquisition cost of a biosimilar is most relevant to
patients who have high deductible plans or who
have co-insurance plans with expenses calculated
as a percentage of a given drug’s list price [24].
Patients with fixed copays are not incentivized
to seek out medications with a lower acquisition cost, since this cost is not directly passed on
to them. In fact, such patients may be likely to
prefer brand name reference products over biosimilars in these instances, given greater name
recognition and overall familiarity.
Patient
Employer
Insurance Coverage
Premium
Payment
Dispenses
Prescriptions
Coinsurance
Contracts and Services
Medication Purchase
(Contracted Price)
In summary, biosimilars are a rapidly growing
sector of the pharmaceutical industry, both in
the US and globally. Despite the slow adoption
of biosimilars in the US to date, there is potential
for greater use of biosimilars in the future; the
adoption of generic agents in the United States
was similarly slow, but now generics account
for the vast majority of prescribed medications
[50]. At present, legal, regulatory, and financial constructs, lack of commercial availability,
and low provider comfort level with the use of
these agents remain barriers to large-scale adoption of biosimilars. Numerous biosimilar agents
are currently in the pipeline as multiple commonly prescribed biologics are approaching
their patent expiration dates. In the future, as
utilization of these novel agents becomes more
widespread, biosimilars have the potential to
decrease healthcare costs globally and increase
patient access to additional valuable diseasemodifying therapies.
Premium Payment
Legend
Payments and Cash Flow
Conclusion
Prescription Reimbursement
(Contracted Rate)
Dispensing
Pharmacy
Health Plan/
Medical Benefit
Network Agreement
Wholesale Agreement
Prescription
Benefit
Pharmacy
Benefit Manager
(PBM)
Pharmaceutical
Wholesaler
Management Fees
Distribution Agreement
Medication Purchase
(Contracted Price)
Rebate
Pharmaceutical
Manufacturer
Formulary Placement
Fig. 22.3 US Pharmaceutical Distribution and Reimbursement System (for self-administered drugs)—complex
­version [36]
Research Pipeline I: Oral
Therapeutics for Psoriasis
23
D. Grand, K. Navrazhina, J. W. Frew,
and J. E. Hawkes
Abstract
Over the last two decades, tremendous
advances have been made in the treatment of
psoriatic disease. Our understanding of the
complex immunopathogenesis of this chronic
inflammatory condition has led to the development of highly effective, safe, targeted
monoclonal antibodies that result in clearance
in the vast majority of treated patients.
However, these recently approved therapies
have multiple drawbacks and limitations that
necessitate the development and testing of
additional treatment modalities. To address
this need, scientists and the pharmaceutical
industry have pursued the identification and
testing of several oral small molecules as
novel treatments for plaque and psoriatic arthritis. These molecules in testing include JAK/
TYK2 inhibitors, phosphodiesterase inhibitors,
RORγt inhibitors, fumarate esters, sphingosine
1 phosphate antagonists, neurokinin-­1 receptor
D. Grand · K. Navrazhina · J. W. Frew
Laboratory for Investigative Dermatology,
The Rockefeller University, New York, NY, USA
e-mail: dgrand@rockefeller.edu;
knavrazhin@rockefeller.edu; jfrew@rockefeller.edu
J. E. Hawkes (*)
Laboratory for Investigative Dermatology,
The Rockefeller University, New York, NY, USA
Department of Dermatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: jhawkes@rockefeller.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_23
antagonists, adenosine A3 receptor agonists,
H4 receptor antagonists, PRINS inhibitors,
and spleen tyrosine kinase inhibitors.
Key Learning Objectives
1. To understand the mechanism of action
of novel oral agents in development for
the treatment of psoriasis
2. To understand the appropriate use and
efficacy of novel oral agents in development for the treatment of psoriasis
3. To understand the safety issues and
appropriate monitoring of novel oral
agents in development for the treatment
of psoriasis
Introduction
Psoriasis is chronic inflammatory skin disease with a complex etiology. Current research
demonstrates that interleukin-23 (IL-23) and
IL-17-­producing T (T17) cells are central to the
pathogenesis of this condition [1]. The effectiveness of current anti-psoriatic therapies is largely
correlated with the ability of the treatment to disrupt the dysregulated IL-23/T17 signaling axis
in the skin. With the recent approval of multiple
selective monoclonal antibodies against IL-23
291
D. Grand et al.
292
Table 23.1 List of novel therapies currently in clinical trials for the treatment of psoriasis
Drug name
Baricitinib
Upadacitinib
Drug class
JAK1/2 inhibitor
JAK1 inhibitor
Phase
2b
3
Company
Eli Lilly
AbbVie
Filgotinib
JAK1 inhibitor
2
Galapagos
ASP015K
BMS-986165
JAK3 inhibitor
Tyk2 inhibitor
2
3
Janssen
BMS
LEO32731
PDE4 inhibitor
2
LEO
VTP-43742
RORγt inhibitor
2
Vitae Pharma
LAS41008
Dimethyl fumarate
3
Almirall
FP187
Fumaric acid
2/3
Forward Pharma
XP23829
Ponesimod
(ACT-128800)
Amiselimod
(MT-1303)
Serlopitant
(VPD-737)
CF101
Fumaric acid
S1P receptor antagonist
2
2
Xenoport
Actelion
S1P receptor antagonist
2
Mitsubishi Tanabe Pharma
Clinical trials
NCT01490632
NCT03104374
NCT03104400
NCT03320876
NCT03101670
NCT03926195
NCT01096862
NCT04036435
NCT03624127
NCT02888236
NCT03231124
NCT03724292
NCT02555709
NCT02955693
NCT01726933
NCT01230138
NCT01815723
NCT02475304
NCT02173301
NCT01208090
NCT00852670
NCT01987843
Neurokinin-1 receptor
antagonist
Adenosine A3 receptor
agonist
H4 receptor antagonist
IL-20 and PRINS inhibitor
3
Menlo Therapeutics
NCT03343639
3
Can-Fite Biopharma
NCT03168256
2
2
Ziarco Pharma
CellCeutix
NCT02618616
NCT02101216
NCT02494479
NCT02949388
ZPL-389
Prurisol
and IL-17, we are witnessing unprecedented
advances in the treatment of patients with psoriasis. Nevertheless, monoclonal antibodies
have limitations including their high cost, insurance accessibility, loss of efficacy over time
potentially due to anti-drug antibodies, and the
need for intravenous or subcutaneous administration. The potential advantage of novel oral
small molecules for the treatment of psoriasis
include a decreased cost, avoidance of proteinrelated immune mechanisms leading to loss of
efficacy with time, and ease of administration.
Accordingly, many companies are testing the
efficacy of a variety of small molecules for the
potential treatment of plaque and psoriatic psoriasis. The purpose of this chapter is to provide an
overview of the research pipeline for novel, oral
therapeutics being studied for the potential treatment of psoriatic disease (Table 23.1).
JAK Inhibitors
The Janus kinase (JAK) family is composed of
four tyrosine kinases (JAK1, JAK2, JAK3, and
TYK2) that have essential roles as signal transducers downstream of activated cytokine receptors. In contrast to c-KIT and insulin, cytokine
receptors lack intrinsic protein kinase domains
and, therefore, rely upon constitutively active JAK
tyrosine kinases (TYK) to convey immune signals [2]. Following JAK activation, one of the six
STAT family members are consequently activated
(STAT1–6) leading to its function as a transcrip-
23 Research Pipeline I: Oral Therapeutics for Psoriasis
H4 Receptor
Pathway
SYK
Pathway
293
GPCR Pathway
(S1P, A3AR, NK1)
NF-kB
Pathway
JAK-STAT
Pathway
CF101
ponesimod
amiselimod
ZPL-399
JAK/
TYK2
SYK
cAMP
fostamatinib
apremilast
LEO32731
Protein
Kinase A
baricitinib
upadacitinib
filgotinib
ASP015k
BMS-986165
MyD88
Protein
Kinase C
NF-kB
JNK/ERK
MEK/ERK
STAT
LAS41008
FP187
XP23829
CYTOPLASM
VTP-43742
RORy
abacavir hydroxyacetate
NUCLEUS
PRINS
Fig. 23.1 Schematic of a T lymphocyte and the proposed mechanisms of action for several small molecules being
tested in clinical trials for the treatment of psoriatic disease
tion factor. Significant overlap between the various
JAK and STAT isoforms have been demonstrated
in mouse knockout models, thus highlighting the
need to carefully study the impact of combination
versus more selective JAK blockade [3].
Novel small molecules target one or more
JAK isoforms (Fig. 23.1). JAK1 and JAK2 are
involved in interferon-gamma signaling, whereas
JAK3 is involved in signaling from type I cytokine receptors that use the common gamma chain
(γc) including IL-2, IL-4, IL-7, IL-9, IL-15 and
IL-21 [4, 5]. Although the JAK-STAT pathway
does not directly suppress IL-17, it works indirectly through other STAT-dependent cytokines
acting upstream (e.g. IL-23) [6, 7]. Novel therapies targeting the JAK-STAT pathway must balance suppression of pro-inflammatory signaling
versus the over-suppression and disruption of
vital developmental functions, such as neuronal
development, protection against infections, and
hematopoiesis [8].
Some of the differences between JAK isoforms can be inferred from the effects observed
in individuals living with JAK deficiencies as
294
D. Grand et al.
well as the clinical results from human studies. [13, 14]. SELECT-PsA 1 is an active phase III
JAK3 deficiency (severe combined immunodefi- study with 640 participants who have had an
ciency or SCID) is associated with decreased T inadequate response to at least one non-biologic
and NK cell numbers, but unaffected B cells [9]. disease-modifying anti-rheumatic medication
TYK2 deficiency is associated with susceptibility (e.g. methotrexate). SELECT-PsA 2 is currently
to viral, fungal, and mycobacterial infection [10]. recruiting participants who have had an inadActivating somatic mutations in JAK1, JAK2, equate response to at least one biologic disease-­
and JAK3 have also been identified in myelopro- modifying anti-rheumatic drug with estimated
liferative disease, leukemia, and lymphoma [11] enrollment of 1640 participants. Both trials
raising the concern for a potential increase in wills compare two daily doses of upadacitinib
malignancy risk with long-term treatment.
versus placebo and adalimumab and will meaIn May 2012, the FDA approved tofacitinib, an sure ACR20 at week 12 as the primary endpoint
oral pan-JAK inhibitor, for the treatment of rheu- [13, 14]. No clinical trials testing this compound
matoid arthritis. This was the first approval of a for the treatment of plaque psoriasis have been
medication in this specific drug class. Subsequent reported.
FDA approval of tofacitinib for the treatment of
The EQUATOR trial evaluated the efficacy
psoriatic arthritis occurred in December 2017. and safety of JAK1-selective inhibitor, filgotinib,
Other first-generation JAK Inhibitors include in patients with psoriatic arthritis [15]. 131 subruxolitinib, baricitinib, and oclacitinib.
jects were randomly assigned to daily filgotinib
A phase 2b trial for a JAK1/2-selective inhibi- 200 mg versus placebo. 80% of the filgotinib
tor, baricitinib, randomized 271 participants to group achieved ACR20 at week 16 compared to
placebo and four daily doses of baricitinib (2, 4, 33% of the placebo group (P value < 0.0001).
8, or 10 mg) for 12 weeks [12]. Based on treat- A greater percentage of participations in the filment response at week 12, doses were either con- gotinib group achieved PASI75 than the placebo
tinued or increased for the next 12 weeks. 75% group (45.2 vs. 15%, P value = 0.0034). The
improvement in the Psoriasis Area and Severity incidence of adverse events was similar between
Index (PASI75) at week 12 was achieved in filgotinib and placebo with nasopharyngitis
42.9% of the 8 mg group and 54.1% of the and headache being the most common reported
10 mg group. Both proportions were statisti- adverse events [15]. An open-label extension
cally significant compared to the placebo group study is ongoing and will provide long-term data
(17%). Greater than 81% of treatment respond- on filgotinib therapy [16]. No clinical trials testers at week 12 maintained a PASI75 at week ing this compound for the treatment of plaque
24. With dose escalation, 48% of those who had psoriasis have been reported.
not achieved PASI75 at week 12 achieved it by
A phase 2a trial evaluating the efficacy and
week 24. The most common adverse events of the safety of JAK3-selective inhibitor, ASP015K,
placebo and baricitinib groups were infection-­ randomized 124 participants to four twice-daily
related (e.g. nasopharyngitis). Cytopenia was doses (10, 25, 60, or 100 mg) or one daily dose
observed in 4.6% of patients receiving baricitinib (50 mg) versus placebo for 6 weeks [17]. A
compared to 0% in placebo; higher cytopenia greater change in PASI score was observed in a
rates were documented in the 8 and 10 mg treat- dose-dependent manner in those receiving active
ment groups. Rates of drug discontinuation due treatment with ASP015K compared to control
to adverse events was highest in the 8 mg (6.3%) (P value < 0.001). Histological studies of biopand 10 mg (5.8%) treatment groups [12]. Phase sied lesional skin demonstrated active treatment
III clinical trials for baricitinib in the treatment of dose-­
dependent decreases in epidermal thickplaque psoriasis are currently underway.
ness, number of proliferating epidermal cells
There are two ongoing phase 3 trials study- (measured by Ki67 staining), number of dermal
ing the efficacy of a JAK1-selective compound, CD3+ T cells, and number of CD11c+ dendritic
upadacitinib, in participants with psoriatic arthritis cells. A greater percentage of ASP015K subjects
23 Research Pipeline I: Oral Therapeutics for Psoriasis
(46.3%) experienced treatment-related adverse
events compared to the placebo group (37.9%),
but the number of drug-related adverse events
were similar among the two groups. No serious
adverse events were reported [17]. No clinical
trials testing this compound for the treatment of
psoriatic arthritis have been reported.
Tyk2 Inhibitor
BMS-986165 is a selective Tyk2 inhibitor. A
phase 2 trial randomized 267 participants to five
doses of BMS-986165 (3 mg every other day,
3 mg daily, 3 mg twice daily, 6 mg twice daily,
or 12 mg daily) versus placebo for 12 weeks followed by a 30-day follow-up period [18]. PASI75
at 12 weeks was observed in 9, 39, 69, 67, and
75% of the treatment doses, respectively, versus
7% of the placebo group. PASI100 was observed
in 18% of the 6 mg twice daily group and 25%
of the 12 mg daily group compared to 0% of the
placebo group. Treatment effects were evident
as early as day 15 and persisted after the 30-day
follow-up period. Nasopharyngitis, headache,
diarrhea, nausea, and upper respiratory infections
were the most common reported adverse effects.
A greater proportion of patients in the active
treatment group experienced mild-to-moderate
acne, possibly due to a change in the microbiome
in response to the altered cytokine profile following treatment. However, no cases of pathologic
agents such as herpes zoster, tuberculosis, or
opportunistic infections, were documented [18].
Two phase 3 trials (POETYK-PSO-1 and 2)
further testing BMS-986165 are currently underway and recruiting participants for a multicenter
study in subjects with moderate-to-severe plaque
psoriasis [19, 20]. An estimated 600 and 1000
participants will be randomized to BMS-986165
versus apremilast or placebo. The proportion of
patients who achieved a Static Physicians Global
Assessment (sPGA) score of 0/1 and PASI75 at
week 16 of treatment will be the primary measure
of treatment efficacy [19, 20]. No clinical trials
testing this compound for the treatment of psoriatic arthritis have been reported.
295
PDE4 Inhibitors
Phosphodiesterases (PDEs) are comprised of 11
families of molecules responsible for the degradation of cyclic nucleotides on adenosine and
guanine monophosphates (cAMP and cGMP,
respectively). PDE4 is a specific isoform found
to be highly expressed in keratinocytes and
inflammatory leukocytes (T cells, monocytes,
dendritic cells, and neutrophils), as well as brain,
cardiovascular, and smooth muscle tissues [21].
Suppression of PDE4 leads to elevation in cAMP
and activation of protein kinase A (Fig. 23.1),
as well as other downstream mediators such as
Epac1/2. Several PDE4 inhibitors have been
developed based upon the subtypes of PDE4 elevated in the primary tissues involved in specific
inflammatory diseases. In psoriasis and psoriatic
arthritis, PDE4B and PDE4D were identified as
differentially expressed in psoriasis peripheral
blood mononuclear cells. Accordingly, apremilast, which has high specificity for PDE4, was
developed as an oral therapy for the treatment
of psoriasis and psoriatic arthritis [22, 23]. The
downstream effects of apremilast in psoriasis
include the downregulation of interferon-γ and
TNF-α with resultant Th17 pathway suppression
and skin clearance [24]. Apremilast was approved
by the FDA for the treatment of moderate-to-­
severe plaque psoriasis in September 2014. It
is also approved for the treatment of psoriatic
arthritis and Behcet’s disease.
Since the FDA’s approval of apremilast,
another PDE4 inhibitor, LEO32731, is currently
being studied in human trials. A phase 2 single-­
center study of 36 participants with moderateto-­severe psoriasis compared twice-daily 30 mg
LEO32731 to placebo. Endpoints included PASI
score and the Itch Numeric Rating Scale score
between baseline and week 16 of treatment. The
study was completed in June 2017, but results
have not yet been published [25]. No clinical
trials testing this compound for the treatment of
psoriatic arthritis have been reported. However,
several other topical PDE4 inhibitors are currently under development, including pefcalcitol
and HFP034.
296
RORγt Inhibitors
D. Grand et al.
New oral formulations of fumarates with
greater gastrointestinal tolerability are being
RAR-related orphan receptor gamma t (RORγt developed, including FP187 and XP23829. A
or RORγ2) is a DNA-binding transcription factor dose-ranging phase 2 clinical trial at two study
(Fig. 23.1) expressed in CD4+ T cells leading to locations in Germany investigated the efficacy
for Th17 differentiation. It is essential for IL-17 of FP187 on moderate-to-severe psoriasis [33].
production and is, therefore, an attractive target Participants were randomized to three-times daily
for small molecule inhibition in psoriatic disease FP187 (250 mg), twice-daily FP187 (375 mg),
[26]. Murine models have shown that RORγt twice-daily and FP187 (250 mg) versus plaknockdown suppressed the Th17 response cebo. The primary endpoint was the proportion
induced by intradermal IL-23 injection. IL-17A/ of patients achieving PASI75 at 20 weeks. This
C/F, CCL20, and CCR6 are relevant genes known study was completed in January 2012, but results
to be regulated by RORγt and RORα [27].
have not yet been published [33]. Additional
A phase 1 single ascending dose study ran- phase 2 and 3 clinical trials involving FP187 for
domized 53 healthy volunteers to a single dose of the treatment of psoriatic arthritis and plaque
VTP-43742 (ranging from 30 to 2000 mg) versus psoriasis, respectively, were initiated but subseplacebo [28]. A phase 1 multiple ascending dose quently withdrawn. A multicenter, dose-­ranging,
study randomized 40 healthy volunteers to VTP-­ phase 2 clinical trial randomized plaque psoria43742 (ranging from 100 to 1400 mg/dL) versus sis participants to three XP23829 doses (400 mg
placebo [29]. In both studies, VTP-43742 was daily, 800 mg daily, or 400 mg twice daily) vershown to be safe and well-tolerated at all doses, sus placebo [34]. Efficacy was assessed as the
and ex vivo whole blood assays showed a dose-­ percent change in PASI score at 12 weeks. This
dependent decrease in IL-17A secretion following study was completed in May 2015, but results
treatment. In the multiple ascending dose study, all have not yet been published [34]. No clinical
but the lowest dose resulted in a >90% inhibition of trials testing this compound for the treatment of
RORγt-dependent IL-17A secretion for 24 h [28– psoriatic arthritis have been reported.
30]. No clinical trials testing this compound for the
The BRIDGE trial was a phase 3 noninferiority
treatment of psoriatic arthritis have been reported. trial where participants were randomly assigned
into three groups: LAS41008 (dimethyl fumarate), fumaderm (dimethyl fumarate combined
Fumarate Esters
with monomethyl fumarate salts), or placebo
[35]. Doses of each were escalated based upon
Oral fumarates are a longstanding treatment clinical response with a maximum daily dimethyl
for moderate-to-severe psoriasis, particularly fumarate dose limited to 720 mg. 37.5% of subin Europe. However, the exact mechanism of jects receiving LAS41008 at week 16 achieved
action by which this class of drugs act is incom- PASI75 making it superior to placebo (15.3%,
pletely understood. The esters of fumaric acid, p < 0.001) and noninferior to fumaderm (40.3%,
monomethyl fumarate and dimethyl fumarate, p < 0.001). LAS41008 demonstrated superiorare the active fumarates responsible for the anti-­ ity to placebo upon assessment with sPGA 0/1
inflammatory properties of this therapeutic class at week 16 (33 vs. 13%, p < 0.001). Rebound
[31]. Multiple mechanisms of action have been was observed in 1.1% of LAS41008 subjects at
proposed, including lowering glutathione levels, 2 months off treatment compared to 9.3% of plaactivation of Nrf2 antioxidant pathways, inhibi- cebo subjects. Lymphopenia is a known adverse
tion of NF-κB activity (Fig. 23.1), shifting Th1/ effect of dimethyl fumarate-­
containing comTh17 to a Th2 dominant phenotype, binding of pounds. In this study, lymphocyte counts lower
monomethyl fumarate to GPR109A (implicated than 0.7 × 109 cells/L were observed in a greater
in the flushing response of patients on fuma- percentage of LAS41008 (7.9%) and fumaderm
rates), and modulation of hypoxia inducible fac- (7.4%) subjects compared to placebo (0.7%).
tor and JAK-STAT signaling pathways [32].
However, the lymphopenia resolved upon treatment
23 Research Pipeline I: Oral Therapeutics for Psoriasis
discontinuation. Most adverse effects were mild
in severity and included gastrointestinal disorders
and flushing [35]. No clinical trials testing this
compound for the treatment of psoriatic arthritis
have been reported.
297
ease, ­
macular degeneration, ulcerative colitis,
pyoderma gangrenosum, and uveitis. Two S1P
modulators, amiselimod and ponesimod, have
undergone Phase 2 trials for chronic plaque psoriasis. A phase 2a study of ponesimod randomized
66 participants with moderate-to-severe chronic
plaque psoriasis to either ponesimod 20 mg daily
S1P Receptor Antagonists
or placebo [40]. The primary endpoint was percentage change in PASI score at week 6. Results
Sphingosine 1 phosphate (S1P) is a bioac- have not yet been published. In 2012, a phase 2
tive lipid molecule first identified as a stimula- trial randomized 326 participants to two daily
tor of fibroblast proliferation. It was originally doses of ponesimod (20 or 40 mg) versus pladescribed as an intracellular second messenger of cebo [41]. A greater proportion of participants in
G protein coupled receptors (GPCR) mediating the 20 and 40 mg groups (46 and 48.1%, respecintracellular calcium levels secondary to platelet-­ tively) achieved PASI75 at week 16 compared
derived growth factor (PDGF) and IgE signaling to placebo (13.4%, P value < 0.0001 for both
(Fig. 23.1). However, the discovery of high affin- groups). Additionally, sPGA 0/1 was noted in
ity cell surface receptors (S1P1–5) and the role 27.8 and 32.3% of the ponesimod 20 and 40 mg
of these receptors in angiogenesis, tissue remod- groups, respectively, compared to only 4.5% of
eling, and inflammatory mediator synthesis have the placebo group. At week 16, those who had
accelerated the development of target molecules received ponesimod and achieved a greater than
to modulate these pathways [36]. The fungus 50% decrease in PASI score either continued ponIsaria sinclairii, used in traditional Chinese med- esimod at the same dose or switched to placebo.
icine, contains Myriocin from which synthetic At week 28, a greater proportion of those who
S1P modulators have subsequently been devel- remained on ponesimod achieved PASI75 comoped for clinical use and testing [37].
pared to those who switched to placebo. In addiFingolimod is a non-selective S1P agonist and tion, those that switched to placebo had a greater
functional antagonist of S1P receptors 1, 3, 4 and likelihood of disease relapse. Laboratory analy5 [38]. The binding of phosphorylated fingoli- sis revealed dose-dependent lymphopenia in the
mod results in intracellular signaling via GPCRs ponesimod groups (56 and 65% mean decrease in
(Fig. 23.1). The overall effect of fingolimod is lymphocyte count, respectively) compared to 2%
immune modulation via trapping of lymphocytes of the control group. The incidence of infection
in secondary lymphoid tissues, thus causing T was similar across all groups. The most common
and B cells to accumulate rather than migrate into reported adverse events associated with ponesithe blood stream. Sustained lymphopenia is the mod were dyspnea, elevated liver enzymes, and
suspected mechanism of action responsible for dizziness [41].
the efficacy of this drug in the treatment of relapsA phase 2a dose-ranging study of amiselimod
ing-remitting multiple sclerosis. Lymphopenia recruited 142 subjects with moderate-to-severe
associated with fingolimod resolves in approxi- psoriasis and randomized them to low, medium,
mately 7 days after cessation of the drug [39]. and high doses of amiselimod versus placebo
The mechanism of action of fingolimod and [42]. The proportion of participants achieving
other S1P modulators makes this class of drug an a PASI75 at week 16 was the primary measure
attractive potential therapy for multiple autoim- of treatment efficacy. This study was completed
mune or inflammatory conditions.
in September 2014, but study results have not
Other S1P modulators are in various stages yet been published. No clinical trials testing
of development for the treatment of psoriasis, ­ponesimod or amiselimod for the treatment of
SLE, dermatomyositis, graft versus host dis- psoriatic arthritis have been reported.
298
Neurokinin-1 Receptor Antagonists
Neurokinin-1 (NK1) is the preferred receptor
for substance P, the binding of which results in
rapid downstream activation of NF-κB, ERK,
and p21 associated pathways (Fig. 23.1) [43, 44].
Substance P has a vital role in the stimulation
of pro-inflammatory leukocytes, as well as the
innate response to viral, parasitic, and bacterial
infections through enhanced production of IL-1,
IL-6, TNF-α, MIP-1B and IFN-γ [45]. NK1 pathways are also implicated in the modulation of itch,
stress, sleep, anxiety, and nausea via the central
nervous system. This has led to the development
of NK1 receptor (NK1R) antagonists for pruritus
as well as chemotherapy-associated nausea and
vomiting [46]. NK1R antagonists have also been
tested in psoriasis given the associated pruritus
and the contribution of pro-inflammatory cytokines to the keratinocyte mediated feed-­forward
pathway in psoriasis [47]. Additionally, localized
TGFβ elevation in psoriatic skin is associated
with delayed internalization of the NK1R complex, which leads to increased elevation of IL-1,
IL-6, and TNFα levels [43].
A phase 2 study randomized participants to a
serlopitant 5 mg daily group or placebo group. The
primary endpoint WI-NRS 4-point responder rate
at 8 weeks was achieved in 33.29% of the serlopitant group versus 21.07% of the placebo group
[48]. Serlopitant was not associated with any serious adverse events. Diarrhea, nasopharyngitis, and
headache were the most common adverse events
reported. An open-label extension study is ongoing and will provide long-term data on serlopitant
therapy for the treatment of psoriasis [49]. No clinical trials testing this compound for the treatment
of psoriatic arthritis have been reported.
Adenosine A3 Receptor Agonists
Adenosine A3 receptors (A3AR) are GPCRs
(Fig. 23.1) associated with regulation of local tissue function in the absence of an adequate energy
supply. They are specifically overexpressed in
inflamed and malignant tissues leading to the
D. Grand et al.
identification of this receptor as a potential therapeutic target [50]. The binding of adenosine to
A3AR constitutively inhibits adenylyl cyclase
and mitogen-activated protein kinase pathways.
Chronic elevation of adenosine in the setting of
pro-inflammatory cytokines leads to increased
levels of membrane bound A3AR, which has been
identified in malignancy and chronic inflammatory disorders [51]. This chronic elevation of
adenosine results in delayed internalization of
A3AR and upregulation of downstream NF-κB
(Fig. 23.1), and β-catenin signaling resulting
in transcriptional alterations leading to a pro-­
inflammatory environment. Therefore, A3AR
agonists are being evaluated for the treatment of
rheumatoid arthritis, inflammatory bowel disease,
and uveitis, as well as melanoma, prostate, colon,
breast, and hepatocellular carcinomas [52].
A phase 2 dose-ranging clinical trial randomized 75 participants to twice-daily doses of
CF101 (1 mg, 2 mg, or 4 mg) versus placebo [53].
Efficacy, as measured by percent change in PASI
score, showed a bell-shaped response in which
the 2 mg group had the greatest change in PASI
score at weeks 4, 8, and 12. Adverse events were
similar among the treatment and placebo groups.
However, the results of this study are limited due to
its small sample size [53]. Another phase 2/3 clinical trial randomized 293 patients with moderate-tosevere plaque psoriasis to either twice daily 2 mg
CF101 versus placebo [54]. 8.5% of participants
in the CF101 group achieved the primary endpoint
(PASI75) at week 16 compared to 6.9% of placebo
group. 31% of the CF101 group achieved the secondary endpoint (PASI50 or 75) at week 16 compared to 17% in the placebo group [54].
An ongoing phase 3 clinical trial will assess
CF101 therapy in those with moderate-tosevere plaque psoriasis [55]. An estimated 407
­participants will be randomized to twice daily
regimens of CF101 2 mg, CF101 3 mg, or apremilast 30 mg versus placebo. The primary endpoint will be the proportion of subjects who
achieve PASI75. This trial is currently recruiting
participants [55]. No clinical trials testing this
compound for the treatment of psoriatic arthritis
have been reported.
23 Research Pipeline I: Oral Therapeutics for Psoriasis
H4 Receptor Antagonists
Histamine, as a ligand for the H1-H4 receptors, is
classically released by mast cells in response to
immunological and non-immunological stimuli.
The localization of histamine receptor subtypes
differs between tissues with H4 receptors predominately expressed on the surface of hematopoietic cells, including eosinophils, T cells,
neutrophils, and other leukocytes (Fig. 23.1)
[56]. Aside from its well-documented effect on
eosinophils migration, H4 receptor antagonists
also inhibit CD4+ T cell activation. While the primary T cell population affected by H4 receptor
blockade are Th2 lymphocytes, modulation of the
Th17 cell population with a subsequent decrease
in the production of IL-17 production has also
been noted [57–59]. This suggests that blockade
of the H4 receptor in psoriasis may represent a
novel therapeutic strategy in psoriatic disease.
A phase 2 trial for ZPL389, a novel H4 receptor antagonist, involving 129 participants with
moderate-to-severe plaque psoriasis was completed in December 2016 [60]. Participants were
randomized to either ZPL389 (30 mg daily) or
placebo, and the primary endpoint was change in
PASI score at week 12. Results have not yet been
published for this trial. No clinical trials testing this compound for the treatment of psoriatic
arthritis have been reported.
IL-20/PRINS Inhibitor
Psoriasis-associated non-protein coding RNA
induced by stress (PRINS) are cytosolic RNA
found in non-lesional psoriatic skin and are purported to oppose chronic inflammation caused by
cytosolic DNA fragments [61]. PRINS expression is modified by UVB irradiation, hypoxia,
and microbial stimulation and interacts with the
innate immune response of keratinocytes via
IL-6 and CCL-5/RANTES [61]. Compounds that
directly inhibit PRINS are attractive as potential
novel therapies in inflammatory conditions like
psoriasis due to their modulation of the inflammatory and immune response.
299
Abacavir hydroxyacetate, also known as
Prurisol, is a chemical known to inhibit PRINS
(Fig. 23.1). Two phase 2 trials investigating the
efficacy of prurisol in chronic plaque psoriasis
have been completed. One trial randomized 115
participants with mild-to-moderate psoriasis into
four daily treatment arms: prurisol 50 mg, prurisol 100 mg, and prurisol 200 mg versus placebo [62]. The primary endpoint was percentage
of participants with a ≥2-point improvement in
IGA rating at day 84. Another trial randomized
199 participants with moderate-to-severe psoriasis to twice daily prurisol 150 or 200 mg versus
placebo [63]. The primary endpoint was the proportion of participants achieving PASI75 at week
12. These studies were completed in April 2016
and June 2017, respectively, but results of these
studies have not yet been published. No clinical
trials testing this compound for the treatment of
psoriatic arthritis have been reported.
SYK Inhibitors
Spleen tyrosine kinase (SYK) is a cytoplasmic
tyrosine kinase (Fig. 23.1) mainly expressed in
hematopoietic cells. It has crucial T cell, macrophage, neutrophil, and mast cell functions via the
IgG and IgE receptors, as well as involvement in
the TLR9-mediated B cell response [64]. It also
demonstrates other diverse functions including
cell adhesion, innate immune recognition, osteoclast maturation, and vascular remodeling [65].
Zap70 is a SYK tyrosine kinase essential to T
cell development, the absence of which results in
SCID [66].
SYK inhibition using fostamatinib (a prodrug
of tamatinib) has been demonstrated as effective
in rheumatoid arthritis as well as in murine models of psoriasis [67, 68]. Interestingly, tamatinib
demonstrates inadequate SYK specificity compared to fostamatinib. The effect of fostamatinib
is mediated through suppression of SYK expression in dendritic cells leading to downstream
Th17 pathway downregulation [69]. SYK inhibition has been suggested as a potential therapeutic
option for lupus, autoimmune ­thrombocytopenic
300
purpura, and B cell malignancies [70–72].
However, no clinical trials testing this compound for the treatment of plaque psoriasis or
psoriatic arthritis have been reported. Clinical
studies involving the treatment of inflammatory
conditions with SYK inhibitors will be of interest to the field and those studying this class of
molecules.
Conclusion
Despite the tremendous scientific and clinical
advances witnessed in the field of psoriatic disease, our understanding of this complex disease
remains incomplete. A noteworthy proportion of
patients are inadequately treated, remain resistant to single or combination therapy, or experience loss of clinical response to previously
effective therapies. This is particularly true for
patients with psoriatic arthritis. Therefore, there
is a continued need for new treatment modalities
that overcome the limitations of first-generation
and subsequent novel monoclonal antibodies.
Several classes of small molecules currently in
early and late phase clinical testing represent an
exciting new frontier for the treatment of psoriatic disease. While promising, the clinical impact
of these novel molecules remains undetermined
and will depend on the results of ongoing, larger
clinical trials and their implementation in realworld clinical scenarios.
References
1. Hawkes JE, et al. Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. J
Immunol. 2018;201(6):1605–13.
2. Babon JJ, et al. The molecular regulation of Janus
kinase (JAK) activation. Biochem J. 2014;462(1):1–13.
3. Welsch K, et al. Targeting JAK/STAT signalling in
inflammatory skin diseases with small molecule
inhibitors. Eur J Immunol. 2017;47(7):1096–107.
4. Igarashi K, et al. Interferon-gamma induces tyrosine
phosphorylation of interferon-gamma receptor and
regulated association of protein tyrosine kinases,
Jak1 and Jak2, with its receptor. J Biol Chem.
1994;269(20):14333–6.
5. Zhou YJ, et al. Hierarchy of protein tyrosine kinases
in interleukin-2 (IL-2) signaling: activation of syk
D. Grand et al.
depends on Jak3; however, neither Syk nor Lck is
required for IL-2-mediated STAT activation. Mol Cell
Biol. 2000;20(12):4371–80.
6. Damsky W, King BA. JAK inhibitors in dermatology:
the promise of a new drug class. J Am Acad Dermatol.
2017;76(4):736–44.
7. Works MG, et al. Inhibition of TYK2 and JAK1 ameliorates imiquimod-induced psoriasis-like dermatitis by inhibiting IL-22 and the IL-23/IL-17 axis. J
Immunol. 2014;193(7):3278–87.
8. Nicolas CS, et al. The role of JAK-STAT signaling
within the CNS. JAKSTAT. 2013;2(1):e22925.
9. Notarangelo LD, et al. Mutations in severe combined
immune deficiency (SCID) due to JAK3 deficiency.
Hum Mutat. 2001;18(4):255–63.
10. Kreins AY, et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med. 2015;212(10):1641–62.
11. Sonbol MB, et al. Comprehensive review of JAK
inhibitors in myeloproliferative neoplasms. Ther Adv
Hematol. 2013;4(1):15–35.
12. Papp KA, et al. A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor,
in patients with moderate-to-severe psoriasis. Br J
Dermatol. 2016;174(6):1266–76.
13. A study comparing Upadacitinib (ABT-494) to placebo in participants with active psoriatic arthritis
who have a history of inadequate response to at least
one biologic disease modifying anti-rheumatic drug
(SELECT—PsA 2) (NCT03104374). https://clinicaltrials.gov/ct2/show/NCT03104374. Updated April
30, 2019. Accessed June 25 2019.
14. A study comparing Upadacitinib (ABT-494) to placebo in participants with active psoriatic arthritis
who have an inadequate response to at least one
non-biologic disease modifying anti-rheumatic drug
(SELECT—PsA 1) (NCT03104400). https://clinicaltrials.gov/ct2/show/NCT03104400. Updated June 28,
2019. Accessed June 25 2019.
15. Mease P, et al. Efficacy and safety of filgotinib, a
selective Janus kinase 1 inhibitor, in patients with
active psoriatic arthritis (EQUATOR): results from a
randomised, placebo-controlled, phase 2 trial. Lancet.
2018;392(10162):2367–77.
16. An open-label, long-term extension study with filgotinib in active psoriatic arthritis (NCT03320876).
https://clinicaltrials.gov/ct2/show/NCT03320876.
Updated April 16, 2019. Accessed June 25 2019.
17. Papp K, et al. A phase 2a randomized, double-blind,
placebo-controlled, sequential dose-escalation study
to evaluate the efficacy and safety of ASP015K, a novel
Janus kinase inhibitor, in patients with moderate-to-­
severe psoriasis. Br J Dermatol. 2015;173(3):767–76.
18. Papp K, et al. Phase 2 trial of selective tyrosine
kinase 2 inhibition in psoriasis. N Engl J Med.
2018;379(14):1313–21.
19. An investigational study to evaluate experimental
medication BMS-986165 compared to placebo and
a currently available treatment in participants with
moderate to severe plaque psoriasis (POETYK-­
Research Pipeline II: Upcoming
Biologic Therapies
24
Ahuva D. Cices and Jeffrey M. Weinberg
Abstract
Psoriasis is a chronic inflammatory condition
mediated by activated T-cells. Cutaneous
manifestations of psoriasis have been shown
to have a tremendous impact on quality of life,
particularly in patients with moderate to
severe disease. Given the high morbidity associated with psoriasis, disease control is paramount. Systemic treatments are indicated for
effective management of cutaneous disease
and the comorbidities that result from chronic
inflammation. Prior systemic treatments were
non-specific and associated with significant
side effect profiles. With the development of
biologics, treatments have become increasingly targeted and efficacious. This chapter
will review biologic drugs currently in development that may eventually add to the growing armamentarium of psoriasis treatments.
Key Learning Objectives
1. To understand the mechanism of action
of novel biologic agents in development
for the treatment of psoriasis
A. D. Cices · J. M. Weinberg (*)
Department of Dermatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: jmw27@columbia.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_24
2. To understand the appropriate use
and efficacy of novel biologic agents
in development for the treatment of
psoriasis
3. To understand the safety issues and
appropriate monitoring of novel biologic agents in development for the
treatment of psoriasis
Introduction
Psoriasis is a chronic, inflammatory, multisystem
disease mediated by activated T-cells with an
estimated prevalence of 3.2% of the adult US
population [1, 2]. Comorbidities of psoriasis
include psoriatic arthritis, metabolic syndrome,
cardiovascular disease, depression, and impaired
quality of life. While mild to moderate disease
can typically be controlled with topical medications or phototherapy, traditional treatments are
often insufficient for moderate to severe disease.
Topical treatments and phototherapy are limited
by logistic issues related to application and do
not target systemic disease manifestations. In
patients with psoriatic arthritis, systemic treatment preventing irreversible joint destruction is
critical.
Prior to the advent of biologics, systemic therapies were non-specific immunosuppressive
303
304
agents with toxic side effects. Cyclosporine,
methotrexate, and acitretin were the cornerstones
of treatment until our understanding of the underlying aberrant pathways allowed for development
of targeted therapies.
Biologics are complex protein based molecules produced by living organisms that are utilized for their ability to target specific genes or
proteins [3]. The relevant proteins in psoriasis are
interleukins, cytokines involved in cell-to-cell
signaling related to immune cell differentiation,
or their receptors. Binding of biologics to these
targets allows for specific modulation of the
immune response.
Overview of Pathogenesis
Advances in our understanding of psoriasis at the
molecular level have paved the way for the development of targeted and safe biologic therapies.
Studying the complex interactions and signaling
between T-cells, dendritic cells, and neutrophils
with keratinocytes has been integral to the development of novel effective psoriasis therapies.
Psoriatic disease is initiated by the interaction
of self-nucleotides and innate antimicrobial peptides with toll-like receptors of plasmacytoid
dendritic cells resulting in production of type I
interferons, which then stimulate myeloid dendritic cells to secrete cytokines including tumor
necrosis factor alpha (TNFα), interleukin 12 (IL-­
12), and interleukin 23 (IL-23) [4, 5]. Dendritic
cells bridge the innate and adaptive immune system by promoting T-helper 1-cell and T-helper
17-cell (Th17) differentiation through activation
of innate pathways. TNFα, IL-23, and interleukin
17 (IL-17) promote inflammatory pathways and
amplification of these responses. IL-23 stimulates hyperproliferation that is a hallmark of psoriasis by inducing differentiation and survival of
Th17 cells, maintaining a favorable cytokine
milieu. Clinical studies supporting the integral
role of these inflammatory mediators include
increased expression of IL-23 subunits p19 and
A. D. Cices and J. M. Weinberg
p40 in psoriatic lesions, and elevated levels of
serum IL-17 and TNFα in patients with psoriasis
[6, 7].
Granulocyte-macrophage colony-stimulating
factor (GM-CSF) has been implicated in maintaining positive feedback loops involved in activated T-cell populations in patients with
autoimmune disease, particularly related to
Il-17A [8]. Programmed cell death- protein 1
(PD-1) or CD279 is an immune checkpoint that
promotes self-tolerance and has been hypothesized to play a role in autoimmune disease including psoriasis as demonstrated in a study showing
decreased levels of PD-1 expression on T-cells of
psoriasis patients compared with healthy controls
as well as case series describing psoriasis flares
in patients treated with PD-1 inhibitors [9, 10].
Overview of Biologic Treatments
TNFα antagonists are the first generation of biologics widely used in the treatment of psoriasis.
While anti-TNFα therapies are effective treatments for psoriasis, they are not without risk.
Due to the broad activity of TNFα throughout the
immune system, TNFα inhibitors have significant side effects including increased risk for TB
reactivation, infections, and certain malignancies
[4]. Meta analysis of rheumatoid arthritis patients
treated with anti-TNFα therapies showed
increased risk of serious infections and a dose-­
depended increase in malignancy; however, meta
analysis of psoriasis patients treated with anti-­
TNFα therapies showed a small increased risk of
infection without increased risk of serious infections or malignancy, suggesting that some of the
risks associated with TNFα antagonists may be
specific to rheumatoid arthritis populations [11,
12]. Second generation biologics for psoriasis
that target IL-17 and IL-23 have improved efficacy and safety profiles with increased risk of
some non-serious infections, but importantly
without increased risk of malignancy or serious
infections [1].
24
Research Pipeline II: Upcoming Biologic Therapies
Clinical Trial Background
Clinical trials consist of organized, prospective,
exposures of patients to interventions [13]. In
order for a new drug to be marketed in the United
States, the U.S. Food and Drug Administration
(FDA) must approve the drug after careful review
of pre-clinical and clinical tests, including Phase
I-III studies.
Phase I studies are initial human studies
designed to document initial safety data. In these
studies, investigational drug is given to a small
number of people, typically 20–80 patients or
healthy volunteers, to evaluate preliminary safety
and dosing.
Phase II studies evaluate the effectiveness of a
drug for a specific medical indication. Typically
these studies consist of several hundred patients
and look at the effect of treatment on clinical outcomes as well as side effects. Ideally, phase II
studies are double blind and placebo controlled.
Phase III studies are conducted for experimental drugs with evidence of efficacy in previously
completed phase II trials in order to gather additional evidence of efficacy and safety. These are
randomized clinical trials conducted in large
populations (often >1000 patients) to further
evaluate efficacy and safety. Typically, at least
two successful phase III clinical trials demonstrating adequate efficacy and safety are required
by the FDA prior to approval.
Standardized measurements are utilized in
clinical trials to allow for consistent comparison
of data across studies. The Psoriasis Area and
Severity Index (PASI) serves as the gold standard
for measuring disease activity. PASI score takes
into account the affected body surface area (BSA)
as well as severity of lesions. Lesions are assessed
separately over four body regions: the head and
neck, upper extremities, trunk, and lower extremities. Average intensity of erythema, thickness,
and scale is graded in each of the four locations
from 0 (none) to 4 (very severe). Within each
region, the severity sum is multiplied by an area
score based on the affected BSA and adjusted by
305
a fixed variable correlated to the BSA of the representative region. The sum of these scores from
each region yields the PASI score, which can
range from 0 (no active disease) to 72. Clinical
trials for biologics tested in moderate to severe
populations typically include inclusion criteria of
BSA ≥10% and PASI ≥12. In clinical trials percent of improvement in PASI score is used to
assess efficacy, with many of the newer drugs
achieving high rates of PASI 90 (90% improvement in PASI score at a given time point from
baseline) and even PASI 100 (no residual
disease).
Physician’s global assessment (PGA) or investigator’s global assessment (IGA) is a useful tool
for measuring cutaneous psoriatic disease activity in clinical trials. It allows for a quick, but subjective method of stratification based on overall
severity without taking into account the affected
BSA. There are multiple versions of the scale
which utilize variations in the criteria for each
score [14]. The IGA mod 2011 scale is a 5 point
scale commonly used in psoriasis clinical trials,
the scores are designated as follows: 0 (clear), 1
(almost clear), 2 (mild), 3 (moderate), and 4
(severe). Inclusion criteria for psoriasis studies
evaluating patients with moderate to severe psoriasis require a PGA/IGA score of 3 or 4 and
treatment success is defined by the FDA as a
PGA/IGA score of 0 or 1 with at least 2 grade
improvement from baseline.
American College of Rheumatology (ACR)
score is an instrument specifically developed for
rheumatoid arthritis and extended for use in psoriatic arthritis, which is utilized in rheumatologic
clinical trials as a measure of disease activity in
inflammatory arthritis. ACR measurement incorporates number of tender or swollen joints, physician global assessment of disease severity,
patient global assessment of disease severity,
patient reported functional ability, patient
reported visual analogue pain scale, and acute
phase reactants, namely erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).
Improvement is measured by the percent
306
improvement in number of tender or swollen
joints as well as at least 3 out of 5 of the above
criteria. Previous biologics were considered successful with achievement of ACR 20, while many
newer medications are evaluating treatment success with ACR 50.
A. D. Cices and J. M. Weinberg
cebo dosed every 4 weeks [17]. Primary endpoint
of PASI 90 at week 12 was achieved in significantly more patients in all bimekizumab treated
groups (46.2–79.1%) compared with placebo
(0%) (p < 0.0001) [17]. Also seen across all doses,
were significant improvements (p ≤ 0.0003) in all
secondary endpoints compared to placebo, which
included PASI 90 at week 8, PASI 75 at week 12,
Psoriasis Biologics Pipeline
PASI 100 at week 12, and IGA 0/1 at weeks 8
and 12. Three serious TEAEs were reported in 2
IL-17
patients, however they were not considered related
to study treatment (viral meningitis in a patient on
Bimekizumab/UCB4940 is a humanized mono- placebo and a large intestinal polyp/colon cancer
clonal IgG1 antibody targeting IL-17A and in a subject 15 days after initiating treatment with
IL-17F being studied as a treatment for chronic bimekizumab 480 mg). There were no unexpected
plaque psoriasis, psoriatic arthritis, ankylosing safety signals: common TEAEs occurring in >5%
spondylitis, non-radiographic axial spondyloar- of bimekizumab treated subjects included nasothritis, hidradenitis suppurativa, and rheumatoid pharyngitis, upper respiratory infections, arthralarthritis. A phase I placebo-controlled, dose-­ gia, elevated GGT, tonsillitis, oral candidiasis,
escalating study (NCT02529956) in 39 subjects headache, leukopenia, vomiting, and neutropenia.
with mild to moderate psoriasis showed efficacy No subjects in the placebo group had neutropenia,
of bimekizumab compared to placebo in treat- while five subjects receiving bimekizumab had
ment of mild to moderate psoriasis with dose-­ transient, non-serious neutropenia that resolved
dependent improvements in PASI and PGA spontaneously and did not interrupt treatment.
following a single dose of intravenous bimeki- Maintenance of response through week 60 was
zumab at doses ranging from 8 to 640 mg [15]. seen in the phase II extension study BE ABLE 2
Statistically significant clinical improvement was (NCT03010527) with PASI 90 in 80–100% and
seen as early as week 2, with maintenance of near PASI 100 in 70–83% of study subjects [18]. No new
maximal response through weeks 12–20 (depend- safety signals were identified, and consistent with
ing on endpoint) following a single IV dose previous data oral candidiasis and nasopharyngi≥160 mg. No unexpected safety signals and simi- tis were the most commonly occurring treatment
lar numbers of treatment emergent adverse events emergent adverse events. The phase II psoriatic
(TEAE) were observed in bimekizumab and pla- arthritis BE ACTIVE study (NCT02969525) rancebo treated groups. PA007, a phase I placebo-­ domized 206 adults with active psoriatic arthricontrolled study (NCT02141763) in 53 subjects tis 1:1:1:1:1 to one of four bimekizumab doses
with psoriatic arthritis, that compared five dos- (16 mg, 160 mg, 160 mg with 320 mg loading, or
ages of bimekizumab (240 mg/160 mg/160 mg; 320 mg) or placebo administered every 4 weeks.
80 mg/40 mg/40 mg; 160 mg/80 mg/80 mg and After week 12, subjects administered placebo and
560 mg/320 mg/320 mg) administered at weeks 0, the lowest bimekizumab dose were re-randomized
3 and 6 demonstrated efficacy in treatment of and maintained through week 48. The primary
arthritis and skin lesions with an ACR 20 in 80% outcome of ACR 50 at week 12 was achieved in
and PASI 100 in 86.7% of subjects in the top 3 significantly more subjects treated with 16 mg
doses at week 8 compared to 16.7 and 0% respec- bimekizumab (OR 4.2, p = 0.032), 160 mg bimetively in placebo treated subjects [16].
kizumab (OR 8.1, p = 0.012), and 160 mg bimeIn the 12 week, phase II BE ABLE 1 trial kizumab with loading dose (OR 9.7, p = 0.0004)
(NCT02905006) subjects were randomized compared to placebo.
1:1:1:1:1:1 to 64 mg, 160 mg, 160 mg with
Multiple phase III studies for bimekizumab in
320 mg loading dose, 320 mg, 480 mg, or pla- the treatment of moderate to severe chronic
24
Research Pipeline II: Upcoming Biologic Therapies
307
plaque psoriasis are underway and have shown
promising preliminary results with all three studies achieving the co-primary endpoints of PASI
90 and IGA 0/1 with at least two-grade improvement and with a safety prolife similar to that
demonstrated in the BE ABLE studies [19]. The
BE VIVID 52 week study (NCT03370133) randomized 570 subjects to bimekizumab, low dose
ustekinumab if weight ≤100 kg, high dose
ustekinumab if weight >100 kg, or placebo, with
subjects randomized to placebo crossed over to
bimekizumab after week 16. Bimekizumab was
superior to ustekinumab and placebo in achieving PASI 90, PASI 100, IGA 0, and IGA 1. The
56-week BE READY study (NCT03410992) randomized 435 subjects to bimekizumab or placebo
for an initial 16-week treatment period followed
by a randomized withdrawal period through
week 56. All ranked secondary endpoints were
met notably PASI 100 at week 16, patient reported
itch, pain and scaling, and scalp IGA 0/1 superior
to placebo. The BE SURE 56-week study
(NCT03412747) randomized 480 subjects to one
of two bimekizumab regimens or adalimumab
for 24 weeks, followed by a dose-blind maintenance through week 56. All ranked secondary
endpoints were achieved, including statistically
significant superior PASI 75 at week 4 and PASI
100 at weeks 16 and 24 compared to adalimumab. Given the positive results from these phase
III studies, plans are underway for bimekizumab
to be submitted for FDA approval in mid-2020.
Additional continuing studies evaluating
bimekizumab for the treatment of moderate
to severe psoriasis include the following: BE
RADIANT (NCT03536884), comparing two
bimekizumab doses and secukinumab with a primary endpoint of PASI 100 at week 16, a phase
III long-term extension study (NCT03598790)
comparing two bimekizumab doses through week
160, and a phase III study (NCT03766685) comparing bimekizumab administered by auto injector or syringe. Ongoing studies for bimekizumab
in the treatment of psoriatic arthritis include the
phase II long term extension study BE ACTIVE 2
(NCT03347110), a phase III, placebo-­controlled
study BE VITAL (NCT03896581), and another
phase III study (NCT03895203) comparing
bimekizumab to adalimumab with placebo control though week 16.
Netakimab/BCD-085 is a humanized monoclonal antibody to IL-17 developed and approved
in Russia for treatment of moderate to severe
plaque psoriasis based on favorable results in the
phase II BCD-085-2 study (NCT02762994) with
long-term extension and phase III BCD-085-7/
PLANETA study (NCT03390101) conducted in
Russia. Results have not been published, but a
press release from the company show PASI
75/90/100 in 83%/92%/59% of subjects at week
12 respectively [20, 21]. Netakimab is also being
evaluated for the treatment of ankylosing spondylitis, psoriatic arthritis, and primary biliary
cholangitis.
Vunakizumab/SHR-1314 is a humanized
IL-17A inhibitor under development for psoriasis
and axial spondyloarthritis. Preliminary safety
was established in healthy adults in a phase I study
(NCT02934412) with doses ranging from 20 to
240 mg. A second phase I study (NCT03710681)
is underway, comparing 160 and 240 mg administered every 2 weeks for 168 days in subjects
with moderate to severe plaque psoriasis. A multiple dose, escalating design, combined phase I
and phase II study (NCT03463187) is ongoing
for moderate to severe plaque psoriasis and an
upcoming phase II study (NCT04121143) will
compare low dose short interval, high dose long
interval, high dose short interval, and placebo
for 16 weeks in subjects with moderate to severe
psoriasis.
M1095/ALX-0761/MSB0010841 is a trivalent monomeric nanobody specific for IL-17A,
IL-17F, and human serum albumin allowing for
increased circulation time in the bloodstream
[22]. Data from a recently completed phase I
placebo-controlled, dose escalation 6 week study
(NCT02156466) showed promising results [22].
44 subjects with moderate to severe psoriasis
were randomized 4:1 to 30 mg, 60 mg, 120 mg or
240 mg M1095 or placebo administered subcutaneously bi-weekly. A dose response relationship
was observed. In the 240 mg cohort, all subjects
achieved PASI 90 and 56% of subjects achieved
PASI 100 at day 85. The most common TEAEs
were pruritus and headaches. 2 patients withdrew
A. D. Cices and J. M. Weinberg
308
due to adverse events, one due to an injection site
reaction and another due to transaminitis. An
upcoming placebo-controlled, active comparator
(secukinumab) phase II study (NCT03384745)
will compare 30 mg every 4 weeks, 60 mg every
4 weeks, 120 mg every 8 weeks, and 120 mg
every 4 weeks subsequent to a loading dose.
ABY-035/AFO2 is a novel multivalent and
specific molecule targeting both IL-17A subunits
as well as albumin. Favorable safety and tolerability was established across multiple doses and
dosing regimens in healthy volunteers and psoriasis subjects in an initial phase I/II study
(NCT02690142) [23]. A two cohort phase I trial
(NCT03580278) evaluating 75 mg daily for
14 days or 150 mg daily for up to 28 days in psoriasis subjects is ongoing. Encouraging interim
results have been reported in the AFFIRM-35
phase II trial (NCT03591887), in which subjects
with moderate to severe psoriasis were randomized 1:1:1:1:1 to 2 mg, 20 mg, 80 mg, 160 mg or
placebo administered subcutaneously every
2 weeks for 12 weeks followed by dose adjustments and re-randomization after week 12 [23].
IL-12/23
Promising results have been shown with mirikizumab, a humanized IgG4 monoclonal antibody
to the p19 subunit of IL-23, which is being tested
for treatment of moderate to severe psoriasis as
well as inflammatory bowel disease. In AMAF, a
placebo controlled phase II trial (NCT02899988)
evaluating single doses of subcutaneous mirikizumab in subjects with moderate to severe psoriasis at weeks 0 and 8, the percentage of patients
meeting the primary objective of PASI 90 at week
16 compared to placebo was clinically significant
in all tested doses with rates of 0, 29, 59 and 67%
for subjects treated with placebo, 30, 100, and
300 mg respectively [24]. Risk of adverse events
was not elevated in subjects treated with mirikizumab compared to placebo. Pivotal phase III
studies OASIS-1/AMAK (NCT03482011) and
OASIS-2/AMAJ (NCT03535194), which compared mirikizumab to placebo and secukinumab
or placebo respectively, have been completed,
with results expected in the near future. OASIS-3
(NCT03556202) is an open label extension study
currently underway comparing two different
mirikizumab doses for 208 weeks.
Miscellaneous
CC-90006 is a PD-1 agonist antibody in the initial stages of development. A phase I study
(NCT03337022) for treatment of mild to moderate plaque psoriasis was recently completed. The
study consists of 40 subjects divided into 4
cohorts of 10 patients with escalating doses
administered at weeks 0, 2, and 4. Data has not
yet been released, but continued development is
underway [25].
Namilumab/MT203/AMG203 is an IgG1 kappa
monoclonal antibody targeting GM-CSF being pursued as a novel treatment for psoriasis, rheumatoid
arthritis, and axial spondyloarthritis. Safety was
established in a phase I, placebo controlled study
(NCT02354599) in healthy Japanese and Caucasian
adult men. The NEPTUNE phase II placebo controlled, proof of concept study (NCT02129777)
randomized 122 subjects with moderate to severe
psoriasis to 20, 50, 80, or 150 mg subcutaneous
namilumab [26]. The number of subjects in all
groups achieving the primary endpoint of PASI 75
at week 12 was low in all cohorts, with no clinical
significance between groups and similar results for
other assessments. Given the results of the phase II
study, which suggest that namilumab inhibition
does not inhibit pathogenic inflammatory processes
of psoriasis Namilumab is no longer being studied
in psoriasis.
Summary
Psoriasis is a multi-system disorder that is not
skin-limited and often has significant effects on
patient quality of life. Recent advances in immunology have vastly expanded our comprehension
of psoriasis. Identifying key mediators of cell
signaling pathways associated with pathogenic
subsets of T-cells paved the way for the development of novel therapies, namely biologics. These
24
Research Pipeline II: Upcoming Biologic Therapies
309
medications are remarkably effective and safe
due to their specificity. New therapeutic targets
will continue to emerge as our understanding of
psoriasis continues to increase, and may include
innate immune pathways or genetic predispositions. The development of novel psoriasis treatments will continue to produce highly effective
and safe medications.
infections and malignancies: systematic review and
meta-analysis of rare harmful effects in randomized
controlled trials. JAMA. 2006;295(19):2275–85.
12. The safety of tumor necrosis factor antagonists in
patients with psoriatic disease: a systematic review
and metaanalysis of randomized controlled trials. J
Am Acad Dermatol. 2011;64(2):AB8.
13. Junod SW. FDA and clinical drug trials: a short history FDA. Available from https://www.fda.gov/
media/110437/download.
14. Langley RG, Feldman SR, Nyirady J, van de Kerkhof
P, Papavassilis C. The 5-point Investigator’s Global
Assessment (IGA) Scale: a modified tool for evaluating plaque psoriasis severity in clinical trials. J
Dermatolog Treat. 2015;26(1):23–31.
15. Glatt S, Helmer E, Haier B, Strimenopoulou F, Price
G, Vajjah P, et al. First-in-human randomized study of
bimekizumab, a humanized monoclonal antibody and
selective dual inhibitor of IL-17A and IL-17F, in mild
psoriasis. Br J Clin Pharmacol. 2017;83(5):991–1001.
16. Glatt S, Baeten D, Baker T, Griffiths M, Ionescu L,
Lawson ADG, et al. Dual IL-17A and IL-17F neutralisation by bimekizumab in psoriatic arthritis: evidence from preclinical experiments and a randomised
placebo-controlled clinical trial that IL-17F contributes to human chronic tissue inflammation. Ann
Rheum Dis. 2018;77(4):523–32.
17. Papp KA, Merola JF, Gottlieb AB, Griffiths CEM,
Cross N, Peterson L, et al. Dual neutralization of
both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: results from BE
ABLE 1, a 12-week randomized, double-blinded,
placebo-­
controlled phase 2b trial. J Am Acad
Dermatol. 2018;79(2):277–86.e10.
18. Blauvelt A, Papp KA, Merola JF, Gottlieb AB, Cross
N, Madden C, et al. AB0738 dual neutralisation of
interleukin (IL)-17A and IL-17F with bimekizumab
in moderate-to-severe plaque psoriasis: 60-week
results from a randomised, double-blinded, phase
2B extension study. Ann Rheum Dis. 2019;78(Suppl
2):1834.
19. Available from: https://www.ucb.com/stories-media/
Press-Releases/article/Bimekizumab-PositiveResults-Confirmed-in-Second-Phase-3-PsoriasisStudy.
20. BIOCAD registered the first Russian original therapeutic monoclonal antibody 2020. Available from:
https://biocadglobal.com/post/Russian_original_
therapeutic_monoclonal_antibody.
21. Bakulev AS, Kubanov AA, Khairutdinov V, Kokhan
M, Artemyeva A, Derbin S, Chernyaeva E, Ivanov
R. Long-term efficacy and safety of netakimab in
patients with moderate-to-severe psoriasis. Results of
phase II open-label extension clinical study BCD-085-­
2-ext. Vestn Dermatol Venerol. 2019;95(3):54–64.
22. Svecova D, Lubell MW, Casset-Semanaz F,
Mackenzie H, Grenningloh R, Krueger JG. A randomized, double-blind, placebo-controlled phase
1 study of multiple ascending doses of subcutaneous M1095, an anti-interleukin 17A/F nanobody, in
References
1. Menter A, Strober BE, Kaplan DH, Kivelevitch
D, Prater EF, Stoff B, et al. Joint AAD-NPF guidelines of care for the management and treatment
of psoriasis with biologics. J Am Acad Dermatol.
2019;80(4):1029–72.
2. Armstrong AW, Siegel MP, Bagel J, Boh EE, Buell
M, Cooper KD, et al. From the Medical Board of
the National Psoriasis Foundation: treatment targets for plaque psoriasis. J Am Acad Dermatol.
2017;76(2):290–8.
3. Morrow T, Felcone LH. Defining the difference:
what makes biologics unique. Biotechnol Healthc.
2004;1(4):24–9.
4. Greb JE, Goldminz AM, Elder JT, Lebwohl MG,
Gladman DD, Wu JJ, et al. Psoriasis. Nat Rev Dis
Primers. 2016;2:16082.
5. Georgescu SR, Tampa M, Caruntu C, Sarbu MI,
Mitran CI, Mitran MI, et al. Advances in understanding the immunological pathways in psoriasis. Int J
Mol Sci. 2019;20(3):739.
6. Lee E, Trepicchio WL, Oestreicher JL, Pittman
D, Wang F, Chamian F, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin
of patients with psoriasis vulgaris. J Exp Med.
2004;199(1):125–30.
7. Arican O, Aral M, Sasmaz S, Ciragil P. Serum levels of TNF-alpha, IFN-gamma, IL-6, IL-8, IL-12,
IL-17, and IL-18 in patients with active psoriasis and
correlation with disease severity. Mediat Inflamm.
2005;2005(5):273–9.
8. Hamilton JA. GM-CSF as a target in inflammatory/
autoimmune disease: current evidence and future
therapeutic potential. Expert Rev Clin Immunol.
2015;11(4):457–65.
9. De Bock M, Hulstaert E, Kruse V, Brochez L. Psoriasis
vulgaris exacerbation during treatment with a PD-1
checkpoint inhibitor: case report and literature review.
Case Rep Dermatol. 2018;10(2):190–7.
10. Shin D, Kim DS, Kim SH, Je JH, Kim HJ, Young
Kim D, et al. Decreased PD-1 positive blood follicular helper T cells in patients with psoriasis. Arch
Dermatol Res. 2016;308(8):593–9.
11. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I,
Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious
Pediatric Psoriasis
25
Starling Tolliver, Amber N. Pepper,
Salma Pothiawala, and Nanette B. Silverberg
Abstract
Psoriasis is a chronic multi-system inflammatory condition with an autoimmune component. One-third to one-half of cases have onset
in childhood. There are a variety of pediatric
variant types of psoriasis, including generalized disease, that is similar to adult psoriasis,
and types distinctive to childhood, including
diaper involvement and pityriasis amiantacea.
Pediatric psoriasis is associated with infectious triggers and exacerbation by the Koebner
phenomenon. Children with psoriasis may
have more of a tendency toward obesity as
reflected by a large waist circumference. More
extensive disease in childhood is associated
with a poor quality of life, anxiety, and depression. Therapeutics of pediatric psoriasis gen-
erally requires a global approach including
identifying infectious triggers, addressing
health risks including obesity, and psychological support. Prescription care includes application of mid-potency topical corticosteroids
and/or calcipotriene, phototherapy with
Narrowband UVB or excimer laser. In severe
cases, cyclic prescribing of systemic agents
for 6–12 months including methotrexate,
cyclosporine, etanercept, adalimumab, and
recently approved agents ixekizumab and
ustekinumab can aid in disease clearance with
minimization of side effects. Emerging studies for the efficacious and safe use of biologics
in children broaden treatment options for
managing severe psoriatic disease early.
Key Learning Objectives
S. Tolliver · N. B. Silverberg (*)
Department of Dermatology, Icahn School of
Medicine at Mount Sinai, New York, NY, USA
e-mail: starling.tolliver@osumc.edu;
nanette.silverberg@mountsinai.org
A. N. Pepper
Department of Internal Medicine, USF Health
Morsani College of Medicine, Tampa, FL, USA
e-mail: apepper1@health.usf.edu
1. To understand the clinical presentation
of psoriasis in the pediatric population
2. To understand the therapeutic management of psoriasis in the pediatric
population
3. To understand the specific safety concerns in the management of psoriasis in
the pediatric population
S. Pothiawala
Department of Dermatology and Cutaneous Surgery,
University of South Florida, Tampa, FL, USA
e-mail: salma.pothiawala@post.harvard.edu
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_25
311
312
Introduction
Psoriasis is a chronic inflammatory disorder,
believed to have an autoimmune basis. It is characterized by aberrant T cell activity causing
hyperproliferation of epidermal keratinocytes,
with development of erythematous skin plaques
covered by a silvery or micaceous scale [1, 2].
Pediatric psoriasis differs from adult onset psoriasis in types of environmental triggers, with
trauma, stress, and bacterial infection being the
most common pediatric disease triggers [1, 3],
while drug-reactions, smoking, alcohol use, and
underlying HIV infection are triggers more common in adulthood [4]. Recently, obesity and the
metabolic syndrome have been linked to both
pediatric and adult psoriasis [5]. Treatment
options are similar for adult and pediatric psoriasis patients, although therapy selection for pediatric psoriasis varies according to patient age and
is limited by the fact that systemic treatments for
pediatric psoriasis are off-label.
In the United States, high-potency topical corticosteroids were the most frequently prescribed
outpatient treatment for pediatric patients overall
from 1979 to 2007 [6]. Few therapies for psoriasis are approved by the FDA for the pediatric age
group, and drug dosages must be altered based on
weight and/or age in children. However, with
emerging data on the safety and efficacy of these
therapies for pediatric patients, this is changing.
This chapter will explore the epidemiology,
pathogenesis, diagnosis, and therapeutic management options of pediatric psoriasis, with a
special focus on aspects of the disease specific to
the pediatric patient.
Epidemiology (Table 25.1)
Psoriasis vulgaris is a common dermatologic disorder, affecting 3.15% of the United States population and 1.5% of the population in the United
Kingdom [14, 15]. Onset occurs before 16 years
of age in approximately one third of all cases [7,
16], making psoriasis a significant dermatologi-
S. Tolliver et al.
cal problem in the pediatric population. These
data likely represent under reported incidences
secondary to potential disparities in access to
care, mild undertreated disease, misdiagnoses,
and racial disparities in patient reporting [17].
The peak age of onset varies in the literature,
but usually ranges anywhere between 2 and
11 years of age [1, 3, 8, 9]. The mean age at diagnosis has been reported to be between 10 and
11 years of age by a recent large populationbased study [10]. Onset may occur slightly earlier for females [18], although studies have shown
nearly equal male to female prevalence ratios [8,
9, 11]. Onset may also occur earlier in those with
a positive family history of psoriasis [18].
Table 25.1 shows a review of worldwide presentation of pediatric psoriasis.
The annual incidence of psoriasis has been
shown to be increasing, nearly doubling (from
29.6 cases per 100,000 to 62.7 cases per 100,000)
from 1970 to 2000 in both pediatric and adult
patients [10, 19]. Recent studies in the United
States have reported a prevalence of mild and
moderate-to-severe pediatric psoriasis to be 128
per 100,000 and 16 per 100,000 respectively
[20]. Plaque psoriasis (Figs. 25.1 and 25.2) is the
most common variant, occurring in 34–74% of
children, with the majority of lesions localized to
the extensor surfaces of elbows and knees, scalp,
face (Fig. 25.3), trunk, and posterior auricular
region (Table 25.1) [8–11, 22]. Guttate psoriasis
is more common in pediatric patients, occurring
in approximately 6–33% of cases of pediatric
psoriasis (Fig. 25.4) [1, 18]. Pustular disease, is a
relatively uncommon presentation in children,
however, a Turkish group reported 13% of their
pediatric patients had pustular lesions [1, 8].
A single study from Greece sited 8% of children as having erythroderma [24] however, most
studies demonstrate that <1% of children present this way [3, 8, 16, 18]. Glossitis and mucosal
diseases are uncommon in childhood [1, 3, 8,
16, 18].
In infants and toddlers (less than 2 years old),
psoriatic diaper rash is the most common presentation sometimes involving the intertriginous
223
India
USA
China
Kumar et al.
2004 [3]
Raychaudhuri
and Gross 2000
[7]
Fan 2007 [8]
277
419
Country
Turkey
Author, year
Seyhan et al.
2006 [1]
Number of
kids
61
1:1.1
47; 53
1:1.3
44; 56
1.1:1
52; 48
Sex
distribution
(M:F and
%M; %F)
1:1.7
38; 62
Table 25.1 Worldwide demographics of pediatric psoriasis
Not discussed
(Chinese)
Not discussed
Not discussed
(Indian)
Race and or
ethnicity
Not discussed
(Turkish)
Median age of
onset 10
Range:
9 months to
15 years
Not discussed
Onset mean
9.1 overall
(M) 8.1 ± 2.1
(F) 9.3 ± 2.3
Range 4–14
Ages of kids
(range, median,
mean)
Onset mean
6.9 ± 4.1
At time of
study
10.0 ± 4.1
Plaque 69%
Guttate 29%
Pustular 1%
Erythroderma 1%
Not discussed
Plaque 61%
Guttate 10%
Pustular <1%
Inverse <1%
Erythrodermic 1%
Palmoplantar 6%
Plantar 13%
Nails 3%
Types of psoriasis (%)
Plaque 54%
Guttate 33%
Pustular 13%
Inverse 7%
Erythrodermic 3%
Palmoplantar 2%
(At onset)
Scalp 57%
Trunk 14%
Extremities
52%
Face 9%
Nails 13%
(At onset)
Scalp 47%
Face 20%
Trunk 43%
Arms 51%
Legs 66%
Nail 6%
Palmoplantar
37%
Areas of
involvement
(At onset)
Trunk 44%
Scalp 36%
Extremities
54%
Diaper rash
5%
Nails 21%
(At onset)
Trunk 8%
Extremities
35%
Scalp 21%
Soles 19%
Palms 3%
Not discussed
4.5%
Only recalled
by 7% of
participants
Trauma 14 pts
Throat
infection ten
patients
Psych 3 pts
Drug rxn 1 pt
Trauma 50%
Stress 50%
Pharyngitis
28%
(continued)
8% (7 1st, 1
2nd)
68%
Family history
23%
Triggers
URTI 15%
+Group B
strep culture
21%
25 Pediatric Psoriasis
313
Country
Korea
USA
Australia
Author, year
Kwon 2011 [9]
Tollefson 2010
[10]
Morris 2001
[11]
Table 25.1 (continued)
1262
357
Number of
kids
358
1:1.1
47;53
1:1.1
48;52
Sex
distribution
(M:F and
%M; %F)
1.1:1
51; 49
Not discussed
Mostly
Caucasian but
not specified
Race and or
ethnicity
Not discussed
No median or
mean
described
Range:
1 month to
15 years
Median age of
onset 10.6
Range
6.8–14.4
Ages of kids
(range, median,
mean)
Mean age
onset:
10.5 ± 4.3
Plaque 34%
Scalp 12%
Diaper rash 13%
Guttate 6%
Face only 4%
Pustular <1%
Nail <1%
Erythrodermic <1%
Types of psoriasis (%)
Plaque 67%
Guttate 18%
Generalized pustular
pustulosis 7%
Palmoplantar 4%
Erythroderma 1%
Plaque 74%
Guttate 14%
Sebo-psoriasis 8%
Pustular 1%
Areas of
involvement
Trunk 70%
Legs 65%
Arms 48%
Face 46%
Palms/soles
22%
Scalp 47%
Extremities
60%
Palms/soles
5%
Trunk 35%
Face 18%
Genital/groin
9%
Nails 17%
Face 38%
Otherwise not
discussed
Family history
32%
Not
discussed
71% (based
on 61% who
responded)
Triggers
Not discussed
Not discussed
Not discussed
314
S. Tolliver et al.
USA
USA
Greece
Vogel 2012 [6]
Wu 2011 [12]
Stefanaki 2011
[13]
125
1361
3.8 million
outpt
VISITS for
ped
psoriasis
1.4:1
59; 41
1:1.2
45; 55
1:1
50;50
Race
White 93%
Black 3%
Asian/
Pacific
Islander 3%
American
Indian/
Eskimo/
Aleut 0.5%
Ethnicity
85%
non-­
Hispanic
8% Hispanic
7% other
Non-Hispanic
white 38%
Hispanic white
38%
Black 3%
Asian or
Pacific Islander
7%
Others 3%
81% Greek
16%
Not discussed
Extremities
56%
Scalp 48%
Trunk 47%
Nails 10%
Plaque 57%
Scalp? 34%
Guttate 12%
Flexural 10%
Erythrodermic 8%
Nails only 5%
Peak age of
onset 9–10 grp
Range:
<1–13 years
No mean or
median given
Not
discussed
Not discussed
Not discussed
Not discussed
Not
discussed
11.8 ± 4.4 in
M
12.5 ± 4.4 in F
Not discussed
Not discussed
Not discussed (NB:
article discusses
outpatient visits and
treatment choices, not
individual patients)
Mean age at
visit 11.3
25 Pediatric Psoriasis
315
316
S. Tolliver et al.
Fig. 25.3 Facial psoriasis can be a challenging condition
due to the combination of disfigurement, psychological
distress and limitations of therapy on the thin-skinned
face
Fig. 25.1 Untreated plaque psoriasis affecting the trunk
with large circinate plaques with overlying micaceous
scale (Reprinted with permission from Silverberg [21])
Fig. 25.2 Close-up of plaque with micaceous scale demonstrates areas of Auspitz sign, pinpoint bleeding due to
manual removal of scale
neck and axillary areas (Fig. 25.5) [11, 22].
Psoriasis presenting in infancy has a better prognosis for long-term remission than childhood
psoriasis [24]. Involvement of the folds, i.e.
inverse psoriasis, is an uncommon appearance in
older children. Inverse psoriasis in any age group
can be exacerbated by concurrent cutaneous
overgrowth of streptococcal, staphylococcal and
candidal species.
Fig. 25.4 Guttate psoriasis of the trunk in a child with
psoriasis flared by an upper respiratory infection (Taken
from Silverberg [23] with permission)
Nail psoriasis can arise in the setting of
plaque-type psoriasis, psoriatic arthritis, or with
25 Pediatric Psoriasis
Fig. 25.5 Inverse psoriasis in an infant (Taken from
Silverberg [23] with permission)
isolated nail disease. This manifestation can be
found in as many 16–32% of pediatric patients
[25, 26]. It is associated with male sex and higher
disease burden at onset as well as follow-up [25,
26]. Nail disease may also suggest a more morbid
disease course for patients [25]. Common features include nail pitting on the fingernails while
onycholysis and pachyonychia were found on the
toenails [25]. Psoriatic arthritis with active joint
involvement is less common in childhood than
adulthood, but should remain in the differential
for children with arthritis [3]. In the majority of
children, dermatologic manifestations precede
the onset of psoriatic arthritis [27].
There is a bimodal age of psoriatic arthritis
onset with peaks during the first few years of life
and in early adolescence [28]. Skin manifestations are often established before joint involvement [22]. The early onset form of psoriatic
arthritis is most likely to be polyarticular, ANA
(antinuclear antibody) positive, and favors the
female sex [29, 30]. The adolescent-onset form
of psoriatic arthritis has a higher incidence of
axial joint involvement and favors the male sex.
The proximal and distal interphalangeal joints of
the hand, knees, and ankles are most commonly
involved initially. Children often present with oligoarthritis, which may progress to polyarthritis;
dactylitis can be associated. Psoriatic arthritis can
be differentiated from idiopathic juvenile rheumatoid arthritis by the presence of blue discoloration of the joints, nail pitting and/ or nail
dystrophy [27]. Predominant involvement of the
wrists and small joints of the hands and feet also
317
point toward a psoriatic etiology of arthritis in
affected children [30]. As many as 25% of
patients with psoriatic arthritis have joint damage
by 5 years after symptoms begin, thus early
screening and treatment is important [31].
Pediatric psoriasis has been shown to negatively affect quality of life. The psychological
impact of skin disease is becoming an important
area of research with some studies reporting
prevalence rates as much as 70% [32]. Studies
have shown that cutaneous diseases such as,
atopic dermatitis, psoriasis and urticaria have a
direct impact on psychological well-being [33].
Pediatric patients with psoriasis are increasingly
being found with higher rates of depression, anxiety, and even bipolar disorder in some studies
[34]. One study showed a 9- and 6-fold risk for
anxiety and depression respectively verses
healthy controls [32]. The psychological stress
caused by psoriasis may even be significantly
higher than other chronic cutaneous diseases.
Multiple studies have determined depression to
be higher in patients with psoriasis compared to
atopic dermatitis [33, 35]. This may be more pronounced in younger children who have less
developed coping mechanisms [36]. Mounting
pressures within their social circles and decreased
levels of maturity may increase the risk of lower
quality of life [32]. Children with moderate-tosevere psoriasis have similar health-related quality of life as compared to children with arthritis
or asthma, but worse than children with diabetes
[37]. Adult females with psoriatic arthritis suffer
greater disability than their male counterparts,
but no gender differences have been reported in
children thus far [32, 38]. Impairment in quality
of life is also described in families with children
who have psoriasis [39]. This phenomenom is
likely multifactorial with emotional well-being
and burden of care being the factors with the
most impact [39, 40].
There is current debate on the role psychiatric
disorders play in the development of psoriasis.
Some studies have shown distress as an important trigger in the onset as well as exacerbating
factor in leading to psoriatic lesions [32, 41]. One
paper described an association between other
autoimmune diseases and schizophrenia suggest-
318
ing potential shared genetic risk factors in the
development of both diseases [42]. The gene
implicated in this pathogenesis is EPHB4, a
transmembrane receptor that has activity in regulating cell migration with multiple roles in
immune cells and neuronal pathways [42].
Lower psoriatic incidence has been noted in
Inuit people; the single most prominent ethnic
variation that has been noted. This information
suggests that diets high in omega-3 fatty acids
may be protective against the development of
psoriasis [43]. New studies on ethnic variations
have suggested Asians and Hispanics are more
likely to have pustular and erythrodermic psoriasis as compared to their Caucasian counter parts
[44]. The authors suggested these differences are
associated with socioeconomic disparities
between these ethnic groups which may allow for
more severe presentations of disease [44]. One
study of children in southern California found the
highest prevalence of pediatric psoriasis to be in
non-Hispanic whites and the lowest but not negligible incidence in blacks. Also, of note, a lower
overall prevalence was noted than historically
would be seen in other areas of the country. The
authors speculated that increased sunlight exposure and a lower population-based proportion of
non-Hispanic whites may have led to this observation [12].
Pathogenesis
Although the exact pathogenesis of psoriasis has
not yet been revealed, it is clear that both genetic
and environmental factors play a role in the
development of psoriasis. A positive family history is present in 23–71% of pediatric psoriatic
cases [1, 11, 45]. There is a higher rate of concordant psoriasis in identical as compared to fraternal twins (65–72 vs. 15–30% respectively)
[46, 47].
Psoriasis vulgaris cannot be linked to a single
gene. It appears that several genes may play a
role in the genetic susceptibility of psoriasis,
most notably HLA-Cw6 [46]. HLA-Cw6 may
S. Tolliver et al.
interact with the susceptibility alleles, cyclindromatosis gene, CYLD; and transglutaminase 5,
TGM5 [48]. Other genes that have been implicated include IL12-B9 (1p31.3); IL-13 (5q31.1);
IL-23R (1p31.3); HLABW6; PSORS6, signal
transducer and activator of transcription gene 2
STAT2 and IL-23A (12q13.2); tumor necrosis
factor α-induced protein 3, TNFAIP3 (6q23.3);
and TNFAIP3 interacting protein 1, TNIP1
(5q33.1) [46]. The gene PSORS1 within HLA-C
and PSORS2 (17q24-q25) have also been implicated as increasing the risk for psoriasis development [49, 50]. Yet another gene, PSORS6
(19p13), has been shown to interact with PSORS1
[49]. SCL12A8, which belongs to the solute carrier gene family, has also been named as a susceptibility gene [48]. The role of these genes is
regulation of Th2 and Th17 lymphocyte activity
as well as the NF-κB signaling pathway, which
indicates both Th2 and Th17 cells may play a role
in the pathogenesis of psoriatic disease.
Collections of Th17, Th2 and Th1 cells have been
found in psoriatic skin lesions [46, 51]. It is theorized interactions among these cells, along with
dendritic cells and neutrophils lead to the release
of cytokines, like IL-17 and IL-23, which causes
hyperproliferation of keratinocytes and the
release of proinflammatory factors within the
skin [52].
New susceptibility genes are continually
being discovered. Additionally, it appears that
susceptibility genes for psoriasis may overlap
with other autoimmune disorders. For example,
the genes IL-12B and IL-23R are shared with
Crohn’s disease and IL-23R is shared with ulcerative colitis. Patients with Crohn’s disease are
five times more likely to develop psoriasis as
compared to the general population, a fact that
may be explained, as least in part, by shared susceptibility genes [46]. Decreased expression of
the CD18 gene, mutations in which result in leukocyte adhesion deficiency type I, may also be
low in certain patients with psoriasis [53].
Another example includes the gene CARD14
which involves the NF-κB signaling pathway.
This aberrant gene is evident in chronic condi-
25 Pediatric Psoriasis
tions such as psoriasis vulgaris, pityriasis rubra
pilaris, and pustular psoriasis [54, 55]. These diseases, especially pityrisiasis rubra pilaris and
psoriasis vulgarius, share similar clinical manifestations that are distinguishable histologically
[54]. Conversely, a gain of function mutation in
CARD14 is associated with developing psoriasis
while a loss of function mutation in the same
gene is associated with developing atopic dermatitis [56]. Although no studies have shown a difference in the genetics of pediatric-onset psoriasis
as compared to adult-onset psoriasis, preliminary
studies have shown differences in inflammatory
composition in adults and pediatric patients [57].
Additional genes such as IL36RN in generalized
pustular psoriasis is a growing area of research.
This gene is an inhibitor of IL-36a, IL-35B, and
IL-36y via competitive binding to the IL1RL2
receptor which leads to downstream inhibitor
effects in the NF-KB and MAPK signaling pathways [58].
New pathogenic mechanisms are being considered in the literature. Emerging studies on
serum levels of IL-22 in adult patients suggest
other potential pathogenic mechanisms for future
therapeutic use. Some studies report higher levels
of IL-22 in psoriatic patients compared to controls and increase with disease burden [59]. Other
studies have linked an IL-22 variant that was
associated with disease manifestation at an earlier age [59]. Psoriasis is increasingly linked to
several autoimmune diseases. Diseases like
celiac disease, IBD, uveitis and non-alcoholic
fatty liver diseases, which involve the gastrointestinal tract, may share a pathogenic link [60].
Some studies are researching the differences in
composition of the gut microbiome in psoriasis
patients [61]. Conflicting studies demonstrate
both increased and decreased bacterial diversity
in their participants necessitating further studies
in this area [61].
Table 25.2 gives a list of potential laboratory
or diagnostic evaluations for children with psoriasis. The most common precipitating environmental factors in pediatric psoriasis appear to
be stress and upper respiratory infections
319
Table 25.2 Suggested work-up for children with psoriasis (Wolverton [62])
At onset:
Throat culture or ASO (especially in guttate psoriasis)
Biopsy in atypical cases
Annually:
Joint evaluation (referral to rheumatology for specific
symptoms)
Cardiac markers: weight, height, body mass index,
blood pressure, lipid profile (cholesterol, triglyceride)
Optional evaluations:
Cultures of macerated or crusted lesions for diagnosis
of superinfection (bacterial culture, fungal culture)
Celiac panel for children with stomach symptoms,
difficulty with clearance or severe disease
Thyroid screen for co-morbid arthritis or vitiligo and
in symptomatic cases
Screening for medications (co-manage with
rheumatology when arthritis suspected):
Cyclosporine: blood pressure, complete blood count,
complete metabolic profile, urinalysis, magnesium,
fasting lipid profile (q1–2 weeks for 2 months or for
dosage elevations then monthly); urine pregnancy
screening at baseline in girls of child bearing age
Methotrexate: PPD (baseline and annually), complete
blood count with platelets, liver function testing and
renal function testing (every few weeks for dosage
escalations and at initiation of therapy, then monthly),
Hepatitis A, B and C screening, HIV testing for
individuals at risk (at baseline); urine pregnancy
screening at baseline in girls of child bearing age
Liver biopsies are rarely performed in children at this
time. Co-management with rheumatology and/or
gastroenterology may be helpful in prolonged usage
Acitretin. Isotretinoin: complete blood count, liver
function tests, cholesterol, triglycerides, urine
pregnancy in girls of child bearing age (monthly for
isotretinoin due to the iPLEDGE program for the
duration of therapy; for acitretin after 6 months can
change to quarterly labs); spiral x-rays for suspected
DISH; ophthalmology with prolonged usage
Etanercept/adalimumab/infliximab/ixekizumab/
ustekinumab: PPD at baseline and annually; screening
for prior hepatitis; periodic evaluation for lymph node
enlargement; periodic laboratory re-evaluation
Referrals:
Endocrinology for comorbid endocrinopathy, obesity
management, work-up for HPA axis suppression in
chronic steroid users
Rheumatology for joint pains, limited mobility,
co-management of methotrexate or biologics
(optional, but suggested for cases with arthritis or
suspicion of)
(continued)
320
Table 25.2 (continued)
Gastroenterology for management/work-up of
suspected comorbid inflammatory bowel disease,
celiac disease; co-management of methotrexate
(optional)
Nutritionists/weight down programs
Ophthalmology screening for issues arising from oral
retinoids
(Table 25.1), especially with group A
β-hemolytic Streptococcus (Streptococcus pyogenes). Upper respiratory tract infections have
been reported to be an inciting factor in 14.8–
28% of pediatric psoriasis cases, while 21.3%
of asymptomatic children have tested positive
for group A ß-hemolytic streptococcus on
throat culture prior to developing psoriasis [1].
Streptococcal pharyngitis may trigger up to 2/3
of all cases of guttate psoriasis [63] as well as
exacerbate existing plaque psoriasis [2].
Children
with
psoriasis
induced
by
Streptococcal infections frequently experience
remission [17, 22]. It appears that patients with
psoriasis have a unique host-specific response
to the streptococcal antigens [63, 64].
Enterotoxin-producing
Staphylococcus
aureus, Candida albicans, and Human papillomavirus DNA has also been isolated from patients
with psoriasis, suggesting that these entities and
the corresponding immune response to them may
also play a role in the pathogenesis of psoriasis
[65–67]. Environmental factors, such as exposure
to cigarette smoke, as well as obesity, have also
recently been associated with the development of
pediatric psoriasis [45].
Psoriasis is an autoimmune disease which, by
definition, means it is characterized by the
immune system mounting a response against
self-antigens. Thus, it is of no surprise that psoriasis is associated with other autoimmune conditions, most frequently of the skin. Patients with
morphea have been found to have a higher prevalence of psoriasis than the general population
[68]. There have also been case reports of familial associations between psoriasis and vitiligo
[69, 70]. Individuals with celiac disease are at
increased risk for the development of psoriasis
and this association is most pronounced in pedi-
S. Tolliver et al.
atric patients, meriting celiac disease screening in
children with severe psoriasis [71]. An uncertain
relationship remains between psoriasis and autoimmune thyroid diseases. In adults, psoriatic
arthritis has been linked to a higher incidence of
autoimmune thyroiditis than the general population, especially in patients with concomitant
rheumatoid arthritis [72]. However no such correlation has been shown with psoriasis localized
to the skin and without associated arthritis, as
thyroiditis markers are statistically similar
between psoriatic adults and age-matched controls [73]. Pediatric studies investigating a link
between psoriasis and autoimmune thyroid diseases have yet to be reported. Since the data in
the adult population is inconsistent and no studies with children participants exist to be used as
guidelines, routine annual screening for thyroid
disorders is not recommended in pediatric
patients with psoriasis. Screening for thyroid disorders may be warranted in children with psoriatic arthritis or in psoriatic pediatric patients with
concomitant vitiligo, or another autoimmune diseases that are more closely associated with thyroid abnormalities [74]. A suggested work-up for
children with psoriasis is included in Table 25.2.
Obesity and Metabolic Syndrome
Recently, an association between psoriasis and
the various characteristics of the metabolic syndrome has surfaced in the literature. A growing
body of evidence points to an increased risk of
cardiovascular mortality in adult patients with
severe psoriatic disease. New research is showing
similar cardiac risk factors present even pediatric
patients [22, 34, 75, 76]. Increased rates of hypertension, hyperlipidemia, diabetes mellitus, and
obesity are seen in children and adolescents with
psoriasis, with the former three comorbidities
occurring twice as often in pediatric psoriatic
patients as compared to healthy controls [77].
Furthermore, there is an association with increasing weight and psoriasis severity with some studies showing that adiposity may precede psoriatic
lesions by 2 years in a majority of patients [17,
25 Pediatric Psoriasis
22]. Waist to height ratio, a tool commonly used
to determine central adiposity, was found to be
more common in patients with moderate to severe
psoriasis, suggesting increased risk for cardiovascular disease [78]. Even in patients with both
normal and overweight, central adiposity was
associated with psoriasis which also suggest that
this chronic condition effects the body even
before lesions are seen [79]. Newly established
screening protocol guidelines for comorbidities
associated with pediatric psoriasis have been created to aid clinicians in early management and
prevention strategies [80]. Adolescents with psoriasis have been found to elevated plasma lipids
irrespective of body mass index, suggesting psoriasis itself may lead to metabolic abnormalities
[5, 81]. Some studies have suggested an association with higher blood pressures in patients with
psoriasis irregardless of weight [82, 83] while
others have found no association with hypertension and psoriasis [34]. Regardless, this evidence
suggests a need for early screening and management of these co-morbidities in children [75, 84].
Recent studies suggest obesity may even be an
independent risk factor in the development of
psoriasis [85]. Pubescent females (aged 12–13)
with an elevated BMI appear to be at an increased
risk for the development of severe psoriasis later
in adolescence [86]. As for obesity in psoriatic
arthritis, no meaningful differences in weight
were found in patients with psoriasis and patients
with psoriatic arthritis [87]. Interestingly, this
study did not show an increased prevalence of
obesity in psoriatic arthritis compared to healthy
controls. Whether this was secondary to unmeasured confounding factors or accounting for a
patients BMI only at the time of the study remains
unclear. Nevertheless, future studies are needed
to understand the association between obesity
and psoriatic arthritis in pediatric patients [87]. In
adults with psoriasis, unhealthy lifestyle habits
such as cigarette smoking, excess alcohol intake,
and poor dietary choices have been linked to an
increased risk of cardiovascular comorbidities
[88]. This highlights the need for prevention
through the early development of healthy habits
in pediatric patients with psoriasis. Referrals to
nutritionists, endocrinology, and weight-down
321
programs are advisable interventions in obese
adolescents with psoriasis.
Diagnosis and Clinical
Characteristics (Tables 25.1 and 25.3)
The various clinical variants of psoriasis are
listed in Tables 25.1 and 25.3. The most common
presentation in children is plaque type, with erythematous plaques with overlying silvery scale
localized to the extensor surfaces and scalp
(Table 25.3). In children, psoriatic lesions are
generally thinner, possess less scale and are more
pruritic as compared to adults [22, 89]. Certain
physical findings are characteristic of psoriasis,
including pediatric cases. These findings include:
(1) The Koebner phenomenon, (2) post-inflammatory pigmentary alteration, especially in children of color, (3) the presence of punctate
bleeding spots when scales are removed or the
Auspitz sign, and (4) nail pitting [90].
The scalp is the leading site of psoriatic lesions
in all age groups with koebnerization as a common initial insult in some studies [22, 91]. Scalp
psoriasis was found to be associated with more
extensive disease process and suggests that it
may indicate scalp involvement as an early clinical marker for more aggressive treatment [91].
Typical presentation include thick erythematous
plaques of the scalp, extending onto the forehead,
over the ears and onto the nape of the neck. The
forehead is an especially important site in childhood psoriasis due to the fact that facial disease is
more prevalent in childhood (Fig. 25.2). It is
important to differentiate scalp psoriasis from
tinea capitis [92]. A specific scalp finding that is
associated with psoriasis, but may be noted even
in the absence of psoriasis, is pityriasis amiantaceia, presenting as thick hyperkeratotic concretions attached to the hairs accompanied by scalp
erythema. Children in Scandinavia with pityriasis amiantaceia have a stronger family history
and personal tendency towards psoriasis than
children in the general population [93]. Some
authors believe pityriasis amiantaceia is de facto
psoriasis, often scalp limited, and usually of
childhood. Staphylococcal overgrowth is noted in
Inverse
Guttate
Type of
psoriasis
Plaque-type
Erythematous, sometimes
macerated thick plaques of the
intertriginous skin, including
axillae and groin
Can be associated with plaque
type psoriasis in other sites
Although clinical diagnosis is
often possible, similarity to
other diseases may require
biopsy for differentiation
Secondary infection
with Candida and/or
Streptococcus may
require cutaneous
culture for diagnosis
and prescription of
topical anti-infectives
Diagnostic features and tests Co-morbidities
Check for recent
Usually a clinical diagnosis
Nail pitting can be noted as a pharyngitis, (Group A
beta hemolytic
clue to the diagnosis of
Streptococcus)
psoriasis in children
Rule out secondary
Biopsy (when needed)
infection with S.
features
aureus
Thickened epidermis,
neutrophils in the horny layer, Consider comorbid
autoimmunity (e.g.
the spongiform pustules of
thyroid disease, celiac
Kogoj and the subcorneal
disease)
microabscess of Munro
(collections of neutrophils in In the setting of
obesity, disease
the epidermis)
Pharyngeal bacterial culture or severity can be a
marker of
ASO testing
cardiovascular risk
Recent pharyngitis,
Clinical diagnosis is often
Small, annular localized
(Group A beta
erythematous to salmon colored possible
hemolytic
Biopsy is similar to that of
plaques with mild
Streptococcus)
plaque-type psoriasis
hyperkeratosis, sometimes
Check for recent pharyngitis,
micacous
Commonly noted on the trunk, (Group A beta hemolytic
Streptococcus), by Pharyngeal
abdomen and back
bacterial culture or ASO
testing
Clinical appearance
Erythematous plaques with
micaceous scale
Typical areas: Scalp extending
to forehead, nuchal,
postauricular, elbows, knees,
umbilical and buttocks
Table 25.3 Clinical variants of pediatric psoriasis [22, 30]
Topical therapy similar to plaque-type
psoriasis
Oral antibiotics are often used initially
due to presumptive infectious
precipitating factors and for anti-­
inflammatory capabilities
(erythromycin, azithromycin
cephalosporins)
Systemic agents and phototherapy may
be needed in moderate to severe disease
unresponsive to oral antibiotics
Topical medications should be
non-steroidal or low-potency topical
corticosteroids to avoid atrophy of the
occluded skin
Oral or topical anti-infectives should be
added where appropriate
Nummular dermatitis
Lichen planus
Secondary syphilis
Pityriasis rosea
ID reaction
Tinea corporis
Pityriasis rubra pilaris
Pityriasis lichenoides
Intertrigo
Erythrasma
Tinea corporis
Langerhans cell
histiocytosis
Candidiasis
Darier’s/Hailey-Hailey
disease
Contact dermatitis
Treatment
Treatments must be tailored based upon:
(1) the age of the patient, (2) quality of
life issues, (3) surface area and (4) sites
affected
Topical therapeutic regimens are
prescribed including keratolytic agents,
topical anti-inflammatory compounds
(e.g. corticosteroids and calcineurin
inhibitors) and topical vitamin A and D
analogues
Systemic agents and phototherapy may
be needed in moderate to severe disease
Differential diagnosis
Nummular dermatitis
Seborrheic dermatitis
Tinea capitis
ID reaction
Pityriasis rubra pilaris
Lichen planopilaris
Tinea corporis
Atopic dermatitis (overlap
can rarely be seen)
322
S. Tolliver et al.
Macerated, well-demarcated
shiny erythema of the groin
region including the folds and
the genital skin
Napkin or
diaper
Psoriasis
(“nappy”)
Erythroderma Generalized erythema and
thickening of the skin,
sometimes with hyperkeratosis
Pitting, onycholysis,
onychodystrophy, splinter
hemorrhages oil spots,
subungual hyperkeratosis
trachyonychia: (i.e. Extensive
pitting and subungual
hyperkeratosis)
Nail
Onychomycosis
Secondary infection
1. Fungal culture and nail
Alopecia areata
plate biopsy to rule out tinea with
Lichen planus
Candida and/or
infection or secondary
Pityriasis rubra pilaris
candidal infection of the nail Streptococcus
bed is needed when subungual And/or dermatophytes Trauma
hyperkeratosis is present
2. Avoid trauma orexcess
manipulation (e.g. aggressive
manicures)
Secondary infections Irritant contact dermatitis
Biopsy may need to be
or perianal strep
Diaper dermatitis
performed
Candidal diaper dermatitis
Bacterial and fungal cultures
Allergic contact dermatitis
may be needed for suspected
secondary infections or
perianal strep
Atopic dermatitis
Fever, chills and
Two biopsies are generally
Congenital nonbullous
required from separate sites to malaise can
ichthyosiform
accompany
differentiate psoriatic
erythroderma, making Atopic dermatitis
erythroderma from other
bacteremia a possible Lichen planus
causes of erythroderma in
Pityriasis rubra pilaris
co-morbidity which
childhood
Seborrheic dermatitis
should be ruled out
conclusively ivia blood Langerhans cell
histiocytosis
cultures
Pityriasis rubra pilaris
Mycosis fungoides
Staph scalded skin
syndrome
(continued)
Topical anti-inflammatory agents can be
used similar to the therapy of extensive
plaque-type psoriasis; however, control
of extensive disease is difficult with
topical agents and systemic antiinflammatory agents and/ or
phototherapy are often required to
control severe and extensive disease
NB: Special care must be taken to acoid
systemic corticosteroids which can
precipitate a pustular flare
1. After treatment of any fungal
super-infection, topical corticosteroids
with tazarotene or calcipotriene can be
applied to the paronychial skin.
Intralesional kenalog can also be used in
the same region to reduce the subungual
inflammation
2. May require usage of topical
anti-infectives
Mild topical corticosteroids with or
without topical anti-candidal agents can
be helpful
Barrier therapy with zinc oxide pastes
reduces secondary irritant reactions
25 Pediatric Psoriasis
323
Source: Modified from Silverberg [24]
Co-morbidities
Bacterial or fungal
infections should be
ruled out through
culture
Generally, a clinical diagnosis, Rarely has any
however, biopsy is similar to morbidity
that of pustular psoriasis
Clinical appearance
Diagnostic features and tests
Erythroderma accompanied by 1. Biopsy is often needed
2. Bacterial culture of the
sterile pustule formation,
sometimes localized to the distal pustules
3. Fungal culture of the
extremities, sometimes
generalized. Prior history of oral pustules
4. ASO titers can be drawn to
steroid usage may be noted
rule out streptococcal
precipitant
Mucosal/oral Annular plaques on the tongue
may be noted in patients with
psoriasis
Type of
psoriasis
Pustular
Table 25.3 (continued)
Differential diagnosis
Blistering distal dactylitis
Acute generalized
exanthamatous pustulosis
Staphylococcal scalded
skin syndrome
Subcorneal pustular
dermatosis
Sweets syndrome Infected
dyshidrotic dermatitis
Tinea infection with Tinea
mentagrophytes
Herpetic whitlow
Hand foot mouth disease
Aphthosis
Lichen planus
White sponge nevus
Lichen sclerosis
Lichen simplex
Acrodermatitis
enteropathica
Contact dermatitis
No therapy is usually needed, however
topical medicaments in an oral base can
be used when needed
Treatment
Topical therapy (see plaque-type
psoriasis) are often ineffective and
systemic agents (especially
cyclosporine, acitretin) or topical PUVA
may be needed
324
S. Tolliver et al.
25 Pediatric Psoriasis
a majority of cases of pityriasis amiantaceia and
may play a causative role in disease [92].
Several case studies in the literature have
reported oral mucosal changes in adult patients
with psoriasis and there is debate over whether
these changes are part of the spectrum of psoriatic disease. Due to the transient nature of these
lesions clinical detection maybe difficult and
may be underdiagnosed [94]. Lesions of all areas
of the oral cavity, including the tongue, lips, buccal mucosa, gingivae and palate have been
reported. However, the overall incidence among
patients with psoriasis is low [95]. One study
found a 7.7% prevalence of this manifestation in
their cohort [94]. Fissured tongue and geographic
tongue (also called benign migratory glossitis)
are the most commonly reported oral lesions [95,
96], and the incidence of geographic tongue
increases as the severity (as measured by the
PASI score) of psoriasis increases [96]. Cases of
geographic tongue in children with psoriasis have
been also reported [97]. In a systematic review of
the literature the authors found no clear association with of tongue psoriasis with plaque psoriasis [94]. The histopathology of geographic tongue
resembles that of pustular psoriasis, leading some
experts in the field to believe that geographic
325
tongue and psoriatic skin lesions may be two
manifestations of the same disease process [98].
Although this manifestation has been difficult to
confirm it as a discrete clinical entity, it is now
commonly accepted in the community [94, 95].
Other potential causes such as candidiasis, lichen
planus, leukoplakia, and other autoimmune
mucosal manifestations must be ruled out before
the diagnosis can be confirmed [94].
The PASI score was devised to give objective
measurement to the severity of psoriasis, especially in regard to clinical research, however the
score has not been validated in childhood and
may not adequately reflect severity of childhood
disease especially as it lacks a pruritus or quality
of life component. It is a calculation based upon
the severity of psoriatic lesions (determined by
erythema, induration, and scale), location of
lesions, and total body surface area involved.
This calculation is outlined in Table 25.4, ranges
from 0 to 72, and can be used in older children
and adults [4]. A website is also available to simplify the PASI calculation [99].
Other methods of psoriasis scoring base the
overall severity of psoriasis on total body surface
area involved, quality of life impairment, and the
presence or absence of psoriatic arthritis. Still
Table 25.4 Psoriasis area severity index (PASI) calculation [4]
Body locations
Head
Trunk
Upper extremity Lower extremity
Severity of psoriatic lesions
0 = none; 1 = slight; 2 = moderate; 3 = severe; 4 = very severe
Erythema
0–4
0–4
0–4
0–4
Induration
0–4
0–4
0–4
0–4
Scaling
0–4
0–4
0–4
0–4
Totals
Head severity
Trunk severity
UE severity
LE severity
total
total
total
total
Surface area (SA) of psoriatic involvement
0 = none; 1 = 10% or less; 2 = 10–29%; 3 = 30–49%; 4 = 50–69%; 5 = 70–89%; 6 = 90–100%
Degree of involvement
0–6
0–6
0–6
0–6
Totals
Head SA total
Trunk SA total
UE SA total
LE SA total
Multiply severity total × SA total
Head combined Trunk combined UE combined
LE combined
total
total
total
total
Correction factor (based on area of
0.10
0.30
0.20
0.40
involvement)
Multiply combined totals × correction
Head corrected
Trunk corrected
UE corrected
LE corrected
factor
total
total
total
total
Add together Corrected Totals for each Body Location to obtain final PASI score
Source: Van de Kerkhof and Schalkwijk [4]
S. Tolliver et al.
326
others are based solely upon the total body surface area involved, with <3% being mild disease,
3–10% being moderate disease, and >10% being
severe disease. However, the latter method may
be oversimplified, as quality of life may be significantly impaired with minimal total body surface area involvement [100, 101]. One such
example is psoriatic lesions localized to the face,
which is much more common in children (affecting 38%) than their adult counterparts [11].
Alterations of PASI with extra weighting for
head and neck disease in children may more adequately reflect body surface area distribution in
smaller children. Facial disease in our experience
is the leading cause of patients and parents seeking systemic therapy.
Differential Diagnosis (Table 25.5)
The differential diagnosis of pediatric psoriasis
includes other papulosquamous diseases of childhood, including psoriaform id reactions, pityriasis rosea, and pityriasis rubra pilaris (PRP), as
well as lichen planus, dermatomyositis and lupus
erythematosus; as well, pustular disease and nail
Table 25.5 Differential diagnosis of pediatric psoriasis
Differential diagnosis of psoriasis
Differential of
generalized psoriasis Clues to diagnosis
Lichen planus
Purple, polygonal, planar
papules over the extensor
surfaces
Hypertrophic skin lesions in
individuals of color
Oral white erosive plaques
Nail changes include
longitudinal ridging and
pterygium formation
Pityriasis rubra
Small follicular papules,
pilaris
disseminated as well as notably
over anterior shins
Disseminated yellowish-pink to
salmon scaling patches including
scalp
Palmoplantar hyperkeratosis
Dermatomyositis
Poikiloderma, atrophy,
heliotrope sign, nailfold changes
Prominent hyperpigmentation in
patients of color
Table 25.5 (continued)
Differential diagnosis of psoriasis
Differential of
generalized psoriasis Clues to diagnosis
Cutaneous lupus
Does not typically involve
erythematosus
extensor surfaces
Discoid lupus with follicular
hyperkeratosis, including ear
comedones and scarring
SCLE usually more annular and
in sun-exposed areas
Photoexacerbation noted
Nasal bridge and cheeks more
commonly involved than
forehead/ nuchal
Malar rash/ photosensitivity
associated with systemic disease
Pityriasis rosea
Herald patch may be present
Disease comes up over 6 weeks
and resolves over 6 weeks
Typically oval lesions with a
collarette of scale that follow
skin cleavage lines of Langer
Differential of scalp psoriasis
Seborrheic
Greasy and yellowish scale
dermatitis
Tinea capitis
Positive potassium hydroxide
stain and fungal culture (for
dermatophyte)
Broken-off stumps of hairs,
often with pustules, alopecia and
cervical lymph nodes
Differential of guttate psoriasis
Small plaque
Variably erythematous (but often
parapsoriasis
less intense than psoriasis)
Covered with a fine scale
Red–brown and finely scaly
Pityriasis
papules
lichenoides
chronica
Indolent course and recurrent
crops
Pityriasis rosea
See above
Differential of inverse psoriasis
Tinea
Annular appearance with central
clearing
Positive potassium hydroxide
prep and fungal culture
Candidiasis
Beefy red macerated plaques
Satellite pustules
Erythrasma
Coral red fluorescence on
Wood’s lamp evaluation
Contact dermatitis Usually follows the pattern of
contactant exposure
Generally spares inguinal folds
(continued)
25 Pediatric Psoriasis
327
Table 25.5 (continued)
hyperkeratosis is distinguished from psoriasis by
the scales, which in psoriasis are silvery, light
and overlapping as well as by the papules with
extend peripherally to form patches in PRP [4].
Only about 1–4% of cases of lichen planus
are seen in children. Lichen planus mainly
affects the flexor surfaces of the wrists and
ankles with purple to violaceous, pruritic papules Nail changes in lichen planus include longitudinal ridging and pterygium formation. In
addition, chronic plaque psoriasis may need to
be distinguished from mycosis fungoides. As
both can have scaling and fissures, palmoplantar
plaque psoriasis mimics keratotic eczema of the
palms and soles. Examination of the rest of the
skin for evidence of psoriasis as well as margination of the lesions, which favors psoriasis, can
provide clues to the diagnosis. Further, chronic
lesions of dermatitis may look clinically and histologically similar to partially treated psoriasis.
Histological examination via biopsy is usually
the best method to differentiate these skin disorders from true psoriasis [4].
In the case of guttate psoriasis, the differential
diagnosis includes small plaque parapsoriasis,
pityriasis lichenoides chronica (PLC), and pityriasis rosea. Small plaque parapsoriasis ­typically
occurs in the middle aged and elderly, but can
occur in childhood. However, the lesions of guttate psoriasis do not typically affect the palms or
soles and are often more erythematous than those
of parapsoriasis. In PLC, the papules are erythematous to red–brown and scaly. There is no
Auspitz sign when the scale is lifted off. The
lesions of PLC come up in successive crops every
6–8 weeks and regress over weeks to months,
often with post-inflammatory hypopigmentation
in individuals of color. Tinea corporis is also on
the differential of guttate psoriasis, when the
lesions are more limited number or are annular.
Psoriasis of the flexures (inverse psoriasis) is
one cause of intertrigo. Other etiologies include
tinea corporis, cutaneous candidiasis, erythrasma,
and contact dermatitis. Candidiasis will usually
present with a beefy red color and satellite pustules. Contact dermatitis (usually irritant in
infants) typically spares the inguinal folds, unlike
psoriasis. Erythrasma can be differentiated by
Differential diagnosis of psoriasis
Differential of
generalized psoriasis Clues to diagnosis
Langerhans cell
Typically also have scalp scaling
histiocytosis
and crust
Adenopathy may accompany
lesions
Differential of palmoplantar psoriasis
Atopic dermatitis
Intensely pruritic vesicles and/or
bullae
May have other classic areas of
involvement (flexural surfaces)
Juvenile plantar
Balls of feet toe pads, and hands
dermatosis
symmetrically tender and
reddened, dry with shiny
appearance, may have scale and
painful cracks and fissures
Palmoplantar
Hereditary vs Acquired thick,
keratoderma
yellow hyperkeratosis, involves
the lateral aspects of the hands
and feet transgredient vs
non-transgredient
Reiter’s syndrome Urethritis, arthritis, ocular
findings, and oral ulcers in
addition to psoriasis form skin
lesions
Lesions on the plantar surface
with thick yellow scale and often
pustular (keratoderma
blennorrhagicum)
changes can be mimicked by cutaneous infections. Like psoriasis, the distribution of dermatomyositis can include extensor surfaces especially
elbows and knees. However, patients with dermatomyositis have skin changes that show poikiloderma, atrophy, a heliotrope sign, and nailfold
changes (on dermoscopy or capillaroscopy),
none of which are typically seen in psoriasis [4].
Lupus erythematosus, however, usually lacks
involvement of extensor surfaces. Furthermore,
psoriasis is generally improved by, not exacerbated by UV exposure [4]. The eruption of pityriasis rosea is typically located on the upper arms,
trunk, and thighs with a duration of a few weeks.
A herald patch is frequently noted, and lesions
are typically oval and follow skin cleavage lines.
Individual lesions only have a collarette of scale
and have crinkling of the epidermis [4]. PRP with
its small follicular papules, disseminated yellowish-pink scaling patches, and palmoplantar
S. Tolliver et al.
328
using a Wood’s lamp, demonstrating coral red
fluorescence. Tinea corporis typically shows an
annular border. In infants especially, the possibility of Langerhans cell histiocytosis needs to be
considered. In these patients, there may also be
scalp involvement with scaling and crust, lymph
node enlargement and internal organ
involvement.
On the scalp, tinea capitis, and seborrheic dermatitis often mimic psoriasis. Distinguishing feature of tinea capitis are broken-off stumps of
hairs, often in patches in which there are crusts
and pustule. When examined, the broken-off
hairs are loose and found to be surrounded by or
contain the fungus. Seborrheic dermatitis often
co-exists with psoriasis, although it’s uncommon
past infancy and prior to puberty. Although typically the scales in psoriasis are dry, shiny and
white, versus those of seborrheic dermatitis
which are greasy and yellowish, distinguishing
the two requires fungal culture.
Biopsy and Histology
Psoriatic lesions contain characteristic histologic
features when biopsied that can help differentiate
psoriasis from other skin diseases if the clinical
picture is unclear. A mixed inflammatory perivascular infiltrate is commonly seen in the dermis.
The epidermis appears acanthotic with focal
areas of spongiosis containing inflammatory
cells. There is thinning of the suprapapillary
plate, and the stratum granulosum may be absent.
Parakeratosis, the persistence of nucleated keratinocytes in the stratum corneum, is common [22].
Psoriatic plaques with dotted vessels can be seen
on dermoscopy [22].
There are two possible pathognomonic findings in psoriasis histology. The first is the spongiform pustule of Kogoj, characterized by a
spongiotic pustule filled with neutrophils in the
stratum spinosum. The second is the microabscess of Munro, characterized by the presence of
neutrophils in the stratum corneum. As the lesion
progresses, the rete ridges elongate and become
blunted, and the hyperproliferation of the epidermal keratinocytes becomes more apparent histo-
logically. In pustular psoriasis, there are more
marked accumulations of neutrophils in the epidermis, similar to the spongiform pustules of
Kogoj and microabscesses of Munro [4]. Lesser
known pathognomonic findings such as sandwich sign depict neutrophils and parakeratosis
alternating in the statum corneaum [102].
Therapeutic Management
(Table 25.2 and Fig. 25.6) [62]
Topical Therapies
Topical therapies are the initial treatment of
choice for pediatric patients with limited psoriasis of the skin (i.e. in the absence of joint disease). In general, thicker vehicles, such as
ointments, are more effective, but the location of
[62] involvement and patient preference will ultimately affect the decision of which vehicle will
be used. Thinner preparations are commonly
used on the scalp and face while thicker ones are
used on the extremities [103].
Keratolytics, such as urea, salicylic acid, and
α-hydroxy acids, are the most simplified of the
topical therapies. The mechanism of action of
these agents is through removal of the characteristic superficial hyperkeratosis of psoriatic
lesions, allowing for better penetration of other
topical therapies [21, 103]. Salicylic acid application can lead to percutaneous salicylism in
infants and is therefore avoided in this age group
[103].
One of the earliest topical therapies developed, and still in use today in some areas of the
world, is the Goeckermann regimen. It involves
topical application of coal tar, or a modified version with addition of a cream called liquor carbons detergents, followed by exposure to UV
light. It is proven to be effective in children, with
85% achieving >80% clearance in psoriatic skin
lesions [104]. The mechanism of action remains
unclear, but antimitotic effects, inhibition of
DNA synthesis, and enzyme inactivation may
play a role [103]. Despite its effectiveness, the
25 Pediatric Psoriasis
329
Diagnosis of
psoriasis in a child
Small BSA
involved
Topical agents
Adjuncts
Corticosteroids
Topical
exfoliants
Goeckermann
regimen
Omega-3 fatty
acids (oral)
Anthalin
Vitamin D3
derivatives
Calcineurin
inhibitors
None
Excimer laser
Oral antibiotic therapy +
topical agents;
tonsillectomy in
recurrent streptococcal
pharyngitis induced
flares
Larger BSA involved;
decreased quality of life
Perform screening tests before
prescribing systemic agents
Prior TB or HBV infection,
prior
malignancy/lymphoma,
immunosuppressed state
Localized
phototherapy
PUVA or
narrowband UVB
Evidence of
streptococcal infection
or rapid-onset
cutaneous disease with
pharyngitis
CBC, liver function
tests, lipid panel,
blood pressure, UA,
pregnancy test
Prior TB, HBV, cancer risk,
or immunosuppressed
TNF-a Inhibitors to
Biologic Agents
Topical agents
Enteracept
Generalized
phototherapy
Adalimumab
infliximab
PUVA or
narrowband UVB
Rotational
therapy
(6–12 mo alternating)
Methotrexate
Cyclosporin A
Acitretin
Ixekizumab
Ustekinumab
BSA = body surface area, TB = tuberculosis, HBV= hepatitis B virus,
CBC = complete blood count, UA = urinalysis, TNF-α = tumor necrosis factor alpha
PUVA = psoralen plus UVA
Fig. 25.6 Schema of psoriasis therapy in childhood, based on Silverberg [21]
Goeckermann treatment has fallen out of favor in
industrialized nations due to concern over its
long-term consequences. The coal tar contains
polycyclic hydrocarbons and, when exposed to
UV irradiation, this combination has been shown
to cause increased chromosomal abnormalities in
peripheral lymphocytes and an elevated Heat
Shock protein (specifically Hsp70) response in
children [105]. However, there is no concrete evidence demonstrating that treatment with coal tar
or its derivatives leads to an increase in skin cancer risk as compared to the general population
[103] A milder variation on this theme is to use
dilute tar bath additives the night before narrowband UVB therapy (1–2 caps tar added to tub and
soak 10–15 min).
Unfortunately, there are no Food and Drug
Administration (FDA) (United States) topical
therapies specifically approved for the treatment
of psoriasis in children under 12 years of age, but
there have been several studies demonstrating
efficacy of off-label agents, including topical corticosteroids, vitamin D2 and D3 derivatives, and
immunosuppressants (e.g. calcineurin inhibitors)
[106–108]. The strength and formulation of therapies should be based on the patient’s age, PASI
score, and impact on quality of life. A recent systematic review of 64 studies from The Netherlands
proposed an algorithm of beginning with topical
synthetic vitamin D3 derivatives with or without
topical corticosteroids, followed by anthralin
cream [106]. However, in the United States, topi-
330
cal corticosteroids are usually the initial treatment of choice [103].
Topical corticosteroids are frequently
employed by practitioners for the treatment of
pediatric psoriasis. The choice of which topical
steroids to use depends upon the skin areas
involved, and parallels the treatment algorithms
for atopic dermatitis in children. Low potency
steroids (classes 5–7) are used for more sensitive
areas such as the head, neck, and intertriginous
regions. Moderate potency (classes 2–4) steroids
are generally used on the scalp and extremities.
Higher potency (class 1) steroids are reserved for
persistent, thickened lesions that do not respond
to lower potency steroids [21, 103]. Two class 1
corticosteroids, clobetasol and halobetasol, have
been studied and found to be effective in children. Clobetasol (in some specific preparations)
is approved for children >12 years of age for
2 weeks or less, while halobetasol is not currently
FDA-approved for use in children. For scalp psoriasis, the combination of calcipotriene 0.005%
and betamethasone dipropionate 0.064%, or
taclonex, has been FDA-approved for patients
12 years or older [17]. Treatment duration with
class 1 steroids is often limited to 2 weeks in children, as these agents have an extensive side effect
profile with long-term use, including skin atrophy, striae, and potential hypothalamic-pituitaryadrenal (HPA) axis dysfunction [106, 107, 109].
All topical corticosteroids if used prolongedly
and especially over large surface areas, including
classes 2–7, are theoretically associated with
these adverse effects as well. The risk of systemic
absorption and HPA dysfunction increases with
the body surface area to which the steroid is
applied increases. This is of particular concern in
children, as they have usually not yet reached
their growth potential [21]. A recent systematic
review of the use of topical corticosteroids
showed no systemic and minimal topical adverse
effects in the studies included. The incidence of
adverse events can be decreased by rotating the
use of topical corticosteroids with other topical
treatments listed below [103].
Anthralin 1% cream, or dithranol, is a topical
therapy that can be used for localized areas of
psoriasis. It is an anti-proliferative and immuno-
S. Tolliver et al.
suppressive agent which inhibits T-lymphocytes
through an unclear mechanism of action. Adverse
effects are minimal due to limited systemic
absorption and include irritation and staining of
clothing or hair [103, 106]. Short contact therapy
for several minutes a day minimizes staining and
irritation of the skin [103].
Vitamin D3 derivatives, such as calcipotriol/
calcipotriene or calcitriol, have also been proven
to be effective in children with psoriasis. Side
effects include local reactions such as erythema,
irritation and pruritis. Mechanistically, they
inhibit keratinocyte proliferation which allows
them to work synergistically with corticosteroids
[22]. There is also a theoretical risk of systemic
absorption leading to elevated serum calcium levels, especially when applied to a large body surface area [106, 110, 111]. Doses of calcipotriene
up to 45 g/m2/week have been shown to have no
significant effect on calcium homeostasis in children [103]. A head-to-­head comparison of calcipotriol and anthralin showed similar efficacy in
psoriatic children [112]. Clinical trials determining the long-term safety and efficacy of calcitriol
ointment, vectical, are underway and may lead to
the first FDA-approved topical treatment for
pediatric patients under 12 years old.
Tazarotene, a topical retinoid, is also effective
for limited psoriatic skin disease and nail psoriasis [103]. Topical calcineurin inhibitors, such as
tacrolimus and pimecrolimus, have also been
shown to promote the clearance of psoriatic
lesions in children [106, 113]. These agents are
immunosuppressants that inhibit cytokine production (IL-2 in particular) by T lymphocytes
and thus limit their proliferation. Tacrolimus
(0.03% for children ages 2–15 years and 0.1%
ointment for ages 16 years and over) and pimecrolimus 1% cream are approved for the treatment of
atopic dermatitis in children >2 years of age, but
its use is off-label for psoriasis [103, 113]. The
advantage of these agents is the lack of potential
skin atrophy, allowing their use in more sensitive
areas such as the face, neck, and intertriginous
areas [103, 113]. However, use of calcineurin
inhibitors on plaque psoriasis how been shown to
be less effective likely secondary to poor absorption rates in the skin [111]. Side effects most fre-
25 Pediatric Psoriasis
quently noted include local irritation and pruritis
[106]. This class of topical medication also carries a black box warning in the US due to a theoretical increased risk of skin cancer and
lymphoma. Sun protection is therefore advisable
concurrent with calcineurin inhibitor products
[114].
331
adults. Therefore, the use of systemic antibiotics
for the treatment of pediatric psoriasis remains
controversial [106, 116, 119]. Tonsillectomy has
been recommended by some as a treatment for
recurrent guttate psoriasis [117], but this has also
not been proven to be effective in an evidencebased manner [106, 119].
Methotrexate was the original therapy available for extensive psoriasis. It is generally safe in
Systemic Therapies (Table 25.2
children and is a well-established treatment for
moderate to severe psoriatic disease. Methotrexate
and Fig. 25.6)
is also the drug of choice for patients with psoriSystemic therapies for the treatment of pediatric atic arthritis in addition to skin disease [120].
psoriasis are usually reserved for those patients Methotrexate is associated with a >75% improvewho have failed topical treatments, have exten- ment in PASI score [121]. Dosages used range
sive body surface area involvement, have signifi- from 0.2 to 0.7 mg/kg per week [120–122]. The
cant impairment in quality of life and/or most common side effect in children is nausea
psychological health, or have concomitant psori- and vomiting. Although routine monitoring of
atic arthritis. Like all systemic medications, the blood counts and liver function tests are recomagents available for use in pediatric psoriasis mended, bone marrow suppression, such as
have side effects. For this reason, many physi- microcytic anemia and pancytopenia, and liver
cians employ a cyclic approach for systemic ther- toxicity are rare adverse drug events.
apy, alternating between different available
Liver toxicity appears to be relatively rare in
treatments every 6–12 months to minimize long- children, although obesity and associated fatty
term adverse events. Systemic therapies include liver changes are associated with an increased
oral antibiotics, methotrexate, cyclosporine A, risk of this adverse reaction [106, 120, 122].
retinoids, TNF-α inhibitors, and biologics.
Concomitant folic acid supplementation (1 mg/
Oral antibiotics are considered the safest of day) is protective against bone marrow suppresthe systemic agents due to their superior side sion and liver enzyme abnormalities [123].
effect profile. Benefits with oral antibiotics are
Cyclosporine, another immunosuppressant
most impactful in the setting of severe, rapid-­ which inhibits cytokine signaling by lymphoonset cutaneous disease following streptococcal cytes, may be effective for psoriatic skin disease
pharyngitis or perianal streptococcal disease, and in children. In doses ranging from 2 to 4 mg/kg/
in pustular and guttate psoriasis [115–117]. A day, cyclosporine can improve the overall severrecent controlled trial of 50 patients (ages ity and appearance of skin lesions, but studies
13–63 years) found that a 48-week course of investigating its effectiveness in children are limazithromycin therapy (4 days of azithromycin ited [124, 106, 125, 126]. Recent studies from
500 mg tab once-daily, followed by 10 days off India followed 8 children’s use of cyclosporine
therapy, with repeat of the cycle every 2 weeks) and found the drug to have few side effects,
resulted in a PASI 75 of 80% at 48 weeks in the abdominal pain and increased creatinine, with
treatment group as compared to no significant significant improvement in psoriatic lesions.
difference in the control group. Only 12 patients These patients were treated until achieving a
had a positive ASLO test for streptococcal infec- PASI 75 then subsequently tapered 50 mg every 2
tion [118]. Despite this and other studies demon- weeks [126]. Because of its rapid onset this medstrating an association between streptococcal ication can be utilized as a “rescue” treatment
infection and the onset of psoriasis, it remains and then switched to a safer drug for maintenance
unclear whether antibiotic therapy improves therapy [126, 127]. In addition, its use is hindered
PASI scores or disease clearance in children or by the side effects of nephrotoxicity, secondary
332
hypertension, hyperlipidemia, and immunosuppression as well as the requirement for close
monitoring of blood pressure and renal functioning, which is more likely to become permanently
impaired in individuals on therapy beyond
6 months (Table 25.2). Cyclosporine is of particular benefit for the therapy of pustular psoriasis
(Poster SPD) [127]. Reports of an increased cancer risk secondary to immunosuppression have
also been reported, but the low doses, diligent
monitoring, short courses and rotational therapies used in treatment of skin-limited psoriasis
decrease these risks [120].
Retinoids, such as acitretin or etretinate, are
other treatment options for children with pustular, erythrodermic, or plaque psoriasis, although
they are not as extensively studied or as safe as
methotrexate [106, 128]. Adverse effects include
teratogenicity, elevation of liver enzymes,
impaired lipid profile, alterations in blood counts,
and bony abnormalities. Due to the ability of retinoids to cause severe birth defects, oral contraceptives are recommended for 1 month before
initiating therapy and for 3 years after the cessation of therapy in girls of childbearing age [22].
Isotretinoin may be a preferred choice for those
at risk of pregnancy. Good pregnancy prevention
(2 methods of birth control) and monitoring for
pregnancy are needed in those of child bearing
age. Close monitoring of liver function tests and
lipid profiles during therapy are necessary as
well. High-dose systemic retinoids used for
greater than 2.5 years have been associated with
premature epiphyseal closure in children.
Hyperostosis and osteoporosis are other potential
bony side effects [129]. However, cyclic shortterm therapy for 6–12 months, as indicated in
rotational therapy, decreases the risk for bony
abnormalities. Longer courses of treatment in
children require periodic skeletal surveys [120].
TNF-α inhibitors, such as etanercept, adalimumab, and infliximab, have been used to treat
pediatric psoriasis, but only entercept is approved
for this purpose. This recent change comes after a
recent randomized double-blinded, placebo-controlled study showed promising long-­term safety
data with beneficial effects on quality of life in
pediatric patients [17, 130]. With the paucity of
S. Tolliver et al.
literature determining long term safety data in
pediatric patients treated specifically for psoriasis, there is much debate on this use of biologics
in this population. Early studies determining long
term safety profiles for these drugs are being conducted. One study followed 12 patients over
8 years and found similar side effects, infections
and injection-site reactions, previously reported
by other investigations [131]. Furthermore, they
found that up to 50% of patients initially treated
with etanercept needed to switch to another biologic. Whether this is due to the changing immunologic make-up in pediatric patients remains to
be seen. However, this suggests a potential treatment strategy for failed biologic therapies [124,
131–134].
TNF-α inhibitors have been used to treat rheumatoid arthritis, tumor necrosis factor
1-­associated fever, juvenile idiopathic arthritis,
ulcerative colitis and Crohn’s disease in children
for more than a decade [21]. The most extensive
studies of the safety of TNF-α inhibitors in children come from research investigating their use
in juvenile rheumatoid arthritis, with up to 8 years
of published data on this subject. Side effects
include reactivation of latent tuberculosis or hepatitis infections as well as increased risks for
malignancies including lymphoma, opportunistic
infections, and demyelinating disease. The FDA
has recently placed a black box warning on
Enbrel for pediatric psoriasis stating, “Lymphoma
and other malignancies, some fatal, have been
reported in children and adolescent patients
treated with TNF blockers, including Enbrel.” A
recent retrospective cohort study comparing 9045
pediatric psoriasis patients and 77, 206 healthy
controls found that there was no overall increased
cancer risk when taking TNF-a inhibitors.
However, lymphoma the primary cancer reported
in these patients [135].
In one study following pediatric patients with
juvenile rheumatoid arthritis treated with etanercept, no cases of tuberculosis, opportunistic
infections, malignancies, lymphomas, lupus,
demyelinating disorders, or deaths were reported
after 8 years [136]. The most commonly reported
side effects with etanercept specifically are injection site irritation and non-­opportunistic infection
25 Pediatric Psoriasis
[106]. Interestingly, there have studies showing
that TNF-α inhibitors are associated with outbreaks of psoriasis and other cutaneous manifestations in children and adults being treated for
other autoimmune disease processes [124, 132,
133, 137, 138]. One study suggests that this
potential is a result from the loss of inhibition of
TNF-α on dermal plasmacytoid dendritic cells
which leads to increases in IFN-γ [132, 133].
Emerging data regarding this phenomenon is
especially seen in children with IBD with one
study demonstrating 8.8 percent of their patients
treated with TNF-α inhibitors developing psoriasis [132]. Another study based on patients with
JIA found a 5.4% prevalence of psoriasis when
using TNF-α inhibitors, with female predominance and low incidence of personal or family
history of psoriasis [132]. As for which TNF-α
drug is most likely to cause this adverse effect
remains to be seen, some studies showed equal
prevalence of psoriasiform lesions when using
both adalimumab, infliximab and etanercept
while other studies implicate infliximab as the
culprit [132–134, 139, 140]. More studies on this
subject are needed to understand this paradoxical
side effect of TNF-α inhibitors.
The literature as well as clinical practice are
trending toward increased use of biologics with
as much as 25% of children with psoriasis being
treated with these medications [141]. When
determining which patients will benefit from biologic therapy consider children and adolescents
with greater than 10% BSA, DLQI >10, failed
standard therapies or other contraindications
[142] with special attention to educating patients
on the risks and benefits of using these medications. Some studies suggest using systemic therapies earlier in mild psoriasis and patients with
lower DLQI scores. Allowing patients to advance
to systemic treatment may improve quality of life
[135]. Vaccinations are another special consideration for patients starting biologic therapy. Live
vaccines are absolute contraindications to biologic therapy [142, 143]. Biologics, over other
systemic treatments like methotrexate and cyclosporine, require less stringent treatment schedules, have fewer adverse effects, decreased need
for monitoring, and greater efficacy [144].
333
However, the safety profile of these medications
are still being elucidated [141].
Biologic agents initially approved in adults have
been examined and approved in childhood and
adolescent psoriasis [145]. Etanercept, which is the
most extensively studied of the TNF-α inhibitors in
children, has recently been approved for use in
children 6 years and older with ulcerative colitis
and Crohn’s disease, and is now approved to treat
psoriatic arthritis and plaque psoriasis in adults and
pediatric patients 4 years and older [130, 146].
Etanercept at doses of 0.8 mg/kg weekly has been
shown to achieve PASI 90 in 27% and PASI 75 in
57% of treated patients as compared to 11 and 7%
of placebo-treated patients after 12 weeks of treatment respectively [147]. This benefit appears to be
maintained in the majority of patients after
96 weeks [148]. Etanercept has also been shown to
improve overall and disease-specific quality of life
in children with moderate to severe plaque-type
psoriasis [149]. It has also been shown to improve
depression in adults, irrespective of disease clearance. This suggests that the inflammatory response
itself, rather than the psychological effects of an
undesirable physical appearance, may contribute to
depressed mood in psoriatic patients [150, 151].
Other TNF-α inhibitors have not been extensively
studied in children with psoriasis [106].
Adalimumab is currently not FDA-approved in
the USA. However, with increasing understanding
of the chronicity of psoriasis and associated co-morbidities, long-term treatment with safe and effective
drugs are an important area of research. Recent
results from Phase 3 clinical trials comparing the
efficacy and safety of adalimumab and methotrexate
are promising [152]. Patients were able to maintain
resolution of disease with 0.8 mg/kg every other
week in this study for 52 weeks. Furthermore,
patient’s refractory to methotrexate were able to
achieve improvement when switched to adalimumab every other week. Patients were found to have
a similar safety profile as adults with nasopharyngitis and upper respiratory infections being the most
common adverse effects [152]. The safety of adalimumab in pediatric patients was further studied in
patients who were being evaluated for its use in JIA,
pediatric enthesitis-related arthritis, psoriasis, and
crohns disease [153]. In 577 patients who partici-
S. Tolliver et al.
334
pated in clinical trials dating back to September
2002 the most common side effects reported were
infections with no malignancies reported at all. This
study adds to the amounting evidence that adalimumab is safe in pediatric patients with similar
adverse events as in adults [153].
Ustekinumab or Stelara, is emerging as safe
and efficacious treatment modality for improvement of moderate to severe psoriasis in adolescents. Ustekinumab is an Il-12 and IL-23 inhibitor
that is FDA approved for patients 6 years or older
[140]. Its dosing schedule recommends starter
doses at week 0 and week 4 then once every
12 weeks thereafter. This less involved dosing
schedule is ideal for adolescents with many time
sensitive activities [128]. It has been shown to
have a favorable side effect profile and efficacy
comparable to adult populations being treated for
psoriasis [140]. The CADMUS Jr trial addressed
efficacy of ustekinumab in 6-12 year old children
with moderate to severe psoriasis, with 84% of
children achieving PASI 75 and 64% PASI 90 by
12 weeks, with no new safety signals [154].
Approval in children 6 years of age and older has
been granted in the United States.
The IXORA-PEDS study addressed the highaffinity IL-17a monoclonal antibody ixekizumab
in pediatric psoriasis. PASI-75 was 89% at week
12. Approval in children 6 years of age and older
has been granted in the United States [155].
Other potential treatments are being considered
for cases refractory to the TNF-a inhibitors,
ixekizumab and ustekinumab such as guselkumab, apremilast, secukinumab. Guselkumab is
an anti-­
interleukin-­
23 monoclonal antibody.
There is a paucity of literature for the use of
guselkumab in even adult patients. However, the
recent NAVIGATE clinical trial demonstrates the
efficacy of guselkumab in ustekinumab refractory patients [156]. In this study guselkumab was
shown to have a greater efficacy when compared
to ustekinumab in patients unable to achieve 0 or
1 investigator assment scores. The safety profile
of guselkumab and ustekinumab were similar
with guselkumab having a slightly higher incidence of adverse events, infection being reported
most often [156]. As for pediatric patients, there
is one case report of guselkumab use in a patient
refractory to high potency topical steroids, phototherapy, and systemic treatments such as methotrexate, adalimumab, and ustekinumab [157]. In
this patient guselkumab was added to the dosage
of methotrexate and the patient’s psoriatic
plaques thinned by week 4 with full resolution by
5 months. No adverse effects were reported. This
case report demonstrates a potential future treatment modality in which patient’s refractory to
other biologics and systemic agents can achieve
remission of their disease [157]. There is one
case report in the literature that details the use of
apremilast an oral phosphodiesterase-4 inhibitor,
in a 14-year-­old boy with guttate psoriasis [102].
Previous therapies used include topical therapies,
natural light exposure, antibiotics. Apremilast
was prescribed at the adult dosing based on the
patient’s weight. After 6 months of therapy the
patient had improved in both his skin disease and
quality of life [102]. There have been reports of
psychological distress in adults taking apremilast, depression and suicidal ideation, thus warranting monitoring [158]. To date there are no
case report detailing the use of secukinumab, and
IL-17 inhibitor, treating plaque psoriasis in pediatric patients. There have been case reports demonstrating its use in patients with recalcitrant
nails disease which suggests other potential indications for pediatric patients [143]. Several clinical trials are underway to determine the safety
profile and efficacy of secukinumab in patients’
children and adolescents with moderate to severe
psoriasis as well as dosing strategies.
Phototherapy
UV light therapy is used to treat a variety of skin
diseases in children, including atopic dermatitis,
vitiligo, acne vulgaris and psoriasis [159]. When
determining what patients are good candidates for
phototherapy a thorough assessment of history,
former unsuccessful treatments, availability and
transportation should be completed [111].
Indications for use include older pediatric patients
with extensive disease, contraindications to systemic treatments, guttate psoriasis, and thinner
plaques. Phototherapy is available in the form of
25 Pediatric Psoriasis
broadband UVB, narrowband UVB or UVA in
combination with psoralen (PUVA). Both UVB
and UVA have been shown to be efficacious when
be used in combination with topical steroids, topical retinoids, emollients, coal tar or vitamin D
analogs [111]. Narrowband UVB (NB UVB) and
PUVA therapy have shown the most success in
treating children with psoriasis [21, 103, 159].
However, NBUVB (311 nm) is the treatment of
choice, as PUVA therapy has been associated with
an increased risk of carcinogenesis in adult
patients with psoriasis and development of cataracts in pediatric patients with psoriasis [111,
159]. NB UVB is also highly effective and safe,
with a response rate approaching 80% in pediatric
patients [111, 160]. Topical PUVA therapy is
therefore recommended for refractory palmoplantar psoriasis based on its side effect profile [111].
If PUVA therapy is used, topical psoralen is preferred, due to the necessity for 24 h of protective
eyewear following treatment with oral psoralen.
For this reason and the increased risk of other systemic adverse reactions, oral psoralen should be
avoided children less than 12 years of age.
Absolute contraindications include diseases characteristically exacerbated by UV light, such as
lupus erythematosus, dermatomyositis, and xeroderma pigmentosum [111].
Common adverse events of phototherapy
include local irritation and erythema. There is
also the possibility of reactivation of a latent herpesvirus infection, photoaging, and the long-term
risk of carcinogenesis [106, 159–162].
Phototherapy maybe administered in the form of
a handheld laser, phototherapy booth, or hand/
foot units. If a phototherapy booth is employed,
the child must be old enough to remain still for
the length of each therapeutic session [21].
Compliance issues in younger children may
restrict treatment, thus phototherapy is often
more useful in adolescents [21, 159]. Although
there are no strict guidelines on the age in which
phototherapy can be initiated, school age children are a reasonable starting point, however
younger patients, if able, can still receive therapy
[111]. Special considerations for teenagers using
phototherapy include tanning bed use. This presents an increased risk for adverse reactions such
335
as burning, redness, and pain because of the
increased amount of ultraviolet exposure [111].
Therapy is required once or twice per week for a
1–3 months before psoriatic lesions clear and a
maintenance phase can be reached [21]. This can
be difficult for many families with busy schedules and varying temperaments in young children. A potential option for this barrier is to
consider home treatment using either 10–15 min
of natural sunlight or at home light boxes. As for
natural sunlight, this option can be considered
during the spring and summer months and is cost
effective [111]. Potential barriers include schedules during day light hours that may make it difficult to be outside like school in adolescent
children. As for home light therapy, this option is
for children in need of long-term therapy and has
the benefit of it less intimidating that a doctor’s
office. As a tradeoff, these treatments are usually
longer because of lower fluences and necessitate
direct parental supervision [111].
Excimer laser, a narrowband UVB 308 nm
laser light source has been described to be effective for the therapy of localized psoriasis. Scalp,
palms and soles and areas on the face and body
can be treated. Some data on usage in childhood
shows benefit for children with localized psoriasis, and children may experience superior benefit
with excimer usage. Therapy has some ultraviolet
light induced side effects, but is generally well
tolerated [163].
Natural Supplements
Various natural supplements have been investigated in the treatment of pediatric psoriasis and this
is a common topic of inquiry among parents. No
natural remedies have found to be curative, but a
few may help alter the disease progress. Omega-3
fatty acids, such as those found in salmon and other
fatty fish, may lead to slight improvements in PASI
score. As previously mentioned, this finding is supported by the observation that Inuit populations,
which consume diets high in omega-3 fatty acids,
have a low incidence of psoriasis. The benefits of
omega-3 fatty acid supplementation are superior to
omega-6 fatty acid supplementation. The mecha-
S. Tolliver et al.
336
nism of action appears to be alterations in the level
of eicosapentanoic acid and arachidonic acid, leading to decreased production of pro-inflammatory
metabolites [43]. The benefits of omega-3 fatty
acids are minimal or possibly non-existent, but this
supplement appears to be essentially harmless, and
thus safe for use in children. There may be a more
important role for dietary changes in pediatric
patients with metabolic syndrome and psoriasis,
due to the recent association between these two disease entities. Diets low in fat and high in fiber have
been found to beneficial in treating metabolic syndrome in children, and along with exercise, can
even cure patients of this condition with lasting
benefits into adulthood [164, 165].
Indigo naturalis, a traditional Chinese medicine, has been reported to aid in clearance of
pediatric psoriatic lesions after 8 weeks of topical
application in one anecdotal study [166]. Other
traditional Chinese medicines and natural supplements may ultimately cause more harm than benefit and it is important for dermatologists to be
aware of the potential side effects of these therapies [167]. The role of this medication in children
is unknown at this time.
Dietary Recommendations
The role of diet and supplementation in the management of psoriasis is controversial. Anecdotally,
some patients report improvement of symptoms
with changes in diet. Healthier food choices lead
to reductions in heart disease, diabetes, and obesity, however, the effect of healthier food choices
on the disease burden of psoriasis remains
unclear. The National Psoriasis Foundation overall recommends meals nutritionally balanced
with lean proteins, whole grains, fresh produce,
and healthy fats, and is sometimes referred to as
the “anti-­
inflammatory” or Mediterranean diet
[168, 169]. Foods that promote inflammation
include fatty red meats, processed foods, refined
sugars, and dairy products [168]. Although there
is limited evidence to justify changing eating
habits there is a well-established linked between
metabolic syndrome, obesity and psoriasis [169].
Body fat has pro inflammatory mediators that
may exacerbate psoriatic lesions [84]. Thus, the
benefits of a healthy balanced diet remains an
important factor in overall management of psoriatic patients. Furthermore, adiposity has been
noted to precede onset of psoriasis, making diet a
potentially important preventive agent [170, 171]
Dietary modifications that eliminate foods and
the role of large supplements in children are concerning for risk of side effects and potential malnutrition. Recent studies investigating dietary
recommendations for adults with psoriasis or psoriatic arthritis have shown that hypocaloric diets
leading to weight loss in overweight and obese
adults has a positive impact on patients regarding
psoriasis severity and dermatologic quality of life
[169]. Hypocaloric diets refer to ranges from 800
to 1400 kcal per day. Diet alone does not maintain
psoriasis remission and adjunctive biologic therapy is recommended [169]. Whether the type of
diet or weight reduction leads to the reduced
severity needs further investigation. The benefit of
calorie restriction in children is unknown and
therefore, it is best to work with the parents, children, nutritionists and the pediatrician to find the
best strategy for healthier weight achievement
and maintenance. Gluten-free diets in psoriatic
with celiac disease were highly recommended.
Psoriatic patients with positive serologic markers
for gluten sensitivity were recommended to
undergo a 3-month trial of gluten-free diet with
adjunctive medical therapy [169]. As for adult
patients with psoriatic arthritis, it was highly recommended that they undergo a trial of vitamin D
supplementation with 0.5 μg alfacalcidol or 0.5–
2.0 μg of calcitriol daily [169]. Usage of oral vitamin D supplements in children with psoriasis and/
or psoriatic arthritis has not been adequately
explored at this time. For other supplements, such
as omega-3 fatty acids, selenium, Vitamin B12,
and micronutrients evidence was limited and
therefore no recommendations were made.
Conclusions
Psoriasis of childhood is a common and complex
disorder that can occur from birth up through
adolescence. Consideration for the child’s emo-
25 Pediatric Psoriasis
tional well-being and general health, including
risk factors for the metabolic syndrome and possible side effects of therapy, have to be given
when choosing therapy for this disease. Recent
advances in phototherapy and biologic therapy
have expanded the armamentarium of this disease. Greater research is needed to assess the
benefits of therapy on long-term disease manifestations and the risks of lymphoma and other
potential side effects of therapy.
References
1. Seyhan M, Coşkun BK, Sağlam H, Ozcan H, et al.
Psoriasis in childhood and adolescence: evaluation
of demographic and clinical features. Pediatr Int.
2006;48(6):525–30.
2. Gudjonsson JE, Thorarinsson AM, Sigurgeirsson B,
Kristinsson KG, et al. Streptococcal throat infections
and exacerbation of chronic plaque psoriasis: a prospective study. Br J Dermatol. 2003;149(3):530–4.
3. Kumar B, Jain R, Sandhu K, Kaur I, et al.
Epidemiology of childhood psoriasis: a study of
419 patients from northern India. Int J Dermatol.
2004;43(9):654–8.
4. Van de Kerkhof PCM, Schalkwijk J. Psoriasis.
In: Bolognia JL, Jorizzo JL, Rapini RP, editors.
Dermatology. 2nd ed. Philadelphia: Mosby Elsevier;
2008.
5. Koebnick C, Black MH, Smith N, Der-Sarkissian
JK, et al. The association of psoriasis and elevated
blood lipids in overweight and obese children. J
Pediatr. 2011;159(4):577–83.
6. Vogel SA, Yentzer B, Davis SA, Feldman SR,
et al. Trends in pediatric psoriasis outpatient health
care delivery in the United States. Arch Dermatol.
2012;148(1):66–71.
7. Raychaudhuri SP, Gross J. Comparative study of
pediatric onset psoriasis with adult onset psoriasis.
Pediatr Dermatol. 2000;17:174–8.
8. Fan X, Xiao FL, Yang S, Liu JB, et al. Childhood
psoriasis: a study of 277 patients from China. J Eur
Acad Dermatol Venereol. 2007;21(6):762–5.
9. Kwon HH, Na SJ, Jo SJ, Youn JI. Epidemiology
and clinical features of pediatric psoriasis in tertiary
referral psoriasis clinic. J Dermatol. 2012;39:260–4.
10. Tollefson MM, Crowson CS, McEvoy MT,
Maradit KH. Incidence of psoriasis in children:
a population-­
based study. J Am Acad Dermatol.
2010;62(6):979–87.
11. Morris A, Rogers M, Fischer G, Williams
K. Childhood psoriasis: a clinical review of 1262
cases. Pediatr Dermatol. 2001;18(3):188–98.
12. Wu JJ, Black MH, Smith N, Porter AH, et al. Low
prevalence of psoriasis among children and adolescents in a large multiethnic cohort in southern
California. J Am Acad Dermatol. 2011;65(5):957–64.
337
13. Stefanaki C, Lagogianni E, Kontochristopoulos G,
et al. Psoriasis in children: a retrospective analysis. J
Eur Acad Dermatol Venereol. 2011;25(4):417–21.
14. Kurd SK, Gelfand JM. The prevalence of previously
diagnosed and undiagnosed psoriasis in US adults:
results from NHANES 2003–2004. J Am Acad
Dermatol. 2009;60:218–24.
15. Gelfand JM, Weinstein R, Porter SB, Neimann AL,
et al. Prevalence and treatment of psoriasis in the
United Kingdom: a population-based study. Arch
Dermatol. 2005;141(12):1537–41.
16. Radtke MA, Fölster-Holst R, Beikert F, Herberger
K, et al. Juvenile psoriasis: rewarding endeavours
in contemporary dermatology and pediatrics. G Ital
Dermatol Venereol. 2011;146(1):31–45.
17. Eichenfield LF, Paller AS, Tom WL, Sugarman J,
Hebert AA, Friedlander SF, Siegfried E, Silverberg
N, Cordoro KM. Pediatric psoriasis: evolving perspectives. Pediatr Dermatol. 2018;35(2):170–81.
18. Zhang X, Wang H, Te-Shao H, Yang S, et al. The
genetic epidemiology of psoriasis vulgaris in
Chinese Han. Int J Dermatol. 2002;41(10):663–9.
19. Icen M, Crowson CS, McEvoy MT, Dann FJ, et al.
Trends in incidence of adult-onset psoriasis over
three decades: a population-based study. J Am Acad
Dermatol. 2009;60(3):394–401.
20. Paller AS, Singh R, Cloutier M, Gauthier-Loiselle
M, Emond B, Guérin A, Ganguli A. Prevalence of
psoriasis in children and adolescents in the United
States: a claims-based analysis. J Drugs Dermatol.
2018;17(2):187–94.
21. Silverberg NB. Update on pediatric psoriasis, part 2:
theurapeutic management. Cutis. 2010;86(4):172–6.
22. Smith R. Pediatric psoriasis treated with apremilast.
JAAD Case Rep. 2016;2(1):89–91.
23. Silverberg NB. Atlas of pediatric cutaneous biodiversity. New York: Springer; 2012.
24. Silverberg NB. Update on pediatric psoriasis,
part 1: clinical features and demographics. Cutis.
2010;86(3):118–24.
25. Schwartz G, Paller AS. Targeted therapies for
pediatric psoriasis. Semin Cutan Med Surg.
2018;37(3):167–72.
26. Pourchot D, Bodemer C, Phan A, Bursztejn AC.
et all. Nail psoriasis: a systematic evaluation in
313 children with psoriasis. Pediatr Dermatol.
2017;34(1):58–63.
27. Lewkowicz D, Gottlieb AB. Pediatric psoriasis and psoriatic arthritis. Dermatol Ther.
2004;17(4):364–75.
28. Stoll ML, Nigrovic PA. Subpopulations within juvenile psoriatic arthritis: a review of the literature. Clin
Dev Immunol. 2006;13(2–4):377–80.
29. Stoll ML, Punaro M. Psoriatic juvenile idiopathic arthritis: a tale of two subgroups. Curr Opin
Rheumatol. 2011;23(5):437–43.
30. Stoll ML, Nigrovic PA, Gotte AC, Punaro
M. Clinical comparison of early-onset psoriatic
and non-­psoriatic oligoarticular juvenile idiopathic
arthritis. Clin Exp Rheumatol. 2011;29(3):582–8.
31. Kaushik SB, Lebwohl MG. Psoriasis: which therapy for which patient: focus on special popula-
Challenges in Psoriasis Treatment:
Nail, Scalp, and Palmoplantar
Involvement
26
Jeffrey J. Crowley
Abstract
Psoriasis can affect many areas of the body
and treatments should target the areas of
involvement. Nail disease is difficult to treat
with topical therapy as the vehicle must be
optimized to penetrate the nail and surrounding tissues. Some of the inflammation in nail
disease is deep in the nail matrix and thus difficult for topical therapies to access. Scalp disease is difficult to treat with topical and
phototherapy due to the presence of hair, bathing habits, and convenience issues. The palms
and soles often have particularly thick plaques
of psoriasis which may prevent absorption of
topical therapy and resist phototherapy.
Patients with primarily palmoplantar disease
often do not respond to multiple therapies, and
many require combination therapy for disease
control. Collectively, nail, scalp, and palmoplantar psoriasis are considered “tough to
treat” and often do not respond as well as
plaque psoriasis elsewhere on the body. This
chapter will critically address the challenges
posed by each condition and evaluate available treatment options.
J. J. Crowley (*)
Bakersfield Dermatology and Skin Cancer Medical
Group, Bakersfield, CA, USA
© Springer Nature Switzerland AG 2021
J. M. Weinberg, M. Lebwohl (eds.), Advances in Psoriasis,
https://doi.org/10.1007/978-3-030-54859-9_26
Key Learning Objectives
1. To understand the diagnosis and management of nail psoriasis
2. To understand the diagnosis and management of scalp psoriasis
3. To understand the diagnosis and management of palmoplantar psoriasis
Nail Psoriasis
Psoriasis is a chronic systemic inflammatory disease involving the skin, nails, and joints.
Approximately 50% of psoriasis patients have
some nail involvement and the lifetime incidence
of nail disease is estimated at 80–90%. Nail disease may rarely be the only manifestation of psoriasis [1]. Nail psoriasis is associated with higher
overall disease severity and male gender.
Importantly, nail psoriasis can cause significant
pain, discomfort, and embarrasment, leading to
impairment in quality of life (QoL) and work
function [2, 3].
There is a strong correlation of nail psoriasis and psoriatic arthritis [4]. Psoriatic arthritis
patients have rates of nail disease as high as 70%
and there is evidence that nail psoriasis may be
a predictor of joint disease developing later in
life [5]. Psoriatic arthritis may involve the distal interphalangeal joints and the anatomic link
343
J. J. Crowley
344
between these joints and the nail unit may result
in nail changes. In fact, nail disease is one of the
components of the CASPAR criteria, which is
used to aid in the diagnosis of psoriatic arthritis [6]. Fingernail psoriasis, due to its visibility
and impacts on function, is more problematic for
many patients compared with toenail disease.
Additionally, psoriatic toenails are often secondarily infected with dermatophytes which may
complicate treatment assessment [7]. Treatment
with immuosuppressive medications may even
contribute to the development of onychomycosis in patients with toenail psoriasis. For these
­reasons, most studies evaluate fingernail psoriasis alone [8].
Clinically, nail disease has many different
presentations which depend on the location of
the infllammatory process. Nail pitting, the most
common finding in nail psoriasis, nail dystrophy,
and leukonychia (white discoloration of nails)
are due to nail matrix involvement [9] (Fig. 26.1).
Nail bed psoriasis is characterized by onycholysis (lifting of the distal nail from the nail bed),
oil drop patches (yellow discolorations below the
nail), subungal hyperkeratosis (thickening of the
nail), and splinter hemorrhages (linear streaks of
dried blood in the nail) [1] (Fig. 26.2a, b). One
recent study demonstrated that nail clippings of
clinically uninvolved nails from patients with
psoriasis may show abnormalities, thus subclinical nail disease exists [10].
a
The methods of reporting changes in nail
disease within clinical trials have not been standardized. The nail psoriasis and severity index
(NAPSI) was developed to measure changes in
nail disease over time [11]. When utilizing this
measure each nail is divided into 4 quadrants and
then assessed for the presence or absence of signs
of both nail matrix and nail bed disease. Each
quadrant of nail with disease present is given a
score of “1” for signs of matrix disease and “1” for
signs of nail bed disease. A normal nail is scored
“0” and the maximum value for each nail is 8, 4
for matrix involvemet and 4 for nail bed disease.
Thus, the maximum NAPSI value for a study
measuring fingernail disease is 80 and the maxi-
Fig. 26.1 Nail matrix psoriasis—note the extensive pitting in this nail. Some of the pits are linear and a splinter
hemorrhage is also present. This patient has concomitant
psoriatic arthritis and inflammatory bowel disease
b
Fig. 26.2 (a) Nail bed psoriasis. Note the hyperkeratosis,
onycholysis, oil droplet formation in the nail bed, and
destruction of the distal nail. (b) Nail bed psoriasis. Note
the onycholysis, oil droplet formation, and distal
hyperkeratosis
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
mum for a target nail is 8. NAPSI measures the
extent of nail disease but not the severity of nail
involvement, so a modified NAPSI (mNAPSI)
has also been used as a clinical endpoint in some
studies [12]. The mNAPSI has a maximum score
of 13 for each nail. Some studies utilize a single
target nail or an overall nail severity score. Other
scales have been used to measure nail involvement but most of the studies reviewed herein utilize some form of the NAPSI. The wide variety
of objective measures used in psoriasis studies
to measure nail disease and the variety of time
points when the measurements are made, make
comparison of treatment outcomes for various
interventions difficult. The goal of treating nail
psoriasis is total clearance of the nail and given
the current highly efficacious therapies, this goal
is attainable for some patients.
Treatment of Nail Psoriasis
An array of treatment options are available for
nail psoriasis including topical products, procedural interventions, and oral systemic and biologic agents. The challenges to treating nail
disease are many; poor penetration of topical
therapy into the nail and surrounding tissue, pain
associated with intralesional injections, side
effects and monitoring of systemic therapies and
patient adherence to therapy [13]. A Cochrane
review has recently been published which
reviewed the published literature on randomized
double-blind placebo controlled trials (RDBPCT)
of nail psoriasis [14]. Unfortunately, many of the
treatments most commonly used to treat psoriasis
do not have published RDBPCT specifically
addressing nail disease. Others have reviewed
nail psoriasis treatments and the results of a
Delphi consensus conference have also been published [15–17].
Topical agents are often the first-line option
for treating patients with nail disease. These
products are readily available, may have cost
advantages, and rarely require laboratory monitoring. Although data are limited and placebo controlled trials rare, there are data to
345
support the efficacy of topical cyclosporine,
topical tacrolimus, clobetasol nail lacquer,
calcipotriol, calcipotriol plus betamethasone,
tazarotene, and indigo naturalis extract [18–
25]. Keratolytics such as urea and salicylic acid
are also used in patients with nail psoriasis and,
in particular, for nail debridement [26]. Topical
preparations, in particular, take several months
to show efficacy and adherence to therapy over
months is challenging. In a study comparing calcipotriol twice daily with calcipotriol/betamethasone once daily, adherence to the twice daily
regimen was only 26% [21]. Therefore, topical
therapy may not only be limited by penetration
into the nail unit but also by adherence to lengthy
treatment regimens lasting weeks or months. In a
Cochrane review of topical agents for nail psoriasis the strongest evidence was for the two compound products (calcipotriol and betamethasone
dipropionate) although this product is only marginally superior to betamethasone dipropionate
alone [27].
Procedures have also been studied in the treatment of nail psoriasis. Phototherapy, a common
treatment for skin disease, in the absence of
psoralen or a retinoid, is not likely to improve
nail disease and is therefore not a viable option
for nail psoriasis. There is limited efficacy data
showing improvement of NAPSI scores with
psoralen plus UVA (PUVA), acitretin plus UVA
(Re-PUVA) and acitretin plus UVB (Re-UVB)
[28]. In a 1999 study of Grenz ray therapy (superficial x-ray therapy), 22 patients with nail psoriasis had one hand treated with weekly radiation
and the other hand serve as an internal control.
The treated hand showed significant but moderate improvement but the effect proved more
limited with hyperkeratotic nails [29]. Limited
access to Grenz ray therapy, a mostly historical
therapy in the United States, may further inhibit
the use of this modality. Several studies evaluated pulsed dye laser (PDL) in nail psoriasis.
The studies noted that therapy is limited by pain,
experienced by all patients, and an incidence of
both petechiae and hyperpigmentation in one
third of patients [30, 31]. A combination of PDL
and tazarotene cream was studied in two groups
J. J. Crowley
346
of nail psoriasis patients; those on stable doses (10 mg/ml) versus methotrexate (25 mg/ml)
of systemic medication and those on no systemic versus cyclosporine (50 mg/ml) showed ≥75%
medication. The study showed efficacy in both improvement in over half of the nails injected
groups but did not show any difference between with triamcinolone and methotrexate but a low
the groups [31]. Another study evaluated PDL response to cyclosporine [35].
both with and without the addition of methyl-­
The systemic agents acitretin, methotrexaminolevulinic acid (photodynamic therapy, ate and cyclosporine, which are effective in
PDT) and found no additional benefit of PDT plaque psoriasis, are also effective in nail disover PDL [32]. Intralesional injection of corti- ease. Apremilast, a newer oral agent for psoriasis
costeroid is an accepted clinical treatment for which targets phosphodiesterase 4, also has data
localized nail psoriasis. Even though this tech- showing efficacy in nail disease. Additionally,
nique has been used for many decades, pub- tofacitinib, approved for psoriatic arthritis but
lished data to support the safety or efficacy of not for psoriasis, shows efficacy in nail disease.
intralesional injections is extremely limited. Appropriate monitoring of both the patient and
Injection techniques vary but generally involve the laboratory values pertinent to the systemic
injection of 0.1–0.2 ml of 5–10 mg/ml triamcin- therapy should be performed.
olone acetonide suspension into the lateral nail
Supporting evidence for the efficacy of oral
folds [33]. Nerve blocks and/or topical anesthet- systemic therapies is detailed in Table 26.1.
ics, to ease the pain associated with injection, Cyclosporine and methotrexate, in a comparamay be performed prior to steroid injection [34]. tor trial, showed a 43.3 and 37.2% mean reducInjections are repeated at various intervals. Side tion in NAPSI, respectively, over a 24 week
effects from intralesional steroids include pain on period [38]. The most robust efficacy data with
injection, skin atrophy, depigmentation, second- methotrexate is from a randomized double blind
ary infection, cyst formation, subungual hemor- trial of methotrexate and the experimental anti-­
rhage, and tendon rupture [34]. Nonetheless, for interleukin-­12/23 antibody briakinumab (a drug
a patient with one or two isolated psoriatic nails, no longer being studied). Methotrexate showed a
intralesional injection after ring block anesthe- 48% improvement in target nail NAPSI at 1 year
sia has been a useful method in the author’s prac- [36]. In a 6 month open label trial of acitretin for
tice. A trial comparing intra-matrix triamcinolone nail psoriasis there was a 41% mean reduction
Table 26.1 Efficacy of systemic therapies in nail psoriasis
Agent
Methotrexate
Dose
15–20 mg/
weeks
Length
52 weeks
Patients
(n)
317
Acitretin
24 weeks
36
Cyclosporine
0.2–0.3 mg/
kg/day
5.0 mg/kg/day
24 weeks
37
Apremilast
30 mg bid
52 weeks
558
Tofacitinib
5 mg bid
10 mg bid
16 weeks
487
476
Trial type
Randomized, double
blind, controlled trial (no
placebo)
Open-label
Comparator (vs.
methotrexate)
Randomized, double
blind, placebo controlled
phase III trials,
subanalysis of patients
with baseline nail disease
Randomized, double
blind, placebo controlled
phase III trials,
subanalysis of patients
with baseline nail disease
NAPSI
improvement
48%
References
[36]
41%
[37]
43.3%
[38]
60.2%
(ESTEEM 1)
59.7%
(ESTEEM 2)
[39]
16.9%
(NAPSI-75)
28.1%
(NAPSI-75)
[40]
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
in NAPSI [37]. Apremilast, FDA approved for
psoriasis and psoriatic arthritis, has been studied
in nail disease. In the phase III ESTEEM 1 and
2 studies, 66.1 and 64.7% of patients had nail
psoriasis (NAPSI ≥ 1). Mean percent change
in target NAPSI score from baseline was −22.5
and −29% at week 16 and −43.6 and −60% at
week 32 for ESTEEM 1 and 2 respectively [41].
In a post-hoc analysis of two phase III clinical trials of tofacitinib in psoriasis, NAPSI was
evaluated for patients with nail disease. NAPSI75 was achieved by 16.9, 28.1, and 8.8% at
16 weeks in the 5 mg bid, 10 mg bid and placebo
groups respectively. Continued tofacitinib use
to 52 weeks demonstrated additional improvement in nail disease [40]. These agents may be
an excellent option for a patient who is otherwise
a candidate for systemic therapy for psoriatic
­disease. Combination treatment for nail psoriasis, though widely used, is little studied. A 2004
study of oral cyclosporine and topical calcipotriol
showed that at 12 weeks the combination group
showed 79% of patients with improvement compared with 47% of patients on cyclosporine alone
[42]. Combination therapy with topical agents
and systemic therapy is frequently employed
in clinical practice and is likely safe and may
be more effective than systemic therapy alone.
Table 26.2 reviews the data on biologics in nail
psoriasis. In a rare trial of a biologic, designed
specifically to target patients with nail psoriasis, adalimumab showed a modified NAPSI 75
response at 26 weeks in patients with and without psoriatic arthritis of 61.5 and 40.9% respectively (placebo 0.5 and 4.6%) [50]. Adalimumab,
in a RPCDBT of patients with psoriasis involving the hands and/or feet, demonstrated 50%
improvement in NAPSI at 16 weeks compared
with 8% for placebo [43]. In a study evaluating
both fingernails and toenails, open label adalimumab showed improvements at 6 months in
NAPSI of 85 and 72% in fingernails and toenails
respectively [51]. An open label study of etanercept in nail psoriasis compared patients randomized to 2 dosing regimens; 50 mg twice weekly
for 12 weeks followed by 50 mg weekly for
12 weeks, or 50 mg weekly for 24 weeks. A 50%
improvement in NAPSI was demonstrated in
347
58.1 and 82.3% of patients in the twice weekly/
weekly group and 50.5 and 80.7% in the weekly
group at 12 and 24 weeks respectively [44]. In
a RDBPCT patients with psoriatic arthritis were
treated with placebo, golimumab 50 mg every
4 weeks, or golimumab 100 mg every 4 weeks
for 24 weeks. Median percent change in NAPSI
at weeks 14 and 24 was 0%, 25%, 43%, and
0%, 33%, and 54% for the placebo, golimumab
50 mg, and golimumab 100 mg groups respectively. Patients in this trial for psoriatic arthritis
were allowed to use stable doses of methotrexate
and prednisone during the study [45]. Currently
golimumab is FDA approved for psoriatic arthritis but not for psoriasis. In a RDBPCT of infliximab, patients were randomized to either placebo
or infliximab 5 mg/kg at weeks 0, 2, 6, and every
8 weeks through week 46, with placebo crossover at week 24. Mean percentage improvement
in target nail NAPSI at week 10 and 24 was 26.8
and 57.2%, compared with −7.7 and −4.1% for
infliximab and placebo respectively [52]. In a
retrospective analysis of patients from this same
infliximab study, mean NAPSI improvement was
28.3, 61.4, and 67.8%, at weeks 10, 24 and 50
respectively [46].
No controlled comparisons of anti-TNF
agents in nail psoriasis have been performed.
However, an open label prospective study showed
that infliximab was superior to adalimumab and
etanercept at 14 weeks [53]. A retrospective comparison of these agents also showed high efficacy
of all the TNF blocking agents in nail psoriasis
with some greater improvement with infliximab
[54]. The differences in efficacy of these agents
in nail psoriasis may parallel the differences
seen in skin response. Infliximab may also have
an advantage in the speed to which clearance is
achieved. However, after 4 months or more, all
anti-TNF therapies are successful in improving nail disease by at least 50%, as measured
by NAPSI.
Robust data is also available for IL-12/23
blockade in nail psoriasis. Data from a large
phase III trial of ustekinumab showed significant
improvement in NAPSI compared with placebo at
12 weeks. Additionally, the ustekinumab 45 and
90 mg groups showed 46.5 and 48.7% NAPSI
J. J. Crowley
348
Table 26.2 Efficacy of biologic therapies in nail psoriasis
Agent
Adalimumab
Dosing
80 mg/40 mg
eow
Etanercept
50 mg biw/50 mg
qw
100 mg q4 weeks
Golimumab
Patients
(n)
Trial type
72
RPCDBT in hand/
foot psoriasis
711
405
Randomized dose
comparison
RPCDBT in
psoriatic arthritis
Infliximab
5 mg/kg weeks
0,2, and 6 then
q8 weeks
378
RPCDBT, data from
the open label
extension
Ustekinumab
45 or 90 mg at
weeks 0, 4, 16
545
RDBPCT
Secukinumab
150 or 300 mg at
weeks 1–5 then
q4 weeks
198
Ixekizumab
80 mg q2 or q4
weeks for
12 weeks then
80 mg q4 weeks
1346
RDBPCT of
patients with nail
disease, data from
the open label
extension
RDBPCT,
retrospective
analysis of open
label period
Outcomes (note different
primary outcome
References
Weeks measures)
[43]
16
50% reduction in
NAPSI (8% for
placebo)
24
82.3% NAPSI 50
[44]
response
[45]
24
54% reduction in
NAPSI (0% for
placebo)
[46]
50
67.8% reduction in
NAPSI (49.2% with
complete nail
clearance)
24
46.5% (45 mg), 48.7% [47]
(90 mg) reduction in
NAPSI
[48]
32
52.6% (150 mg) and
63.2% (300 mg)
reduction in NAPSI
24
34 and 30% with no
nail involvement
(NAPSI = 0) on q2 and
q4 doses, respectively
[49]
eow every other week, NAPSI nail area psoriasis severity index, RDBPCT randomized double-blind placebo controlled trial
improvement, respectively, at 24 weeks [47].
Long-term data with 68 weeks of ustekinumab
in a Japanese study showed a 56.6 and 67.8%
improvement from baseline NAPSI in patients
treated with 45 or 90 mg of ustekinumab respectively [55].
Antibodies to interleukin 17-A and an interleukin 17 receptor antagonist are currently approved
for psoriasis. Data from a phase II dose finding
trial of the anti-interleukin 17 antibody ixekizumab showed improvement of 57.1 and 49.3% in
NAPSI scores at the 75 and 150 mg doses respectively at 16 weeks [56]. Further data with ixekizumab from the UNCOVER 3 phase III clinical
trial has also been published [49]. At week 12,
patients with baseline nail involvement showed
reduction in NAPSI of 39, 40, 28, and −4.7%
in the ixekizumab every 2 weeks, ­ixekizumab
every 4 weeks, etanercept 50 mg twice weekly,
and placebo groups, respectively. Additionally,
at 24 weeks, 34 and 30% of patients had no nail
involvement on ixekizumab q2weeks/q4 weeks,
and ixekizumab q4 weeks/q4 weeks, respectively.
At 60 weeks, half of the patients with initial nail
disease had a NAPSI = 0 while on continuous
ixekizumab. Secukinumab, another antibody to
IL-17A, was studied in a clinical trial specifically
designed to study patients with nail psoriasis.
In the TRANSFIGURE study, mean improvement of NAPSI from baseline was 10.8, 37.9,
and 45.3 at week 16 for placebo, secukinumab
150 mg, and secukinumab 300 mg, respectively.
At week 32, in the open label period, a 52.6 and
63.2% improvement in mean NAPSI was seen
for secukinumab 150 and 300 mg respectively
[48]. Currently in development for psoriasis and
psoriatic arthritis is bimekizumab which targets
both IL-17A and IL-17F and data on efficacy in
nail disease will be forthcoming [57]. The rapid
onset of action and high levels of efficacy make
these anti-IL-17 agents particularly attractive
for patients with extensive nail disease.
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
Treatment Approach to Nail Disease
A treatment algorithm for nail psoriasis, based on
published data for treatment of nail psoriasis and
expert opinion where data is lacking, has been
previously published by the Medical Board of the
National Psoriasis Foundation [58] and is summarized here. All psoriasis patients should be
evaluated for nail disease and the extent to which
their nail disease contributes to overall disease
burden. Nail disease should be classified as mild
if it has minimal impact on QoL and poses no
functional impact for the patient. Significant or
extensive nail disease has real impact on daily
activities, may be disfiguring, and may be associated with significant pain. Patients with significant nail disease need therapies to address their
nail psoriasis. Patients with moderate to severe
psoriasis and significant nail disease should be
treated with appropriate therapy which addresses
skin and nail disease. Previous consensus guidelines for the treatment of moderate to severe psoriasis also apply to the patient with nail disease
[59]. Options include cyclosporine, methotrexate, acitretin, apremilast, and the biologics.
Patients with significant nail disease and psoriatic arthritis (PsA) should be treated with an
appropriate systemic treatment for PsA that has
efficacy in nails. Data support the following
options in this patient group; methotrexate, apremilast, the TNF inhibitors, IL-17 inhibitors and
the IL-12/23 inhibitor. For the rare patient with
nail disease as the primary manifestation of their
psoriatic disease, a 3–6 month trial of topical
therapy and/or intralesional injections may be
appropriate. For patients with severe nail disease
affecting QoL, systemic and biologic therapies
may be needed. Patients who have their skin and/
or joint disease well controlled but still have significant nail involvement may need combination
topical therapy or intralesional injections. If this
fails, a change in the systemic or biologic therapy
may be warranted.
Improvements in nail psoriasis often trail
the improvements in skin and joint disease.
Fingernails grow at a rate of 3–4 mm/month,
thus it takes 5–7 months for a nail to grow from
matrix to distal fingertip [60]. Therefore, the
349
length of a clinical trial must reflect this delay.
Few studies, with the exception of the anti-IL
17 inhibitors and infliximab, demonstrate any
significant improvement before 12 weeks and
several studies with adalimumab, etanercept,
infliximab, ustekinumab, ixekizumab, and
scukinumab demonstrate continued improvement up to and even beyond 6 months [44, 46,
53, 61].
One of the problems in reviewing data on
nail psoriasis is the lack of consistent outcome
reporting among the studies. Even when NAPSI
data is presented, it may be presented in different
ways. Target nail NAPSI, mean improvement in
NAPSI, percent of patients with no nail disease
(NAPSI = 0), and modified NAPSI, are some
of the many outcomes reported. The dermatology life quality index (DLQI) contains some
questions pertinent to nail signs and symptoms
but does not specifically account for the influence of nail disease on QoL. Some researchers
have used QoL measures validated in onychomycosis and applied these to psoriasis [62]. A
validated measure specific to nail psoriasis, the
NPQ10, has been published but not extensively
utilized [63]. Additionally, the Nail Assessment
in Psoriasis and Psoriatic Arthritis (NAPPA) may
prove useful in evaluating response to therapy in
nail disease [64]. Clearly there is a need for more
uniform reporting of nail outcomes and adoption
of a valid and easily performed QoL metric that
is specific to nail disease.
Scalp Psoriasis
Is scalp psoriasis difficult to treat? Indeed, it may
respond faster than other body regions to some
biologic therapies but it remains a challenge to
obtain good results with both topical and phototherapy. While the head and neck represent about
10% of the body surface area, the impact of psoriasis in this region may be disproportionate to
the area, and may have social and emotional
impacts on affected individuals. Most scalp psoriasis is treated with topical therapies including
shampoos, oils, foams, liquids, and gels. Over the
counter remedies, containing tar, salicylic acid,
J. J. Crowley
350
zinc, and others are relatively inexpensive and
widely available. One of the reasons that scalp
psoriasis has been labeled “tough to treat” is the
difficulty with using and complying with topical
medications. Prescription topical therapy mainly
involves the use of mid to high potency topical
steroids and topical vitamin D analogues. Many
larger trials for the biologics have had measures
of scalp psoriasis as secondary endpoints. A few
trials have been designed specifically to assess
scalp disease and these will be highlighted in this
chapter. Indeed, scalp psoriasis provides challenges to both practitioner and patient.
The incidence of scalp psoriasis in patients
with psoriasis is estimated between 40 and 90
percent. In up to half of patients, psoriasis may
initially present on the scalp [65, 66]. Some
patients only have psoriasis on the scalp. The
scalp is characterized by the presence of the
prominent pilosebaceous unit and has a microbiome that differs from other skin sites. Both
yeast and bacteria colonize the scalp [67]. Indeed
Malessazia furfur, M. globosa, candida, and
other commensal organisms are found on the
scalp in significant numbers and may influence
scalp diseases such as seborrheic dermatitis and
psoriasis [68, 69]. The role of these organisms in
psoriasis is not well established but they likely
play a role. Treatments targeting these organisms
have shown some efficacy in seborrheic dermatitis [70, 71]. Friction and trauma to the scalp from
scratching and hair grooming my also contribute
to scalp disease severity [72, 73].
Recent studies have shown that the hair in
patients with scalp psoriasis may also be modified
by the presence of psoriatic inflammation. Indeed,
hair shafts evaluated in patients with psoriasis
reveal pits, thought to be analogous to the pitting seen in nails [74]. Additionally, recent studies evaluating the transcriptome of both scalp and
body psoriasis suggest there may be differences in
gene activation between the scalp and body [75].
­ ell-­defined plaques with silvery scale and an
w
erythematous border (Fig. 26.3). Classic scalp
lesions are asymmetric, sharply demarcated, covered with silvery-white or gray scale, and may
extend beyond scalp margins to affect the forehead, ear, and neck [76]. Most patients with psoriasis of the face also have scalp disease [77].
Multiple surveys have cited itching and scaling as
the most disturbing aspects of scalp psoriasis [78,
79]. This itch may be so severe that it can interfere with sleep and lead to actual hair loss due to
hair breakage and trauma.
Scalp psoriasis is usually not associated with
significant hair loss, however, some patients may
have alopecia due to the trauma of chronic itching leading to hair breakage. In an analysis of
47 patients with psoriatic alopecia followed for
several years, many patients only had alopecia in
some of the scalp plaques and indeed, as the psoriasis cleared, the hair regrew [80]. In some cases
the differentiation of scalp psoriasis and seborrheic dermatitis can be difficult. Seborrheic
dermatitis is characterized by diffuse thin
scale that is localized to the hair bearing scalp
and may involve the central face and chest.
Psoriasis, on the other hand, may extend
beyond the scalp, is sharply marginated, and
may occur elsewhere on the body [81].
Measuring Scalp Disease
A variety of measures have been developed to
assess the extent and burden of scalp psoriasis
linical Presentation of Scalp
C
Psoriasis
Scalp lesions may vary from mild, with minimal
erythema and scaling, to severe with thick
Fig. 26.3 Scalp psoriasis
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
351
Table 26.3 Measures of scalp psoriasis
Measure
Psoriasis Scalp
Severity Index
(PSSI)
Scalp-modified
PASI (S-mPASI)
Parameters measured
Extent of involvement,
erythema, induration, and
desquamation of scalp
Extent of involvement,
erythema, induration,
desquamation of scalp
Head and Neck
PASI (HN-PASI)
Extent of involvement,
erythema, induration,
desquamation of head and
neck
Erythema, induration,
desquamation of scalp
Overall scalp disease, as
judged by the patient, as
compared to baseline
involvement
Overall scalp disease
measured by investigator
Measure of symptoms,
functioning, and emotions
on scalp disease (23 items)
Total Severity Score
(TSS)
Scalp-specific
Patient’s Global
Assessment
(SPaGA)
Global Severity
Score (GSS)
Scalpdex
Max. score Description
72
Sum of 3 parameter scores (0–4)
multiplied by a score for the area of
involvement (1–6)
7.2
Sum of 3 parameter scores (0–4)
multiplied by a score for the area of
involvement (1–6) times a constant
(0.1)
7.2
Sum of 3 parameter scores (0–4)
multiplied by a score for the area of
involvement (1–6) times a constant
(0.1)
9
Sum of scores (0–3) for erythema,
induration, and desquamation
−2 to +2 Current scalp disease severity
compared with baseline visit on a
5-point scale; “much worse” (−2)
through “much improved” (+2)
5
Assessment of scalp disease from
“none” (0) to “very severe” (5)
0–100
Measures may be combined to form
subscores for symptoms,
functioning, and emotions
References
[82]
[83]
[84]
[85]
[83]
[85]
[78]
(Table 26.3). The Psoriasis Scalp Severity Index issue for many scalp psoriasis patients, may be
(PSSI) and the Scalp-modified PASI (S-mPASI) measured by a visual analogue scale [87] of itch.
are modifications of the standard PASI measure- Scalpdex is a validated measure of quality of life
ment of psoriasis [82, 83]. Both the PSSI and the for scalp conditions (not specific to psoriasis)
Sm-PASI measure erythema, induration, and des- that utilizes 23 questions that address symptoms,
quamation of the plaques of psoriasis on the scalp emotions, and functions surrounding the scalp
only in contrast to PASI where the entire body is condition [78].
evaluated. Some studies, including one on the
IL-17 inhibitor secukinumab, have utilized the
head and neck portion of the PASI score Management of Scalp Psoriasis:
(HN-PASI) as a proxy for scalp involvement Topical Therapies
[84]. Other measures have also been used for
evaluation of scalp psoriasis including the Total Topical therapies are the foundation in the manSeverity Scale (TSS), the Scalp-specific agement of scalp psoriasis and utilized by
Physicians Global Assessment (S-PGA), and the approximately 60% of patients [66]. These theraGlobal Severity Scale (GSS) [85]. A recent study pies have been formulated into shampoos, gels,
of 102 patients with predominately scalp psoria- foams, oils, and solutions. Some of these prodsis treated with secukinumab or placebo utilized ucts have been evaluated in large clinical trials.
a 90% improvement of PSSI and a 2 point High costs limit the use of many of these propriimprovement in Investigators Global Assessment etary products. Calcipotriol is a synthetic derivaas the two primary endpoints to the study [86].
tive of calcitriol (Vitamin D3); calcipotriol binds
Patient assessment tools have also been devel- to the vitamin D3 receptor, but unlike calcitriol,
oped to evaluate scalp psoriasis. The Scalp-­ is a poor regulator of calcium metabolism. The
specific Patient’s Global Assessment (S-PaGA) efficacy and safety of calcipotriol solution suphas been utilized to gauge patient assessment of port its use as a first-line therapy as well as its use
disease change from baseline. Pruritus, a major as maintenance therapy [88, 89]. This treatment,
J. J. Crowley
352
however, can be associated with some burning,
redness, dryness, and itching in some patients.
The combination of calcipotriol and topical steroids decreases some of the irritation of calcipotriol and is certainly more efficacious than
calcipotriol monotherapy. There may also be an
advantage to this combination due to the potential protective effect of calcipotriol on corticosteroid induced skin atrophy.
Shampoos and foams containing high potency
topical steroids such as clobetasol propionate
0.05% have demonstrated improvement in scalp
psoriasis in as little as 2 weeks. In these short, 2–4
week studies, skin atrophy, folliculitis and telangiectasia were not observed [90, 91]. Clobetasol
propionate 0.05% shampoo was superior in efficacy and tolerability compared with calcipotriol
0.005% solution [85]. In a study comparing 1%
tar blend shampoo with clobetasol shampoo,
the clobetasol product was cosmetically more
acceptable to patients [91]. Betamethasone valerate 0.12% in a mousse (foam) vehicle was
compared to topical corticosteroid solution and
calcipotriol lotion and showed superior efficacy
over 4 weeks. Most of these patients preferred
the foam formulation [88]. An open label study
of the combination product (betamethasone/calcipotriene) in patients 12–17 years of age showed
efficacy over 8 weeks with one patient demonstrating mild adrenal suppression and no patients
demonstrating hypercalcemia [92]. The authors
concluded that this treatment was safe and efficacious in adolescents with scalp psoriasis.
A 2016 Cochrane review of topical therapies
reviewed 59 randomized controlled clinical trials in scalp psoriasis [93]. They concluded that
a corticosteroid of high or very high potency
or a combination of a corticosteroid and vitamin D (calcipotriol) was superior to vitamin D
alone. The two-compound combination also led
to fewer withdrawals from treatment compared
to the other treatments. Further the authors concluded “Given the comparable safety profile and
only slim benefit of the two-compound combination over the corticosteroid alone, monotherapy
with generic topical steroids of high and very
high potency may be fully acceptable for short
term therapy.”
However, do patients adhere to treatment with
topical therapy? There is some evidence that
optimizing the vehicle may improve adherence
to scalp psoriasis treatments, however adherence
to topical therapy for psoriasis is low [94]. Even
with interventions to assist and remind patients
to apply topical therapies, adherence is less than
50% after several weeks [95]. In clinical practice,
the use of anti-dandruff shampoos is generally
encouraged by dermatologists to help remove the
scale from the plaques of psoriasis. The use of
high potency topical steroids is usually limited
to a few weeks but patients may continue to use
these products intermittently for months and even
years. The use of topical vitamin D products,
when available and when well tolerated, is also
a reasonable approach to maintenance therapy.
Many practitioners will utilize a high potency
topical steroid 1 or 2 days per week and a topical
vitamin D analogue on the other days in an effort
to minimize potential side effects of long term
topical steroid use [96].
Procedural Therapies for Scalp
Psoriasis
Intralesional injection of corticosteroids has also
been used by dermatologists to address localized
treatment resistant plaques of psoriasis with some
success. Triamcinolone acetonide (5–10 mg/ml)
is injected directly into the psoriatic plaques in
small (0.1–0.2 ml) aliquots. The aim is to deliver
the steroid directly into the area of inflammation
in the dermis. This technique, however, has not
been studied in a rigorous fashion [34].
Phototherapy for scalp psoriasis is limited
due to hair blocking the penetration of the light.
Devices have been designed and are available
to help deliver phototherapy to the scalp. These
devices use fiber-optics that penetrate through
the hair and deliver the phototherapy, broadband or narrow-band UVB, directly to the scalp
[97]. Additionally, the 308-nM laser can be used
to treat scalp psoriasis. In one study, 17 of 35
patients had >95% clearance after a mean of 21
treatments [98]. In this study the hair was manually parted to gain access to the psoriatic plaques.
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
Notably, all patients demonstrated erythema and
some blistering to treated sites. In another study,
patients treated with the laser administered with
a blow dryer to part the hair, had significant
improvement after twice weekly treatments for
up to 15 weeks [99]. Grenz ray therapy has also
been efficacious in scalp psoriasis. The lack of
availability of Grenz ray therapy units and the
potential for skin cancer formation in the treated
area significantly limit this modality [100, 101].
Systemic Therapy for Scalp Psoriasis
There are few studies that specifically address the
efficacy of methotrexate, cyclosporine, and
acitretin in scalp psoriasis. Nonetheless, these
therapies may be effective in treating scalp disease. Appropriate monitoring of liver function
(methotrexate, acitretin), creatinine (cyclosporine, methotrexate), complete blood counts
(methotrexate), triglycerides (acitretin), and
blood pressure (cyclosporine) should be maintained during treatment with these agents.
353
Apremilast, an oral phosphodiesterase 4
inhibitor, is approved for psoriasis and psoriatic
arthritis. Scalp disease was evaluated as a secondary endpoint in the two phase III psoriasis
programs for apremilast. Scalp disease was moderate or greater in about two thirds of patients
in these trials. Approximately half of those with
baseline moderate scalp involvement achieved
a clear or almost clear PGA at 16 weeks. Most
patients who continued in trial maintained this
response out to 1 year [39, 41]. Apremilast may
be a reasonable option for patients with significant scalp disease.
Biologic Therapy for Scalp Psoriasis
The treatment of scalp psoriasis with biologics is
summarized in Table 26.4. There have been some
studies specifically designed to evaluate scalp
psoriasis. Etanercept, a TNF-fusion protein that
binds TNF-alpha, was used in a study specifically
addressing patients with scalp disease [102]. In
this placebo-controlled trial, PSSI at week 12
Table 26.4 Efficacy of systemic therapies in scalp psoriasis
Agent
Apremilast
Dosing
30 mg biw
Etanercept
50 mg biw or
placebo
Adalimumab
80 mg weeks. 0,
then 40 mg eow
Secukinumab
300 mg weeks.
0–4, then 300 mg
q4 weeks
80 mg weeks. 0,
then 80 mg q2 or
q4 weeks, also
comparator arm
with etanercept biw
Ixekizumab
Patients
(n)
Trial type
558
RPCDBT,
subanalysis of
patients with
moderate scalp
involvement
124
Placebo controlled
study in moderate
scalp disease
730
RPCDBT,
subanalysis of
patients with
baseline scalp
disease
102
RPCDBT in
patients with scalp
psoriasis
3866
RDBPCT with
etanercept
comparator arm
Outcomes (note different
primary outcome
References
Weeks measures)
[41]
16
Scalp PGA of clear or
almost clear (0 or 1) of
46.5% (ESTEEM 1)
and 40.9% (ESTEEM
2)
[102]
12
Improvement in PSSI
from baseline 86.8%
(vs. 20.4% for placebo)
16
77.2% improvement in
[103]
PSSI
12
12
52.9% PSSI
improvement (2% for
placebo)
PSSI 100 response of
74.6, 68.8, 48.1, and
6.7% in Ixe q2w, Ixe q4
wk, etanercept, and
placebo respectively
[86]
[104]
biw twice weekly, eow every other week, RPCDBT randomized placebo-controlled double blind clinical trial, PGA
physician’s global assessment, PSSI psoriasis scalp severity index
J. J. Crowley
354
was improved by 86.8 and 20.4% in the etanercept 50 mg biw group and placebo group respectively. Improvement continued in the open label
period to week 24. In a subanalysis of a larger
trial of adalimumab in psoriasis, PSSI was
improved by an median of 100% (mean 77.2%)
at 16 weeks [103].
Blockade of interleukin-17 has also been studied in scalp psoriasis. In a placebo controlled study
designed specifically for scalp disease patients,
secukinumab 300 mg achieved 90% improvement in PSSI in 52.9% of patients compared with
2% on placebo at 12 weeks. Investigators global
assessment of clear or almost clear was achieved
by 56.9% on secukinumab and 5.9% on placebo
at 12 weeks [105]. In a subanalysis of larger phase
III trials for ixekizumab, scalp psoriasis was evaluated [104]. Of patients with baseline scalp psoriasis, PSSI 90 and PSSI 100 at 12 weeks were
obtained by 81.7 and 74.6, 75.6 and 68.8, 55.5 and
48.1, and 7.6 and 6.7, in the ixekizumab q2 weeks,
ixekizumab q4 weeks, etanercept 50 mg biw, and
placebo groups, respectively. Thus, more than half
of patients on etanercept, and over three quarters
of patients on ixekizumab had complete clearance
of scalp psoriasis at 12 weeks.
reatment Algorithm for Scalp
T
Psoriasis
For limited scalp disease, treatment with potent
topical steroids with or without vitamin D derivatives is a reasonable initial treatment. This may be
augmented by OTC shampoos to remove scale.
For patients who fail to respond to a trial of topical therapy, phototherapy (if available), and oral
treatment with methotrexate or apremilast may be
appropriate. For patients who prove recalcitrant to
these therapies or for patients with significant
psoriasis elsewhere, biologic therapies that target
TNF or interleukin-17 are recommended.
TNF Induced Psoriasis
Paradoxically, treatment with anti-TNF agents
may induce scalp psoriasis in patients who have
not had a previous history of psoriasis [106, 107].
These cases have been reported with all the anti-­
TNF agents and the patients are often being
treated for rheumatoid arthritis and inflammatory
bowel disease. The scalp, palms, soles, and other
body areas may be involved. Occasionally, these
patients may have lesions consistent with pustular psoriasis [107]. Some patients can be treated
with topical or phototherapy and remain on the
TNF agent while others may require discontinuation of the TNF inhibitor to control the eruption.
The incidence of this eruption is between 1 and
2% of patients treated with anti-TNF agents
[108]. The cause of this phenomenon is not well
elucidated but may involve compensatory
increases in interferon in patients treated with
anti-TNF’s [109].
Palmoplantar Psoriasis
Psoriasis of the hands and feet may be one of the
most difficult therapeutic dilemmas for the dermatologist. Palmoplantar psoriasis affects up to
5% of patients with psoriasis [110]. First, however, we need to define the spectrum of psoriatic
disease that can affect the palms and soles. There
are several distinct presentations of psoriasis on
the palms and soles:
• Plaque psoriasis of the hands and feet with
significant psoriasis elsewhere (Fig. 26.4)
• Plaque psoriasis of the hands and feet with
little psoriasis elsewhere (palmoplantar psoriasis, PPP, Fig. 26.5)
• Pustular psoriasis of the hands and feet (palmoplantar pustulosis, PPPP, Fig. 26.6). This
may also be called Acrodermatitis Continua of
Hallopeau, particularly when it involves bony
resorption of the distal phalanx [111].
• Psoriasiform dermatitis of the hands and
feet—with features of hand dermatitis and
psoriasis
These presentations represent distinct patient
populations that may respond differently to various therapies and may have differing genetic and
environmental factors involved in their disease
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
Fig. 26.4 Palm psoriasis in a patient with chronic plaque
psoriasis
Fig. 26.5 Severe palmoplantar plaque psoriasis in a
patient with minimal psoriasis on body
Fig. 26.6 Palmar pustular psoriasis. Note resorption of
distal digits and extensive pustules. These are features of
a variant of pustular psoriasis termed acrodermatitis continua of Hallopeau
development. This review will focus on plaque
psoriasis of the hands and feet (PPP) and pustular
psoriasis of the hands and feet (PPPP).
355
Recently, pustular psoriasis (particularly the
generalized form) has been associated with mutations in the IL-36 receptor [112]. There is also
a small clinical trial demonstrating that an antibody that targets the IL-36 receptor is effective
in treating generalized pustular psoriasis [113].
Some PPPP patients have mutations in the IL-36
receptor but other genes are also implicated
including CARD14 and AP1S3. Notably, patients
with PPPP do not have mutations in PSORS1
which is common in patients with plaque psoriasis [114]. These genetic associations may provide
therapeutic targets to address PPPP in the future.
A key factor in palmoplantar disease is disability. The use of the hands and feet may be
significantly compromised by disease. The
scale, fissures, cracking, and hyperkeratosis can
lead to pain with movement. Chung et al. evaluated the quality of life (QoL) of patients with
PPP and compared them with plaque psoriasis
[115]. These patients were receiving treatment
with systemic or phototherapy. The palmoplantar psoriasis patients had significantly more
impairment in QoL characterized by limitations
of mobility, self-care, and pursuing usual activities. Additionally, palmoplantar patients were
more likely to be taking multiple topical and oral
therapies for their disease. Others have reported
on physical disability and discomfort associated
with PPP [116]. Smoking appears to play a role
in palmoplantar disease and there is some data
suggesting that pustular disease severity may
improve with smoking cessation [117].
There are few controlled clinical trials
addressing treatments for palmoplantar disease.
Most treatment has been based on case series,
small clinical trials, and anecdotal clinical evidence. If you were to ask 10 dermatologists for
their top five treatments for hand and foot psoriatic disease, you would get dramatically different answers. Reviews of the literature have also
yielded differing recommendations for treatment
of palmoplantar psoriasis. Seravin et al. concluded in 2013 “Phototherapy, cyclosporine and
topical corticosteroids seem to be able to control
PPPP. However, the standard of care for PPPP
remains an issue and there is a strong need for reliable RCTs to better define treatment strategies for
356
PPPP” [118]. The National Psoriasis Foundation
concluded in a 2012 review of treatments for pustular psoriasis that “acitretin, cyclosporine, methotrexate, and infliximab are considered to be first
line therapies in generalized pustular disease”
[119]. All sources conclude that better data is
needed to guide clinical decisions regarding treatment. Topical steroids, Vitamin D analogues, tar
and anthralin preparations, either by themselves
or in combination, and under occlusion have all
been reported to improve psoriasis and are regularly used in palmoplantar disease. In a comparative trial, in PPP, of clobetasol plus tar compared
with topical psoralen plus UVA, both treatments
were effective [120]. Phototherapy with psoralen
plus UVA (PUVA), and narrowband UVB, have
shown some efficacy in hand and foot disease
[121]. Multiple small studies and case series have
demonstrated the efficacy of the 308 nM laser in
the treatment of palmoplantar disease [122–124].
A recent comparison of paint PUVA (psoralen
not ingested but instead painted on the skin) and
broad band UVB showed improvement with both
treatments but more complete and longer remissions with paint PUVA [125]. Another study used
a split hand design to treat one side with narrowband-UVB and the other with topical PUVA. The
PUVA side fared better than the hand treated with
narrowband UVB [126]. Thus, topical therapies
and phototherapy may be beneficial in treating
palmoplantar psoriasis.
Systemic treatments for palmoplantar disease
have also been studied. Methotrexate (0.4 mg/
kg weekly) and acitretin (0.5 mg/kg daily) were
studied in an active comparator trial of 111 PPP
patients [127]. Both treatments showed improvement but methotrexate significantly improved
more patients. Wald et al. published a series
of 48 hand foot psoriasis patients treated with
methotrexate, most in combination with other
therapies, and concluded that methotrexate was
effective in PPP [128]. In a study of cyclosporine
in PPPP, most patients improved on relatively low
doses (1–2 mg/kg/day) of cyclosporine [129]. In
a pooled analysis of phase II and two phase III
trials of apremilast, a phosphodiesterase 4 inhibitor, in psoriasis, patients with baseline palmoplantar physicians global assessment (PP-PGA)
of moderate or greater were evaluated during
J. J. Crowley
the 16 week placebo controlled period. At week
16, 46 and 25% of patients showed a PP-PGA
of clear or almost clear for the apremilast and
placebo groups, respectively [130]. Thus, acitretin, cyclosporine, and apremilast all demonstrate
some efficacy in PPP and/or PPPP. However,
there are no randomized placebo controlled studies specifically addressing these systemic agents
in PPP or PPPP.
The biologics have also been studied in PPP
and PPPP. Adalimumab was studied in patients
with at least moderate plaque psoriasis of the
hands and feet and moderate to severe plaque psoriasis elsewhere [43]. In this placebo c­ ontrolled
trial, 31% of patients in the adalimumab group
were able to achieve a hand/foot PGA of clear or
almost clear at week 16, compared to only 4% in
the placebo group. In a study of 24 palmoplantar psoriasis patients randomized to placebo or
infliximab infusions, more patients reached 75%
improvement in palmoplantar PASI in the infliximab group (33.3 vs. 8.3%), but this did not reach
statistical significance [131]. Success with treating PPP and PPPP has also been demonstrated
in case reports with etanercept [132, 133]. The
TNF inhibitors do appear to show some efficacy
in treating PPP, but this efficacy is significantly
attenuated compared with overall plaque psoriasis results.
Ustekinumab, in an open label study of
patients with PPP and PPPP, cleared 35% (7/20),
however the 90 mg dose was superior to 45 mg
[134]. The interleukin-17 inhibitors have been
studied in both PPP and PPPP. In a subanalysis of the large phase III trials of ixekizumab in
psoriasis, patients with significant palmoplantar
disease (PP-PASI of ≥8) at baseline were evaluated [135]. This analysis involved 105 patients
(total study n = 1224) and revealed PP-PASI
75 and PP-PASI-100 results of 16.7, 44.1, 81.8,
74.2 and 5.6, 29.4, 45.5, and 51.6 in the placebo,
etanercept 50 mg biw, ixekizumab q2 weeks,
and ixekizumab q4 weeks, respectively. Thus,
roughly half of the ixekizumab treated patients
achieved total clearance of their plaque psoriasis of the hands and feet. Secukinumab was
studied in a placebo controlled trial of patients
with moderate to severe palmoplantar psoriasis
[136]. Many of these patients would not have had
26
Challenges in Psoriasis Treatment: Nail, Scalp, and Palmoplantar Involvement
enough ­psoriasis to meet enrollment criteria for
typical phase III psoriasis trials and thus may better represent the vexing patients with primarily
palmoplantar disease. 205 patients were randomized 1:1:1 to secukinumab 300 mg, secukinumab
150 mg, and placebo. In this study, palmoplantar IGA of clear or almost clear at week 16 was
achieved by 33.3, 22.1, and 1.5% of patients
treated with secukinumab 300 mg, secukinumab
150 mg, and placebo respectively. These results
are impressive but are not as robust as seen in the
larger phase III trials of plaque psoriasis. An additional study of secukinumab in PPPP was also
performed [137]. In this study 237 patients with
palmoplantar pustulosis (PPPP) were randomized
to placebo, secukinumab 150 mg, or secukinumab
300 mg. Forty percent of these patients did not
have plaque psoriasis elsewhere. Change in
PP-PASI was measured at week 16 and 29.7,
30.2, and 42.3% improvement was noted in the
placebo, secukinumab 150 mg, and secukinumab
300 mg, respectively. Thus, there was minimal
response of PPPP to IL-17 inhibition. More studies are needed to confirm this finding but it does
appear that IL-17 is not a key target for PPPP.
PPP remains a difficult disease to treat.
Multiple therapies and often necessary, and a trial
of many treatments is often needed in order to
achieve adequate control. There are some data to
support topical therapy, phototherapy (especially
PUVA), cyclosporine, methotrexate, acitretin,
and apremilast. The anti-TNF antibodies may
also improve some patients. The anti-IL-17 antibodies may offer some additional efficacy with
PPP. Treatment options for PPPP are even more
dismal, with few studies to guide treatment. The
inflammatory cascade in PPPP is different from
plaque psoriasis and this disease will likely need
different targets to control disease. Cyclosporine
is likely the best oral option for pustular disease.
References
1. Jiaravuthisan MM, Sasseville D, Vender RB,
Murphy F, Muhn CY. Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review
of the literature on therapy. J Am Acad Dermatol.
2007;57(1):1–27.
357
2. de Jong EM, Seegers BA, Gulinck MK, Boezeman
JB, van de Kerkhof PC. Psoriasis of the nails associated with disability in a large number of patients:
results of a recent interview with 1,728 patients.
Dermatology. 1996;193(4):300–3.
3. van der Velden HM, Klaassen KM, van de Kerkhof
PC, Pasch MC. The impact of fingernail psoriasis on
patients’ health-related and disease-specific quality
of life. Dermatology. 2014;229(2):76–82.
4. Langenbruch A, Radtke MA, Krensel M, Jacobi A,
Reich K, Augustin M. Nail involvement as a predictor of concomitant psoriatic arthritis in patients with
psoriasis. Br J Dermatol. 2014;171(5):1123–8.
5. Armesto S, Esteve A, Coto-Segura P, Drake M,
Galache C, Martinez-Borra J, et al. Nail psoriasis in
individuals with psoriasis vulgaris: a study of 661
patients. Actas Dermosifiliogr. 2011;102(5):365–72.
6. Chandran V, Schentag CT, Gladman DD. Sensitivity
and specificity of the CASPAR criteria for psoriatic arthritis in a family medicine clinic setting. J
Rheumatol. 2008;35(10):2069–70. author reply 70
7. Gupta AK, Lynde CW, Jain HC, Sibbald RG,
Elewski BE, Daniel CR 3rd, et al. A higher prevalence of onychomycosis in psoriatics compared with
non-psoriatics: a multicentre study. Br J Dermatol.
1997;136(5):786–9.
8. Al-Mutairi N, Nour T, Al-Rqobah D. Onychomycosis
in patients of nail psoriasis on biologic therapy: a
randomized, prospective open label study comparing Etanercept, Infliximab and Adalimumab. Expert
Opin Biol Ther. 2013;13(5):625–9.
9. Halprin KM. Afflictions of a vestigial appendage.
II. Inflammatory processes affecting the nail matrix.
(trauma, eczema, psoriasis, lichen planus, alopecia
areata). JAMA. 1967;202(11):1045.
10. Werner B, Fonseca GP, Seidel G. Microscopic nail
clipping findings in patients with psoriasis. Am J
Dermatopathol. 2015;37(6):429–39.
11. Rich P, Scher RK. Nail Psoriasis Severity Index:
a useful tool for evaluation of nail psoriasis. J Am
Acad Dermatol. 2003;49(2):206–12.
12. Cassell SE, Bieber JD, Rich P, Tutuncu ZN, Lee
SJ, Kalunian KC, et al. The modified Nail Psoriasis
Severity Index: validation of an instrument to assess
psoriatic nail involvement in patients with psoriatic
arthritis. J Rheumatol. 2007;34(1):123–9.
13. Radtke MA, Beikert FC, Augustin M. Nail psoriasis—a treatment challenge. J Dtsch Dermatol Ges.
2013;11(3):203–19. quiz 20
14. de Vries AC, Bogaards NA, Hooft L, Velema
M, Pasch M, Lebwohl M, et al. Interventions
for nail psoriasis. Cochrane Database Syst Rev.
2013;1:CD007633.
15. Oram Y, Akkaya AD. Treatment of nail psoriasis:
common concepts and new trends. Dermatol Res
Pract. 2013;2013:180496.
16. Langley RG, Saurat JH, Reich K, Na