Review article
The role for JAK inhibitors in the treatment of
immune-mediated rheumatic and related
conditions
George E. Fragoulis, MD, PhD,a,b James Brock, MD,a Neil Basu, MD, PhD,a Iain B. McInnes, MD, PhD,a and
Stefan Siebert, MD, PhDa
Glasgow, United Kingdom, and Athens, Greece
JAK inhibitors (JAKIs) are a new class of targeted therapy that
have entered clinical practice for the treatment of
immune-mediated rheumatic conditions. JAKIs can block the
signaling activity of a variety of proinflammatory cytokines and
therefore have the potential to mediate therapeutic benefits
across a wide range of immune-mediated conditions. Several
JAKIs are licensed, and many more are undergoing clinical
trials. Here we provide a narrative review of the current and
upcoming JAKIs for adult immune-mediated rheumatic and
related conditions, with a specific focus on efficacy in
rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis,
psoriasis, and inflammatory bowel disease. The overall safety
profile of JAKIs appears largely comparable to that of existing
biologic cytokine-targeting agents, particularly, TNF inhibitors,
apart from risk of herpes zoster, which is increased for JAKIs.
Importantly however, unresolved safety concerns remain,
particularly relating to increased venous thromboembolism. (J
Allergy Clin Immunol 2021;148:941-52.)
Key words: JAK inhibitors, randomized controlled trials, biologics,
rheumatoid arthritis, psoriasis, inflammatory bowel disease
Abbreviations used
ACR20: American College of Rheumatology 20% improvement
criteria
AS: Ankylosing spondylitis
ASAS: Assessment of SpondyloArthritis International Society
axSpA: Axial spondyloarthritis
bDMARD: Biologic disease-modifying antirheumatic drug
CRP: C-reactive protein
csDMARD: Conventional synthetic disease-modifying antirheumatic
drug
DAS28: Disease Activity Score in 28 Joints
DMARD: Disease-modifying antirheumatic drug
EMA: European Medicines Agency
FDA: US Food and Drug Administration
IBD: Inflammatory bowel disease
IR: Inadequate responder
JAKI: JAK inhibitor
LTE: Long-term extension
MTX: Methotrexate
NMSC: Nonmelanoma skin cancer
PsA: Psoriatic arthritis
RA: Rheumatoid arthritis
RCT: Randomized controlled trial
SpA: Spondyloarthritis
STAT: Signal transducer and activator of transcription
UC: Ulcerative colitis
VTE: Venous thromboembolism
The therapeutic landscape in the field of immune-mediated
rheumatic diseases has been rapidly changing over recent years.
After the initial revolution of biologic disease-modifying antirheumatic drugs (DMARDs) targeting TNF and subsequently
other single-cytokine or inflammatory targets, a new class of
drugs has recently been introduced. They are the JAK inhibitors
(JAKIs), also known as JAKinibs, with several already licensed
for immune-mediated rheumatic diseases and many more in the
pipeline (Table I). JAKIs are classified as targeted synthetic
DMARDs, and although on a superficial level they may appear
to share many immunologic, efficacy, and safety features with
the classic biologic DMARDs (bDMARDs) that have
transformed clinical practice in the past 2 decades, there are
important differences between them. Despite often targeting
many of the same inflammatory pathways as the existing
bDMARDs, JAKIs do this by inhibiting the JAK/STAT pathway
to block intracellular signaling mediated by a variety of cytokines
and other molecules rather than by targeting a specific, usually
extracellular molecule, as is the case for the bDMARDs. JAKIs
are small molecules and not mAbs, avoiding the immunogenicity
issues associated with the latter. However, the broader targeting of
From athe Institute of Infection, Immunity and Inflammation, University of Glasgow,
Glasgow, and bthe First Department of Propaedeutic Internal Medicine, National
and Kapodistrian University of Athens, Laiko General Hospital, Athens.
Disclosure of potential conflict of interest: N. Basu has received institution research
funding from Eli Lilly and Pfizer and honoraria from Eli Lilly and AbbVie. I. B.
McInnes has received honoraria or research funding from AbbVie, AstraZeneca, BMS,
Boerhinger Ingelheim, Eli Lilly, Causeway Therapeutics, Cabaletta, Gilead, Janssen,
Novartis, Moonlake, Leo, Pfizer, Celgene, Sanofi, and UCB. S. Siebert has received
institution research funding from Boehringer Ingelheim, BMS, Celgene, Eli Lilly,
Janssen, and UCB and honoraria from AbbVie, Biogen, Celgene, Janssen, Novartis,
and UCB. The rest of the authors declare that they have no relevant conflicts of interest.
Received for publication July 6, 2021; revised August 17, 2021; accepted for publication
August 18, 2021.
Available online August 24, 2021.
Corresponding author: Stefan Siebert, MD, PhD, 4th Floor, Sir Graeme Davies Building,
Institute of Infection, Immunity and Inflammation, 120 University Place, Glasgow,
G12 8TA, United Kingdom. E-mail: stefan.siebert@glasgow.ac.uk.
The CrossMark symbol notifies online readers when updates have been made to the
article such as errata or minor corrections
0091-6749/$36.00
Ó 2021 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaci.2021.08.010
941
942 FRAGOULIS ET AL
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
TABLE I. JAK inhibitors approved by the FDA or EMA or at the phase II or III trial stage for adult immune-mediated rheumatic and
related diseases
Drug
JAK specificity
Stage of approval
Tofacitinib
JAK3/JAK1 > JAK2, TYK2
Baricitinib
JAK1/JAK2
Upadacitinib
JAK1
Filgotinib
JAK1
Peficitinib
PAN-JAK
Approved: RA, PsA, and UC
Phase III: AS
Phase II: Systemic sclerosis, uveitis, and PMR
Approved: RA
Phase III: SLE
Phase II: Psoriasis, GCA, PMR, and myositis
Approved: RA (PsA* and AS*)
Phase III: nr-axSpA, CD, UC, GCA, and Takayasu arteritis
Phase II: HS and SLE
Approved: RA
Phase III: CD and UC
Phase II: PsA, AS, CLE, and Sj€ogren syndrome
Approved*: RA (Japan only)
Phase III: RA (Japan only)
Phase II: RA and UC
CD, Crohn disease; CLE, cutaneous lupus erythematosus; GCA, giant cell arteritis; HS, hidradenitis suppurativa; nr-AxSpA, nonradiographic SpA, PMR, polymyalgia rheumatica.
*Still awaiting FDA review.
Rejected by the FDA.
JAKIs may be associated with effects in pathways beyond those
being targeted, so their safety profile needs careful further investigation, as highlighted by the ongoing concerns regarding their
unexpected association with thromboses.1 On the other hand,
thanks to their pleiotropic actions, JAKIs have been found to be
effective for a variety of immune-mediated diseases with different
underlying pathogenetic mechanisms.2 Herein, we give an overview of their efficacy in the main immune-mediated diseases
and discuss the general safety concerns raised.
NOMENCLATURE AND PATHOPHYSIOLOGY
JAKs are a family of intracellular tyrosine kinases consisting of
4 members: JAK1, JAK2, JAK3, and TYK2. JAKs phosphorylate
tyrosine residues on themselves (autophosphorylation) or on
other adjacent molecules (transphosphorylation). The latter
include signal transducers and activators of transcription
(STATs), an important family of transcription factors. The
JAK/STAT pathway is highly conserved and mediates the effects
of a large number of molecules, including a range of inflammatory
cytokines, as well as important physiologic molecules such as
erythropoietin and GM-CSF.3 Binding of these protein ligands to
their cognate receptors leads to activation of the JAK/STAT
pathway, ultimately resulting in dimerized STATs translocating
to the nucleus and regulating gene expression.
JAK signaling, and therefore therapeutic targeting, are associated
with significant complexity. Although receptor subunits are linked
with specific JAKs, many are associated with more than 1 JAK and
several different pathways may signal via the same JAK (Fig 1).
Therefore, inhibiting a specific JAK family member may interfere
with a number of pathways (possibly with differing intensities)
associated with a variety of receptors and their cognate extracellular
cytokines or ligands. Furthermore, JAKIs may block several JAKs
to differing degrees, resulting in differential effects. As the
understanding of JAK/STAT pathway inhibition has advanced, there
has been a move from less specific (blocking >1 JAK molecule)
first-generation JAKIs to more selective JAKIs (Table I).
RA
Rheumatoid arthritis (RA) is the most common chronic
inflammatory arthritis. A large number of cytokines have been
implicated in the pathogenesis of RA, including hierarchically
dominant proinflammatory cytokines such as TNF and IL-6. The
widespread use of targeted bDMARDs has resulted in significant
improvements in outcomes for people with RA. However, much
unmet clinical need remains, with some patients not responding
and a significant majority achieving only a partial response.
Alternative treatment modalities are urgently required.
Many cytokines implicated in RA signal via the JAK/STAT
pathway, so the broader effects of JAKIs may potentially be
advantageous. There are currently 3 JAKIs licensed for the
treatment of RA, namely, tofacitinib (a first-generation JAKI
with mainly JAK3/JAK1 selectivity), baricitinib (with
JAK 1/JAK2 selectivity), and upadacitinib (JAK1 selective),
while filgotinib is licensed in the European Union and Japan
(Table I). Several other JAKIs, including peficitinib and itacitinib,
are in early-phase studies for treatment of RA.4
The efficacy of tofacitinib, baricitinib, and upadacitinib in RA
has been demonstrated in several placebo-controlled phase III
randomized controlled trials (RCTs) (Table II5-19). Most RA
RCTs use the American College of Rheumatology 20%
improvement criteria (ACR20) response rates as the primary
outcome. The ACR20 are a composite measure requiring at least
a 20% improvement in the number of both swollen and tender
joints and at least a 20% improvement in 3 of 5 other criteria
(patient and physician global assessments, functional ability
measuremernt, and pain and acute-phase response).20
The initial efficacy and safety of tofacitinib in patients with RA
who were inadequate responders (IRs) to methotrexate (MTX)
was demonstrated in the ORAL Standard study.5 All 3 primary
end points at 6 months, which were assessed sequentially, were
achieved by significantly more participants receiving tofacitinib,
5 mg or 10 mg twice daily, or adalimumab (a TNF inhibitor) than
by participants receiving placebo (Table II). The efficacy of 5-mg
and 10-mg doses of tofacitinib in biologic-naive patients with RA
J ALLERGY CLIN IMMUNOL
VOLUME 148, NUMBER 4
FRAGOULIS ET AL 943
FIG 1. Immune-mediated rheumatic diseases and the key cytokines and related JAK molecules targeted by
JAKIs (approved or currently at phase II/III. EPO, Erythropoietin, GCA, giant cell arteritis; PsO, psoriasis;
€ gren syndrome; SSC, systemic sclerosis; TPO, thrombopoietin.
SS, Sjo
was confirmed both in combination with a range of conventional
synthetic DMARDs (csDMARDs), including MTX,6 and as
monotherapy.7 ORAL Scan demonstrated that tofacitinib with
MTX both improves disease activity and inhibits the progression
of radiographic structural damage in patients with RA who were
MTX IRs.8 In MTX-naive patients with early RA, twice-daily
doses of both 5 mg and 10 mg of tofacitinib monotherapy were
superior to MTX monotherapy in terms of ACR70 response rates
and radiographic progression at 6 months.9
The ORAL Step study evaluated patients with RA who were
IRs to TNF inhibitors; the study reported ACR20 response rates at
3 months of 41.7% for tofacitinib, 5 mg, and 48.1% for tofacitinib,
10 mg, versus 24.4% for placebo.10 The lower response rates in
TNF IRs than in biologic-naive patients are similar to the rates
that are seen with bDMARDs in similar cohorts.
Additionally, the ORAL Sequel long-term extension (LTE)
study demonstrated the safety and sustained efficacy of tofacitinib
for up to 9.5 years.21 Furthermore, the ORAL Strategy study
demonstrated that tofacitinib plus MTX was noninferior to
adalimumab plus MTX in MTX IRs.22
The efficacy of baricitinib, in doses of 2 mg and 4 mg once
daily, in patients with RA who were csDMARD IRs was
demonstrated in the RA-BUILD study.11 RA-BEAM, compared
baricitinib, 4 mg, with placebo and adalimumab, all with
background MTX, in MTX IRs.12 At 12 weeks, significantly
more participants in the baricitinib group achieved ACR20
than did participants in the placebo group (70% vs 40%,
respectively), with all major secondary end points met. The baricitinib group had a statistically higher ACR20 response rate at
12 weeks compared with the adalimumab group (61%), with
significant improvements for a number of outcomes seen as
early as 2 to 4 weeks after the start of treatment. Baricitinib
was also evaluated earlier in the management of RA in
MTX-naive or bDMARD-naive patients in the RA-BEGIN
study.13 Baricitinib, 4 mg, monotherapy was superior to MTX
monotherapy at 24 weeks (ACR20 rates of 77% vs 62%,
respectively), with similar results for baricitinib and MTX
combination therapy (ACR20 rate 78%).
The efficacy of baricitinib for the treatment of patients with RA
who were bDMARD IRs was demonstrated in the RA-BEACON
study, with 49% and 55% of the baricitinib groups (those
receiving 2 mg and 4 mg, respectively) achieving ACR20 at
week 12 versus 27% of the group receiving placebo.14
RA-BRANCH and RA-BRIDGE are ongoing phase IV trials
evaluating the longer-term effects of baricitinib treatment in
RA, with a particular focus on thromboembolic events.23
For upadacitinib, 6 phase III trials have been conducted in RA.
In these studies 2 separate primary end points were used, namely,
ACR20 response (for the US Food and Drug Administration
[FDA]) and the proportion achieving a Disease Activity Score in
28 joints (DAS28) with use of a C-reactive protein (CRP) level of
<
_3.2 or <
_2.6 (for the European Medicines Agency [EMA]).
SELECT-NEXT assessed 2 doses of upadacitinib (15 mg and
30 mg once daily) in nonresponders to csDMARDs,15 with week
12 ACR20 response rates of 64% and 66% for the upadacitinib
group, 15 mg and 30 mg, respectively, compared with a rate of
_3.2 was
36% for the placebo group. A DAS28-CRP level of <
achieved by 48% in both upadacitinib arms versus by 17% in
the placebo arm. SELECT-MONOTHERAPY demonstrated significant improvements in patients with active RA who were
switched from MTX to upadacitinib monotherapy versus in those
who continued taking MTX.16 SELECT-COMPARE, compared
upadacitinib, 15 mg, with adalimumab and placebo in patients
who were MTX IRs.17 Upadacitinib demonstrated efficacy for
_2.6 at week 12
both the ACR20 and a DAS28-CRP level of <
and met the multiplicity-controlled superiority comparison to
944 FRAGOULIS ET AL
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
TABLE II. Key phase III RCTs for tofacitinib, baricitinib and upadacitinib in RA
Study name (reference)
Study population
N
Intervention
ACR20 result (%)
ORAL Standard5
MTX IRs
717
ORAL Sync6
csDMARD IRs
792
ORAL Solo7
csDMARD IRs
611
ORAL Scan8
MTX IRs
797
ORAL Start9
MTX-naive
958
ORAL Step10
TNF inhibitor IRs
399
RA-BUILD11
csDMARD IRs
(biologic-naive)
684
RA-BEAM12
MTX IRs
1307
RA-BEGIN13
MTX naive/limited
exposure
588
RA-BEACON14
bDMARD IRs
527
SELECT-NEXT15
csDMARD IRs
661
SELECT-MONOTHERAPY16
MTX IRs
648
SELECT-COMPARE17
MTX IRs
1629
SELECT-EARLY18
MTX naive/limited
exposure
947
SELECT-BEYOND19
bDMARD IRs
499
Tofacitinib, 5 mg twice daily
Tofacitinib, 10 mg twice daily
Placebo
Adalimumab
Tofacitinib, 5 mg twice daily
Tofacitinib, 10 mg twice daily
Placebo
Tofacitinib, 5 mg twice daily*
Tofacitinib, 10 mg twice daily*
Placebo
Tofacitinib, 5 mg twice daily
Tofacitinib, 10 mg twice daily
Placebo
Tofacitinib, 5 mg twice daily*
Tofacitinib, 10 mg twice daily*
MTX
Tofacitinib, 5 mg twice daily
Tofacitinib, 10 mg twice daily
Placebo
Baricitinib, 2 mg once daily
Baricitinib, 4 mg once daily
Placebo
Baricitinib, 4 mg once daily
Placebo
Adalimumab
Baricitinib, 4 mg once daily*
Baricitinib, 4 mg, 1 MTX
MTX
Baricitinib, 2 mg once daily
Baricitinib, 4 mg once daily
Placebo
Upadacitinib, 15 mg once daily
Upadacitinib, 30 mg once daily
Placebo
Upadacitinib, 15 mg once daily*
Upadacitinib, 30 mg once daily*
Placebo (continue MTX)
Upadacitinib, 15 mg once daily
Placebo
Adalimumab
Upadacitinib, 15 mg once daily*
Upadacitinib, 30 mg once daily*
MTX
Upadacitinib, 15 mg once daily
Upadacitinib, 30 mg once daily
Placebo
51.5
52.6
28.3
47.2
52.1
56.6
30.8
59.8
65.7
26.7
51.5
61.8
25.3
71.3
76.1
50.5
41.7
48.1
24.4
66
62
39
70
40
61
77
78
62
49
55
27
64
66
36
68
71
41
71
36
63
76
77
54
65
56
28
ACR20
Time point
6 mo
6 mo
3 mo
6 mo
6 mo
3 mo
12 wk
12 wk
24 wk
12 wk
12 wk
14 wk
12 wk
12 wk
12 wk
*Used as monotherapy (ie, not in combination with MTX and/or another csDMARD).
ACR20 not the primary end point.
_2.6, pain severity,
adalimumab for ACR50, DAS28-CRP level of <
and other clinical outcomes at week 12, with significant
improvements between upadacitinib and adalimumab already
evident by weeks 4 to 8. By using ACR50 at week 12,
SELECT-EARLY demonstrated that upadacitinib monotherapy
was superior to MTX monotherapy in patients with relatively
early RA who either had not received or had limited exposure
to MTX.18
SELECT-BEYOND assessed the efficacy of upadacitinib in
patients with RA who had failed to respond to at least 1
bDMARD.19 ACR20 was achieved at week 12 by 65% of those
who received upadacitinib in a dose of 15 mg and 56% of those
who received upadacitinib in a dose of 30 mg compared with
by 28% of patients who received placebo. A DAS28-CRP level
_3.2 was achieved by 43%, 42%, and 14% of these patients,
of <
respectively. Finally, SELECT-CHOICE compared upadacitinib,
15 mg, with intravenous abatacept (a T-cell costimulation modulator) in patients with RA with active disease despite treatment
with at least 1 bDMARD.24 Upadacitinib was superior to abatacept for the primary end point (ie, the change from baseline in
DAS28-CRP at week 12), and it was noninferior or superior for
a number of other outcomes. However, there were more serious
adverse events associated with upadacitinib than with abatacept
in this study.
J ALLERGY CLIN IMMUNOL
VOLUME 148, NUMBER 4
Filgotinib was evaluated for RA in the FINCH phase III trial
program. FINCH1 randomized patients with RA who were MTX
IRs to receive filgotinib (100 mg and 200 mg), adalimumab, or
placebo.25 Significantly more patients in both filgotinib arms
(69% for 100 mg and 77% for 200 mg) achieved ACR20 at 12
weeks than in the placebo group (50%). Filgotinib, in a dose of
200 mg but not in a dose of 100 mg, was noninferior to
adalimumab. FINCH2 evaluated filgotinib in patients who failed
or were intolerant of bDMARDs, with week 12 ACR20 response
rates of 58% (for 100 mg) and 66% (for 200 mg) compared with
31% for placebo.26 FINCH 3 evaluated filgotinib as monotherapy
(200 mg) and in combination (100 mg and 200 mg) with MTX
versus MTX monotherapy in patients with limited or no prior
exposure to MTX.27 Although significantly more patients
receiving filgotinib in combination with MTX (80%-81%)
achieved ACR20 at week 24 than did patients receiving MTX
monotherapy (71% [P < .001]), the response rate in those
receiving filgotinib, 200 mg, as monotherapy (78%) was not
superior to that in patients receiving MTX (P 5 .058). Although
the EMA approved filgotinib for the treatment of RA, the FDA
rejected filgotinib for RA over concerns of potential testicular
toxicity and requested additional data from ongoing clinical
studies evaluating the impact of filgotinib on sperm parameters.28
Peficitinib, a pan-JAKI, has been reported to be characterized
by efficacy and acceptable safety in RA in phase II studies, as well
as in 2 phase III studies in Japanese patients.29,30 Although
decernotinib, a selective JAK3 inhibitor, was efficacious in phase
II trials, there were safety signals with infections and increased
liver transaminase and lipid levels.31,32 Itacitinib, a selective
JAK1 inhibitor, also demonstrated efficacy in a phase II trial in
RA. However, it is mainly in development for hematologic and
oncologic indications, with no further trials in RA currently
planned.33
In summary, there are now several licensed JAKIs for RA with
evidence of efficacy across the spectrum of the disease. The exact
role of JAKIs in clinical practice remains to be determined and, in
addition to efficacy, their role will also be influenced by factors
such as safety, preferred route of administration, and cost. There
have been no direct head-to-head studies between different JAKIs
in RA; however, indirect comparisons have suggested differential
effects between JAKIs in RA, with possibly better ACR response
rates achievable with agents targeting JAK1, although this
remains to be confirmed.34,35
PsA
Psoriatic arthritis (PsA) is a chronic rheumatic condition
characterized by inflammatory musculoskeletal (synovitis and
enthesitis [inflammation at site of tendon insertion into bone]) and
skin (psoriasis) disease. As with other conditions in the
spondyloarthritis (SpA) spectrum, the IL-23/IL-17 axis plays a
central role in the pathophysiology of PsA.36 Importantly, many
of the cytokines involved in this axis exert their function through
the JAK/STAT pathway.2,37
The efficacy of tofacitinib and upadacitinib in PsA has been
demonstrated in phase III RCTs, and phase II trial results have
been published for filgotinib. Most clinical trials in PsA also use
ACR response rates as primary outcomes, although it should be
noted that doing so places the focus on the peripheral joint disease
and does not capture the full musculoskeletal or skin components
of PsA.
FRAGOULIS ET AL 945
The OPAL Broaden study demonstrated the efficacy of
tofacitinib in patients with PsA who are csDMARD IRs. At 3
months, ACR20 response rates of 50% and 61% were observed
for tofacitinib, 5 mg and 10 mg twice daily, respectively, versus
33% for placebo.38 This study also included an adalimumab
active comparator arm, with an ACR20 response rate of 52%.
Similarly, for IRs to a TNF inhibitor, tofacitinib was superior to
placebo at 3 months, (ACR20 rates of 50% for tofacitinib in a
dose of 5 mg, 47% for tofacitinib in a dose of 10 mg, and 24%
for placebo [P < .001]).39 Tofacitinib also improved other
musculoskeletal and cutaneous domains in PsA, as well as a range
of patient-reported outcomes, with responses maintained at 12
months and similar to those obtained for patients treated with
adalimumab.40,41
The efficacy of upadacitinib in PsA was demonstrated in the
SELECT-PsA phase III RCTs. In csDMARD IRs, the ACR20
response rates at 12 weeks for upadacitinib, 15 mg (70.6%) and 30
mg (78.5%), were superior to those for placebo (36.2%) and
noninferior to the results for the adalimumab active comparator
(65.0%).42 Both doses of upadacitinib also demonstrated efficacy
in patients with PsA with inadequate response to at least 1
previous bDMARD (ACR20 rates at week 12 of 56.9% for
upadacitinib in a dose of 15 mg, 63.8% for upadacitinib in a
dose of 30 mg, and 24.1% for placebo).43 Several other JAKIs
are undergoing active clinical trials in PsA, with 80% of patients
who received filgotinib, 200 mg, achieving the ACR20 response
at week 16, compared with 33% of the patients in the placebo
group in the phase II EQUATOR trial.44
JAKIs are therefore an emerging therapeutic option for the
management of PsA. However, determining their exact role in
clinical practice for PsA will be more complex than for RA on
account of the more heterogeneous nature and multiple domains
involved in PsA. These agents will also need to demonstrate
efficacy comparable to that of established biologic agents,
including the impressive results in the skin that have been
achieved with biologic agents targeting the IL-23/IL-17 pathway.
AxSpA
Axial SpA (AxSpA) is part of the SpA spectrum and
encompasses a group of inflammatory rheumatic conditions
characterized by chronic inflammation in the axial skeleton
(spine). In clinical practice, patients with ankylosing
spondylitis (AS) and without established radiographic damage
(nonradiographic axSpA) are now generally considered together
under the umbrella term axSpA, although the regulators generally
still require separate studies for licencing purposes. The
pathogenesis of axSpA is not yet fully understood but includes
many pathways that are shared with related conditions in the
SpA spectrum. IL-23 and IL-22, both of which are central players
in the IL-23/IL-17 axis, use this pathway to mediate their effects
via IL-17, as described previously.2,37,45 Polymorphisms in JAK2
and TYK2 have been reported in association with axSpA.46 Data
from animal models further support the relationship between the
JAK/STAT pathway and SpA.47
Despite the completion of phase III studies of tofacitinib and
upadacitinib in AS and the submission of regulatory applications,
there are to date no JAKIs licensed by the FDA or EMA for the
treatment of axSpA.
A phase II study suggested greater efficacy of tofacitinib than
that of placebo in AS, with evidence of a dose response for
946 FRAGOULIS ET AL
objective end points such as magnetic resonance imaging scores
but not for more subjective patient-reported outcomes.48 The
subsequent phase III trial in AS evaluated tofacitinib only in the
dose of 5 mg twice daily, with significantly more patients
receiving tofacitinib than placebo achieving (at week 16) the
primary composite of Assessment of SpondyloArthritis International Society (ASAS) response of at least 20% (ASAS20)
(56.4% vs 29.4%, respectively) and the key secondary improvement of at least a 40% in ASAS response (ASAS40) (40.6% vs
12.5%, respectively) end points.49 Tofacitinib also led to rapid
reduction in CRP level and improvement in other secondary
outcome measures.
Upadacitinib, 15 mg once daily, was evaluated in the
SELECT-AXIS 1 phase II/III trial, which enrolled 187
biologic-naive patients with AS.50 The primary ASAS40
response end point at week 14 was achieved by significantly
more patients in the upadacitinib group (52%) than in the placebo
group (26%). Regarding filgotinib, the phase II TORTUGA trial
reported that patients with active AS receiving filgotinib in a
dose of 200 mg daily had a greater change in mean Ankylosing
Spondylitis Disease Activity Score (ASDAS) from baseline at
week 12 than did those receiving placebo, with a least squares
mean difference of –0.85 (95% CI 5 –1.17 to –0.53) between
groups.51 However, as a result of the FDA responding to the RA
submission by requesting further data from phase II studies and
expressing concerns regarding the overall benefit-risk profile of
a 200-mg dose of filgotinib,52 the phase III studies in AS, PsA,
psoriasis, and uveitis have been terminated.53
In summary, although several JAKIs have evidence of efficacy
and are awaiting licensing for use in AS, the results to date are
fairly modest compared with those for bDMARDs, and the results
for nonradiographic axSpA are still awaited.
PSORIASIS
Psoriasis is a common cutaneous inflammatory skin disease.
Genetic studies implicate innate immunity, barrier function, and
the IL-23/IL-17 pathway in its pathogenesis,54 with many of the
key processes linked to JAK/STAT signaling pathways. For
example, IL-12 signals via JAK2 and TYK2 phosphorylation of
STAT4 to trigger TH1 and IFN-g production. Type II interferon
signaling is in turn mediated by JAK1 and JAK2, which
phosphorylate STAT1, and IL-23 activates JAK2 and TYK2,
leading to phosphorylation of STAT3 and STAT4, which in turn
leads to IL-17 production.2,55-57
Tofacitinib is the most extensively evaluated JAKI for
psoriasis. Two phase III trials (OPT Pivotal 1 and 2) evaluated
tofacitinib, 5 mg and 10 mg twice daily, in patients with
moderate-to-severe plaque psoriasis.58 In both studies,
significantly more participants receiving either dose of tofacitinib
compared with placebo achieved the week 16 coprimary
outcomes of a Physician’s Global Assessment (PGA) of ‘‘clear’’
or ‘‘almost clear’’ (for OPT Pivotal 1, 41.9% and 59.2% vs
9.0%; for OPT Pivotal 2, 46.0% and 59.1% vs 10.9%) and at least
a 75% reduction in Psoriasis Area and Severity Index (PASI75)
(for OPT Pivotal 1, 39.9% and 59.2% vs 6.2%; for OPT Pivotal
2, 46.0% and 59.6% vs 11.4%).
A phase III noninferiority trial using the same coprimary end
points assessed at week 12, randomized participants to receive
tofacitinib, 5 mg or 10 mg; etanercept, 50 mg twice weekly; or
placebo.59 The Physician’s Global Assessment response was
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
achieved by 47.1%, 68.2%, 66.3%, and 15% participants, and
the PASI75 response rates were 39.5%, 63.6%, 58.8%, and
5.6% for 5 mg of tofacitinib, 10 mg of tofacitinib, etanercept,
and placebo, respectively. Tofacitinib, in a dose of 10 mg twice
daily but not in a dose of 5 mg twice daily, was not inferior to
etanercept. Tofacitinib has also been evaluated as an ointment
for topical treatment of psoriasis in a phase IIb trial, showing
greater efficacy than that of control vehicle at the week 8 but
not week 12 end points.60
In summary, although oral tofacitinib has efficacy in psoriasis,
the results are considerably lower than those seen with current
biologic agents targeting key cytokines in the IL-23/IL-17 axis,
which have demonstrated high hurdle (90%-100% PASI)
responses. Therefore, although tofacitinib has been approved
for the treatment of the related condition PsA, it is not approved
for the treatment of psoriasis and no further trials are currently
ongoing.61
Phase II trials have been performed for several other JAK1-3
inhibitors; they have suggested modest efficacy for psoriasis,
although not all of them have published results. Currently, there
are no ongoing active studies for these agents.62
However, there is recent interest in selectively targeting TYK2,
another member of the JAK family.63 Following encouraging
phase II results of deucravacitinib in psoriasis,64 phase III studies
are due to start shortly.65 Brepocitinib, a TYK2/JAK1 inhibitor,
was reported to have similarly encouraging phase IIa trial
results,66 whereas oral ropsacitinib, another TYK2/JAK1
inhibitor67 and a topical version of brepocitinib,68 recently
completed phase II studies, with the results still awaited.61
IBD
Inflammatory bowel disease (IBD) encompasses Crohn disease
and ulcerative colitis (UC). The pathogenesis is multifactorial and
includes genetic susceptibility, microbiome alterations, and
proinflammatory cytokine response. TH1 and TH17 cells have
been shown to be strongly correlated with Crohn disease, and
TH2 cells, with an additional smaller presence of TH17 cells,
are implicated in UC.69-71 TH1 cell activity is linked to
IL-12/STAT4 pathways via JAK2 and TYK2, as well as to the
IFNg/STAT1 route using JAK1 and JAK2. TH2 cell activity
involves IL-4/STAT6 with JAK1 and JAK3, along with
IL-2/STAT5 processes. As described previously, the
IL-23/IL-17 pathway involves JAK2 and TYK2, with
phosphorylation of STAT3 and STAT4.70
In contrast to the inflammatory conditions covered previously,
for which the same DMARD therapy is generally used to suppress
and maintain the inflammatory disease, IBD therapy traditionally
involves both induction therapy to control active inflammatory
gut disease and maintenance therapy. Tofacitinib was approved
for UC on the basis of the outcome of the OCTAVE trials, which
compared tofacitinib with placebo for induction and maintenance
of remission in UC. In the OCTAVE Induction 1 and 2 trials,
participants with moderate-to-severe UC who had failed
conventional therapy or a TNF inhibitor reported remission rates
at 8 weeks for tofacitinib twice daily of 18.5% and 16.6% versus
8.2% and 3.6% for placebo, respectively.72
Participants who had a clinical response to induction therapy
were then randomized in the OCTAVE Sustain trial to receive
maintenance therapy with either tofacitinib (5 mg or 10 mg twice
daily) or placebo for 52 weeks.72 Remission at 52 weeks was
J ALLERGY CLIN IMMUNOL
VOLUME 148, NUMBER 4
reported in 34.3% of patients treated with 5 mg of tofacitinib, in
40.6% treated with 10 mg of tofacitinib, and in 11.1% who
received placebo.
OCTAVE Open, an open-label LTE study, demonstrated that
most patients with UC in remission maintained this state with a
tofacitinib dose reduction (from 10 mg twice daily to 5 mg twice
daily), although a quarter lost remission.73 However, in light of
emerging concerns about a possible dose-dependent increased
thrombotic risk, both the FDA and EMA recommended tofacitinib in a dose of 10 mg twice daily for induction for 8 weeks
and then 5 mg twice daily as maintenance therapy for UC.
Despite the positive results in UC, tofacitinib, 5 mg and 10 mg
twice daily, failed to reach the induction and maintenance primary
efficacy end points in a phase II trial in Crohn disease.74
Filgotinib was evaluated as induction and maintenance therapy
for moderately to severely active UC in the SELECTION phase
IIb/III trial, which included 2 induction studies and 1 maintenance
study.75 Filgotinib, 200 mg (but not filgotinib, 100 mg) resulted in
significantly greater clinical remission rates at 10 weeks than did
placebo in both induction studies (biologic-naive and biologicexperienced participants), whereas both doses of filgotinib were
more effective than placebo at maintaining remission at 58 weeks.
Filgotinib, 200 mg once daily, induced clinical remission in
significantly more patients with active Crohn disease than did placebo in a phase II trial, although endoscopic improvement was
numerically but not statistically higher.76 Phase III trials for CD
are under way (ClinicalTrials.gov identifiers NCT02914561 and
NCT02914600).69
Upadacitinib has demonstrated promising results in phase II
trials for both UC and Crohn disease. The phase IIb ACHIEVE
trial reported that upadacitinib was more effective than placebo at
inducing remission at 8 weeks in patients with active UC.77 The
CELEST trial evaluated a range of upadacitinib doses compared
with placebo in patients with moderate-to-severe Crohn disease,
with variable results for the clinical remission primary end point
but a dose response with upadacitinib for the endoscopic primary
end point.78 A number of phase III trials of upadacitinib are
planned or under way for UC (ClinicalTrials.gov identifiers
NCT03653026, NCT02819635, and NCT03006068) and Crohn
disease
(ClinicalTrials.gov
identifiers
NCT02365649,
NCT03345849,
NCT03345836,
NCT03345823,
and
NCT02782663).71
Peficitinib did not demonstrate a significant dose response in a
phase IIb study in patients with moderate-to-severe active UC,
although numerically, more participants receiving peficitinib
doses of 75 mg or higher once daily achieved clinical response,
remission, and mucosal healing at week 8 and also reported more
treatment-emergent adverse events.79
To maximize efficacy in gut inflammation in IBD and minimize
systemic exposure and toxicity, a novel gut-selective pan-JAKI
(TD-1473) has been shown in a phase Ib study to achieve
high intestinal drug levels compared with plasma drug
levels, with a trend toward reduced disease activity in patients
with UC.80 This agent is now undergoing further studies in
patients with UC and Crohn disease. A number of other JAKIs,
including brepocitinib (a TYK2/JAK1 inhibitor), ritlecitinib (a
novel JAK3/TEC inhibitor), and BMS-986165 (a TYK2selective inhibitor), have ongoing or planned trials for UC and/
or Crohn disease.69,71
Therefore, although tofacitinib and filgotinib have
demonstrated efficacy for induction and maintenance in
FRAGOULIS ET AL 947
moderate-to-severe UC, the results have been more mixed for
Crohn disease and the exact role of JAKIs in the management of
IBD remains to be determined.
OTHER ADULT IMMUNE-MEDIATED CONDITIONS
In addition to the rheumatic conditions for which biologic
anticytokine therapies are already established in clinical practice,
there are increasing preclinical and trial data supporting the
potential efficacy of JAKIs for a range of other immune-mediated
rheumatic diseases, such as SLE, Sj€
ogren syndrome, and
sarcoidosis, for which current therapeutic options are limited.
The current state of the JAKI studies for these conditions is
summarized in Table III.81-92 JAKIs therefore offer hope to
address the significant unmet clinical need for people living
with these conditions. However, it should be noted that clinical
trials for these conditions pose significant challenges for trialists
and for industry, as these conditions are uncommon and have
significant complexity and heterogeneity that is often poorly
captured by outcome measures in trials.93 The variability of
JAKI selectivity will add an additional layer of complexity, so
carefully designed studies will need to be performed to confirm
the efficacy of JAKIs in general for these conditions and to
determine the best strategy of JAK inhibition for each condition.
SAFETY OF JAKIs
General remarks
As this is a new drug class, data about the safety profile of JAKIs
are still accumulating. The current longer-term data are related
mostly to tofacitinib, the first licensed JAKI, and are mostly derived
from the studies in RA. However, a recent interim analysis of an LTE
study of tofacitinib in patients with PsA did not reveal any new safety
signals.94 In general, the frequency of adverse events seems to be
generally comparable with that of other bDMARDs,95 with
infections being the most common adverse event. Some concerns
have been expressed for gastrointestinal perforation in patients
treated with JAKIs, especially with tofacitinib and baricitinib, but
robust data are lacking so far.1 In a study using data from insurance
databases, gastrointestinal perforation risk for patients with RA was
statistically significantly higher for patients treated with tocilizumab
(an IL-6 receptor inhibitor) and numerically higher for patients
treated with tofacitinib than for those treated with other
bDMARDs.96,97 Hematologic abnormalities such as anemia,
elevated transaminase levels, mild elevation of creatine kinase levels,
and alteration in the lipid profile are often seen in patients treated
with JAKIs. These are usually mild and generally do not lead to treatment discontinuation. It is recommended in the European Alliance of
Associations for Rheumatology points to consider guidance for treatment with JAKIs that full blood count, liver function, and serum
creatinine level be checked at baseline, at approximately 3 months
after the start of JAKI treatment, and then periodically. Low numbers
of neutrophils or lymphocytes might require dose adjustments or
discontinuation of treatment, whereas significant anemia should
lead to discontinuation of the drug.1 It should be noted that
erythropoietin signals through JAK2,98 so selective JAK1 inhibitors
might be better in the setting of preexisting anemia.1
On the other hand, there have been some specific safety
concerns with JAKIs, namely, herpes zoster infections, venous
thromboembolism (VTE), and malignancies, which will be
covered in more detail.
948 FRAGOULIS ET AL
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
TABLE III. Summary of the current state of evidence for JAKIs for other immune-mediated rheumatic disorders in adults
Condition
SLE
Sj€
ogren syndrome
Giant cell arteritis
Sarcoid
DM
Relapsing polychondritis
Systemic sclerosis
Study
81
JAKI
Outcome
Phase II RCT
Baricitinib, 2 mg and 4 mg
once daily
Resolution of arthritis or rash observed in patients given
baricitinib in a dose of 4 mg but not 2 mg
Case series (n 5 10)82
Murine lupus model83
Tofacitinib, 5 mg twice daily
Tofacitinib
Improvements in arthritis and rash
Improved SLE activity markers and manifestations including
nephritis and skin lesions
Phase II RCT84,85
Topical tofacitinib
Ongoing phase II study86
Animal model87
Phase II trial88
Phase III trial88
Case (n 5 1)89
Case (n 5 1)90
Case reports86,88
Case report (n 5 1)91
Case report (n 5 1)92
Phase I/II trial
Filgotinib
Tofacitinib
Baricitinib
Upadacitinib
Ruxolitinib
Tofacitinib
Tofacitinib and ruxolitinib
Tofacitinib
Tofacitinib
Both studies showed improvements in dry eyes and related
activity markers
Trial ongoing
Increased remission in the mice given tofacitinib
Trial ongoing, patients with relapsing GCA
Trial ongoing, patients with relapsing GCA
Refractory sarcoid, improved lung infiltrates and skin disease
Refractory cutaneous sarcoid, good skin response
Several case reports of improvement of refractory DM
Remission achieved
Polyarthropathy and skin improved.
Study completed; no results
DM, Dermatomyositis; GCA, giant cell arteritis.
Infections
Analysis of phase II, phase III, and LTE studies for tofacitinib
in RA estimate the risk of serious infections at about 2.7 events
per 100 patient years, which has remained stable over time.96,99
The data are largely similar for baricitinib, for which the risk is
about 3.0 per 100 patient years.100 Studies using insurance
databases reported no significantly increased risk for serious
infections in patients treated with tofacitinib compared with in
those treated with bDMARDs.101,102 However, results from the
interim analysis of the ongoing FDA-mandated open-label
ORAL Surveillance safety study (ClinicalTrials.gov identifier
NCT02092467) in patients with RA comparing tofacitinib with
adalimumab showed that serious infections were more common
with tofacitinib in patients older than 65 years, prompting the
EMA to issue a warning that tofacitinib should be considered in
these patients only if no other suitable alternative treatment is
available.103 Another study that combined data from RA RCTs
and the CORRONA registry reported that serious infections
were more common in older (>65 years) individuals receiving
10 mg of tofacitinib twice daily (but not 5 mg twice daily) than
in patients receiving adalimumab.104 Of note, data from 6 phase
III studies for patients with RA treated with tofacitinib indicated
that combination therapy with csDMARDs was associated with
higher rates of serious infections.105 Whether these findings
will also be seen with other, more selective JAKIs remains to be
seen.
So far, no safety signal has arisen for opportunistic infections,
whereas for tuberculosis, JAKIs do not seem to offer an advantage
over TNF inhibitors.96,106
Herpes zoster infection
As the JAK/STAT pathway is central in IFN signaling and the
immune response to viruses, the impact of JAKIs on viral
infections, particularly herpes viruses in immunocompromised
patients, warrants specific attention and has implications for
screening and vaccination strategies in these patients. This topic
has recently been reviewed in detail.107 It is clear that herpes zoster infection is more common (the incidence is approximately
double) in patients treated with JAKIs than in those receiving
other biologics,108,109 although it is usually mild and typically
limited to 1 dermatome.107 The recognized risk factors for herpes
zoster reactivation in these patients include older age, female sex,
and cotreatment with prednisolone in a dose higher than 7.5 mg
per day, whereas reactivation is also more frequent in individuals
of Asian origin.1 Furthermore, herpes zoster risk was more
pronounced for patients being treated with the higher dosing
regimens of 10 mg twice daily for tofacitinib21,105 and 4 mg
once daily for baricitinib than for those being treated with the
equivalent lower doses, suggesting a dose response.110
Although the risk of herpes zoster in the individual phase II/III
trials appears similar for the various JAKIs, it has been postulated
from laboratory and pooled data that JAK2 and JAK3 inhibition
may be associated with higher risk of varicella-zoster infection
than JAK1 inhibition is, although this remains to be confirmed in
the clinical setting.97,99
VTE and cardiovascular outcomes
Although the risk of infections associated with JAK inhibition
was expected and consistent with the mechanism of action, the
putative increased risk of VTE was not expected and remains
poorly understood despite intense research efforts.111 It should be
noted that patients with RA are known to already be at increased
risk of cardiovascular events compared with the general
population.112 In light of concerns about the safety of JAKIs,
the regulator mandated the postmarketing ORAL Surveillance
trial comparing tofacitinib, 5 mg or 10 mg twice daily, with a
TNF inhibitor in patients with RA who were older than 50 years
and had at least 1 other cardiovascular risk factor. Although the
final results have yet to be published, interim analysis has indicated that the risk of pulmonary embolism was increased about
3-fold by tofacitinib, 5 mg twice daily, and about 6-fold with
tofacitinib, 10 mg twice daily, compared with the risk in the
TNF inhibitor comparator group.103 There was also a signal for
increased dose-dependent all-cause mortality with tofacitinib.
The tofacitinib, 10 mg twice daily, arm in the study was therefore
stopped; the EMA recommended that tofacitinib be used with
J ALLERGY CLIN IMMUNOL
VOLUME 148, NUMBER 4
caution, regardless of the indication and dose, in patients with
known risk factors for VTE,103 and it recently sent a direct health
care professional communication about this to all prescribers.113
For baricitinib, an analysis of pooled data from 8 RA RCTs and
1 LTE study reported an incidence rate for VTE and/or pulmonary
embolism of 0.5 per 100 patient years, which was comparable to
the incidence rate for the 2-mg and 4-mg doses of baricitinib,
although there was a trend for VTE risk in older patients.110
Similar results were reported in separate analysis of data from 9
pooled RA studies, although numerically, more VTEs were
observed in patients who received baricitinib in a dose of 4 mg
(6 of 997 patients, all of whom had other cardiovascular risk
factors) than in patients who received placebo (0 of 1070
patients).114 For upadacitinib, an integrated analysis of phase III
trials and an FDA review both found that major adverse
cardiovascular events and VTE rates for upadacitinib in RA
were comparable to those with MTX and adalimumab.115,116
Although it remains to be determined whether the putative VTE
risk is a class effect, in response to the tofacitinib ORAL
Surveillance interim results, the FDA broadened the black box
warning for increased thromboembolic risk to all include
approved JAKIs. Until this issue is resolved, these agents should
be used with caution in older patients and in those with other VTE
risk factors, particularly where other suitable therapeutic options
exist.1
Malignancies
To date, the evidence regarding malignancies does not appear
to differ from that seen with bDMARDs, with a systematic
literature review and meta-analysis reporting that tofacitinib and
bDMARDs were not found to be associated with increased risk
for malignancy compared with placebo or csDMARDs in RA.117
Although the incidence rate for nonmelanoma skin cancers
(NMSCs) was generally low and not significantly increased
with JAKIs, it was numerically higher with tofacitinib in a dose
of 10 mg twice daily than in a dose of 5 mg twice daily.118 The
recent European Alliance of Associations for Rheumatology
points to consider guidance concludes that the risk of
malignancies does not appear to be increased with use of JAKIs,
with the possible exception of the risk of NMSC, for which
regular skin examination is advised, as patients may already be
at increased risk owing to prior exposure to other
immunomodulatory therapies.1 Interestingly, in the interim
analysis of the ORAL Surveillance study, the noninferiority
criterion for malignancies excluding NMSC was not met for the
combined tofacitinib doses versus the TNF inhibitor, so this
was included as a warning in the recent EMA direct health care
professional communication.113 Longer-term data, as well as
referents other than TNF inhibitors, will be required to determine
whether there is an increased risk, and if so, whether this is a class
effect or an effect related to specific JAKIs.
CONCLUSION
A number of JAKIs have been approved or are in clinical trials
for a wide range of immune-mediated diseases, with largely
promising but also some mixed and unexpected results. Although
their safety profile is largely (apart from the higher risk for herpes
zoster infection) comparable with that of the existing bDMARDs,
important issues remain to be clarified—most notably, the
FRAGOULIS ET AL 949
hitherto unexplained signal for VTE. The role for JAKIs in
clinical practice for the management of immune-mediated
rheumatic and related conditions remains to be determined, and
in addition to the usual efficacy and safety considerations, this
role will likely vary between conditions with existing effective
biologic therapies, particularly in cases in which these therapies
already achieve high hurdle responses, as is the case with
IL-23/IL-17 inhibition in psoriasis, and conditions with currently
limited therapeutic options. The individual JAKIs are currently
being studied in isolation, so a further important area will be to
understand the optimal JAKI selectivity for specific conditions,
which may ultimately require head-to-head studies of different
JAKIs.
In summary, the JAKIs represent a major therapeutic advance
for immune-mediated diseases, although it remains to be seen
whether this will be reflected in improved outcomes for patients
with the aforementioned debilitating conditions beyond those
seen with current therapies. As with all new targeted therapies,
the arrival of the JAKIs demands that we develop a detailed
understanding of the pharmacology of these agents and the
underlying pathophysiology of these conditions, perform robust
clinical trials, and learn the lessons from these results,
particularly in cases in which they are unexpected, in order to
deliver transformational outcomes for our patients.
REFERENCES
1. Nash P, Kerschbaumer A, Dorner T, Dougados M, Fleischmann RM, Geissler K,
et al. Points to consider for the treatment of immune-mediated inflammatory
diseases with Janus kinase inhibitors: a consensus statement. Ann Rheum Dis
2021;80:71-87.
2. Fragoulis GE, McInnes IB, Siebert S. JAK-inhibitors. New players in the field of
immune-mediated diseases, beyond rheumatoid arthritis. Rheumatology (Oxford)
2019;58:i43-54.
3. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase
inhibitors in autoimmune diseases. Ann Rheum Dis 2013;72(suppl 2):ii111-5.
4. Angelini J, Talotta R, Roncato R, Fornasier G, Barbiero G, Dal Cin L, et al.
JAK-inhibitors for the treatment of rheumatoid arthritis: a focus on the present
and an outlook on the future. Biomolecules 2020;10:1002.
5. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA,
Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid
arthritis. N Engl J Med 2012;367:508-19.
6. Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al.
Tofacitinib in combination with nonbiologic disease-modifying antirheumatic
drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern
Med 2013;159:253-61.
7. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD,
et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.
N Engl J Med 2012;367:495-507.
8. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C,
et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving
methotrexate: twelve-month data from a twenty-four-month phase III randomized
radiographic study. Arthritis Rheum 2013;65:559-70.
9. Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al.
Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014;
370:2377-86.
10. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda
B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients
with active rheumatoid arthritis with an inadequate response to tumour necrosis
factor inhibitors: a randomised phase 3 trial. Lancet 2013;381:451-60.
11. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al.
Baricitinib in patients with inadequate response or intolerance to conventional
synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017;
76:88-95.
12. Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales
L, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in
rheumatoid arthritis. N Engl J Med 2017;376:652-62.
13. Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A,
Stanislav M, et al. Baricitinib, methotrexate, or combination in patients
950 FRAGOULIS ET AL
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
with rheumatoid arthritis and no or limited prior disease-modifying
antirheumatic drug treatment. Arthritis Rheumatol 2017;69:506-17.
Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al.
Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016;
374:1243-52.
Burmester GR, Kremer JM, Van den Bosch F, Kivitz A, Bessette L, Li Y, et al.
Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and
inadequate response to conventional synthetic disease-modifying anti-rheumatic
drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase
3 trial. Lancet 2018;391:2503-12.
Smolen JS, Pangan AL, Emery P, Rigby W, Tanaka Y, Vargas JI, et al.
Upadacitinib as monotherapy in patients with active rheumatoid arthritis and
inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 2019;393:2303-11.
Fleischmann R, Pangan AL, Song IH, Mysler E, Bessette L, Peterfy C, et al.
Upadacitinib versus placebo or adalimumab in patients with rheumatoid arthritis
and an inadequate response to methotrexate: results of a phase III, double-blind,
randomized controlled trial. Arthritis Rheumatol 2019;71:1788-800.
van Vollenhoven R, Takeuchi T, Pangan AL, Friedman A, Mohamed MF, Chen S,
et al. Efficacy and safety of upadacitinib monotherapy in methotrexate-naive
patients
with
moderately-to-severely
active
rheumatoid
arthritis
(SELECT-EARLY): a multicenter, multi-country, randomized, double-blind,
active comparator-controlled trial. Arthritis Rheumatol 2020;72:1607-20.
Genovese MC, Fleischmann R, Combe B, Hall S, Rubbert-Roth A, Zhang Y, et al.
Safety and efficacy of upadacitinib in patients with active rheumatoid
arthritis refractory to biologic disease-modifying anti-rheumatic drugs
(SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial.
Lancet 2018;391:2513-24.
American College of Rheumatology Committee to Reevaluate Improvement C. A
proposed revision to the ACR20: the hybrid measure of American College of
Rheumatology response. Arthritis Rheum 2007;57:193-202.
Wollenhaupt J, Lee EB, Curtis JR, Silverfield J, Terry K, Soma K, et al. Safety
and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid
arthritis: final results of a global, open-label, long-term extension study. Arthritis
Res Ther 2019;21:89.
Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, et al. Efficacy and
safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab
with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase
3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017;390:
457-68.
El Jammal T, Seve P, Gerfaud-Valentin M, Jamilloux Y. State of the art: approved
and emerging JAK inhibitors for rheumatoid arthritis. Expert Opin Pharmacother
2021;22:205-18.
Rubbert-Roth A, Enejosa J, Pangan AL, Haraoui B, Rischmueller M, Khan N,
et al. Trial of upadacitinib or abatacept in rheumatoid arthritis. N Engl J Med
2020;383:1511-21.
Combe B, Kivitz A, Tanaka Y, van der Heijde D, Simon JA, Baraf HSB, et al.
Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis
and inadequate response to methotrexate: a phase III randomised clinical trial.
Ann Rheum Dis 2021;80:848-58.
Genovese MC, Kalunian K, Gottenberg JE, Mozaffarian N, Bartok B, Matzkies F,
et al. Effect of filgotinib vs placebo on clinical response in patients with moderate
to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug
therapy: the FINCH 2 randomized clinical trial. JAMA 2019;322:315-25.
Westhovens R, Rigby WFC, van der Heijde D, Ching DWT, Stohl W, Kay J, et al.
Filgotinib in combination with methotrexate or as monotherapy versus
methotrexate monotherapy in patients with active rheumatoid arthritis and limited
or no prior exposure to methotrexate: the phase 3, randomised controlled FINCH
3 trial. Ann Rheum Dis 2021;80:727-38.
Tanaka Y, Kavanaugh A, Wicklund J, McInnes IB. Filgotinib, a novel
JAK1-preferential inhibitor for the treatment of rheumatoid arthritis: an overview
from clinical trials. Mod Rheumatol 2021;1-11.
Takeuchi T, Tanaka Y, Tanaka S, Kawakami A, Iwasaki M, Katayama K, et al.
Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis
and an inadequate response to methotrexate: results of a phase III randomised,
double-blind, placebo-controlled trial (RAJ4) in Japan. Ann Rheum Dis 2019;
78:1305-19.
Tanaka Y, Takeuchi T, Tanaka S, Kawakami A, Iwasaki M, Song YW, et al.
Efficacy and safety of peficitinib (ASP015K) in patients with rheumatoid arthritis
and an inadequate response to conventional DMARDs: a randomised,
double-blind, placebo-controlled phase III trial (RAJ3). Ann Rheum Dis 2019;
78:1320-32.
Fleischmann RM, Damjanov NS, Kivitz AJ, Legedza A, Hoock T, Kinnman N. A
randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients
with active rheumatoid arthritis. Arthritis Rheumatol 2015;67:334-43.
Genovese MC, van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N.
VX-509 (decernotinib), an oral selective JAK-3 inhibitor, in combination with
methotrexate in patients with rheumatoid arthritis. Arthritis Rheumatol 2016;
68:46-55.
Avci AB, Feist E, Burmester GR. Early phase studies of JAK1 selective inhibitors
in rheumatoid arthritis. Rheumatology (Oxford) 2021;60:ii11-6.
Harrington R, Al Nokhatha SA, Conway R. JAK inhibitors in rheumatoid
arthritis: an evidence-based review on the emerging clinical data. J Inflamm
Res 2020;13:519-31.
Lee YH, Song GG. Relative efficacy and safety of tofacitinib, baricitinib,
upadacitinib, and filgotinib in comparison to adalimumab in patients with active
rheumatoid arthritis. Z Rheumatol 2020;79:785-96.
Fragoulis GE, Siebert S, McInnes IB. Therapeutic Targeting of IL-17 and IL-23
Cytokines in immune-mediated diseases. Annu Rev Med 2016;67:337-53.
Hammitzsch A, Lorenz G, Moog P. Impact of Janus kinase inhibition on the
treatment of axial spondyloarthropathies. Front Immunol 2020;11:591176.
Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, et al.
Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med
2017;377:1537-50.
Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, et al.
Tofacitinib for psoriatic arthritis in patients with an inadequate response to
TNF inhibitors. N Engl J Med 2017;377:1525-36.
Strand V, de Vlam K, Covarrubias-Cobos JA, Mease PJ, Gladman DD, Graham
D, et al. Tofacitinib or adalimumab versus placebo: patient-reported outcomes
from OPAL Broaden-a phase III study of active psoriatic arthritis in patients
with an inadequate response to conventional synthetic disease-modifying
antirheumatic drugs. RMD Open 2019;5:e000806.
Strand V, de Vlam K, Covarrubias-Cobos JA, Mease PJ, Gladman DD, Chen L,
et al. Effect of tofacitinib on patient-reported outcomes in patients with active
psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors
in the phase III, randomised controlled trial: OPAL Beyond. RMD Open 2019;5:
e000808.
McInnes IB, Anderson JK, Magrey M, Merola JF, Liu Y, Kishimoto M, et al. Trial
of upadacitinib and adalimumab for psoriatic arthritis. N Engl J Med 2021;384:
1227-39.
Mease PJ, Lertratanakul A, Anderson JK, Papp K, Van den Bosch F, Tsuji S, et al.
Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2. Ann
Rheum Dis 2020;80:312-20.
Mease P, Coates LC, Helliwell PS, Stanislavchuk M, Rychlewska-Hanczewska A,
Dudek A, 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;392:2367-77.
Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a
target for inflammatory and autoimmune diseases: current and future prospects.
Drugs 2017;77:521-46.
Brown MA, Wordsworth BP. Genetics in ankylosing spondylitis - current state of
the art and translation into clinical outcomes. Best Pract Res Clin Rheumatol
2017;31:763-76.
De Wilde K, Martens A, Lambrecht S, Jacques P, Drennan MB, Debusschere K,
et al. A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous
regulatory mechanism preventing development of enthesitis. Ann Rheum Dis
2017;76:585-92.
van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T,
et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week,
randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis 2017;76:
1340-7.
Deodhar A, Sliwinska-Stanczyk P, Xu H, Baraliakos X, Gensler LS, Fleishaker D,
et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III,
randomised, double-blind, placebo-controlled study. Ann Rheum Dis 2021;80:
1004-13.
van der Heijde D, Song IH, Pangan AL, Deodhar A, van den Bosch F,
Maksymowych WP, et al. Efficacy and safety of upadacitinib in patients
with active ankylosing spondylitis (SELECT-AXIS 1): a multicentre,
randomised, double-blind, placebo-controlled, phase 2/3 trial. Lancet
2019;394:2108-17.
van der Heijde D, Baraliakos X, Gensler LS, Maksymowych WP, Tseluyko V,
Nadashkevich O, et al. Efficacy and safety of filgotinib, a selective Janus kinase
1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results
from a randomised, placebo-controlled, phase 2 trial. Lancet 2018;392:2378-87.
Gilead Press Release. Gilead receives complete response letter for filgotinib for
the treatment of moderately to severely active rheumatoid arthritis. Available
at:
https://www.gilead.com/news-and-press/press-room/press-releases/2020/8/
J ALLERGY CLIN IMMUNOL
VOLUME 148, NUMBER 4
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
gilead-receives-complete-response-letter-for-filgotinib-for-the-treatment-ofmoderately-to-severely-active-rheumatoid-arthritis. Accessed August 18, 2020.
ClinicalTrials.gov. Bethesda (Md): National Library of Medicine (US). Targeted
search for the intervention filgotinib and recruitment terminated or withdrawn.
Available at: https://clinicaltrials.gov/ct2/results?term5filgotinib&Search5
Apply&recrs5h&recrs5i&age_v5&gndr5&type5&rslt5. Accessed July 1,
2021.
Boehncke WH, Brembilla NC. Unmet needs in the field of psoriasis: pathogenesis
and treatment. Clin Rev Allergy Immunol 2018;55:295-311.
Ghoreschi K, Balato A, Enerback C, Sabat R. Therapeutics targeting the IL-23
and IL-17 pathway in psoriasis. Lancet 2021;397:754-66.
Kvist-Hansen A, Hansen PR, Skov L. Systemic treatment of psoriasis with JAK
Inhibitors: a review. Dermatol Ther (Heidelb) 2020;10:29-42.
Sideris N, Vakirlis E, Tsentemeidou A, Kourouklidou A, Ioannides D, Sotiriou E.
Under development JAK inhibitors for dermatologic diseases. Mediterr J
Rheumatol 2020;31:137-44.
Papp KA, Menter MA, Abe M, Elewski B, Feldman SR, Gottlieb AB, et al.
Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque
psoriasis: results from two randomized, placebo-controlled, phase III trials. Br
J Dermatol 2015;173:949-61.
Bachelez H, van de Kerkhof PC, Strohal R, Kubanov A, Valenzuela F, Lee JH,
et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic
plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 2015;386:
552-61.
Papp KA, Bissonnette R, Gooderham M, Feldman SR, Iversen L, Soung J, et al.
Treatment of plaque psoriasis with an ointment formulation of the Janus kinase
inhibitor, tofacitinib: a Phase 2b randomized clinical trial. BMC Dermatol
2016;16:15.
Nogueira M, Puig L, Torres T. JAK Inhibitors for treatment of psoriasis: focus on
selective TYK2 inhibitors. Drugs 2020;80:341-52.
ClinicalTrials.gov. Bethesda (Md): National Library of Medicine (US). Targeted
search for condition psoriasis and recruitment recruiting or active not recruiting.
Available at: https://clinicaltrials.gov/ct2/results?cond5psoriasis&term5&intr5
&cntry5&state5&city5&dist5&Search5Search&recrs5a&recrs5d. Accessed
July 1, 2021.
Dendrou CA, Cortes A, Shipman L, Evans HG, Attfield KE, Jostins L, et al.
Resolving TYK2 locus genotype-to-phenotype differences in autoimmunity. Sci
Transl Med 2016;8:363ra149.
Papp K, Gordon K, Thaci D, Morita A, Gooderham M, Foley P, et al. Phase 2 trial
of selective tyrosine kinase 2 inhibition in psoriasis. N Engl J Med 2018;379:
1313-21.
ClinicalTrials.gov. Bethesda (Md): National Library of Medicine (US). Targeted
search for condition psoriais and intervention deucravacitinib. Available at:
https://clinicaltrials.gov/ct2/results?cond5Psoriasis&term5deucravacitinib&cntry5&
state5&city5&dist5&Search5Search. Accessed July 1, 2021.
Forman SB, Pariser DM, Poulin Y, Vincent MS, Gilbert SA, Kieras EM, et al.
TYK2/JAK1 inhibitor PF-06700841 in patients with plaque psoriasis: phase IIa,
randomized, double-blind, placebo-controlled trial. J Invest Dermatol 2020;140:
2359-70.e5.
ClinicalTrials.gov. Bethesda (Md): National Library of Medicine (US).
2021 Apr 5 - Identifier NCT03895372. A study to evaluate safety and
efficacy of PF-06826647 for moderate to severe plaque psoriasis. Available at:
https://clinicaltrials.gov/ct2/show/NCT03895372?cond5NCT03895372&draw5
2&rank51. Accessed July 1, 2021.
ClinicalTrials.gov. Bethesda (Md): National Library of Medicine (US). 2021
Jun 21 - Identifier NCT03850483. Dose ranging study to assess efficacy, safety
and tolerability of PF-06700841 topical cream in psoriasis. Available at:
https://clinicaltrials.gov/ct2/show/NCT03850483?cond5NCT03850483&draw5
2&rank51. Accessed July 1, 2021.
Al-Bawardy B, Shivashankar R, Proctor DD. Novel and emerging therapies for
inflammatory bowel disease. Front Pharmacol 2021;12:651415.
Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT
signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res
2013;76:1-8.
Lefevre PLC, Vande Casteele N. Clinical pharmacology of Janus kinase inhibitors
in inflammatory bowel disease. J Crohns Colitis 2020;14:S725-36.
Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J
Med 2017;376:1723-36.
Sands BE, Armuzzi A, Marshall JK, Lindsay JO, Sandborn WJ, Danese S, et al.
Efficacy and safety of tofacitinib dose de-escalation and dose escalation for patients with ulcerative colitis: results from OCTAVE Open. Aliment Pharmacol
Ther 2020;51:271-80.
FRAGOULIS ET AL 951
74. Panes J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D’Haens G, et al. Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of two
phase IIb randomised placebo-controlled trials. Gut 2017;66:1049-59.
75. Feagan BG, Danese S, Loftus EV Jr, Vermeire S, Schreiber S, Ritter T, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet
2021;397:2372-84.
76. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al.
Clinical remission in patients with moderate-to-severe Crohn’s disease treated
with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet 2017;389:266-75.
77. Sandborn WJ, Ghosh S, Panes J, Schreiber S, D’Haens G, Tanida S, et al. Efficacy
of upadacitinib in a randomized trial of patients with active ulcerative colitis.
Gastroenterology 2020;158:2139-49.e14.
78. Sandborn WJ, Feagan BG, Loftus EV Jr, Peyrin-Biroulet L, Van Assche G,
D’Haens G, et al. Efficacy and safety of upadacitinib in a randomized trial of patients with Crohn’s disease. Gastroenterology 2020;158:2123-38.e8.
79. Sands BE, Sandborn WJ, Feagan BG, Lichtenstein GR, Zhang H, Strauss R, et al.
Peficitinib, an oral Janus kinase inhibitor, in moderate-to-severe ulcerative colitis:
results from a randomised, phase 2 study. J Crohns Colitis 2018;12:1158-69.
80. Sandborn WJ, Nguyen DD, Beattie DT, Brassil P, Krey W, Woo J, et al. Development of gut-selective pan-Janus kinase inhibitor TD-1473 for ulcerative colitis:
a translational medicine programme. J Crohns Colitis 2020;14:1202-13.
81. Wallace DJ, Furie RA, Tanaka Y, Kalunian KC, Mosca M, Petri MA, et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebocontrolled, phase 2 trial. Lancet 2018;392:222-31.
82. You H, Zhang G, Wang Q, Zhang S, Zhao J, Tian X, et al. Successful treatment of
arthritis and rash with tofacitinib in systemic lupus erythematosus: the experience
from a single centre. Ann Rheum Dis 2019;78:1441-3.
83. Furumoto Y, Smith CK, Blanco L, Zhao W, Brooks SR, Thacker SG, et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis
Rheumatol 2017;69:148-60.
84. Huang JF, Yafawi R, Zhang M, McDowell M, Rittenhouse KD, Sace F, et al.
Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690,550) in patients with dry eye disease. Ophthalmology 2012;
119:e43-50.
85. Liew SH, Nichols KK, Klamerus KJ, Li JZ, Zhang M, Foulks GN. Tofacitinib
(CP-690,550), a Janus kinase inhibitor for dry eye disease: results from a phase
1/2 trial. Ophthalmology 2012;119:1328-35.
86. You H, Xu D, Zhao J, Li J, Wang Q, Tian X, et al. JAK inhibitors: prospects in
connective tissue diseases. Clin Rev Allergy Immunol 2020;59:334-51.
87. Zhang H, Watanabe R, Berry GJ, Tian L, Goronzy JJ, Weyand CM. Inhibition of
JAK-STAT signaling suppresses pathogenic immune responses in medium and
large vessel vasculitis. Circulation 2018;137:1934-48.
88. Jamilloux Y, El Jammal T, Vuitton L, Gerfaud-Valentin M, Kerever S, Seve P.
JAK inhibitors for the treatment of autoimmune and inflammatory diseases. Autoimmun Rev 2019;18:102390.
89. Rotenberg C, Besnard V, Brillet PY, Giraudier S, Nunes H, Valeyre D. Dramatic
response of refractory sarcoidosis under ruxolitinib in a patient with associated
JAK2-mutated polycythemia. Eur Respir J 2018;52.
90. Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib
treatment and molecular analysis of cutaneous sarcoidosis. N Engl J Med
2018;379:2540-6.
91. Meshkov AD, Novikov PI, Zhilyaev EV, Ilevsky IDJ, Moiseev SV. Tofacitinib in
steroid-dependent relapsing polychondritis. Ann Rheum Dis 2019;78:e72.
92. Komai T, Shoda H, Hanata N, Fujio K. Tofacitinib rapidly ameliorated polyarthropathy in a patient with systemic sclerosis. Scand J Rheumatol 2018;47:505-6.
93. Mahieu MA, Strand V, Simon LS, Lipsky PE, Ramsey-Goldman R. A critical
review of clinical trials in systemic lupus erythematosus. Lupus 2016;25:
1122-40.
94. Nash P, Coates LC, Kivitz AJ, Mease PJ, Gladman DD, Covarrubias-Cobos JA,
et al. Safety and efficacy of tofacitinib in patients with active psoriatic arthritis:
interim analysis of OPAL Balance, an open-label, long-term extension study.
Rheumatol Ther 2020;7:553-80.
95. Vieira MC, Zwillich SH, Jansen JP, Smiechowski B, Spurden D, Wallenstein GV.
Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis
who have had an inadequate response to tumor necrosis factor inhibitors: results
from a network meta-analysis. Clin Ther 2016;38:2628-41.e5.
96. Harigai M. Growing evidence of the safety of JAK inhibitors in patients with
rheumatoid arthritis. Rheumatology (Oxford) 2019;58:i34-42.
97. Xie F, Yun H, Bernatsky S, Curtis JR. Brief Report: Risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or
other biologic treatments. Arthritis Rheumatol 2016;68:2612-7.
952 FRAGOULIS ET AL
98. Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, et al. JAK2
associates with the erythropoietin receptor and is tyrosine phosphorylated and
activated following stimulation with erythropoietin. Cell 1993;74:227-36.
99. Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, et al. Long-term
safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the
rheumatoid arthritis clinical development programme. RMD Open 2020;6:
e001395.
100. Winthrop KL, Harigai M, Genovese MC, Lindsey S, Takeuchi T, Fleischmann R,
et al. Infections in baricitinib clinical trials for patients with active rheumatoid
arthritis. Ann Rheum Dis 2020;79:1290-7.
101. Machado MAA, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky
S. Effectiveness and safety of tofacitinib in rheumatoid arthritis: a cohort study.
Arthritis Res Ther 2018;20:60.
102. Sepriano A, Kerschbaumer A, Smolen JS, van der Heijde D, Dougados M, van
Vollenhoven R, et al. Safety of synthetic and biological DMARDs: a systematic
literature review informing the 2019 update of the EULAR recommendations
for the management of rheumatoid arthritis. Ann Rheum Dis 2020;79:760-70.
103. AGENCY EM. EMA confirms Xeljanz to be used with caution in patients at
high risk of blood clots. EMA/92517/2020, 31 January 2020. Available at:
https://www.ema.europa.eu/en/medicines/human/referrals/xeljanz#all-documentssection. Accessed July 1, 2021.
104. Winthrop KL, Citera G, Gold D, Henrohn D, Connell CA, Shapiro AB, et al. Agebased (<65 vs >/565 years) incidence of infections and serious infections with
tofacitinib versus biological DMARDs in rheumatoid arthritis clinical trials and
the US Corrona RA registry. Ann Rheum Dis 2021;80:134-6.
105. Kivitz AJ, Cohen S, Keystone E, van Vollenhoven RF, Haraoui B, Kaine J, et al. A
pooled analysis of the safety of tofacitinib as monotherapy or in combination
with background conventional synthetic disease-modifying antirheumatic drugs
in a phase 3 rheumatoid arthritis population. Semin Arthritis Rheum 2018;48:
406-15.
106. Evangelatos G, Koulouri V, Iliopoulos A, Fragoulis GE. Tuberculosis and targeted
synthetic or biologic DMARDs, beyond tumor necrosis factor inhibitors. Ther
Adv Musculoskelet Dis 2020;12:1759720X20930116.
107. Sunzini F, McInnes I, Siebert S. JAK inhibitors and infections risk: focus on herpes zoster. Ther Adv Musculoskelet Dis 2020;12:1759720X20936059.
J ALLERGY CLIN IMMUNOL
OCTOBER 2021
108. Curtis JR, Xie F, Yun H, Bernatsky S, Winthrop KL. Real-world comparative
risks of herpes virus infections in tofacitinib and biologic-treated patients with
rheumatoid arthritis. Ann Rheum Dis 2016;75:1843-7.
109. Bechman K, Subesinghe S, Norton S, Atzeni F, Galli M, Cope AP, et al. A systematic review and meta-analysis of infection risk with small molecule JAK inhibitors in rheumatoid arthritis. Rheumatology (Oxford) 2019;58:1755-66.
110. Smolen JS, Genovese MC, Takeuchi T, Hyslop DL, Macias WL, Rooney T, et al.
Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2
years median time in treatment. J Rheumatol 2019;46:7-18.
111. Rajasimhan S, Pamuk O, Katz JD. Safety of Janus kinase inhibitors in older patients: a focus on the thromboembolic risk. Drugs Aging 2020;37:551-8.
112. Lee JJ, Pope JE. A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res Ther 2014;16:435.
113. Xeljanz (tofacitinib): Initial clinical trial results of increased risk of major adverse
cardiovascular events and malignancies (excluding NMSC) with use of tofacitinib
relative to TNF— alpha inhibitors, 24 March 2021. Available at: https://www.
ema.europa.eu/en/documents/dhpc/direct-healthcare-professional-communica
tion-dhpc-xeljanz-tofacitinib-initial-clinical-trial-results_en.pdf. Accessed July 1,
2021.
114. Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, et al.
Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis.
Arthritis Rheumatol 2019;71:1042-55.
115. FDA-Upadacitinib: risk assessment and risk mitigation review – FDA 15 Aug
2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/
211675Orig1s000RiskR.pdf. Accessed July 1, 2021.
116. Choy E, McInnes I, Cush J, Aelion J, Zhang Y, Khan N, et al. MACE and VTE
across multiple upadacitinib studies in rheumatoid arthritis: integrated analysis
from the SELECT phase 3 clinical program [abstract]. Arthritis Rheum 2019;
71(suppl 10).
117. Maneiro JR, Souto A, Gomez-Reino JJ. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: systematic review, meta-analysis,
and network meta-analysis. Semin Arthritis Rheum 2017;47:149-56.
118. Curtis JR, Lee EB, Martin G, Mariette X, Terry KK, Chen Y, et al. Analysis of
non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical programme. Clin Exp Rheumatol 2017;35:614-22.