Understanding and Managing Side Effects
Due to Immunomodulators and Biologics
What are the skin side effects due
to immunomodulators and/or
biologics?
Jean-Frédéric Colombel, MD
Icahn School of Medicine at Mount Sinai
New York
Joana Torres, MD
Hospital Beatriz Ângelo
Portugal
Conflicts of interest disclosure
J-F Colombel has served as consultant, advisory board member or speaker for or
received research grants from
Abbvie, Amgen, Bristol Meyers Squibb, Celltrion, Ferring, Genentech, Giuliani SPA,
Given Imaging, Janssend and Janssen, Merck & Co., Millenium Pharmaceuticals Inc.,
Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Sanofi,
Schering Plough Corporation, Takeda, Teva Pharmaceuticals, UCB Pharma, Vertex,
Dr. August Wolff GmbH & Co.
Skin manifestations are a common
complication of IBD
IBD-related
Nutritional deficiencies
Therapy-related
Skin side effects due to immunomodulators
and/or biologics
Immunomodulators
(thiopurines)
Biologics1
• Rash
• Non-melanoma skin cancer
• Infections (viral mainly)
• Infusion reactions and injection site reactions
• Infectious complications
• Bacterial cellulitis, erysipelas, abscess
• HSV, VZV, CMV, HPV, MCV
• Candida species
• Immune mediated and toxic complications
• Psoriasis
• Cutaneous lupus, lupus-like syndrome
• Cutaneous vasculitis
• Erythema multiforme
• Stevens Johnson syndrome
• Toxic epidermal necrolysis
• Alopecia
• Skin cancers
• Melanoma and non-melanoma skin cancer
1 – Mocci G et al. JCC 2013
Skin side effects due to immunomodulators
and/or biologics?
Immunomodulators
(thiopurines)
Biologics1
• Rash
• Non-melanoma skin cancer
• Infections (viral mainly)
• Infusion reactions and injection site reactions
• Infectious complications
• Bacterial cellulitis, erysipelas, abscess
• HSV, VZV, CMV, HPV, MCV
• Candida species
• Immune mediated and toxic complications
• Psoriasis
• Cutaneous lupus, lupus-like syndrome
• Cutaneous vasculitis
• Erythema multiforme
• Stevens Johnson syndrome
• Toxic epidermal necrolysis
• Alopecia
• Skin cancers
• Melanoma and non-melanoma skin cancer
1 – Mocci G et al. JCC 2013
Skin cancer
• Do IBD patients have an increased baseline
risk of developing skin cancer ?
• Do Immunomodulators increase the risk
of skin cancer ?
• Do Anti-TNF increase the risk of skin cancer ?
Baseline risk
Population-based cohorts – true spectrum
Referral center studies
Devroede et al. New Engl J Med 1971
Weedon et al. N Engl J Med 1973
Gyde et al. Gut 1982
Greenstein et al. Cancer 1981
Mild
Severe
Meta-analysis of population-based studies
IBD and extra-intestinal cancer
Ekbom et al, Sweden
Bernstein et al, Canada
Persson et al, Sweden
Karlen et al, Sweden
Loftus et al, USA
Jess et al, Denmark
Katsanos et al, EC-IBD
Palli et al, Italy
Pedersen et al. Am J Gastro 2010
Meta-analysis: extra-intestinal cancers in IBD
Crohn’s disease
Lung cancer
Ulcerative colitis
Lung cancer: SIR, 1.8 (95% CI, 1.2-2.8)
Lung cancer: SIR, 0.4 (95% CI, 0.2-0.7)
Upper GI: SIR, 2.9 (95% CI, 1.7-5.0)
Liver-biliary: SIR, 2.6 (95% CI, 1.6-4.2)
Bladder: SIR, 2.0 (95% CI, 1.1-3.6)
Leukemia: SIR, 2.0 (95% CI, 1.3-3.1)
NMSC: SIR, 2.4 (95% CI, 1.4-3.9)
Pedersen et al. Am J Gastroenterol 2010
What about melanoma?
IBD appears to be associated with a 37% increased
risk of melanoma, independent of the use of
immunomodulator and anti–TNFα therapy
Pooled relative risk in the pre-immunosuppressive era: 1.52 (95% CI: 1.02-2.25)
Singh et al. Clin Gastroenterol Hepatol, 2013
Skin cancer
• Do IBD patients have an increased baseline
risk of developing skin cancer ?
• Do Immunomodulators increase the risk
of skin cancer ?
• Do Anti-TNF increase the risk of skin cancer ?
Thiopurines and non-melanoma skin cancer
Ramiscal and Brewer. JAMA Dermatol 2013
Past and current exposure increases the
risk for NMSC
Yearly incidence rate (per 1,000 patient-years)
6
>65 years
Thiopurine therapy
5.70
Continuing
5
Discontinued
4.04
Never received
4
50-65 years
3
2.59
<50 years
2
1.96
1
0.84
0.66
0.60
0.38
0
Cases of NMSC (n)
0
9
3
0
6
3
3
3
3
2
Peyrin-Biroulet. Gastroenterology 2011
Other immunomodulators and NMSC
Recent use
(<90 d)
Persistent
use
(>365d)
Meds
Cases
(n=742) N,%
Controls
(n=2968)
N,%
P value
Methotrexate
9 (1.2)
22 (0.7)
.21
Calcineurin inhibitor
8 (1.1)
17 (0.6)
.13
Mycophenolate mofetil
2 (0.3)
5 (0.2)
.57
Meds
Cases
(n=452) N,%
Controls
(n=1812)
N,%
P value
Methotrexate
6 (1.3)
9 (0.5)
.05
Calcineurin inhibitor
3 (0.7)
7 (0.4)
.43
Mycophenolate mofetil
2 (0.4)
2 (0.1)
.13
Recent and persistent medication use by the cases of NMSC, in nested case-control study, matched
by CD or UC, age, gender and region of the country
Adapted from Long et al. CGH 2010
Thiopurines and NMSC in IBD
Baseline risk of NMSC
• Population-based cohort studies:
• 2-fold increased risk (at least in CD)
Thiopurine-related risk of NMSC
• Additional 2-fold increase
• Risk persists after drug withdrawal
What about melanoma and thiopurines?
Case-control study
LifeLink Health Plan Claims Database
209 melanoma cases and 823 matched controls
Exposure to thiopurines:
OR: 1.10 (95% CI, 0.72–1.67)
Confirmed in letter AJG 2012 by Peyrin-Biroulet et al from CESAME
Long et al, Gastroenterology 2012
Thiopurines and melanoma in IBD
Baseline risk of melanoma
• 1.4-fold increased
• Thiopurines do not increase this risk
Skin cancer
• Do IBD patients have an increased baseline
risk of developing skin cancer ?
• Do Immunomodulators increase the risk
of skin cancer ?
• Do Anti-TNF increase the risk of skin cancer ?
Risk of NMSC in IBD patients exposed to
biologics
Long et al,
CGH 2010
Biologic
Risk estimate
Biologics
increase the
risk of NMSC
IFX/ ADA
in CD
Recent use (<90 days):
1OR 2.07 (95%CI 1.28-3.33)
YES
Persistent use (>365 days):
1OR 2.18 (95%CI 1.07-4.46)
Long et al,
Gastroenterology
2012
IFX/ ADA/ CZP
in IBD
Any use
1OR 1.14 (95%CI 0.95-1.36)
NO
Burmester et al,
Ann Rheum Dis
2013
ADA
in CD
SIR 2.29 (95%CI 1.44-3.47)
YES
1 – adjusted OR
Risk of Melanoma in IBD patients exposed
to biologics
Pooled relative risk after Anti-TNF-α exposure: 1.10 (95% CI: 0.73-1.66)
Singh et al. Clin Gastroenterol Hepatol, 2013
What about combination therapy ?
Medication
No
immunosuppressant
Any thiopurine
alone
Any biologic alone
Combined
thiopurine and
biologic
NMSC cases (n =
1895)
n (%)
Controls (n = 8914)
n (%)
OR (95% CI)
1587 (83.8)
8290 (93.0)
Referent
265 (14.0)
484 (5.4)
2.72 (2.27-3.26)
74 (3.9)
181 (2.0)
1.63 (-2.36)
31 (1.6)
40 (0.5)
3.89 (2.33-6.46)
“In a sub-analysis, combined use of thiopurines and biologics
>1year was associated with the greatest increased NMSC risk”
Long et al, Gastroenterology 2012
Take-home messages regarding skin cancer
• IBD patients are at increased risk of developing skin cancer
(baseline risk, pre-IM era)
– 2-fold increased risk of NMSC
– 1.5-fold increased risk of melanoma
• Thiopurines increase the risk of developing skin cancer
– 2-fold increased risk of NMSC (persisting after withdrawal)
– Probably no increased risk of melanoma
• Biologics may increase the risk of NMSC and melanoma (needs
further investigation)
• Combination therapy may act synergistically to increase the
risk of NMSC
Proposed algorithm for skin cancer prevention in
patients with IBD
Patient proposed to start
immunosuppression
(thiopurines/ antiTNF)
• Information about dermatological complications
• Identify risk factors for development of skin cancer: premalignant skin lesions,
evidence of HPV infection, sun exposure history, family history of skin cancer, skin
type, solar lentigines, etc
• Advice on adequate skin protection and on self-monitoring
• Advice on modifiable risk factors protection
• Dermatology evaluation at baseline
Torres J et al. IBD 2013
Surveillance based on risk
stratification
Low-risk patients
• Dark skin
• No pre-malignant lesions
• No history of BCC/SCC
• No outdoor occupation
• Young age
Moderate-high risk patients
• Sunburns/ exposure to ionizing radiation
• Light skin, Freckling or facial telangiectasia
• Outdoor occupations
• Living in high sun exposure countries
• High exposure to sun as a child
• Psoriasis treatment with oral psoralen and
PUVA
• High cumulative exposure to thiopurines
• Combination therapy
• Increasing age
Very high-risk
patients
History of cutaneous
malignancies
Torres J et al. IBD 2013
Surveillance based on risk
stratification
Low-risk patients
• Dark skin
• No pre-malignant lesions
• No history of BCC/SCC
• No outdoor occupation
• Young age
Moderate-high risk patients
• Sunburns/ exposure to ionizing radiation
• Light skin, Freckling or facial telangiectasia
• Outdoor occupations
• Living in high sun exposure countries
• High exposure to sun as a child
• Psoriasis treatment with oral psoralen and
PUVA
• High cumulative exposure to thiopurines
• Combination therapy
• Increasing age
New medical skin
exam in 3-5 years
Very high-risk
patients
History of cutaneous
malignancies
Manage on
individual
basis
Skin examination every other
year
Torres J et al. IBD 2013
Skin side effects due to immunomodulators
and/or biologics?
Immunomodulators
(thiopurines)
Biologics1
• Rash
• Non-melanoma skin cancer
• Infections (viral mainly)
• Infusion reactions and injection site reactions
• Infectious complications
• Bacterial cellulitis, erysipelas, abscess
• HSV, VZV, CMV, HPV, MCV
• Candida species
• Immune mediated and toxic complications
• Psoriasis
• Cutaneous lupus, lupus-like syndrome
• Cutaneous vasculitis
• Erythema multiforme
• Stevens Johnson syndrome
• Toxic epidermal necrolysis
• Alopecia
• Skin cancers
• Melanoma and non-melanoma skin cancer
1 – Mocci G et al. JCC 2013
Psoriasis
• Psoriasis is a common chronic, autoimmune skin disorder typically characterized by
hyperkeratosis and hyperproliferation of T cells, manifested by erythematous papules
and plaques.
• Several phenotypes: learn to recognize them
• Chronic plaque lesions (psoriasis vulgaris): most common form in the
psoriasis population
In Psoriasis – Manson publishing; Courtesy of Franck Delesalle
Psoriasis
• Several phenotypes:
• Guttate eruptions
In Psoriasis – Manson publishing
Psoriasis
• Several phenotypes:
• Nail psoriasis
In Psoriasis – Manson publishing
Psoriasis
• Several phenotypes:
• Pustular psoriasis
In Psoriasis – Manson publishing; Courtesy of Franck Delesalle
Psoriasis
• Several phenotypes:
• Inverse psoriasis (type of psoriasis in plaques)
In Psoriasis – Manson publishing; Courtesy of Franck Delesalle
Psoriasis
• Several phenotypes:
• Palmoplantar pustular psoriasis: form commonly associated with anti-TNF
therapy (even in patients treated for plaque psoriasis)
JF Rahier.CGH 2010; Courtesy of Franck Delesalle
Psoriasis associated with Anti-TNF therapy
• Described with all the anti-TNF: class effect
• Described in patients receiving treatment for diverse indications (RA, IBD,
psoriasis, psoriatic arthritis, ankylosing spondylitis)
• Often leads to therapy discontinuation
• First IBD case reported in 2004 in a CD patient treated with infliximab
Increasingly recognised sideeffect of anti-TNF therapy in the
IBD literature
Denadai et al. JCC 2012
Psoriasis associated with Anti-TNF therapy
What is the prevalence in IBD?
Cohort
n
Number of patients
developing
psoriasis/psoriasifor
m lesions
Spain
1294
21
1.62%
US (presented as an abstract)
1003
22
2%
GETAID1
562
11
2%
Belgian (presented as an
abstract)
922
81
8.8%
Germany
434
21
4.8%
1 – only refers to incidence in Lille center
Guerra et al, JCC 2012; Afzila IBD 2011; Rahier CGH 2010; Cleynen JCC 2009; Tillack C. et al Gut. 2013
Psoriasis associated with Anti-TNF therapy
Proposed mechanisms
Niess J. Gut 2013
Psoriasis associated with Anti-TNF therapy
Risk factors
• 434 patients with IBD treated with anti-TNF antibodies infliximab
(n=416) and/or adalimumab (n=141)
21 (4.8%) developed psoriasiform skin lesions
Predictors of skin lesions
Smoking (active smoking or a history of smoking) OR 4.24, 95%
CI 1.55 to 13.60)
Increased BMI: OR 1.12, 95% CI 1.01 to 1.24
Short disease duration: OR 0.92, 95% CI 0.85 to 0.99
Tillack C. et al Gut. 2013
Psoriasis associated with Anti-TNF therapy
What is the clinical scenario in IBD patients?
• Most cases in patients with CD and in women
• Patients with personal or family history of psoriasis
•
•
•
may have a higher risk of developing this
complication but the majority of cases corresponds
to a new onset of disease
Unpredictable
Not related to disease activity, location or phenotype
Concomitant immunosuppression with agents that
themselves are effective for psoriasis does not seem
to be protective.
Torres J et al, IBD 2013
Psoriasis associated with Anti-TNF therapy
What is the clinical scenario in IBD patients?
• Lesions can be restricted to a single site or affect
•
•
multiple sites
Several types of psoriatic lesions have been observed
Palmoplantar pustular and inverse psoriasis (that
normally affects 15% to 20% of the psoriatic
population) are more commonly associated with antiTNF therapy
Torres J et al, IBD 2013
Psoriasis associated with Anti-TNF therapy
What is the clinical scenario in IBD patients?
• Discontinuation of anti-TNF therapy combined with
•
•
•
topical therapy will result in partial or complete
improvement of psoriasis in most patients
Temporary discontinuation of anti-TNF may be an
option
Switching results in recurrence in around ¾ of
patients; however, it seems that recurrences are
milder and easier to manage
Second anti-TNF maintenance is possible in more
than half of the cases.
Torres J et al, IBD 2013
Anti-TNF therapy-induced psoriasiform respond to antiIL-12/IL-23 antibody treatment (ustekinumab)
Tillack C. et al Gut. 2013
Psoriasis associated with anti-TNF
How to manage?
• Decisions need to be made on individual basis
Consider
1.
extent and severity of skin disease and response to the antipsoriatic therapy
2.
efficacy of the anti-TNF in treating the condition for which it was initiated
3.
existence of therapeutic alternatives
Shale M. Can J Gastroenterol 2009
Development of a psoriasiform lesion
following anti-TNF therapy
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol,
emotional stress, smoking)
Exclude infection
Refer for Dermatology evaluation and eventual biopsy
Evaluate severity of skin disease
Evaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
• Mild psoriasis
(tolerable, <5% BSA)
or
• IBD requiring anti-TNF
• Moderate psoriasis
(tolerable, >5% BSA, or PPP)
Severe psoriasis
Intolerable lesions
Adapted from Collamer et al. Arthritis Rheum 2008 and Conklin L.S. et al. Nature Gastro Nat Rev Gastroenterol Hepatol. 2010
Development of a psoriasiform lesion
following anti-TNF therapy
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol,
emotional stress, smoking)
Exclude infection
Refer for Dermatology evaluation and eventual biopsy
Evaluate severity of skin disease
Evaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
• Mild psoriasis
(tolerable, <5% BSA)
or
• IBD requiring anti-TNF
Treat psoriasis
-Topical therapy (steroids, keratolytic,
vitamin D analogs)
- Maintain anti-TNF/ consider
temporary discontinuation
Persistent psoriasis
Consider switching to alternative
anti-TNF
Adapted from Collamer et al. Arthritis Rheum 2008 and Conklin L.S. et al. Nature Gastro Nat Rev Gastroenterol Hepatol. 2010
Development of a psoriasiform lesion
following anti-TNF therapy
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol,
emotional stress, smoking)
Exclude infection
Refer for Dermatology evaluation and eventual biopsy
Evaluate severity of skin disease
Evaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
• Mild psoriasis
(tolerable, <5% BSA)
or
• IBD requiring anti-TNF
Treat psoriasis
-Topical therapy ( steroids, keratolytic,
vitamin D analogs
- Maintain anti-TNF/ consider
temporary discontinuation
Persistent psoriasis
Consider switching to alternative
anti-TNF
• Moderate psoriasis
(tolerable, >5% BSA, or PPP)
Treat psoriasis
- Palm and sole occlusion, PUVA therapy,
methotrexate (?), acitretin, cyclosporine
and
Consider temporary discontinuation
and/or switching to alternative anti-TNF if
sub-optimal or non-response to treatment
Persistent/ worsening psoriasis
Consider anti-TNF discontinuation
Adapted from Collamer et al. Arthritis Rheum 2008 and Conklin L.S. et al. Nature Gastro Nat Rev Gastroenterol Hepatol. 2010
Development of a psoriasiform lesion
following anti-TNF therapy
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol,
emotional stress, smoking)
Exclude infection
Refer for Dermatology evaluation and eventual biopsy
Evaluate severity of skin disease
Evaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
• Mild psoriasis
(tolerable, <5% BSA)
or
• IBD requiring anti-TNF
Treat psoriasis
-Topical therapy (steroids, keratolytic,
vitamin D analogs)
- Maintain anti-TNF/ consider
temporary discontinuation
• Moderate psoriasis
(tolerable, >5% BSA, or PPP)
Treat psoriasis
- Palm and sole occlusion, PUVA therapy,
methotrexate (?), acitretin, cyclosporine
and
Consider temporary discontinuation
and/or switching to alternative anti-TNF if
sub-optimal or non-response to treatment
Severe psoriasis
Intolerable lesions
Treat psoriasis
- Palm and sole occlusion, PUVA
therapy, methotrexate (?)acitretin,
cyclosporine
STOP anti-TNF (permanently?)
Discuss alternative medical and
surgical interventions
Consider ustekinumab
Persistent psoriasis
Consider switching to alternative
anti-TNF
Persistent/ worsening psoriasis
Consider anti-TNF discontinuation
Adapted from Collamer et al. Arthritis Rheum 2008 and Conklin L.S. et al. Nature Gastro Nat Rev Gastroenterol Hepatol. 2010
Conclusions
• As the use of anti-TNF and immunosuppressors continues to
increase the diagnosis and management of cutaneous sideeffects will become an increasingly important challenge
• Counsel your patients about signs and symptoms of cutaneous
reactions
• Advice properly about sun protection
• Refer patients to the Dermatologist