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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. - PowerPoint PPT Presentation
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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, MDIcahn School of Medicine at Mount Sinai
New York
Joana Torres, MDHospital 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
Skin side effects due to immunomodulators and/or biologics
1 – Mocci G et al. JCC 2013
Skin side effects due to immunomodulators and/or biologics?
1 – Mocci G et al. JCC 2013
• 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 ?
Skin cancer
Baseline risk
Severe
Referral center studiesDevroede et al. New Engl J Med 1971Weedon et al. N Engl J Med 1973Gyde et al. Gut 1982 Greenstein et al. Cancer 1981
Population-based cohorts – true spectrum
Mild
Meta-analysis of population-based studiesIBD and extra-intestinal cancer
Ekbom et al, Sweden
Katsanos et al, EC-IBD
Persson et al, Sweden
Loftus et al, USA
Karlen et al, Sweden
Bernstein et al, Canada
Palli et al, Italy
Jess et al, Denmark
Pedersen et al. Am J Gastro 2010
Meta-analysis: extra-intestinal cancers in IBD
Pedersen et al. Am J Gastroenterol 2010
Lung cancer: SIR, 1.8 (95% CI, 1.2-2.8)
Crohn’s disease Ulcerative colitisLung cancer
Lung cancer: SIR, 0.4 (95% CI, 0.2-0.7)
Upper GI: SIR, 2.9 (95% CI, 1.7-5.0)
Bladder: SIR, 2.0 (95% CI, 1.1-3.6)
NMSC: SIR, 2.4 (95% CI, 1.4-3.9)
Liver-biliary: SIR, 2.6 (95% CI, 1.6-4.2)
Leukemia: SIR, 2.0 (95% CI, 1.3-3.1)
What about melanoma?
Pooled relative risk in the pre-immunosuppressive era: 1.52 (95% CI: 1.02-2.25)
Singh et al. Clin Gastroenterol Hepatol, 2013
IBD appears to be associated with a 37% increased risk of melanoma, independent of the use of immunomodulator and anti–TNFα therapy
IBD appears to be associated with a 37% increased risk of melanoma, independent of the use of immunomodulator and anti–TNFα therapy
• 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 ?
Skin cancer
Thiopurines and non-melanoma skin cancer
Ramiscal and Brewer. JAMA Dermatol 2013
Past and current exposure increases the risk for NMSC
Continuing
Discontinued
Never received
<50 years
50-65 years
>65 yearsThiopurine therapy
Cases of NMSC (n) 039 336 233
6
3
4
5
1
2
0
Peyrin-Biroulet. Gastroenterology 2011
Yea
rly
inci
den
ce r
ate
(per
1,0
00
pat
ien
t-ye
ars)
Other immunomodulators and NMSC
Adapted from Long et al. CGH 2010
Meds Cases(n=742) N,%
Controls(n=2968) N,
%
P value
Recent use (<90 d)
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
Persistent use
(>365d)
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
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?
Long et al, Gastroenterology 2012
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
Thiopurines and melanoma in IBD
Baseline risk of melanoma•1.4-fold increased
•Thiopurines do not increase this risk
• 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 ?
Skin cancer
Risk of NMSC in IBD patients exposed to biologics
Biologic Risk estimate Biologics increase the risk of NMSC
Long et al, CGH 2010
IFX/ ADAin CD
Recent use (<90 days): 1OR 2.07 (95%CI 1.28-3.33)
Persistent use (>365 days): 1OR 2.18 (95%CI 1.07-4.46)
YES
Long et al, Gastroenterology
2012
IFX/ ADA/ CZPin IBD
Any use1OR 1.14 (95%CI 0.95-1.36)
NO
Burmester et al,Ann Rheum Dis
2013
ADAin CD
SIR 2.29 (95%CI 1.44-3.47) YES
1 – adjusted OR
Risk of Melanoma in IBD patients exposed to biologics
Singh et al. Clin Gastroenterol Hepatol, 2013
Pooled relative risk after Anti-TNF-α exposure: 1.10 (95% CI: 0.73-1.66)
What about combination therapy ?
Medication NMSC cases (n = 1895) n (%)
Controls (n = 8914) n (%)
OR (95% CI)
No immunosuppressant 1587 (83.8) 8290 (93.0) Referent
Any thiopurine alone 265 (14.0) 484 (5.4) 2.72 (2.27-3.26)
Any biologic alone 74 (3.9) 181 (2.0) 1.63 (-2.36)Combined
thiopurine and biologic
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”“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
Torres J et al. IBD 2013
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
Proposed algorithm for skin cancer prevention in patients with IBD
Torres J et al. IBD 2013
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
Surveillance based on risk stratification
Very high-risk patients
History of cutaneous malignancies
Torres J et al. IBD 2013
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 ageNew medical skin exam in 3-5 years
Surveillance based on risk stratification
Skin examination every other year
Very high-risk patients
History of cutaneous malignancies
Manage on individual
basis
Skin side effects due to immunomodulators and/or biologics?
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
• 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
• 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
Psoriasis associated with Anti-TNF therapy
Denadai et al. JCC 2012
Increasingly recognised side-effect of anti-TNF therapy in the
IBD literature
Psoriasis associated with Anti-TNF therapyWhat is the prevalence in IBD?
Cohort n Number of patients developing
psoriasis/psoriasiform 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 therapyProposed mechanisms
Niess J. Gut 2013
• 434 patients with IBD treated with anti-TNF antibodies infliximab (n=416) and/or adalimumab (n=141)
21 (4.8%) developed psoriasiform skin lesions
Psoriasis associated with Anti-TNF therapyRisk factors
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 1.24Short disease duration: OR 0.92, 95% CI 0.85 to 0.99
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 1.24Short disease duration: OR 0.92, 95% CI 0.85 to 0.99
Tillack C. et al Gut. 2013
• 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.
Psoriasis associated with Anti-TNF therapyWhat is the clinical scenario in IBD patients?
Torres J et al, IBD 2013
• 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 anti-TNF therapy
Psoriasis associated with Anti-TNF therapyWhat is the clinical scenario in IBD patients?
Torres J et al, IBD 2013
• 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.
Psoriasis associated with Anti-TNF therapyWhat is the clinical scenario in IBD patients?
Torres J et al, IBD 2013
Anti-TNF therapy-induced psoriasiform respond to anti-IL-12/IL-23 antibody treatment (ustekinumab)
Tillack C. et al Gut. 2013
Shale M. Can J Gastroenterol 2009
• Decisions need to be made on individual basis
Psoriasis associated with anti-TNFHow to manage?
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
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 infectionRefer for Dermatology evaluation and eventual biopsy
Severe psoriasisIntolerable lesions
• Mild psoriasis (tolerable, <5% BSA)
or• IBD requiring anti-TNF
• Moderate psoriasis(tolerable, >5% BSA, or PPP)
Evaluate severity of skin diseaseEvaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
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
Persistent psoriasisConsider switching to alternative
anti-TNF
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol, emotional stress, smoking)
Exclude infectionRefer for Dermatology evaluation and eventual biopsy
• 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
Evaluate severity of skin diseaseEvaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
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
Persistent psoriasisConsider switching to alternative
anti-TNF
Persistent/ worsening psoriasisConsider anti-TNF discontinuation
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol, emotional stress, smoking)
Exclude infectionRefer for Dermatology evaluation and eventual biopsy
• Mild psoriasis (tolerable, <5% BSA)
or• IBD requiring anti-TNF
• Moderate psoriasis(tolerable, >5% BSA, or PPP)
Treat psoriasis-Topical therapy ( steroids,
keratolytic, vitamin D analogs- Maintain anti-TNF/ consider
temporary discontinuation
Treat psoriasis-Palm and sole occlusion, PUVA therapy, methotrexate (?), acitretin, cyclosporine
andConsider temporary discontinuation
and/or switching to alternative anti-TNF if sub-optimal or non-response to treatment
Evaluate severity of skin diseaseEvaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
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
Persistent psoriasisConsider switching to alternative
anti-TNF
Persistent/ worsening psoriasisConsider anti-TNF discontinuation
Search for other potential triggers (antimalarials; lithium; NSAIDs; beta-blockers; alcohol, emotional stress, smoking)
Exclude infectionRefer for Dermatology evaluation and eventual biopsy
Severe psoriasisIntolerable lesions
• Mild psoriasis (tolerable, <5% BSA)
or• IBD requiring anti-TNF
• Moderate psoriasis(tolerable, >5% BSA, or PPP)
STOP anti-TNF (permanently?)Discuss alternative medical and
surgical interventions
Consider ustekinumab
Treat psoriasis-Topical therapy (steroids, keratolytic,
vitamin D analogs)- Maintain anti-TNF/ consider
temporary discontinuation
Treat psoriasis-Palm and sole occlusion, PUVA therapy, methotrexate (?), acitretin, cyclosporine
andConsider temporary discontinuation
and/or switching to alternative anti-TNF if sub-optimal or non-response to treatment
Evaluate severity of skin diseaseEvaluate the need for maintaining anti-TNF therapy/ alternative therapies
Discuss with patient the willingness to continue therapy
Treat psoriasis-Palm and sole occlusion, PUVA
therapy, methotrexate (?)acitretin, cyclosporine
• As the use of anti-TNF and immunosuppressors continues to increase the diagnosis and management of cutaneous side-effects 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
Conclusions