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Understanding and Managing Side Effects Due to Immunomodulators and Biologics

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.

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Understanding and Managing Side Effects Due to Immunomodulators and Biologics

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  1. 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

  2. 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.

  3. Skin manifestations are a common complication of IBD

  4. Skin side effects due to immunomodulators and/or biologics 1 – Mocci G et al. JCC 2013

  5. Skin side effects due to immunomodulators and/or biologics? 1 – Mocci G et al. JCC 2013

  6. 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 ?

  7. 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

  8. Meta-analysis of population-based studiesIBD 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

  9. Meta-analysis: extra-intestinal cancers in IBD Lung cancer Crohn’s disease Ulcerative colitis Lung cancer: SIR, 0.4 (95% CI, 0.2-0.7) Lung cancer: SIR, 1.8 (95% CI, 1.2-2.8) 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

  10. 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

  11. 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 ?

  12. Thiopurines and non-melanoma skin cancer Ramiscal and Brewer. JAMA Dermatol 2013

  13. Past and current exposure increases the risk for NMSC 6 >65 years Thiopurine therapy Continuing 5 Discontinued Never received 4 Yearly incidence rate (per 1,000 patient-years) 50-65 years 3 <50 years 2 1 0 Cases of NMSC (n) 9 3 0 6 3 3 3 3 2 Peyrin-Biroulet. Gastroenterology 2011

  14. Other immunomodulators and NMSC 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

  15. Thiopurines and NMSC in IBD Baseline risk of NMSC • Population-basedcohort studies: • 2-fold increasedrisk (at least in CD) Thiopurine-relatedrisk of NMSC • Additional 2-fold increase • Risk persists after drug withdrawal

  16. 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

  17. Thiopurines and melanoma in IBD Baseline risk of melanoma • 1.4-fold increased • Thiopurines do not increasethisrisk

  18. 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 ?

  19. Risk of NMSC in IBD patients exposed to biologics 1 – adjusted OR

  20. 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

  21. What about combination therapy ? “In a sub-analysis, combined use of thiopurines and biologics >1year was associated with the greatest increased NMSC risk” Long et al, Gastroenterology 2012

  22. Take-home messages regarding skin cancer • IBD patients are at increased risk of developing skin cancer (baseline risk, pre-IM era) • 2-fold increasedrisk of NMSC • 1.5-fold increasedrisk of melanoma • Thiopurines increase the risk of developing skin cancer • 2-fold increased risk of NMSC (persisting after withdrawal) • Probablynoincreasedrisk of melanoma • Biologics may increase the risk of NMSC and melanoma (needsfurtherinvestigation) • Combination therapy may act synergistically to increase the risk of NMSC

  23. 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

  24. Surveillance based on risk stratification • 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 • Low-risk patients • Dark skin • No pre-malignant lesions • No history of BCC/SCC • No outdoor occupation • Young age Torres J et al. IBD 2013

  25. Surveillance based on risk stratification • 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 • Low-risk patients • Dark skin • No pre-malignant lesions • No history of BCC/SCC • No outdoor occupation • Young age Manage on individual basis New medical skin exam in 3-5 years Skin examination every other year Torres J et al. IBD 2013

  26. Skin side effects due to immunomodulators and/or biologics? 1 – Mocci G et al. JCC 2013

  27. 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

  28. Psoriasis • Several phenotypes: • Guttate eruptions In Psoriasis – Manson publishing

  29. Psoriasis • Several phenotypes: • Nail psoriasis In Psoriasis – Manson publishing

  30. Psoriasis • Several phenotypes: • Pustular psoriasis In Psoriasis – Manson publishing; Courtesy of Franck Delesalle

  31. Psoriasis • Several phenotypes: • Inverse psoriasis (type of psoriasis in plaques) In Psoriasis – Manson publishing; Courtesy of Franck Delesalle

  32. 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

  33. 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 side-effect of anti-TNF therapy in the IBD literature Denadai et al. JCC 2012

  34. Psoriasis associated with Anti-TNF therapyWhat is the prevalence in IBD? 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

  35. Psoriasis associated with Anti-TNF therapyProposed mechanisms Niess J. Gut 2013

  36. Psoriasis associated with Anti-TNF therapyRisk 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

  37. Psoriasis associated with Anti-TNF therapyWhat 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

  38. Psoriasis associated with Anti-TNF therapyWhat 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 anti-TNF therapy Torres J et al, IBD 2013

  39. Psoriasis associated with Anti-TNF therapyWhat 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

  40. Anti-TNF therapy-induced psoriasiform respond to anti-IL-12/IL-23 antibody treatment (ustekinumab) Tillack C. et al Gut. 2013

  41. Psoriasis associated with anti-TNFHow to manage? • Decisions need to be made on individual basis Consider extent and severity of skin disease and response to the antipsoriatic therapy efficacy of the anti-TNF in treating the condition for which it was initiated existence of therapeutic alternatives Shale M. Can J Gastroenterol 2009

  42. 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 Severe psoriasis Intolerable lesions • Mild psoriasis • (tolerable, <5% BSA) • or • IBD requiring anti-TNF • Moderate psoriasis • (tolerable, >5% BSA, or PPP) Adapted from Collamer et al. Arthritis Rheum 2008 and Conklin L.S. et al. Nature Gastro Nat Rev Gastroenterol Hepatol. 2010

  43. 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

  44. 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) • 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 • Treat psoriasis • Topical therapy ( steroids, keratolytic, vitamin D analogs • Maintain anti-TNF/ consider temporary discontinuation 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

  45. 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 Severe psoriasis Intolerable lesions • Mild psoriasis • (tolerable, <5% BSA) • or • IBD requiring 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 • Treat psoriasis • Palm and sole occlusion, PUVA therapy, methotrexate (?)acitretin, cyclosporine • Treat psoriasis • Topical therapy (steroids, keratolytic, vitamin D analogs) • Maintain anti-TNF/ consider temporary discontinuation 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

  46. Conclusions • 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

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