understanding and managing side effects due to immunomodulators and biologics what are the skin side...

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?


• 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




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

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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




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


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


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?


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


Psoriasis

•Several phenotypes:• Inverse psoriasis (type of psoriasis in plaques)


• 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



• 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.



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



Persistent psoriasisConsider switching to alternative

anti-TNF





Treat psoriasis-Topical therapy (steroids, keratolytic,

vitamin D analogs)- Maintain anti-TNF/ consider

temporary discontinuation






anti-TNF

Persistent/ worsening psoriasisConsider anti-TNF discontinuation






Treat psoriasis-Topical therapy ( steroids,

keratolytic, vitamin D analogs- Maintain anti-TNF/ consider


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






anti-TNF

Persistent/ worsening psoriasisConsider anti-TNF discontinuation



Severe psoriasisIntolerable lesions




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


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



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

understanding and managing side effects due to immunomodulators and biologics what are the skin side...

Documents

risk of skin cancer

skin cancerthiopurines

skin manifestations

increased risk of melanoma

pooled relative risk

swedenkatsanos et

swedenloftus et

canadapalli et