August 11, 2020

Cutaneous Adverse Effects of Biologic Medications

TNF alpha inhibitors: cutaneous side effects and management strategies

by Anthony Fernadez, MD, and Christie Warren, MD

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Note: This is an abridged version of an article originally published in the Cleveland Clinic Journal of Medicine.

Biologic therapies have revolutionized medicine and offer targeted therapy for an increasing number of diseases, particularly in rheumatology, gastroenterology, hematology/oncology and dermatology. But along with these advances and their ensuing expanded use have come many unique adverse effects.

Some of the most commonly reported adverse effects with these new therapies are cutaneous, and can potentially limit the use of these agents and add cost to already expensive treatment regimens.1

It is important for physicians and other healthcare providers to be aware of these effects, have a basic understanding of how to manage patients with these reactions, and to know when to refer to a dermatologist. This article is the first in a four-part series that reviews recent literature on cutaneous adverse reactions experienced with commonly prescribed biologic and targeted therapies, specifically tumor necrosis factor (TNF) alpha inhibitors, epidermal growth factor receptor (EGFR) inhibitors, small-molecule tyrosine kinase inhibitors (TKIs), and frequently used cell surface-targeted monoclonal antibodies.

TNF Alpha Inhibitors

TNF alpha is a proinflammatory cytokine that plays an important role in regulation of immune cells. Dysregulation of TNF alpha is involved in the pathogenesis of numerous inflammatory conditions, most notably rheumatoid arthritis, inflammatory bowel disease, psoriasis vulgaris and psoriatic arthritis. Therefore, TNF alpha inhibitors have been successfully used to treat numerous autoimmune and inflammatory conditions.

However, these medications also have been implicated in a number of cutaneous adverse events, including infusion and injection site reactions, infection, inflammatory dermatoses and malignancy.

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Five TNF alpha inhibitors are currently available: infliximab, adalimumab, etanercept, certolizumab pegol and golimumab.

Palmar psoriasis eruption in a patient receiving infliximab treatment for Crohn disease.

Palmar psoriasis eruption in a patient receiving infliximab treatment for Crohn disease.

An algorithm for treating TNF alpha inhibitor psoriasiform eruptions has been proposed and is based on severity of skin eruption and control of the underlying disease:11

  • If the skin eruption is mild and the underlying disease is controlled, continue the TNF alpha inhibitor and treat the eruption topically.
  • If the skin eruption is mild but the underlying disease is not controlled, switching within the same class is reasonable.
  • If the skin eruption is moderate to severe and the underlying disease is controlled, switching within the same class is reasonable.
  • If the skin eruption is moderate to severe and the disease is not well controlled, discontinuing TNF alpha inhibitors altogether is warranted.

Malignancy risk

Findings are mixed on whether TNF alpha inhibitors increase the risk of nonmelanoma skin cancer.14 In a meta-analysis of four observational studies with 28,000 patients, the risk of non-melanoma skin cancer was significantly higher among patients exposed to these drugs.14 However, the data are confounded by past or concomitant use of phototherapy or other immunosuppressive agents.

There is some evidence to suggest that patients receiving methotrexate, commonly used in rheumatoid arthritis, are at increased risk of nonmelanoma skin cancer, possibly due to the photosensitizing nature of methotrexate.15 One study in particular15 examined the rate of development of a second nonmelanoma skin cancer in 9,460 patients with rheumatoid arthritis or inflammatory bowel disease. It found that anti-TNF use may increase the nonmelanoma skin cancer risk when used in combination with methotrexate. However, further study is needed to eliminate confounding factors.

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The link between melanoma and TNF alpha inhibitors is also not straightforward. In a Swedish cohort study,16 there was a higher risk of a first invasive melanoma in patients with rheumatoid arthritis receiving TNF alpha inhibitors than in those not treated with them. Another study,16 however, examined 130,315 patients who had rheumatoid arthritis and found 287 first-time melanomas. The risk was slightly higher than in the general population in the entire cohort and in those on TNF alpha inhibitors, but the differences were not statistically significant, and the overall absolute incidence was quite low.

Given the mixed findings, it is therefore reasonable that all patients treated with a TNF alpha inhibitor undergo skin cancer surveillance for both melanoma and nonmelanoma skin cancer, use broad-spectrum sunscreens, and practice sun avoidance and skin self-examination. If malignant melanoma is found, it is reasonable to stop the TNF inhibitor.

References

  1. Treudler R. New drug therapies and their effect on the skin. J Dtsch Dermatol Ges. 2009; 7(7):623–637.
  2. Steenholdt C, Svenson M, Bendtzen K, Thomsen O, Brynskov J, Ainsworth M. Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2011; 34(1):51–58.
  3. AbbVie, Inc. HUMIRA (adalimumab) injection, for subcutaneous use. Highlights of prescribing information. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125057s399lbl.pdf. Accessed April 7, 2020.
  4. Capogrosso Sansone A, Mantarro S, Tuccori M, et al. Safety profile of certolizumab pegol in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis. Drug Saf. 2015; 38(10):869–888.
  5. Fréling E, Baumann C, Cuny JF, et al. Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience. Am J Gastroenterol. 2015; 110(8):1186–1196.
  6. Hernández MV, Sanmartí R, Cañete JD, et al; BIOBADASER 2.0 Study Group. Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumor necrosis factor antagonists: study using the Spanish registry of adverse events of biological therapies in rheumatic diseases. Arthritis Care Res (Hoboken). 2013; 65(12):2024–2031.
  7. Mocci G, Marzo M, Papa A, Armuzzi A, Guidi L. Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease. J Crohns Colitis. 2013; 7(10):769–779.
  8. Kane S, Khatibi B, Reddy D. Higher incidence of abnormal Pap smears in women with inflammatory bowel disease. Am J Gastroenterol. 2008; 103(3):631–636.
  9. George LA, Gadani A, Cross RK, Jambaulikar G, Ghazi LJ. Psoriasiform skin lesions are caused by anti-TNF agents used for the treatment of inflammatory bowel disease. Dig Dis Sci. 2015; 60(11):3424–3430.
  10. Mazloom SE, Yan D, Hu JZ, et al. TNF-a inhibitor-induced psoriasis: a decade of experience at the Cleveland Clinic. J Am Acad Dermatol. 2018. doi:10.1016/j.jaad.2018.12.018. Epub ahead of print.
  11. Li SJ, Perez-Chada LM, Merola JF. TNF inhibitor-induced psoriasis: proposed algorithm for treatment and management. J Psoriasis Psoriatic Arthritis. 2019; 4(2):70–80.
  12. Cleynen I, Van Moerkercke W, Billiet T, et al. Characteristics of skin lesions associated with anti-tumor necrosis factor therapy in patients with infl ammatory bowel disease: a cohort study. Ann Intern Med. 2016; 164(1):10–22.
  13. Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol. 2008; 22(5):847–861.
  14. Mariette X, Matucci-Cerinic M, Pavelka K, et al. Malignancies associated with tumour necrosis factor inhibitors in registries and prospective observational studies: a systematic review and meta-analysis. Ann Rheum Dis. 2011; 70(11):1895–1904.
  15. Scott FI, Mamtani R, Brensinger CM, et al. Risk of nonmelanoma skin cancer associated with the use of immunosuppressant and biologic agents in patients with a history of autoimmune disease and nonmelanoma skin cancer. JAMA Dermatol. 2016; 152(2):164–172.
  16. Mercer LK, Askling J, Raaschou P, et al. Risk of invasive melanoma in patients with rheumatoid arthritis treated with biologics: results from a collaborative project of 11 European biologic registers. Ann Rheum Dis. 2017; 76(2):386–391.

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