Cutaneous Adverse Effects of Surface-Targeted Monoclonal Antibodies

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 is the final article of a four-part series that reviews recent literature on cutaneous adverse reactions experienced with commonly prescribed biologic and targeted therapies.

Cell surface-targeted monoclonal antibodies

Monoclonal antibodies are drugs directed against specific antigens on cells that cause disease. These drugs may assist in immune modulation, cell killing or blocking a physiologic ligand-receptor interaction. Not surprisingly, monoclonal antibodies are used in the treatment of immunologic diseases and cancer therapy. Although the number of monoclonal antibodies designed as drugs has been increasing substantially since 1985, common ones include rituximab, anakinra, tocilizumab, ipilimumab, nivolumab, pembrolizumab, avelumab and tofacitinib.

Rituximab, an anti-CD20 monoclonal antibody

Rituximab is a chimeric murine-human monoclonal antibody against CD20 used in rheumatoid arthritis, autoimmune disorders and lymphoproliferative disorders. While dermatologically it is relatively benign, it has been reported to cause infusion reactions. Standard practice is to premedicate with acetaminophen and diphenhydramine 30 minutes before the first and second infusions.

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Serum sickness has also been reported with rituximab, and is seen visibly as a morbilliform skin eruption with acral accentuation.35 Treatment for this reaction includes pulse methylprednisolone therapy, which can be effective in resolving symptoms over 48 hours.

Less commonly, Stevens-Johnson syndrome-toxic epidermal necrolysis and vesiculobullous dermatitis can occur with rituximab, in which case discontinuation is recommended.

Other monoclonal antibodies

Other commonly used monoclonal antibodies include anakinra, tocilizumab and ipilimumab.

Anakinra is a recombinant human interleukin 1 receptor antagonist used to treat rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still disease, and, in select patients, recurrent pericarditis. Case reports note new-onset psoriasis with this drug, as well as injection-site reactions.36

Tocilizumab is an anti-human interleukin 6 receptor antibody used for rheumatoid arthritis and giant cell arteritis. It rarely presents with skin rash, but is most notable for hypersensitivity reactions upon infusion.37

Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 used to treat patients with advanced melanoma.

In 41 patients treated with ipilimumab, 34.1% developed cutaneous adverse events that included rash (7.3%), folliculitis (7.3%), mucositis (2.4%), rosacea (2.4%), eczema (2.4%), acneiform eruption (2.4%), syringometaplasia mucinosa (2.4%;), Stevens-Johnson syndrome (2.4%) and vitiligo (4.9%). Approximately 5% of the patients complained of severe xerosis and 10% of pruritus.38

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Treatment for these cutaneous manifestations is similar to that described in previous sections.

Nivolumab, pembrolizumab and avelumab bind to programmed cell death ligand-1 (PD-L1), enhancing the host immune response by preventing tumor cells from suppressing endogenous T-cell activity. Cutaneous eruptions described with these medications include lichenoid, bullous, psoriasiform, macular and morbilliform morphologies. Cases of Stevens-Johnson syndrome-toxic epidermal necrolysis (as pictured above) have also been reported.

Treatment with topical corticosteroids, systemic steroids, or discontinuation of the anti-PD-L1 inhibitor may be effective depending on the severity of the eruption.39

Be on the lookout

Biologic medications are becoming critical in medicine, for treating conditions ranging from autoimmune diseases to metastatic cancers. They are reducing mortality and substantially improving quality of life.

It is therefore important that physicians be armed with knowledge about the cutaneous adverse events of these medications and basic treatment steps. For example, knowing when to reduce the dose or discontinue the drug, supplement with topical or oral steroids or antibiotics, or refer to a dermatologist will be highly useful when caring for patients on these biologics. These innovative medications will only reach their maximum effectiveness when we as providers understand and manage adverse events appropriately.

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