REVIEW CME MOC Selena R. Pasadyn, BA Daniel Knabel, MD Anthony P. Fernandez, MD, PhD Christine B. Warren, MD, MS Cleveland Clinic Lerner College Department of Pathology Co-Medical Director of Continuing Medical Education; Department of Dermatology, Cleveland Clinic; of Medicine of Case Western and Department of Dermatology, W.D. Steck Chair of Clinical Dermatology; Director of Clinical Assistant Professor, Cleveland Clinic Reserve University, Cleveland, OH Cleveland Clinic Medical and Inpatient Dermatology; Departments of Lerner College of Medicine of Case Western Dermatology and Pathology, Cleveland Clinic; Assistant Reserve University, Cleveland, OH Clinical Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH Cutaneous adverse effects of biologic medications ABSTRACT iologic therapy encompasses an expo- B nentially expanding arena of medicine. Biologic therapies have become widely used but often As the name implies, biologic therapies are de- cause cutaneous adverse effects. The authors discuss the rived from living organisms and consist largely cutaneous adverse effects of tumor necrosis factor (TNF) of proteins, sugars, and nucleic acids. A clas- alpha inhibitors, epidermal growth factor receptor (EGFR) sic example of an early biologic medication is inhibitors, small-molecule tyrosine kinase inhibitors insulin. These therapies have revolutionized (TKIs), and cell surface-targeted monoclonal antibodies, medicine and offer targeted therapy for an including how to manage these reactions and when to increasing number of diseases, particularly in refer to a dermatologist. rheumatology, gastroenterology, hematology- oncology, and dermatology. KEY POINTS But along with these advances and the en- suing expanded use of biologic and targeted TNF alpha inhibitors (infl iximab, adalimumab, etanercept, therapies have come many unique adverse ef- certolizumab pegol, and golimumab) have been impli- fects, and some of the most commonly report- cated in infusion and injection site reactions, infection, ed adverse effects with these new therapies are infl ammatory dermatoses, and malignancy. cutaneous. Cutaneous adverse effects can po- tentially limit the use of these agents and add The most common cutaneous reaction with EGFR inhibi- cost to already expensive treatment regimens.1 tors (eg, gefi tinib, cetuximab, erlotinib, and panitumu- It is important for physicians and other mab) is a widespread papulopustular acneiform eruption. healthcare providers to be aware of these ef- fects, have a basic understanding of how to manage patients with these reactions, and to Small-molecule TKIs include imatinib, dasatinib, nilotinib, know when to refer to a dermatologist. ponatinib, bosutinib, sorafenib, sunitinib, pazopanib, This article reviews recent literature on axitinib, vandetanib, dovitinib, vemurafenib, dabrafenib, cutaneous adverse reactions experienced with and ruxolitinib. commonly prescribed biologic and targeted therapies, specifi cally tumor necrosis factor Commonly used monoclonal antibodies include ritux- (TNF) alpha inhibitors, epidermal growth fac- imab, anakinra, tocilizumab, ipilimumab, nivolumab, tor receptor (EGFR) inhibitors, small-mole- pembrolizumab, and avelumab. cule tyrosine kinase inhibitors (TKIs), and fre- quently used cell surface-targeted monoclonal antibodies. ■ TNF ALPHA INHIBITORS Dr. Fernandez has disclosed fi nancial relationships (consulting, membership on advisory committee or review panels, research, independent contracting, or teaching and speaking) TNF alpha is a proinfl ammatory cytokine with commercial interests (Abbview Pharmaceuticals, Corbus Pharmaceuticals, Mallinckrodt, that plays an important role in regulation of Novartis, Pfi zer, and UCB). immune cells. Dysregulation of TNF alpha doi:10.3949/ccjm.87a.19119 is involved in the pathogenesis of numer- 288 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 5 MAY 2020 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. PASADYN AND COLLEAGUES TABLE 1 Cutaneous adverse effects of tumor necrosis factor alpha antagonists Examples Cutaneous side effects Management strategies Adalimumab Infusion reactions and injection Preinfusion treatment with oral antihistamines, Certolizumab site reactions acetaminophen, and intravenous steroids Etanercept Golimumab Cutaneous infections (bacterial, Frequent skin examinations, low threshold to perform Infl iximab viral) cultures and initiate bacterial or fungal-targeted topi- cal or oral therapy Consider varicella zoster vaccination before starting therapy Psoriasis Topical therapy, methotrexate, cyclosporine, phototherapy Eczematous dermatitis Gentle skin care, liberal emollients, topical steroids Lichenoid reactions Discontinuation or reduction of therapy dose, topical steroids Cutaneous leukocytoclastic Discontinuation of therapy, initiation of systemic vasculitis prednisone, switch to other immunosuppressive medication Nonmelanoma and melanoma Routine skin cancer surveillance, broad-spectrum skin cancer sunscreen, sun avoidance, skin self-examination Biologic therapies have ous infl ammatory conditions, most notably In a Danish cohort of patients with infl am- revolutionized rheumatoid arthritis, infl ammatory bowel dis- matory bowel disease receiving infl iximab, ease, psoriasis vulgaris, and psoriatic arthritis. infusion reactions were most strongly associ- medicine, Therefore, TNF alpha inhibitors have been ated with younger patients and with episodic but come 2 successfully used to treat numerous autoim- therapy. with many mune and infl ammatory conditions. Treatment for these infusion reactions is However, these medications also have largely supportive. Preventive measures in- unique adverse been implicated in a number of cutaneous ad- clude preinfusion treatment with oral anti- effects verse events, including infusion and injection histamines, acetaminophen, and occasionally site reactions, infection, infl ammatory derma- intravenous steroids and slowing the rate of toses, and malignancy. infusion. Adding concomitant immunosup- Five TNF alpha inhibitors are currently pressive medications and avoiding drug-free available: infl iximab, adalimumab, etanercept, intervals have also been recommended. certolizumab pegol, and golimumab (Table 1). Injection site reactions Infusion reactions with infl iximab Injection site reactions have been reported Infusion reactions associated with infl iximab to occur in 6% to 37% of patients receiving have been reported to occur in as many as adalimumab, 17% to 37% of patients receiv- 18% of recipients.2 These reactions may be ing etanercept, 6% of patients receiving goli- acute (onset within minutes to hours) or de- mumab, and 3.1% of those receiving certoli- layed (days to weeks), with cutaneous mani- zumab pegol.3,4 festations of fl ushing, urticaria, pruritus, an- Patients can experience itching, pain, red- gioedema, and a serum sickness-like reaction. ness, irritation, bruising, or swelling at the in- CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 87 • NUMBER 5 MAY 2020 289 Downloaded from www.ccjm.org on September 23, 2021. For personal use only. All other uses require permission. CUTANEOUS ADVERSE EFFECTS OF BIOLOGICS jection site. This can be seen during the fi rst virus skin infections. This population-based month of treatment and can last 3 to 5 days. study from Spain6 found cutaneous bacterial Absence of warmth or drainage and improve- infections occurred at an incidence of 10.4 per ment within a few days can distinguish injec- 1,000 patient-years, and zoster infections at an tion site reactions from infection. incidence of 7.2 per 1,000 patient-years. Zos- Management of these reactions is again pri- ter infections were found more often in those marily supportive. Preventive therapies similar receiving infl iximab and adalimumab. In addi- to those described for infusion reactions, as tion, immunosuppressive therapy in conjunc- well as cooling pads or ice packs for symptom- tion with a TNF alpha inhibitor increased atic relief, may be helpful. Varying the site of the risk of zoster dissemination and complica- injection is another useful strategy. Most of tions, including bacterial superinfection and these reactions are considered moderate, and postherpetic neuralgia. rarely do patients need to discontinue the TNF Cutaneous infections during anti-TNF alpha inhibitor because of them. alpha therapy are rarely serious, and manage- ment should include frequent skin examina- Cutaneous infections tions and initiation of appropriate antibacte- TNF alpha plays an important role in numer- rial or antifungal topical or oral therapy. For ous complex immune signaling pathways, example, acyclovir, valacyclovir, and famci- including cell proliferation, differentiation, clovir can be used for acute varicella zoster apoptosis, macrophage activation, and mor- virus infection. phogenesis of lymphoid tissue. Not surpris- Given the current guidelines and the in- ingly, inhibition of this cytokine leads to cidence of herpes zoster in patients receiv- increased risk of cutaneous infection. Risk ing TNF alpha inhibitors, clinicians should factors for increased cutaneous infections dur- strongly consider vaccination before starting ing TNF alpha inhibitor therapy include addi- therapy.6 Safe use and effi cacy of the recom- tional immunosuppressive therapy, malnutri- binant vaccine in these individuals are not tion, age, and comorbidities such as chronic entirely clear. There are currently