Safety reviews of tumor necrosis factor-alpha ( TNF-a ) antagonists, Infliximab ( Remicade ), Etanercept ( Enbrel ), and Adalimumab ( Humira ) identified rare cases of serious skin reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, associated with the use of these biological products.

Infliximab, Etanercept, and Adalimumab block TNF-alpha, an inflammatory cytokine, but via different mechanisms. Infliximab and Adalimumab are monoclonal antibodies that bind TNF-a while Etanercept is a dimeric fusion protein consisting of a portion of the human TNF receptor linked to the Fc portion of human IgG1.

TNF-alpha antagonists have been approved to reduce the signs and symptoms of rheumatoid arthritis ( Remicade, Enbrel, Humira ), psoriatic arthritis ( Remicade, Enbrel, Humira ), ankylosing spondylitis ( Remicade, Enbrel, Humira ), polyarticular juvenile idiopathic arthritis ( Enbrel and Humira only ), ulcerative colitis ( Remicade only ), and Crohn's disease ( Humira and Remicade only ) and treat adult patients with chronic plaque psoriasis of certain severity ( Enbrel, Remicade, Humira ).
Infliximab is administered as an infusion; Etanercept and Adalimumab are given subcutaneously.

The presenting signs and symptoms of the serious skin reactions were mainly rash and skin lesions on the trunk, legs, arms, shoulder, back, hands, and face. Oral mucositis or ulceration, genital ulceration, and/or fever were reported in some Stevens-Johnson syndrome cases. One patient experienced an allergic type reaction; she initially experienced hives and swollen lips, eyes, and face, then developed erythema multiforme lesions on her back and subsequently became hypoxic.
A few cases of toxic epidermal necrolysis described the skin reactions as skin desquamation and progressive pruritis over the whole body; generalized whole body skin peeling; a severe, scaly, pigmented necrotizing rash over the body; and erythema with blepharoconjunctivitis, angioedema, and throat tightness.

Infliximab

From the date of approval in August 1998 to August 2006, FDA received 21 reports of cases in adult patients of severe cutaneous adverse reactions associated with infliximab, including erythema multiforme ( 15 cases ), Stevens-Johnson syndrome ( 5 cases ), and toxic epidermal necrolysis ( 1 case ). Of these 21 cases, 16 were postmarketing reports.
The majority of the cases ( 76% ) were female. Most cases ( 62% ) received Infliximab for the treatment of rheumatoid arthritis. The median time to onset between the first infusion and onset of the adverse reaction was 28 days.
Although fifteen cases ( 71% ) reported one or more concomitant medications that have been associated with erythema multiforme, Stevens-Johnson syndrome, and/or toxic epidermal necrolysis, in only five of these cases were the concomitant medications ( Sulfasalazine, Mercaptopurine, and Leflunomide ) reported as co-suspect medications.
Twelve patients required hospitalization due to their cutaneous reactions.

Etanercept

From the date of approval in November 1998 to November 2006, FDA received 22 reports of cases of severe cutaneous adverse reactions associated with Etanercept, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, involving an adolescent and adult patients. Of these cases, 17 were postmarketing.
There were reports of 13 cases of erythema multiforme, four cases of toxic epidermal necrolysis, four cases of Stevens-Johnson syndrome, and one case of Stevens-Johnson syndrome / toxic epidermal necrolysis. Fourteen ( 64% ) patients were female. Most patients used Etanercept for the treatment of rheumatoid arthritis.
Time to onset since last etanercept dose was provided for two cases and was reported as five days and nine days.
Fifteen cases ( 68% ) reported the use of concomitant medications associated with erythema multiforme, Stevens-Johnson syndrome, and/or TEN. Five of these cases reported a co-suspect medication ( Isoniazid, Indapamide, Ciprofloxacin, Terbinafine, or Ethinyl estradiol / Levonorgestrel ) in addition to Etanercept.
Eleven patients required hospitalization due to their skin reaction.

Adalimumab

From the date of approval in December 2002 to November 2006, FDA received 7 reports of cases of severe skin reactions. There were four cases of erythema multiforme, two cases of Stevens-Johnson syndrome, and one case reporting both erythema multiforme and Stevens-Johnson syndrome.
Most patients ( 85% ) were female, and five patients ( 71% ) received Adalimumab to treat rheumatoid arthritis. The median time to onset of skin reactions since starting Adalimumab was 60 days.
Two cases reported the use of Methotrexate as a concomitant medication associated with erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis, but none of the seven cases reported suspect medications other than Adalimumab.
One patient required hospitalization.

Source: FDA, 2008

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