Gastrointestinal: Herpes simplex virus‐associated erythema multiforme (HAEM) during infliximab treatment for ulcerative colitis

Abstract

Anti-TNF-α antibodies are effective in the treatment of inflammatory bowel diseases. These biologic drugs, however, may result in adverse effects that include opportunistic infections. Viral infections may also reactivate following immunosuppression. Molecular and immunologic evidence demonstrate that herpes simplex virus (HSV) can cause erythema multiforme (EM), which may appear as a polymorphous eruption with symmetrically distributed macules, papules, bullae, and typical target lesions with a central vesicle or bulla. EM caused by HSV, also known as HSV-associated EM (HAEM), is dissimilar to drug-induced EM (DIEM). IFN-γ and TNF-α are pro-inflammatory cytokines produced by different cell types: T cells accumulating in HAEM lesions are primarily CD4+ (Vβ2+) cells that are activated by HSV antigen while non-T and CD8+ T cells are predominant in DIEM lesions. There is a strong correlation between IFN-γ and HSV-protein expression in the skin tissues. HAEM lesions are positive for IFN-γ, a product of HSV antigen-triggered CD4+ cells; DIEM, in contrast, is a distinct condition in which keratinocytes are positive for TNF-α, a sign of toxic injury, primarily produced by monocytes/macrophage. This finding indicates that HAEM and DIEM are mechanistically distinct syndromes. A 19-year-old girl with UC on oral prednisone and mesalamine, presented with an active pancolitis. Clinical picture did not improve after intravenous corticosteroids, so infliximab (5 mg/kg at week 0,2,6 then every 8 weeks) was commenced. She clinically improved. However, at the time of the third drug infusion, she reported 2 days' history of a diffuse, mildly pruritic cutaneous rash. She denied constitutional symptoms such as fever or chills. A symmetric erythematous, annular macular rash was seen on the acral extremities, including palms and soles, and on the face (Figure 1). Herpes-like vesicles were also evident on her lips (Figure 2). Some lesions were edematous and slightly raised from scratching, whereas others were target lesions with central vesicles. The herpes lesions on the lips had appeared 5 days after the first infliximab infusion. Vesicle fluid polymerase chain reaction was positive for HSV type I. The skin lesion was positive for HSV-DNA and IFN-γ on immunohistochemistry. The diagnosis was HAEM due to infliximab-related immunosuppression reactivating a latent HSV infection. Infliximab was suspended to avoid HSV-related complications, and the cutaneous rash gradually vanished and she was treated with valaciclovir. The patient subsequently underwent restorative proctocolectomy with J-pouch construction, and a loop-ileostomy. Symmetric erythematous rash on acral extremities and on the face. Some lesions were edematous and slightly raised due to scratching; some target lesion were observed. Lesions on patient's face. Note herpes signs on her lips. At our knowledge, this is the first case of HAEM associated with infliximab administration causing reactivation of HSV infection. Infliximab does not cause DIEM as it suppresses TNF-α. Contributed by