Tumor Necrosis Factor-α and Interleukin-1 Antagonists Alleviate Inflammatory Skin Changes Associated with Epidermal Growth Factor Receptor Antibody Therapy in Mice

Cancer patients receiving epidermal growth factor receptor (EGFR) antibody therapy often experience an acneiform rash of uncertain etiology in skin regions rich in pilosebaceous units. Currently, this condition is treated symptomatically with very limited, often anecdotal success. Here, we show that a monoclonal antibody targeting murine EGFR, ME1, caused a neutrophil-rich hair follicle inflammation in mice, similar to that reported in patients. This effect was preceded by the appearance of lipid-filled hair follicle distensions adjacent to enlarged sebaceous glands. The cytokine tumor necrosis factor-alpha (TNF alpha), localized immunohistochemically to this affected region of the pilosebaceous unit, was specifically upregulated by ME1 in skin but not in other tissues examined. Moreover, skin inflammation was reduced by cotreatment with the TNF alpha signaling inhibitor, etanercept, indicating the involvement of TNF alpha in this inflammatory process. Interleukin-1, a cytokine that frequently acts in concert with TNF alpha, is also involved in this process given the efficacy of the interleukin-1 antagonist Kineret. Our results provide a mechanistic framework to develop evidence-based trials for EGFR antibody-induced skin rash in patients with cancer. [Cancer Res 2009;69(14):5643-7]