Tumor necrosis factor ALPHA Inhibitor Associated Köhlmeier-Degos Disease as a Novel Iatrogenic Paradigm That Underscores Excessive Type I Interferon in Its Pathogenesis.

Abstract

Malignant atrophic papulosis/Köhlmeier-Degos disease was first described in 1941 by Köhlmeier in an anecdotal case report that described a young man who presented with extensive multiple intestinal perforations and a papular skin rash. Köhlmeier-Degos disease represents a unique vasculopathy targeting both the microvasculature and the arterial system. One of its most characteristic features is reflected by the discrete multifocal depressed porcelain lesions involving the skin and gastrointestinal tract. The pathological findings are striking and can be broadly categorized into those that are vascular in nature versus extravascular matrix production in the context of extensive extravascular hyaluronic acid and collagen deposition. A dynamic evolutionary morphology is observed not only clinically but also histologically. The microvascular alterations are particularly evident in the skin and are characterized by endothelial cell necrosis with subsequent endothelial cell detachment accompanied by intraluminal fibrin deposition, defining a thrombogenic microangiopathy that in later stage lesions is typically pauci-inflammatory. The arterial lesions are very distinctive and include significant neointimal proliferation with vascular luminal occlusion by amorphous plugs of collagen intimately admixed with platelets. Pathogenetically enhanced type I interferon signaling and endothelial cell injury mediated by the membranolytic attack complex (ie, C5b-9) are key in the evolution of the thrombotic microvascular and obliterative fibrosing arteriopathic changes. We describe a case of Köhlmeier-Degos disease that developed in the setting of tumor necrosis factor (TNF)-alpha inhibitor therapy with the drug golimumab. The clinical features, light microscopic findings, and a pathophysiologic paradigm based on the critical role of TNF-alpha in controlling the type I interferon response are discussed.