Case 4 -

Small Vessel Vasculitis / Venulitis, Related to Trazodone Therapy Allen P. Burke University of Maryland School of Medicine Baltimore, MD

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Clinical History A 50-year-old woman was taking trazodone for fibromyalgia. She developed bowel symptoms with right lower quadrant mass. There was a vague recent history of a rash, but the physical examination on admission did not note any skin lesions. Peripheral eosinophil count was mildly elevated at 3%. Imaging demonstrates markedly thickened wall of the cecum and ascending colon. A right hemicolectomy was performed. Microscopic Findings There was edema of the submucosal layer (figure 1) and inflammation of the veins, with sparing of the accompanying arteries (figure 2). The venous inflammation destroyed the wall and resulted, in many segments, in luminal thrombosis (figure 3). A higher magnification of the vein showed eosinophils in a chronic inflammatory infiltrate (figure 4). There was less striking involvement of smaller venules and capillaries. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 4 - Figure 1 Low magnification of the bowel showing submucosal edema. Case 4 - Figure 2 Submucosa demonstrating inflammation of veins with sparing of arteries. Case 4 - Figure 3 Normal artery (above) with inflamed vein (below) with luminal thrombosis. Case 4 - Figure 4 Numerous eosinophils are present in the venous inflammation. Diagnosis Small vessel vasculitis / venulitis, related to trazodone therapy. Discussion Small vessel vasculitis involves arterioles, capillaries, and venules, and is associated with immune complex deposition or may be pauci-immune. The histologic hallmark is fibrinoid necrosis with leukocytoclasia, or apoptotic degeneration of neutrophils, especially in the acute phase. Pauci-immune small vessel vasculitis is frequently associated with anti-neutrophil cytoplasmic antibodies and is loosely synonymous with microscopic polyangiitis. Immune small vessel vasculitis may be idiopathic, drug-related and short-lived, or a manifestation of systemic autoimmune disease. Small vessel vasculitis, either pauci-immune or immune complex-related, may be associated with necrotizing muscular arteritis in Wegener's granulomatosis and rheumatoid arthritis and other autoimmune disorders, respectively. An antigen-antibody complex mediated small vessel vasculitis may be induced by drugs, especially penicillins, aminopenicillins, D-penicillamine, sulfonamides, allopurinol, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, phenytoin, isotretinoin, methotrexate, thiazides, pyrazolones, retinoids, quinolones, hydantoins, and propylthiouracil. Some drugs, such as penicillins, cause vasculitis by conjugating to serum proteins and mediating immune-complex vasculitis that is similar to serum-sickness vasculitis. Other vasculitis-inducing drugs that cause immune-complex formation are foreign proteins, such as streptokinase, cytokines, and monoclonal antibodies. In addition, such drugs as propylthiouracil and hydralazine appear to cause vasculitis by inducing ANCA. Trazodone has been associated with small vessel vasculitis in the skin. [1] The interval between the first exposure and appearance of symptoms is variable. Although typically benign and self-limiting, patients with severe manifestations have required corticosteroids, plasmapheresis, hemodialysis, or cyclophosphamide. Bowel involvement is not uncommon in systemic immune-related vasculitis, such as Henoch Schonlein purpura, and ANCA-related microscopic polyangiitis. However, small vessel vasculitis localized to the gastrointestinal tract is rare. Among cases of isolated vasculitis of the bowel, small vessel vasculitis accounts for about 10%, the others consisting primarily of polyarteritis, phlebitis, and Churg-Strauss vasculitis. [2] It is and often associated with reaction to drugs or a manifestation of lupus. [1, 3, 4, 5, 6] Giant cell phlebitis is a rare form of vasculitis that occurs most commonly in the right colon and omentum. [2] The symptoms are generally those related to a mass, and intestinal strictures and even perforation may occur. The etiology is unknown, but there may be an association with reactions to medications, and eosinophils are often present within the lesions. Histologically, giant cell phlebitis is characterized by granulomatous destruction of muscular veins. It is possible that giant cell phlebitis, limited Churg-Strauss syndrome, and small vessel vasculitis are part of a spectrum representing differing expressions of a form of allergic or hypersensitivity phenomenon. References Mann SC, Walker MM, Messenger GG, Greenstein RA. Leukocytoclastic vasculitis secondary to trazodone treatment. J Am Acad Dermatol 1984;10:669-70. Burke AP, Sobin LH, Virmani R. Localized vasculitis of the gastrointestinal tract. Am J Surg Pathol 1995;19:338-49. Bisceglia M, Germani G, Tardio B, Di Mattia A, Li Bergoli M. Leukocytoclastic vasculitis of the colon. Ital J Surg Sci 1989;19:269-72. Hugl B, Lhotta K, Ensinger C, et al. Colonic perforation associated with leukocytoclastic vasculitis caused by Sirolimus toxicity following renal transplantation. Transpl Int 2006;19:430-1. Makary R, Davis C, Shuja S. Medium- and small-vessel vasculitis with large bowel infarction in systemic lupus erythematosus: a case report. Am J Gastroenterol 2009;104:1859-60. Stipic Markovic A, Pekic P, Schmidt S, Stulhofer Buzina D. Small and large bowel manifestation of leukocytoclastic vasculitis. Wien Klin Wochenschr 2005;117:565-8.