Gastroenterology & Hepatology
January 2016, Volume 12, Issue 1
Seth Lipka, MD1
Seymour Katz, MD2
James M. Crawford, MD, PhD3
1Division of Digestive Diseases and Nutrition, University of South Florida Morsani College of Medicine, Tampa, Florida; 2New York University School of Medicine, New York, New York; North Shore University Hospital-Long Island Jewish Health System, Manhasset, New York; and St. Francis Hospital, Roslyn, New York; 3Hofstra School of Medicine, North Shore-Long Island Jewish Health System, Hempstead, New York
Rituximab (RTX; Rituxan, Genentech) is the clinical formulation of a murine immunoglobulin G (IgG) 1 monoclonal anti-CD20 antibody and is widely used in the initial treatment of CD20-positive hematologic malignancies and a variety of autoimmune disorders. Rarely, fulminant colitis has been reported with the use of RTX (Table).1-7 We report a patient who developed 2 episodes of fulminant colitis after 2 infusions with RTX for the treatment of disseminated B-cell marginal lymphoma. The first episode of colitis required subtotal colectomy, and the second episode required completion proctectomy.
A 62-year-old woman presented in October 2002 with a left lower abdominal wall mass. The patient’s peripheral blood smear showed atypical lymphocytes. After an excisional biopsy and histologic and flow cytometry, the patient was diagnosed with marginal zone B-cell lymphoma. The patient was offered a combination treatment of CHOP chemotherapy with RTX or RTX alone. The patient decided to undergo therapy with RTX alone.
After receiving several cycles of RTX therapy from 2002 to 2005 and another 4 doses in September 2005, the patient developed severe abdominal pain and diarrhea. Her stool studies were negative for an infectious etiology. A computed tomography scan showed diffuse wall thickening and distention of the entire colon with areas of pneumatosis. The patient’s condition deteriorated and required a subtotal colectomy with ileostomy. Three months later, the ileostomy was closed.
In September 2010, after receiving a second course of 4 cycles of RTX therapy for recurrent lymphoma, the patient developed severe abdominal pain and diarrhea. Her stool studies were again negative for an infectious source. Diffuse severe colitis was noted on a sigmoidoscopy. The biopsies revealed severely inflamed tissue (Figure). The patient’s clinical course worsened later, requiring a proctectomy.
Discussion
Recent case reports have cited RTX as a trigger for severe colitis.1-7 RTX is a murine IgG 1 monoclonal anti-CD20 antibody that has become a successful treatment for several hematologic malignancies. The CD20 antigen is expressed on more than 90% of B-cell lymphomas.8 B cells regulate a number of immune functions, including production of both cytokines and immunoglobulins as well as antigen presentation.9-11
The normal mucosal immunity of the gastrointestinal tract maintains an equilibrium between proinflammatory and anti-inflammatory stimuli from the innate immune system, T cells, B cells, and their associated cytokines. Although the complete pathogenesis of ulcerative colitis (UC) is not understood, the presence of antigoblet cell antibodies, perinuclear antineutrophil cytoplasmic antibodies, and antihuman tropomyosin 5 hints toward B-cell involvement.12 RTX was reported to exacerbate UC in a patient with refractory disease, leading to a hypothesis that B cells may play a protective role.4 Mizoguchi and colleagues revealed that B-cell–depleted T-cell receptor alpha mu double-knockout mice developed severe colitis.13 B cells produce interleukin-10, a regulatory cytokine that maintains immune equilibrium and prevents the development of autoimmune disease.14,15 B cells in gut-associated lymphoid tissue were shown to protect against autoimmune disease through the promotion of transforming growth factor beta and interleukin-4 in mice.16 B-cell regulation of CD4 T-cell activity or B-cell effect on mucosal clearance of apoptotic cells plays a role in the development of inflammatory bowel disease in murine models.17,18 B-cell depletion may lead to T-regulatory cell dysfunction with subsequent stimulation of autoreactive T cells.19 This disequilibrium of the innate immune system of the gastrointestinal tract may lead to the activation of cytotoxic T cells and colitis in susceptible RTX patients. In corticosteroid-refractory UC, RTX was well tolerated with no reported cases of fulminant colitis; however, RTX failed to show a significant effect on inducing remission in 24 UC patients in a double-blind, randomized, controlled trial.20
In conclusion, RTX therapy is extensively used in a variety of hematologic malignancies and autoimmune diseases, but acute severe colitis is an underappreciated complication. B cells have both an inflammatory and anti-inflammatory function in humans, and disruption of this equilibrium in susceptible individuals may result in severe colitis.
The authors have no relevant conflicts of interest to disclose.
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Address correspondence to:
Dr Seymour Katz, 1000 Northern Blvd, Great Neck, NY 11021;
Tel: 516-466-3240; Fax: 516-829-6421; E-mail: Seymourkatz.md@gmail.com