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.
Table.
Cases of RTX and Colitis
| Case | Age, Sex | Indication(s) | Treatment(s)/Outcome |
|---|---|---|---|
| 1 | 67, M | Relapse of follicular lymphoma | Subtotal colectomy; died of recurrent bacterial pneumonia 4 months after surgery1 |
| 2 | 26, F | Non-Hodgkin lymphoma treatment | Colectomy2 |
| 3 | 45, F | Clinical trial for Grave’s disease | Mesalamine-induced remission3 |
| 4 | 58, M | Long-standing ulcerative colitis unresponsive to corticosteroids, immunosuppressants, and biologics | 5-ASA, corticosteroids, and ciprofloxacin; patient suffered from 10-15 loose stools/day and was considered for proctocolectomy4 |
| 5 | 4, M | Refractory minimal-change disease nephrotic syndrome | Corticosteroid-induced remission. Eventually, the nephrotic syndrome relapsed5 |
| 6 | 34, unknown | Corticosteroid-, cyclophosphamide-, and methotrexate-resistant bullous systemic lupus erythematous | Episode of acute appendicitis with appendectomy. Later developed ulcerative colitis. When RTX was withdrawn, symptoms resolved6 |
| 7 | 38, F | Refractory seronegative rheumatoid arthritis | Corticosteroid- and 5-ASA–induced remission7 |
| 8 | 62, F | Disseminated marginal zone B-cell lymphoma | Initially patient underwent subtotal colectomy and on subsequent RTX re-exposure patient experienced active proctitis requiring completion proctectomya |
5-ASA, 5-aminosalicylic acid; F, female; M, male; RTX, rituximab.
The current case.
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.
Figure.
Colonic mucosa, submucosa, and muscularis propria on the left show the lateral edge of an ulcer on the right that undermines residual mucosa and submucosa. Ulceration extends to the level of the muscularis propria with partial penetration of the ulcer into it (100x magnification, hematoxylin and eosin stain).
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.
Footnotes
The authors have no relevant conflicts of interest to disclose.
References
- 1.Blombery P, Prince HM, Levinson M, Pianko S, Maxwell E. Bhathal P Rituximab-induced immunodysregulatory ileocolitis in a patient with follicular lymphoma. J Clin Oncol. 2011;29(5):e110–e112. doi: 10.1200/JCO.2010.31.8899. [DOI] [PubMed] [Google Scholar]
- 2.Fernandez-Blanco I, Cara C, Perez M. De novo fulminant colitis after rituximab therapy on a non-Hodgkin lymphoma. Presented at United European Gastroenterology Week 2008 October 18-22, 2008 Vienna, Austria.
- 3.El Fassi D, Nielsen CH, Kjeldsen J, Clemmensen O, Hegedüs L. Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease. Gut. 2008;57(5):714–715. doi: 10.1136/gut.2007.138305. [DOI] [PubMed] [Google Scholar]
- 4.Goetz M, Atreya R, Ghalibafian M, Galle PR, Neurath MF. Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflamm Bowel Dis. 2007;13(11):1365–1368. doi: 10.1002/ibd.20215. [DOI] [PubMed] [Google Scholar]
- 5.Ardelean DS, Gonska T, Wires S, et al. Severe ulcerative colitis after rituximab therapy. Pediatrics. 2010;126(1):e243–e246. doi: 10.1542/peds.2009-3395. [DOI] [PubMed] [Google Scholar]
- 6.Sekkach Y, Hammi S, Elqatni M, et al. Ulcerative colitis: exceptional consequence after rituximab therapy [in French] Ann Pharm Fr. 2011;69(5):265–269. doi: 10.1016/j.pharma.2011.06.005. [DOI] [PubMed] [Google Scholar]
- 7.Bhalme M, Hayes S, Norton A, Lal S, Chinoy H, Paine P. Rituximab-associated colitis. Inflamm Bowel Dis. 2013;19(3):e41–e43. doi: 10.1002/ibd.22963. [DOI] [PubMed] [Google Scholar]
- 8.McLaughlin P, Grillo-López AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825–2833. doi: 10.1200/JCO.1998.16.8.2825. [DOI] [PubMed] [Google Scholar]
- 9.Wolf SD, Dittel BN, Hardardottir F, Janeway CA., Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med. 1996;184(6):2271–2278. doi: 10.1084/jem.184.6.2271. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Moulin V, Andris F, Thielemans K, Maliszewski C, Urbain J, Moser M. B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation. J Exp Med. 2000;192(4):475–482. doi: 10.1084/jem.192.4.475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Harris DP, Haynes L, Sayles PC, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol. 2000;1(6):475–482. doi: 10.1038/82717. [DOI] [PubMed] [Google Scholar]
- 12.Bossuyt X. Serologic markers in inflammatory bowel disease. Clin Chem. 2006;52(2):171–181. doi: 10.1373/clinchem.2005.058560. [DOI] [PubMed] [Google Scholar]
- 13.Mizoguchi A, Mizoguchi E, Takedatsu H, Blumberg RS, Bhan AK. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity. 2002;16(2):219–230. doi: 10.1016/s1074-7613(02)00274-1. [DOI] [PubMed] [Google Scholar]
- 14.de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE. Interleukin-10. Curr Opin Immunol. 1992;4(3):314–320. doi: 10.1016/0952-7915(92)90082-p. [DOI] [PubMed] [Google Scholar]
- 15.Davidson NJ, Leach MW, Fort MM, et al. T helper cell 1-type CD4+ T cells, but not B cells, mediate colitis in interleukin 10-deficient mice. J Exp Med. 1996;184(1):241–251. doi: 10.1084/jem.184.1.241. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Gonnella PA, Waldner HP, Weiner HL. B cell-deficient (mu MT) mice have alterations in the cytokine microenvironment of the gut-associated lymphoid tissue (GALT) and a defect in the low dose mechanism of oral tolerance. J Immunol. 2001;166(7):4456–4464. doi: 10.4049/jimmunol.166.7.4456. [DOI] [PubMed] [Google Scholar]
- 17.Mizoguchi E, Mizoguchi A, Preffer FI, Bhan AK. Regulatory role of mature B cells in a murine model of inflammatory bowel disease. Int Immunol. 2000;12(5):597–605. doi: 10.1093/intimm/12.5.597. [DOI] [PubMed] [Google Scholar]
- 18.Mizoguchi A, Mizoguchi E, Smith RN, Preffer FI, Bhan AK. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med. 1997;186(10):1749–1756. doi: 10.1084/jem.186.10.1749. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Jamin C, Morva A, Lemoine S, Daridon C, de Mendoza AR, Youinou P. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthritis Rheum. 2008;58(7):1900–1906. doi: 10.1002/art.23487. [DOI] [PubMed] [Google Scholar]
- 20.Leiper K, Martin K, Ellis A, et al. Randomised placebo-controlled trial of rituximab (anti-CD20) in active ulcerative colitis. Gut. 2011;60(11):1520–1526. doi: 10.1136/gut.2010.225482. [DOI] [PubMed] [Google Scholar]