Severe Colitis Induced by Rituximab Zachary Feinberg MD1, Hwa Jeong Lee MD2, Richard Blinkhorn MD3, James Wymer MD4, Xinjun Zhu MD1

Albany Medical College and Center; Department of Medicine; Division of Gastroenterology1, Division of Anatomic Pathology2, Infectious Disease Center3; Department of Neurology4, Albany, New York

Rituximab, a well-known chimeric monoclonal antibody directed against the CD20 antigen on B-Cells, depletes CD19-positive and CD20-positive B-cells. It is used for treatment of NHL, CLL, RA, and multiple sclerosis (MS). There are 4 case reports of “rituximab-associated Colitis”. We report a patient treated with rituximab, developed fulminant severe colitis when the B-cells were depleted and resolved once the B-cells were restored.

References: Elsevier, comp. Rituximab. Tech. N.p.: n.p., n.d. Clinical Pharmacology. Web. 10 Jan. 2014. www.clinicalpharmacology-ip.com/Forms/Monograph/monograph.aspx?cpnum=2212&sec=monindi&t=0>. Bhalme, Mahesh, Stephen Hayes, and Andrew Norton, et al. "Rituximab-associated Colitis." Inflammatory Bowel Disease 19.3 (2013): E41-43. Web. Goetz M, Atreya R, Ghalibafian M, et al. Exacerbation of ulcerative colitis after rituximab salvage therapy. Inflamm Bowel Dis. 2007; 13:1365-1368. El Fassi D, Nielsen CH, Kjeldsen J, et al. Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease. Gut. 2008;57:714-715. Ardelean DS, Gonska T, Wires S, et al. Severe ulcerative colitis after rituximab therapy. Pediatrics. 2010;126:e243-246. Castillo-Trivino T, Braithwaite D, Bacchetti P, et al. Rituximab in relapsing and progressive forms of multiple sclerosis: a systemic review. PLoS One. 2013;8:e66308. Jamin C, Morva A, Lemoine S, et al. Regulatory B lymphocytes in humans: a potential role in autoimmunity. Arthritis Rheum. 2008;58(7):1900-1906.

We present a 34 year-old Caucasian female receiving rituximab for refractory MS. She would receive one infusion on day zero and day 14 with a dose of375mg/m2/24hr. After her infusion her MS improved and her levels of B-cells were undetectable. She had a repeat infusion eight months after initial infusion. Several days after her second treatment, the patient developed nausea. Her nausea continued and then one month later the patient developed watery diarrhea. Four months later she had a colonoscopy to evaluate her persistent diarrhea. The endoscopic findings appeared normal; however, the biopsy showed lymphocytic colitis (LC) associated with surface injury. Immunohistochemistry revealed that B-cells were depleted with absence of CD20+ B-cells in the mucosa. Of note, there were abundant macrophages in the mucosa. The patient improved and after eight months the patient was at her baseline and received her third infusion of rituximab. Twelve hours after infusion, the diarrhea recurred accompanied by arthralgias. The non-bloody diarrhea persisted and when she presented to neurology clinic she was unable to tolerate a diet. A CT scan showed, circumferential thickening of the left colon. Infectious etiologies were negative. The CRP was 212 and ESR was 32. A repeat colonoscopy was performed to evaluate abdominal pain and diarrhea. Findings were of severe colitis with ulcerations in the entire left side of the colon. The biopsy showed fulminant active colitis with frequent cryptitis, crypt abscess, and ulceration. Immunohistochemisry revealed absence of B-cells by CD20 immunostaining. The number of macrophages was similar to that of the initial biopsy. Though steroids were offered to the patient, she opted to be treated conservatively. She was discharged and monitored closely as outpatient.

Eight months after her previous infusions of rituximab, she finally had a detectable level of CD19 and CD20 cells. A colonoscopy with biopsy revealed normal colon without colitis or injury. Immunostaining of CD20 confirmed partial recovery of B-cells in the colon. There was no significant change in the number of macrophages.

There was a clear relation between colitis and lack of B-cell in colonic tissues

Severity increased with each infusion of Rituximab

Resolution of both clinical and histologic findings was obtained after discontinuation of Rituximab.

Review of the literature and this case seems to be showing an association between depletion of B-cells, specifically CD19+ and CD20+ cells and severe colitis with ulcerations. In our case each subsequent infusion of rituximab led to more severe gastrointestinal symptoms. It has been proposed that B-cells both prevent the development of these autoimmune diseases and reduce their severity. It appears that although the depletion of B-cells improve the symptoms of MS, that there is a severe dysfunction of regulation of the cellular immunity that can lead to autoimmune processes. We are hypothesizing that the loss of B-cells causes dysfunction of the cellular immunity and led to severe colitis with ulceration. Currently our patient is off all therapy for her MS and doing well but further investigations are underway for future options that do not work by affecting the B-cells.

Figure 1:

A) Demonstrates the endoscopic findings during the first colonoscopy 5 months after 2nd infusion of Rituximab with normal appearance. B) Displays the H&E stain of the mucosal biopsy during first colonoscopy, which shows numerous intraepithelial lymphocytes involving colonic crypts and surface, with surface epithelial injury. These findings were consistent of lymphocytic colitis. C) Demonstrates the ulcerated mucosa found endoscopically during the 2nd colonoscopy shortly after the 3rd infusion of Rituximab. D) Shows the H&E stain of the 2nd colonoscopy biopsies with ulcerated mucosa demonstrating active colitis with surface ulcer, cryptitis, crypt abscesses, and decreased goblet cells in the crypts. E) Demonstrates the normal endoscopic findings 12 months after the last infusion of Rituximab. F) Shows the most recent colon biopsies with H&E stain with unremarkable colonic mucosa with no ulcer, inflammation, or increased intraepithelial lymphocytes.

Figure 2:

A) Demonstrates there are no CD20 positive B cells in the mucosa of the first colonoscopy biopsy. B) CD68 immunostain shows macrophages in the lamina propria from the first colonoscopy biopsy. C) Despite numerous inflammatory cells in the lamina propria, no CD20 positive B cells are present on 2nd colonoscopy biopsy. D) Less inflamed colonic mucosa harbors CD68 positive macrophages in the lamina propria. The intensity of the staining is similar to prior biopsy from first colonoscopy. E) CD20 immunostain shows B-Lymphocytes in the lamina propria. F) CD68 immunostain shows macrophages in the lamina propria. The intensity of the staining is similar to prior biopsies.

Figure 3:

This graph displays the percent number of B-cells present in the peripheral blood over the span of 2 years of treatment with Rituximab. Initially, prior to the first infusion of Rituximab the B- cells were present and shortly after the first infusion of Rituximab drop to zero. Then by April in 2014, 9 months after the last infusion of Rituximab, the B-cells return.