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Ulcerative colitis following B lymphocyte depletion with rituximab in a patient with Graves’ disease
  1. Daniel El Fassi1,
  2. Claus H Nielsen2,
  3. Jens Kjeldsen3,
  4. Ole Clemmensen4,
  5. Laszlo Hegedüs1
  1. 1 Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark
  2. 2 Department of Clinical Immunology Sect. 7631, Rigshospitalet National University Hospital, Copenhagen, Denmark
  3. 3 Department of Gastroenterology, Odense University Hospital, Odense, Denmark
  4. 4 Department of Clinical Pathology, Odense University Hospital, Odense, Denmark
  1. Dr Daniel El Fassi, Department of Endocrinology and Metabolism, Odense University Hospital, 5000 Odense, Denmark; Fassi{at}dadlnet.dk

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The possible adverse consequences of biological therapies in inflammatory bowel diseases (IBDs) were recently highlighted in this journal by D’Haens (Gut 2007;56:725–32). We here describe a hitherto unappreciated adverse effect to treatment with the B lymphocyte (B cell) depleting agent rituximab (RTX),1 namely the occurrence of ulcerative colitis and arthritis shortly after treatment with RTX. Our patient, a 45-year-old Caucasian female, had had mild irritable bowel symptoms since 1992 at which time rigid sigmoidoscopy and bowel x ray were normal. She had never received any therapy, had never previously had joint pain, and was not predisposed to IBD.

In April 2005 she was diagnosed with Graves’ disease, and after uncomplicated standard methimazole therapy she received four weekly doses of 375 mg/m2 RTX from day 1 to 22 as part of a clinical trial.2 The trial was approved by the local ethics committee and recorded on www.clinicaltrials.gov.

After the second RTX infusion the patient developed bloody and slimy diarrhoea (up to 20 stools/day). At day 39, non-infectious febrile episodes with temperatures up to 39°C, and joint pain ensued. She was started on oral mesalazine on day 54, and at day 69 the diagnosis of ulcerative colitis was confirmed by sigmoidoscopy (fig 1), after which prednisolone enemas were given for 14 days (37.5 mg/day). For her joint pain she received the maximal recommended daily doses of paracetamol, ibuprofen and tramadol. From day 65 to 90 she received oral prednisolone, which, in doses of 20 mg or more daily, relieved the joint pain. Blood tests are shown in table 1.

Figure 1 Colonic biopsies taken 67 days after initiation of rituximab therapy. Panel A shows mucosa with inflammation, irregular crypts, and crypt abscesses. No granulomas were seen (haematoxylin and eosin). Panel B demonstrates the absence of B lymphocytes (stained for CD20). Panel C shows the persistence of plasma cells (stained for CD79a). Panel D shows T lymphocytes (stained for CD3). Antibodies were purchased from DAKO, Glostrup, Denmark. All images are magnified ×100.
Table 1 Inflammatory parameters, haematology and overall antibody levels after rituximab therapy*

The patient had no IgM rheumafactors or any autoantibodies associated with rheumatic disease. However, plasmocytic anti-neutrophil cytoplasmatic antibodies, associated with ulcerative colitis, emerged during follow-up. The patient is HLA-B27 negative, and bone scintigraphy showed no signs of inflammation.

Notably, B cells were completely absent from the colon at the first biopsy (day 69) (fig 1B), but had reappeared 3 months later; months before the return of circulating B cells (data not shown). Presently (day 650), on oral mesalazine, the patient has no activity in her ulcerative colitis, while she still has joint pain.

Previous, reports describe only two patients with manifest ulcerative colitis or Crohn’s disease treated with RTX. Both of these patients suffered worsening of bowel symptoms.3 ,4 This contrasts with the amelioration of other autoimmune diseases seen after RTX therapy.5

Antigen presentation by B cells is known to be detrimental in the pathogenesis of diseases such as Graves’ disease, systemic lupus erythematosus (SLE), and diabetes (reviewed by Nielsen et al5), but may be beneficial in IBD.6

B cells per se secrete regulatory cytokines including interleukin (IL)-10, which may protect against development of colitis.7 In accordance, Goetz et al3 found ample IL-10 production by colonic lymphocytes from non-RTX-treated ulcerative colitis patients, whereas lymphocytes from their RTX-treated patient did not produce IL-10.

Apart from IL-10, B cells from the gut-associated lymphoid tissue also produce or promote the production of IL-4 and transforming growth factor beta,8 which offers protection against autoimmune disease in mice.

By virtue of antigen presentation and the production of cytokines, B cells modulate the function of other cell types, including T cells.9 Thus, the number of mucosal T cells with regulatory functions increased after adoptive transfer of B cells.9 By contrast, B cells may inhibit regulatory T cells (Tregs) at extra-mucosal sites, since RTX therapy enhances Treg function in patients with SLE (reviewed by Nielsen et al5).

As the limited evidence available suggests that RTX may cause or aggravate manifest ulcerative colitis, we advocate that RTX is used with caution in patients with bowel symptoms.

REFERENCES

Footnotes

  • Competing interests: DEF, CHN and LH have conducted a trial on the use of rituximab in Graves’ disease which received funding support from Roche Denmark A/S. CHN has received lecture fees from Roche Denmark A/S. JK and OC have nothing to declare.

  • Funding: The Agnes and Knut Mørk Foundation, The Danish Thyroid League, The Novo Nordisk Foundation, and Roche Denmark A/S provided grant support. DEF is the recipient of a research fellowship from the Institute of Clinical Research at The University of Southern Denmark. The funding sources have had no influence on the design of the study; on collection, analysis or interpretation of the data; in the writing of the report; nor on the decision to submit the paper for publication.

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