Development of Crohn's Disease in a Patient with Multiple Sclerosis ...

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Jul 8, 2008 - Crohn's disease Multiple sclerosis Copaxone. Adverse drug effects. Abstract. Background: Copaxone (glatiramer acetate) is a synthetic.
Case Report Published online: July 8, 2008

Digestion 2008;77:198–200 DOI: 10.1159/000143156

Development of Crohn’s Disease in a Patient with Multiple Sclerosis Treated with Copaxone Gideon Charach Itamar Grosskopf Moshe Weintraub Department of Internal Medicine ‘C’, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

Key Words Crohn’s disease ⴢ Multiple sclerosis ⴢ Copaxone ⴢ Adverse drug effects

Abstract Background: Copaxone (glatiramer acetate) is a synthetic copolymer mimicking a portion of myelin basic protein, one of several putative autoantigens in multiple sclerosis (MS). Copaxone suppresses the production of tumor necrosis factor (TNF)- ␣, a key mediator of inflammation in MS as well as in other pathologies, such as colitis of interstitial bowel disease (IBD). Copaxone is a drug approved for the treatment of MS, and one that is very well tolerated with a high safety profile and relatively few side effects. Crohn’s disease has not been associated with its administration. Methods: We describe a patient with MS in remission who had not exhibited any signs of IBD in the past. She had been on Copaxone 20 mg/day treatment for 2 years when she first exhibited gastrointestinal symptoms. Results: Our patient developed Crohn’s disease while on Copaxone treatment as a consequence of long-term immunosuppression. Conclusions: Clinicians should be aware that Crohn’s disease is a potential novel adverse drug effect of Copaxone.

Patient Description A 27-year-old female was admitted because of abdominal pain, 6 weeks of bloody diarrhea, fever, and an 8-kg weight loss over 6 weeks. The patient had been diagnosed clinically and by brain magnetic resonance imaging as having multiple sclerosis (MS) after several episodes of vertigo, dizziness and falls 2 years previously. She achieved long-term remission with Copaxone 20 mg/day. On admission, the clinical examination revealed fever of 38 ° C, a right mid-abdominal tenderness, a mass measuring 8 ! 8 cm and increased peristaltic sounds. Rectal examination showed traces of blood. Laboratory results indicated iron deficiency anemia: Hb 7 g%; ESR 98 mm/h, and CRP 230 mg/l. An abdominal computerized tomogram demonstrated an enlarged loop of small intestine in the right abdomen and stenosis of the terminal ileum. Conservative treatment consisting of fluids, and a combination of intravenous ampicillin, gentamycin and metronidazole was started. The patient also received two transfusions of packed red blood cells. Colonoscopy revealed diffuse right-sided colitis and ileitis which were histologically compatible with Crohn’s disease (fig. 1). Immunologic tests for ASCA IgA was 83 (normal ! 20) units, ASCA IgG was 132 (normal ! 20) units, and pANCA was positive. Copaxone was discontinued and oral methylprednisolone (80 mg) was started. She underwent a right hemicolectomy with a partial ileectomy because of obstructive ileus and hematochezia 10 months later. The findings at the 2-year follow-up were prolonged complete remission of both Crohn’s disease and MS while she was being treated by 6-mercaptopurine 50 mg/day.

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Gideon Charach, MD Department of Internal Medicine ‘C’ Tel Aviv Sourasky Medical Center, 6 Weizman Street IL–64239 Tel Aviv (Israel) Tel. +972 3 697 3766, Fax +972 3 697 3929, E-Mail [email protected]

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Fig. 1. Biopsy of the terminal ileum showing loss of villi, crypt distortions, a fissure, transmural chronic inflammation, lymphoid aggregates, and submucosal fibrosis compatible with chronic ileitis.

Discussion

An association between MS and inflammatory bowel disease (IBD) has been described in several reports [1, 2]. Copaxone, a drug approved for the treatment of MS, is very well tolerated with a high safety profile and relatively few side effects [3]. It is a synthetic copolymer mimicking a portion of myelin basic protein, one of several putative autoantigens in MS. Copaxone suppresses the production of TNF-␣, a key mediator of inflammation in MS as well as in other pathological conditions, among them colitis of IBD [3–5]. Copaxone was shown to ameliorate experimental colitis induced by trinitrobenzene sulfonic acid, a murine model that resembles human Crohn’s disease [3]. IBD is characterized by detrimental immune reactivity in the gut and an imbalance between proinflammatory and anti-inflammatory reactivity [4]. The mechanism of the colitis suppression process was identified as being decreased lymphocyte reactivity and decreased secretion of TNF-␣, a key mediator of inflammation in MS as well as in other diseases, such as colitis of IBD [3–5] and transforming growth factor-␤ [6]. Copaxone suppressed local mesenteric lymphocyte proliferation and induced a beneficial secretion of transforming growth factor-␤ [3, 6, 7]. It demonstrated a significant reduction in macroscopic colonic damage, such as preservation of Copaxone and Crohn’s Disease

microscopic colonic structure, reduced weight loss and improved long-term survival [3, 6, 7]. Copaxone modifies the TH1 immune response in MS [3, 6, 7]. Since Crohn’s disease is also characterized by TH1 predominance, it is reasonable to consider that Copaxone inhibits the inflammation process. Indeed, Copaxone markedly alleviated macroscopic and microscopic experimental colitis in an animal model: CD4 and natural killer cell subsets markedly decreased following Copaxone treatment [5, 6]. Copaxone also led to amelioration of T-cell proliferation in in vitro studies [3, 6]. Anti-MS drugs (interferon-␤1a and Copaxone) with anti-inflammatory and anti-immune characteristics were shown to be effective in IBD treatment [7–9]. Interferon-␤1a was shown to be effective in steroid-refractory active ulcerative colitis [9]. Several reports, however, have recently appeared in the literature showing ‘paradoxical’ findings in terms of the development or aggravation of ulcerative colitis after treatment with interferons [9]. Our patient had no signs or history of IBD before the initiation of Copaxone treatment. She was in remission from MS and developed Crohn’s disease as consequence of long-term immunosuppression while on Copaxone treatment. We wish to alert clinicians to a heretofore unidentified potential adverse effect of Copaxone.

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References 1 Pokorny CS, Beran RG, Pokorny MJ: Association between ulcerative colitis and multiple sclerosis. Intern Med J 2007; 37:721–724. 2 Ramagopalan SV, Dyment DA, Valdar W, Herrera BM, Criscuoli M, Yee IM, Sadovnic AD, Ebers GC; Canadian Collaborative Study Group: Autoimmune disease in families with multiple sclerosis: a populationbased study. Lancet Neurol 2007;6:604–610. 3 Sela M, Teitelbaum D: Glatiramer acetate in the treatment of multiple sclerosis. Expert Opin Pharmacother 2001:2:1149–1165.

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4 Aharoni R, Kayhan B, Arnon R: Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acid-induced experimental colitis. Inflamm Bowel Dis 2005;11:106–115. 5 Shanahan F: IBD: immunodiagnostics, immunotherapeutics and ectotherapeutics. Gastroenterology 2001; 120:622–635. 6 Baumgart D, Carding S: Inflammatory bowel disease: cause and immunobiology. Lancet 2007;369:1627–1640. 7 Gur C, Karussis D, Golden E, Doron S, Ilan Y, Safadi R: Amelioration of experimental colitis by Copaxone is associated with class2-restricted CD4 immune blocking. Clin Immunol 2006;118:307–316.

8 Wirz S, Neurath MF: Animal models of intestinal inflammation: new insights into the molecular pathogenesis and immunotherapy of IBD. Int J Colorectal Dis 2000;15:144– 160. 9 Schott E, Paul F, Wuerfel JT, Zipp F, Rudolf B, Wiedenmann B, Baumgart DC: Development of ulcerative colitis in a patient with multiple sclerosis following treatment with interferon beta 1a. World Gastroenterol 2007;13:3638–3640.

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