L Marthey1, C Mateus2, C Mussini3, M Nachury4, S Nancey5, F Grange6, C Zallot7, L Peyrin-Biroulet7, J F Rahier8, M Bourdier de Beauregard9, L Mortier10, C Coutzac11, E Soularue12, E Lanoy13, N Kapel14, D Planchard15, N Chaput16, C Robert2, F Carbonnel17. 1. Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France Department of Gastroenterology, Antoine Béclère Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Clamart, France. 2. Dermatology Unit, Department of Medical Oncology, Gustave Roussy, Paris Sud University, Villejuif, F-94805, France. 3. Department of Pathology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France. 4. Department of Gastroenterology, Claude Huriez Hospital, Lille, France. 5. Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, Pierre-Benite, France. 6. Department of Dermatology, Robert Debré Hospital, Reims, France. 7. Department of Gastroenterology, Nancy Hospital, Inserm U954, Lorraine University, Vandoeuvre Les Nancy, France. 8. Department of Hepato-Gastroenterology, CHU Dinant Godinne UCL Namur, Yvoir, Belgium. 9. Department of Gastroenterology, Jean Minjoz Hospital, Besançon, France. 10. Department of Dermatology, Claude Huriez Hospital, Lille, France. 11. Laboratoire d'Immunomonitoring en Oncologie, Gustave Roussy, Villejuif, F-94805, France. 12. Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France. 13. Biostatistics and Epidemiology Unit, Gustave-Roussy, Villejuif, France Inserm Unit U1018, CESP, Paris Sud University, Paris-Saclay University, Villejuif, France. 14. Department of Functional Coprology, Pitié Salpêtrière Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris, France. 15. Pneumology Unit, Department of Medical Oncology, Gustave Roussy, Villejuif, F-94805, France. 16. Laboratoire d'Immunomonitoring en Oncologie, Gustave Roussy, Villejuif, F-94805, France CNRS, UMS 3655, Villejuif, F-94805, France INSERM, US23, Villejuif, F-94805, France. 17. Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France fcarbonnel7@gmail.com.
Abstract
BACKGROUND: Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim of this study was to provide a detailed description of this entity. METHODS: We included patients with endoscopic signs of inflammation after anti-CTLA-4 infusions for cancer treatment. Other causes of enterocolitis were excluded. Clinical, biological and endoscopic data were recorded. A single pathologist reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients with and without enterocolitis after ipilimumab-treated melanoma were compared, to identify clinical factors associated with enterocolitis. RESULTS: Thirty-nine patients with anti-CTLA-4 enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003). CONCLUSIONS: Ipilimumab and tremelimumab may induce a severe and extensive form of inflammatory bowel disease. Rapid escalation to infliximab should be advocated in patients who do not respond to steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.
BACKGROUND: Therapeutic monoclonal anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies are associated with immune-mediated enterocolitis. The aim of this study was to provide a detailed description of this entity. METHODS: We included patients with endoscopic signs of inflammation after anti-CTLA-4 infusions for cancer treatment. Other causes of enterocolitis were excluded. Clinical, biological and endoscopic data were recorded. A single pathologist reviewed endoscopic biopsies and colectomy specimens from 27 patients. Patients with and without enterocolitis after ipilimumab-treated melanoma were compared, to identify clinical factors associated with enterocolitis. RESULTS: Thirty-nine patients with anti-CTLA-4enterocolitis were included (ipilimumab n = 37; tremelimumab n = 2). The most frequent symptom was diarrhoea. Ten patients had extra-intestinal manifestations. Most colonoscopies showed ulcerations involving the rectum and sigmoid, 66% of patients had extensive colitis, 55% had patchy distribution and 20% had ileal inflammation. Endoscopic colonic biopsies showed acute colitis in most patients, while half of the patients had chronic duodenitis. Thirty-five patients received steroids that led to complete clinical remission in 13 patients (37%). Twelve patients required infliximab, of whom 10 (83%) responded. Six patients underwent colectomy (perforation n = 5; toxic megacolon n = 1); one of them died postoperatively. Four patients had a persistent enterocolitis at follow-up colonoscopy. Patients with enterocolitis were more frequently prescribed NSAIDs compared with patients without enterocolitis (31 vs 5%, p = 0.003). CONCLUSIONS:Ipilimumab and tremelimumab may induce a severe and extensive form of inflammatory bowel disease. Rapid escalation to infliximab should be advocated in patients who do not respond to steroids. Patients treated with anti-CTLA-4 should be advised to avoid NSAIDs.
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