title: Cancer Immunotherapy with Anti-CTLA-4 Monoclonal Antibodies Induces an Inflammatory Bowel Disease.
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.
authors.affiliation: 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.
authors.forename: L
authors.initials: L
authors.lastname: Marthey
authors.affiliation: Dermatology Unit, Department of Medical Oncology, Gustave Roussy, Paris Sud University, Villejuif, F-94805, France.
authors.forename: C
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Department of Pathology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France.
authors.forename: C
authors.initials: C
authors.lastname: Mussini
authors.affiliation: Department of Gastroenterology, Claude Huriez Hospital, Lille, France.
authors.forename: M
authors.initials: M
authors.lastname: Nachury
authors.affiliation: Department of Gastroenterology, Lyon Sud Hospital, Hospices Civils de Lyon, Pierre-Benite, France.
authors.forename: S
authors.initials: S
authors.lastname: Nancey
authors.affiliation: Department of Dermatology, Robert Debré Hospital, Reims, France.
authors.forename: F
authors.initials: F
authors.lastname: Grange
authors.affiliation: Department of Gastroenterology, Nancy Hospital, Inserm U954, Lorraine University, Vandoeuvre Les Nancy, France.
authors.forename: C
authors.initials: C
authors.lastname: Zallot
authors.affiliation: Department of Gastroenterology, Nancy Hospital, Inserm U954, Lorraine University, Vandoeuvre Les Nancy, France.
authors.forename: L
authors.initials: L
authors.lastname: Peyrin-Biroulet
authors.affiliation: Department of Hepato-Gastroenterology, CHU Dinant Godinne UCL Namur, Yvoir, Belgium.
authors.forename: J F
authors.initials: JF
authors.lastname: Rahier
authors.affiliation: Department of Gastroenterology, Jean Minjoz Hospital, Besançon, France.
authors.forename: M
authors.initials: M
authors.lastname: Bourdier de Beauregard
authors.affiliation: Department of Dermatology, Claude Huriez Hospital, Lille, France.
authors.forename: L
authors.initials: L
authors.lastname: Mortier
authors.affiliation: Laboratoire d'Immunomonitoring en Oncologie, Gustave Roussy, Villejuif, F-94805, France.
authors.forename: C
authors.initials: C
authors.lastname: Coutzac
authors.affiliation: Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France.
authors.forename: E
authors.initials: E
authors.lastname: Soularue
authors.affiliation: Biostatistics and Epidemiology Unit, Gustave-Roussy, Villejuif, France Inserm Unit U1018, CESP, Paris Sud University, Paris-Saclay University, Villejuif, France.
authors.forename: E
authors.initials: E
authors.lastname: Lanoy
authors.affiliation: Department of Functional Coprology, Pitié Salpêtrière Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Kapel
authors.affiliation: Pneumology Unit, Department of Medical Oncology, Gustave Roussy, Villejuif, F-94805, France.
authors.forename: D
authors.initials: D
authors.lastname: Planchard
authors.affiliation: Laboratoire d'Immunomonitoring en Oncologie, Gustave Roussy, Villejuif, F-94805, France CNRS, UMS 3655, Villejuif, F-94805, France INSERM, US23, Villejuif, F-94805, France.
authors.forename: N
authors.initials: N
authors.lastname: Chaput
authors.affiliation: Dermatology Unit, Department of Medical Oncology, Gustave Roussy, Paris Sud University, Villejuif, F-94805, France.
authors.forename: C
authors.initials: C
authors.lastname: Robert
authors.affiliation: Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Paris Sud University, Le Kremlin Bicêtre, France fcarbonnel7@gmail.com.
authors.forename: F
authors.initials: F
authors.lastname: Carbonnel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000276:immunology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen / Q000276:immunology*; D003082:Colectomy; D003106:Colon / Q000473:pathology; D004760:Enterocolitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; C520704:tremelimumab
keywords: Anti-CTLA-4; enterocolitis; ipilimumab