title: PD-1 inhibitor gastroenterocolitis: case series and appraisal of 'immunomodulatory gastroenterocolitis'.
abstract: OBJECTIVE
  PD-1 inhibitors facilitate immune response against certain tumour types, including melanoma. These drugs have led to prolonged survival but can also result in autoimmune-type side effects, including gastrointestinal inflammation. The histopathological effects of this medication class have not been well studied.
  
  
  RESULTS
  We identified 37 gastrointestinal tract biopsies from 20 patients taking a PD-1 or PD-L1 inhibitor and evaluated clinicopathological findings. Diarrhoea was the most common symptom, and endoscopic findings ranged from mild erythema to erosion/ulceration. Common histological findings included lamina propria expansion, villous blunting (if applicable), intra-epithelial neutrophils and increased crypt/gland apoptosis, although intra-epithelial lymphocytes were rarely prominent. A few cases showed crypt rupture with resultant histiocytic/granulomatous response. Most patients responded to drug cessation and/or steroids, but follow-up endoscopies were not performed.
  
  
  CONCLUSIONS
  PD-1/PD-L1 inhibitors can cause gastritis, enteritis and colitis, similar to other immunomodulatory antibodies (such as CTLA-4 inhibitors and PI3Kδ inhibitors), but the histological findings vary somewhat among drug classes. Clinical history, lack of prominent intra-epithelial lymphocytes and crypt rupture may help to distinguish PD-1 inhibitor gastroenterocolitis from mimics, which include other medication effect, inflammatory bowel disease, graft-versus-host disease, cytomegalovirus infection and autoimmune enteropathy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Raul S
authors.identifier: http://orcid.org/0000-0001-5526-4220
authors.initials: RS
authors.lastname: Gonzalez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Safia N
authors.initials: SN
authors.lastname: Salaria
authors.affiliation: Immunology and Pathogenesis Branch, Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA.
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: Bohannon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Huber
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Feely
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Shi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000009:adverse effects*; D004760:Enterocolitis / Q000139:chemically induced* / Q000473:pathology*; D005260:Female; D005756:Gastritis / Q000139:chemically induced* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
keywords: colitis; gastroenteritis; gastrointestinal tract; immunotherapy; programmed cell death protein 1