Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists.
OBJECTIVE
To investigate whether drugs others than mycophenolic acid and ipilimumab might cause graft-versus-host-like apoptotic enteropathy, the clinicopathological findings in four patients were examined who had developed watery diarrhoea and apoptotic enteropathy (three cases from colon and one case from ileal pouch) after intake of antimetabolites (methotrexate and capecitabine) and/or tumour necrosis factor-α inhibitors (etanercept and infliximab).


METHODS
The clinical charts, endoscopy reports and intestinal biopsies from all endoscopies were reviewed for all patients. Biopsies were evaluated semiquantitatively for apoptosis of basal crypts, dilated damaged crypts, defined as cystically dilated crypts with flattened degenerated epithelium containing apoptotic debris and few neutrophils, and mucosal architecture. Further, the presence of intraepithelial lymphocytes, chronic inflammatory cells in the lamina propria and mucosal ulcerations was recorded and immunohistochemical analysis for human cytomegalovirus and herpes simplex virus was performed.


RESULTS
Endoscopic examination revealed normal mucosa in two patients, whereas the other two showed focal ulcerations. Histological changes included increased apoptosis of basal crypts, the presence of dilated damaged crypts and architecture distortion. In all cases, a temporal association between drug intake and/or dose increase, and onset of diarrhoea, was observed, and no convincing evidence of other potentially underlying causes of colitis/enteritis was found, including infections.


CONCLUSIONS
Pathologists should be aware of the expanding spectrum of drugs that can cause apoptotic enteropathy, including antimetabolites and tumour necrosis factor-α inhibitors.
Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
Davide
D
Soldini
Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
Ariana
A
Gaspert
Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland Institute of Pathology, University Hospital and University of Berne, Berne, Switzerland.
Matteo
M
Montani
Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
Tanja
T
Reineke
Division of Gastroenterology and Hepatology, Zurich Center for Integrative Human Physiology, University Hospital and University of Zurich, Zurich, Switzerland.
Gerhard
G
Rogler
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Robert
R
Odze
Institute for Surgical Pathology, University Hospital and University of Zurich, Zurich, Switzerland.
Achim
A
Weber
D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D000069287:Capecitabine; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D003108:Colonic Diseases / Q000139:chemically induced* / Q000473:pathology; D039021:Colonic Pouches / Q000473:pathology; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives; D003967:Diarrhea / Q000139:chemically induced; D016099:Endoscopy, Gastrointestinal; D000068800:Etanercept; D005472:Fluorouracil / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects; D007150:Immunohistochemistry; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000473:pathology; D008727:Methotrexate / Q000009:adverse effects; D018124:Receptors, Tumor Necrosis Factor; D012307:Risk Factors; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069287:Capecitabine; D000069285:Infliximab; D000068800:Etanercept; D005472:Fluorouracil; D008727:Methotrexate
Apoptosis; Diagnostics; Gastroenterology