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Apoptotic enteropathy caused by antimetabolites and TNF-α antagonists.

Journal of clinical pathology (2014-04-12)
Davide Soldini, Ariana Gaspert, Matteo Montani, Tanja Reineke, Gerhard Rogler, Robert Odze, Achim Weber
ABSTRACT

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). 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. 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. Pathologists should be aware of the expanding spectrum of drugs that can cause apoptotic enteropathy, including antimetabolites and tumour necrosis factor-α inhibitors.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Capecitabine, ≥98% (HPLC)
Methotrexate for system suitability, European Pharmacopoeia (EP) Reference Standard
Capecitabine, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Methotrexate hydrate, ≥99.0% (sum of enantiomers, HPLC)
Sigma-Aldrich
Methotrexate, meets USP testing specifications
Sigma-Aldrich
Methotrexate hydrate, ≥98% (HPLC), powder
Sigma-Aldrich
Methotrexate hydrate, powder, BioReagent, suitable for cell culture, ≥98% (HPLC)
Methotrexate for peak identification, European Pharmacopoeia (EP) Reference Standard
Methotrexate, European Pharmacopoeia (EP) Reference Standard
Supelco
Methotrexate solution, 1.0 mg/mL in methanol with 0.1N NaOH, ampule of 1 mL, certified reference material, Cerilliant®
Supelco
Methotrexate, Pharmaceutical Secondary Standard; Certified Reference Material
SAFC
Methotrexate