Research Article: A Celiac Disease Phenotype After Checkpoint Inhibitor Exposure: An Example of Immune Dysregulation After Immunotherapy

Date Published: August 08, 2019

Publisher: Wolters Kluwer

Author(s): Joud Arnouk, Don Mathew, Ethan Nulton, Vikrant Rachakonda.


Celiac disease is characterized by duodenal inflammation after exposure to gluten. Checkpoint inhibitors are antibodies that inhibit the inhibitory signals of the cytotoxic T lymphocytes to enhance antitumor responses. A 79-year-old man with an unknown history of celiac disease underwent treatment with pembrolizumab for recurrent left maxillary melanoma. He subsequently developed diarrhea and weight loss. Serology was positive for anti-tissue transglutaminase immunoglobulin A. Upper endoscopy revealed duodenal villous atrophy, which was confirmed on biopsy. A gluten-free diet was not tolerated, and symptoms resolved with withdrawal of pembrolizumab and steroid administration for another medical reason.

Partial Text

Celiac disease (CD) is a malabsorptive immune-mediated disease characterized by local inflammation in the duodenum due to intolerance of a gluten-rich diet in patients with a genetic predisposition.1 Immune checkpoint inhibitors (ICPIs) have been widely used in the management of many cancers by blocking the inhibitory receptors on cytotoxic T cells, leading to immune stimulation.2 Although colitis and hepatitis are known gastrointestinal toxicities related to immunotherapy, one case has described the association between CD and ipilimumab.2,3 We present the first case of a new-onset CD after exposure to pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor.

A 79-year-old man with a history of stage IIa left maxillary superficial melanoma developed local recurrence 2 years after initial resection. The patient had an unknown history of CD. He was treated with local radiation and 200 mg of intravenous pembrolizumab every 3 weeks. One week after initiating the therapy, he developed loss of appetite and episodic, twice daily, watery, and nonbloody diarrhea. His symptoms progressed after 4 months of therapy with abnormal laboratory findings of hemoglobin 10.4 g/dL, potassium 3.1 mEq/L, albumin 2.4 g/dL, vitamin D 25-OH 16 ng/mL, and zinc 54 mcg/dL.

CD is suggested by a combination of clinical characteristics and positive serology for celiac antibodies (tissue transglutaminase [TTG] antibody IgA is 95% sensitive and 95% specific). It is confirmed with villous blunting and mucosal inflammation on biopsy.1 CD has a wide variety of intraintestinal and extraintestinal manifestations; it can also be a silent disease in many patients.1,4 CD usually responds well to the elimination of gluten from the diet.1 However, patients may respond to systemic steroids when a gluten-free diet is not tolerated or in refractory cases.1

Author contributions: J. Arnouk wrote the manuscript and is the article guarantor. D. Mathew, E. Nulton, and V. Rachakonda edited the manuscript.




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