Immune checkpoint inhibitor-associated celiac disease

Yousef Badran

Angela Shih

Donna Leet

Meghan Mooradian

Jennifer Borowsky+3 authors

^{Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA,}

^{Harvard Medical School, Boston, MA, USA,}

^{Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA,}

^{Division of Oncology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA,}

^{Department of Medicine, Columbia University, New York, New York, USA,}

^{Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA,}

^{Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA,}

^{Corresponding author.}

^{Contributed equally.}

^{Dr Michael Dougan;}gro.srentrap@naguodlm

Accepted 2020 May 23.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.

Abstract

Background

Rare cases of immune checkpoint inhibitor (ICI)-associated celiac disease (ICI-CeD) have been reported, suggesting that disruption of tolerance mechanisms by ICIs can unmask celiac disease (CeD). This study aims to characterize the clinicopathological and immunophenotypic features of ICI-CeD in comparison to ICI-associated duodenitis (ICI-Duo) and usual CeD.

Methods

A medical and pathological records search between 2015 and 2019 identified eight cases of ICI-CeD, confirmed by tTG-IgA. Nine cases of ICI-Duo, 28 cases of moderate CeD, as well as 5 normal controls were used as comparison groups. Clinical information was collected from the electronic medical records. Immunohistochemistry for CD3, CD8, T-cell receptor gamma/delta (γδ), programmed death ligand 1 (PD-L1), and programmed death 1 (PD-1) were performed, with quantification of intraepithelial lymphocyte (IEL) subsets in three well-oriented villi. CD68, PD-L1, and PD-1 were assessed as a percentage of lamina propria surface area infiltrated by positive cells. Statistical significance was calculated by the Student’s t-test and Fisher’s exact test.

Results

The eight patients with ICI-CeD (F:M=1:3) and nine patients with ICI-Duo (F:M=5:4) presented similarly with diarrhea (13/17) and abdominal pain (11/17) after a median of 1.6 months on ICI therapy. In patients with ICI-CeD, tTG-IgA ranged from 104 to >300 IU/mL. Histological findings in ICI-CeD and ICI-Duo were similar and included expansion of the lamina propria, active neutrophilic duodenitis, variably increased IELs, and villous blunting. Immunohistochemistry showed that the average number of IELs per 100 enterocytes is comparable between ICI-CeD and ICI-Duo, with increased CD3^CD8^{T cells compared with normal duodenum but decreased γδ T cells compared with CeD. Average PD-L1 percentage was 9% in ICI-CeD and 18% in ICI-Duo, in comparison to <1% in CeD and normal duodenum; average PD-1 percentage was very low to absent in all cases (<3%). On follow-up, five patients with ICI-CeD improved on a gluten-free diet (GFD) as the sole therapeutic intervention (with down-trending tTG-IgA) while the other three required immunosuppression. All patients who developed ICI-Duo received immunosuppression with variable improvement in symptoms.}

Conclusions

ICI-CeD resembles ICI-Duo clinically and histologically but shares the serological features and response to gluten withdrawal with classic CeD. Immunophenotyping of IELs in ICI-CeD and ICI-Duo also shows similar CD3, CD8, γδ T cell subsets, and PD-L1 populations, all of which differed quantitatively from usual CeD. We conclude that ICI-CeD is biologically similar to ICI-Duo and is likely a variant of ICI-Duo, but treatment strategies differ, with ICI-CeD often improving with GFD alone, whereas ICI-Duo requires systemic immunosuppression.

Keywords: costimulatory and inhibitory T-cell receptors, immunotherapy, inflammation

Background

Methods

Results

Conclusions

Footnotes

Twitter: @YRBadran

YRB and AS contributed equally.

MM-K and MD contributed equally.

Correction notice: Since the online publication of this article, the authors have noticed that the middle initial for author Yousef R Badran was missing. This has been corrected.

Contributors: YB, AS, DL, AC and MM-K compiled and reviewed all of the data. MJM assessed and confirmed the accuracy of the details relating to the patients’ oncological history and treatment. AS and MM-K performed the histopathological and immunohistochemical analysis of the patients’ samples. AS, JC, MK, JB, JM, and MM-K collected patient samples and identified the appropriate immunohistochemical panel. MD assessed and confirmed the accuracy of the patients’ gastroenterological history, treatment, and endoscopy results. YB, AS, and MD wrote the manuscript with contributions from all of the authors.

Funding: Funding was provided by National Institutes of Health Mentored Clinical Scientist Development Award 1K08DK114563-01 and the American Gastroenterological Association Research Scholars Award (MD).

Competing interests: MD is a consultant for Genentech-Roche, Tillotts Pharma, and Partner Therapeutics. He received research funding from Novartis. He is on the scientific advisory board for Neoleukin Therapeutics.

Patient consent for publication: Not required.

Ethics approval: This retrospective analysis was approved by the Partners Human Research Committee and the Institutional Review Board of the Massachusetts General Hospital (MGH).

Provenance and peer review: Not commissioned; externally peer reviewed.

Data availability statement: Data sharing not applicable as no datasets generated and/or analyzed for this study.

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