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

Arnouk, Joud; Mathew, Don; Nulton, Ethan; Rachakonda, Vikrant

doi:10.14309/crj.0000000000000158

Cited by 13 publications

(16 citation statements)

References 12 publications

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“…Ultimately, the patient's symptoms resolved with glucocorticoids administered for postural hypotension management. 17 The responsiveness of ICI-CeD to GFD alone in five out of the eight cases (62%) indicates that gluten is an important antigen driving ICI-CeD, similar to standard CeD, despite the noted phenotypic differences in the immune infiltrate. Intriguingly, the similarities between ICI-CeD and ICI-Duo suggest that duodenitis may result from as of yet unidentified dietary triggers.…”

Section: Open Accessmentioning

confidence: 92%

“…Another group reported the development of ICI-CeD in a patient who received pembrolizumab for locally recurrent melanoma. 17 The patient developed symptoms within a week of the first infusion of pembrolizumab, and ICI-CeD was confirmed by histology and serum tTG-IgA. ICI therapy was discontinued due to persistence of symptoms, as the patient was unable to adhere to a GFD.…”

Section: Open Accessmentioning

confidence: 93%

“…[14][15][16] Interestingly, rare cases of patients with de novo elevation of serum tTG antibodies in the setting of treatment with ICIs have been reported. [17][18][19] The nature of the relationship between serum tTG antibodies and ICI-Duo is currently unclear, but it has been hypothesized to reflect treatment-emergent CeD. 17 20 Whether ICI-associated celiac disease (ICI-CeD) reflects new onset gluten sensitivity or is the first manifestation of previously asymptomatic CeD remains an open question.…”

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitor-associated celiac disease

Badran

Shih

Leet

et al. 2020

J Immunother Cancer

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BackgroundRare 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.MethodsA 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.ResultsThe 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.ConclusionsICI-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.

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Section: Open Accessmentioning

confidence: 92%

Section: Open Accessmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitor-associated celiac disease

Badran

Shih

Leet

et al. 2020

J Immunother Cancer

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“…Arnouck et al (12) presented a case of a new-onset CeD after exposure to pembrolizumab. This 79-year-old melanoma patient developed loss of appetite and episodic diarrhea and a malabsorption.…”

Section: Discussionmentioning

confidence: 99%

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report

et al. 2021

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Immune checkpoint inhibitors (ICI) reinvigorate the immune system to recognize and destroy tumor cells. Because of this biological mechanism, patients might develop autoimmune toxicities, notably in the digestive tract (most frequently, hepatitis or colitis). A 70-year-old man with relapsed mesothelioma was treated with nivolumab in 3rd line. He was hospitalized for watery and foul-smelling diarrhea. He underwent gastrointestinal endoscopy, showing duodenitis and villous atrophy and measurement of serum IgA antibodies to tissue transglutaminase (tTG-IgA+), leading to the diagnosis of ICI-induced celiac disease. He was treated with steroids, proton pump inhibitors, and a gluten-free diet. If ICI-induced celiac disease is rare in the literature, increasing reports suggest that celiac disease might represent an underestimated ICI toxicity. This case highlights the necessity of complementary investigation (including tTG-IgA and endoscopic biopsies) in patients with atypical digestive symptoms during immunotherapy.

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“…These data are summarized in Table 1. Regarding CD patients, a genetic evaluation for DQ2 and DQ8 was reported only in one case [50], EMA was tested in two cases [50,57], TTGA IgA class in ten cases [33,50,53,55,56], and TTGA of IgG class in one case [57] (Table 1). ICIs-CD: celiac disease arising during therapy with immune checkpoint inhibitors; NR: not reported; TTGA: tansglutaminase antibodies; EMA: antiendomysial antibodies; IELs: intraepithelial lymphocytes/100 enterocytes; CD: celiac disease; GI: gastrointestinal; GFD: gluten-free diet.…”

Section: Resultsmentioning

confidence: 99%

Histological Features of Celiac-Disease-like Conditions Related to Immune Checkpoint Inhibitors Therapy: A Signal to Keep in Mind for Pathologists

et al. 2022

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Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, are finding increasing application in the treatment of malignant neoplasms. The widespread clinical use of these drugs, however, resulted in the discovery of side effects. The occurrence of celiac disease (CD) after ICIs therapy has been reported in the literature, but its incidence remains unknown and the role of ICIs in its onset is not yet clear. In this review, we examine the published data on this topic in order to better understand and define this entity from a histological point of view. We performed an electronic literature search to identify original reports in which CD or pathological CD-like conditions were documented histologically in patients treated with ICIs. We identified ten papers. A total of twenty-five patients were included in these publications, eleven of them receiving a serologic and histological diagnosis of CD, and four a histological diagnosis of CD-like conditions, in which pathogenesis appears to be multifactorial. ICIs can cause a CD-like enteropathy and biopsies with clinical integration are crucial to diagnose this condition. CD rarely has been observed during treatment with ICIs and its morphological aspects are similar to ICIs-CD enteropathy. Moreover, the onset of ICIs-CD may have a distinct immune mechanism compared to classical CD. Thus, the pathologists must make a histological diagnosis of CD with caution and only in adequate clinical and serological context.

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

Cited by 13 publications

References 12 publications

Immune checkpoint inhibitor-associated celiac disease

Immune checkpoint inhibitor-associated celiac disease

Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report

Histological Features of Celiac-Disease-like Conditions Related to Immune Checkpoint Inhibitors Therapy: A Signal to Keep in Mind for Pathologists

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