Introduction
The immune regulatory proteins, such as cytotoxic T lymphocyte antigen (CTLA)-4 as well as programmed death (PD)−1 and its ligand PD-L1 are important immune regulatory proteins collectively referred to as immune checkpoint receptors. These pathways can be used by malignant tumors as a mechanism to avert antitumoral immune responses.
Immune checkpoint inhibitors (ICIs) target these immune checkpoint receptors. ICIs have demonstrated impressive clinical activity and are now approved for the treatment of diverse malignant neoplasms. However, inhibition of these regulatory receptors leads to loss of tolerance and a wide spectrum of inflammatory toxicities known as immune-related adverse events (ir-AEs). Colitis or enterocolitis are the most frequent GI irAEs, affecting 15%–20% of patients who undergo endoscopic evaluation. When severe, irAEs can necessitate ICI therapy interruption, discontinuation, and treatment escalation with powerful immunosuppressive agents.
Isolated ICI-associated duodenitis has been reported after treatment with different immunotherapies.
Interestingly, de novo celiac disease (CeD) specific antibodies (serum tTG antibodies) with
histological features consistent with CeD in the setting of treatment with ICIs have been reported.
Aims & Methods
A literature search in Pubmed and Scopus to identify original reports in which CeD was documented histologically in patients treated with ICIs. Clinical, endoscopic and histopathological and immunological background were reviewed.
Results
Eleven papers were identified, all case reports or case series. A total of 26 pts were described. Twelve patients had a serologic and histological diagnosis of CeD.
CeD has been rarely observed during treatment with ICIs and is morphologically similar to ICI-CeD
enteropathy. Endoscopically, duodenal congestion, nodularity, or erythema were seen in 67% of patients with ICI-duodenitis, compared with 33% of patients with ICI-CeD. Few patients had concomitant upper and lower GI tract mucosal inflammatory changes.
Correlation with medication history, the finding of typical histologic changes, and re-evaluation of pathologic changes after checkpoint receptor inhibitor therapy will help confirm if an injury is likely to be an irAE.
Patients with ICI-CeD were reported to improve on a gluten free diet (GFD) as the single therapy, while some patients required the addition of immunosuppression with variable improvement in symptoms.
Conclusion
Whether ICI-associated celiac disease (ICI-CeD) reflects new onset gluten sensitivity or unmasking of previously asymptomatic CeD remains to be answered.
There is some evidence that ICI-CeD is biologically similar to ICI-duodenitis, but treatment strategies differ. ICI-CeD often improves with GFD alone, whereas ICI-duodenitis may require systemic immunosuppression.
In patients with atypical digestive symptoms in the context of ICI treatment, there is a necessity of complementary/additional investigation. Celiac disease specific antibodies (tTG-IgA assay) and duodenal biopsy are required. In the case of morphological lesions resembling CeD, serological and genetic testing should be performed for differentiating true CeD from ICI-drug-induced villous atrophy.
It might be useful to check for CeD before scheduled ICI therapy in patients with known high susceptibility to CeD, such as a family history of CeD, dermatitis herpetiformis, or chronic unexplained bowel symptoms.
