Select biomarkers for celiac disease are sensitive and responsive to gluten exposure, and interleukin (IL)-2 levels were found to be the earliest and most sensitive biomarker of acute gluten exposure, according to study data published in Gastroenterology. “After gluten challenge, IL-2 increases rapidly in patients with [celiac disease] but not in healthy controls. The increase is associated with symptom severity,” the investigators said.

The researchers of the randomized, double-blind gluten challenge trial (ClinicalTrials.gov Identifier: NCT03409796)  evaluated multiple biomarkers in an effort to identify predictors of celiac disease activity induced by 2 gluten doses and uncover biomarkers that could supplement or replace histology.

The study, conducted across 2 US centers, was designed to enroll as many as 20 patients, with plans for interim analysis after 12 patients completed a gluten challenge. Cessation was pursued if a statistically significant change was observed from baseline in villous height:crypt depth ratio (Vh:Cd).

Study end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with human leukocyte antigen (HLA)-DQ2-gluten tetramers and enzyme-linked immune absorbent spot (ELISpot), gut-homing CD8 T cells, IL-2, symptoms, video capsule endoscopy (VCE), intraepithelial leukocytes (IELs), and tissue multiplex immunofluorescence. Blood biomarkers were measured 4 hours after the first dose (cytokines only) and at days 6 and 15. The study authors repeated endoscopic duodenal biopsy, VCE, and blood collection after gluten challenge on day 15.


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The study enrolled 14 adults (mean age 43.7; 11 female; 14 White) with biopsy-proven celiac disease determined to be in clinical and histological remission. Patients must have been on a gluten-free diet for at least 1 year.

The investigators randomly assigned the patients to receive 3 g (low-gluten) or 10 g gluten (high-gluten) per day for 14 days. The investigators found that all assessments demonstrated changes with the gluten challenge, although the time to maximal change, change magnitude, and gluten dose-response relationship varied.

Vh:Cd, VCE enteropathy score, ELISpot, gut-homing CD8 T cells, IEL counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten, and the symptoms were significant at 3 g. At both doses, symptoms and plasma IL-2 levels increased significantly or near significantly, and IL-2 appeared to be the earliest, most sensitive marker of acute gluten exposure.

“Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion,” the study authors stated, adding that the findings provide “a preliminary framework for rational design of gluten challenge for [celiac disease] research.”

A major limitation to the research was the small sample size, which was partially due to the primary end point being met at interim analysis. The study population was also demographically homogeneous and had a significant amount of intestinal damage before gluten challenge. Confirmation of the study results in other populations, including patients with “better treated” celiac disease, is necessary, according to the investigators.

“This study provides a comprehensive assessment of celiac disease biomarkers and performance in gluten challenge across 2 commonly utilized gluten doses, and underscores the challenges of diagnosing celiac disease and monitoring therapy,” the researchers concluded. “Selected celiac disease biomarkers are sensitive and responsive to gluten exposure, providing the potential for less-invasive, lower-dose, and shorter-duration gluten ingestion.”

Disclosures: This research was funded by Takeda Pharmaceutical Company Ltd. Some of the study authors reported affiliations with the pharmaceutical industry. Please see the original reference for a full list of the authors’ disclosures.

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Reference

Leonard MM, Silvester JA, Leffler D, et al. Evaluating responses to gluten challenge: a randomized, double-blind, 2-dose gluten challenge trial. Gastroenterology. Published online October 29, 2020. doi: 10.1053/j.gastro.2020.10.040