A Randomized Double-Blind, Placebo-Controlled Dose-Response Study to Assess the Gluten Threshold Dose in Celiac Disease.

Abstract

Celiac disease is an immune-mediated enteropathy triggered by gluten ingestion. The effect of very small gluten exposures remains uncertain, contributing to international variations in food-labeling standards. Interleukin 2 (IL2) rises rapidly after gluten ingestion, serving as a biomarker of immune activation. We aimed to identify the lowest gluten dose that elicits a measurable IL2 response and accompanying symptoms in treated celiac disease. We conducted a randomized double-blind, placebo-controlled adaptive dose-response trial in adults with biopsy-proven celiac disease on a gluten-free diet for >2 years. Participants (n = 51; median age, 52 years; 69% were female) underwent 3 oral gluten (1-1000 mg) or placebo challenges at 4-week intervals at a tertiary clinical trials center in Brisbane, Australia. The primary outcome was a ≥2-fold rise in serum IL2 within 6 hours. Secondary outcomes were patient-reported symptoms. Eliciting dose (ED_p, ie, the dose at which p% of people respond) was estimated by interval-censored survival analysis. Fifty-one participants completed 153 challenges. Gluten induced dose-dependent IL2 elevations, with ≥2-fold increases in 83% at 1000 mg, 83% at 610 mg, 36% at 90 mg, 17% at 13 mg, 27% at 8 mg, and 17% at 3 mg; none responded to 5 mg, 2 mg, 1 mg, or placebo. Estimated ED₅₀ was 111 mg (95% CI, 0-244 mg), ED₁₀ was 2.4 mg (95% CI, 0-5.3 mg), ED₀₅ was 0.8 mg (95% CI, 0-1.8 mg), and ED₀₁ was 0.1 mg (95% CI, 0.0-0.3 mg). Symptom scores increased after challenges but not beyond placebo. Acute IL2 release occurs at gluten doses below current food-labeling thresholds. Symptoms are unreliable at exposures <1000 mg. These findings provide a framework for defining exposure limits based on immune activation. (Australian and New Zealand Clinical Trials Registry, Number: 12621000781842).