Review Article: Accelerating Coeliac Disease Clinical Trials-Beyond Celiac Meeting With Industry, Academics, Patients and the FDA.

Per the Salerno Experts' Criteria, non-celiac gluten sensitivity is confirmed only after celiac disease and wheat allergy have been excluded while the patient is still on a gluten-containing diet (negative tTG-IgA with adequate total IgA/EMA and negative or near-normal duodenal histology, i.e. Marsh 0-1, on gluten; negative wheat-specific IgE / skin-prick testing), using a standardized two-step protocol. Step 1 - assess symptom response to a gluten-free diet over AT LEAST 6 weeks, scored with a validated instrument (a modified Gastrointestinal Symptom Rating Scale rating up to three main symptoms on a 1-10 numerical rating scale); a responder shows a >=30% reduction from baseline in at least 3 of the 6 weekly assessments (>=50% of the observation period). Step 2 - confirm responders with a double-blind, placebo-controlled crossover gluten challenge: after >=4 weeks of strict (celiac-level) gluten-free diet, give 8 g gluten/day for 1 week in a vehicle that is FODMAP-free, contains amylase-trypsin inhibitors, and is indistinguishable from placebo, then a 1-week strict-GFD washout, then crossover to the other arm for 1 week; the test is positive only for gluten-directed worsening - the symptom score must be >=30% HIGHER (worse) during the gluten week than during the placebo week; a >=30% difference in the opposite direction (symptoms worse on placebo) is a negative result and does not support the diagnosis. Patients who do not respond to the gluten-free diet should be investigated for other causes (e.g., FODMAP intolerance, small-intestinal bacterial overgrowth). The document stresses that, absent any validated biomarker, this blinded challenge is the reference standard precisely because self-reported gluten sensitivity is frequently not reproduced under blinding.