Dynamics of Serologic Change to Gluten in Celiac Disease Patients.

Serologic measures of tissue transglutaminase (tTG) immunoglobulin A (IgA) and deamidated gliadin peptide (DGP) IgA and immunoglobulin G (IgG) are hallmark tests utilized when diagnosing individuals for celiac disease (CeD) and for monitoring adherence to a gluten-free diet (GFD), currently the only available treatment for CeD. We address two issues in this study: (i) the relapse to seropositivity for CeD patients who resume a gluten containing diet and (ii) the correlation between two different tTG-IgA assays near the upper limit of normal (ULN) designated thresholds. Regarding the first issue, often a suspected CeD individual is put back on a gluten diet to return to their serologic levels. However, we show it requires a substantial amount of gluten for serology to return to a positive level. For example, in one study of 22 patients treated with placebo and taking 84 g of gluten over 6 weeks, only two converted from seronegative to seropositive for tTG-IgA. Regarding the second topic, we compare the relationship for different serologic assays, namely tTG-IgA AB (recombinant, ULN = 4 units/mL) vs. tTG-IgA (non-recombinant, ULN = 20 units). There is a strong correlation between both measurements as evidenced by a Pearson coefficient of R = 0.8584; however, we observed that the cross-correlation in terms of sensitivity and specificity improved substantially by using an ULN value of three instead of four for the tTG-IgA AB (recombinant) assay. This result suggests that assay thresholds used for initial diagnosis in patients who have not yet started a GFD may need to be adjusted for monitoring and in the setting of a diagnostic gluten challenge.

Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients With Celiac Disease Exposed to a Gluten Challenge.

BACKGROUND & AIMS: Gluten ingestion in patients with celiac disease can lead to gastrointestinal symptoms and small intestinal mucosal injury. METHODS: This gluten challenge phase 2 trial was double blind and placebo controlled, and it assessed the efficacy and safety of a 1200-mg dose of IMGX003 in patients with celiac disease exposed to 2 g of gluten per day for 6 weeks. The change in the ratio of villus height to crypt depth was the primary endpoint. Secondary endpoints included density of intraepithelial lymphocytes and symptom severity. These endpoints were evaluated by analysis of covariance. Additional endpoints included serology and gluten-immunogenic peptides in urine. RESULTS: Fifty patients were randomized, and 43 patients completed the study (IMGX003, n = 21; placebo, n = 22). The mean change in the ratio of villus height to crypt depth (primary endpoint) for IMGX003 vs placebo was -0.04 vs -0.35 (P = .057). The mean change in the density of intraepithelial lymphocytes (secondary endpoint) for IMGX003 vs placebo was 9.8 vs 24.8 cells/mm epithelium (P = .018). The mean change (worsening) in symptom severity in relative units (secondary endpoint) for IMGX003 vs placebo was 0.22 vs 1.63 (abdominal pain, P = .231), 0.96 vs 3.29 (bloating, P = .204), and 0.02 vs 3.20 (tiredness, P = .113). The 3 × 2-week trend line significance values for these symptoms, respectively, were P = .014, .030, and .002. CONCLUSIONS: IMGX003 reduced gluten-induced intestinal mucosal damage and symptom severity. (ClinicalTrials.gov, Number: NCT03585478).

Determination of gluten consumption in celiac disease patients on a gluten-free diet.

Background: Celiac disease (CD) patients adhering to a gluten-free diet (GFD) are exposed frequently to low levels of gluten that contribute to symptoms and persistent intestinal histologic damage. Objective: We analyzed prior clinical data to determine how much gluten is accidentally consumed while on a GFD. The aim was to understand the range of gluten consumption for a wide distribution of CD patients. Design: A meta-analysis was conducted on data from 2 different clinical programs: 1) measurements of gluten in stool and urine in CD and non-CD populations; and 2) analysis of data from trials for the investigational therapeutic latiglutenase. The stool and urine studies included controlled gluten challenges. A calibration factor was applied that allowed normal ingestion of gluten to be computed from the urine and stool measurements. From the latiglutenase trial data, a determination of gluten consumption was made by estimating how much gluten was eliminated from patients' diets due to a trial effect that led to improved histology even in the placebo group. Results: The average inadvertent exposure to gluten by CD individuals on a GFD was estimated to be ∼150-400 (mean) and ∼100-150 (median) mg/d using the stool test and ∼300-400 (mean) and ∼150 (median) mg/d using the urine test. The analyses of the latiglutenase data for CD individuals with moderate to severe symptoms indicate that patients ingested significantly >200 mg/d of gluten. Conclusions: These surrogate biomarkers of gluten ingestion indicate that many individuals following a GFD regularly consume sufficient gluten to trigger symptoms and perpetuate intestinal histologic damage.