Introduction

Gastro-esophageal reflux disease (GERD) is a multifactorial disease that manifests in patients with different degrees of anti-reflux barrier impairment. GERD significantly impacts quality of life despite the fact that symptom burden may not always correlate with disease severity. Precise pathophysiologic evaluation can identify patients with actionable GERD who may benefit from anti-reflux surgery or escalation of medical therapy. The Milan Score, a novel high-resolution manometry (HRM) metric, numerically quantifies the degree of anti-reflux barrier disruption¹. While the Milan Score has been proven to predict pathologic GERD, its ability to distinguish non-severe from severe GERD and to identify patients with a higher grade of anti-reflux barrier disruption requires further study.

Aims & Methods

A database of prospectively collected data from a cohort of patients undergoing HRM and pH-study for persistent GERD symptoms was queried. Using Lyon 2.0 consensus, pathologic GERD was defined as AET >6%, grade B-C-D esophagitis or Barrett’s esophagus on endoscopy. Severe reflux was defined as AET >12%, DeMeester score >50, grade C-D esophagitis or Barrett’s esophagus². Demographic, HRM and pH data were extracted, classified and compared between groups with varying GERD severity (no GERD, non-severe GERD, severe GERD). The Milan Score integrates the main manometric parameters related with the pathophysiology of GERD (ineffective esophageal motility, esophago-gastric junction (EGJ) contractile integral, EGJ morphology and straight leg raise maneuver response). In order to simplify the use of the Milan Score, risk rates have been classified into six categories, from extremely unlikely to extremely likely. A cumulative odds ordinal logistic regression was run to determine the independent effect of HRM variables on reflux severity. The ability of the Milan Score to predict severe reflux was assessed, as well as its association with the pH-study criteria proposed by Lyon 2.0 as adjunctive evidence for pathologic GERD (>80 reflux episodes, mean nocturnal baseline impedance (MNBI) <1500 W or positive reflux-symptom association).

Results

Among 603 patients enrolled (median age 49.9 years, median body mass index (BMI) 25.3 Kg/m², 50.5% males), 124 (20.6%) had non-severe and 142 (23.5%) had severe GERD. Non-severe and severe GERD patients had similar demographic and clinical characteristics, but were significantly different from the no-GERD group (Table). On univariate analysis, presence and size of hiatal hernia, Milan Score and Milan Score categories were significantly different among the groups (p <0.001). On ordinal logistic regression, hiatal hernia size and Milan Score category were found to be independent predictors of GERD severity (OR 1.28, 95% CI, 1.04-1.57, p=0.018 and OR 2.92, 95% CI, 2.47-4.45, p=<0.001 respectively). A significantly higher Milan Score (p <0.001) was found in patients with >80 reflux episodes, MNBI <1500 W, positive reflux-symptom association and any criteria of severe GERD.

Conclusion

Hiatal hernia size and Milan Score assessed at HRM are independent factors associated with severe GERD. The Milan Score is significantly higher in patients with pathologic adjunctive pH-impedance metrics and in patients with severe GERD.

References

1. Siboni S, Sozzi M, Kristo I et al. The Milan score: A novel manometric tool for a more efficient diagnosis of gastro-esophageal reflux disease. United European Gastroenterol J. 2024 Mar 27. doi: 10.1002/ueg2.12565. Epub ahead of print. PMID: 38536701.
2. Horvath KD, Jobe BA, Herron DM et al. Laparoscopic Toupet fundoplication is an inadequate procedure for patients with severe reflux disease. J Gastrointest Surg. 1999 Nov-Dec;3(6):583-91. doi: 10.1016/s1091-255x(99)80079-1. PMID: 10554364.

Introduction

Anti-tissue transglutaminase IgA antibodies (tTG) are used in the follow-up of celiac disease (CD) to assess adherence to a gluten-free diet (GFD). Persistent positivity may indicate the need for histological reassessment. There is limited information about the rate of complete normalization of tTG and associated factors. Our objective was to evaluate the percentage, kinetics, and factors related to tTG normalization.

Aims & Methods

This was a retrospective observational study including patients with tTG testing at diagnosis and follow-up monitoring of these antibodies from 1991 to 2023 in a specialized unit dedicated to patients with CD. Inclusion criteria were: patients over 16 years of age at diagnosis, initially elevated tTG titres, and at least one serological follow-up after starting a GFD. Time to tTG normalization was estimated using the Kaplan-Meier method. Comparisons between groups were performed using the log-rank test. The association between demographic and clinicopathological characteristics at diagnosis and time to tTG normalization was assessed using Cox regression analysis.

Results

A total of 179 patients were included (75% female, mean age 40 ± 16 years). Duodenal atrophy was present in 81%, and 79% had symptoms. 83% strictly adhered to a GFD. Median follow-up was 3 years. The incidence rate of tTG normalization was 35% per patient-year. The cumulative tTG normalization rate was 38% (95% CI: 30-45) at 1 year, 61% (53-69) at 2 years, 70% (63-77) at 3 years, 80% (73-87) at 4 years, 81% (74-89) at 5 years, and 95% (88-100) at 10 years. The median time to tTG normalization was 24 months (95% CI: 20–28). Table 1 shows Kaplan–Meier estimates expressed as percentages of tTG normalization by adherece to GFD and baseline tTG. In the multivariable analysis, two factors were found to be significantly associated with the normalization of tTG: lower baseline tTG and good adherence to a GFD. Regarding baseline tTG level, patients with titres ≤ 286 U/ml (median) had 2.46 times higher likelihood of antibody normalization compared to those with higher titres (HR: 2.46; 95% CI: 1.69–3.56; p < 0.001). Regarding adherence to a GFD, patients who followed a strict GFD had 5.38 times higher likelihood of tTG normalization (HR: 5.38; 95% CI: 2.79–10.36; p < 0.001).

Table 1. Kaplan–Meier estimates expressed as percentages of normalization (with 95% CIs) after CD diagnosis, by adherece to GFD and baseline tGA titres.

Conclusion

1. The incidence rate of tTG normalization in CD patients after initiating a GFD was 35% per patient-year of follow-up.
2. In the long-term (10 years), 95% of CD patients achieved tTG normalization.
3. Lower tTG titres at diagnosis and good adherence to the GFD were predictive factors for tTG normalization.
4. Understanding the kinetics of tTG normalization according to various factors is essential before considering histological reassessment for suspected poor disease progression.

Introduction

While wide-scale screening for celiac disease (CeD) is increasingly being considered, its overall benefits are not well established.

Aims & Methods

We investigated the general health at diagnosis and long-term outcomes in CeD patients identified through screening in a population-representative cohort. Comprehensive health data from individuals participating in the nationally representative Health 2000 survey (N=6,376) were analyzed using registry data and interviews. Additionally, blood was collected to measure tissue transglutaminase antibodies (TGA) and endomysial antibodies (EmA) if TGA was positive, as well as other laboratory parameters. Altogether, 3254 subjects participated in a follow-up study in 2011. Mortality among subjects in the Health 2000 cohort was evaluated at the 17-year follow-up using the national statistics registry.

Results

Ninety CeD patients were identified in 2000, of whom 54 participated in the follow-up in 2011 while on a gluten-free diet. At diagnosis, patients more often had pre-eclampsia (13% vs. 5%, p=0.016), and lower levels of hemoglobin (median 140 vs 143 g/L, p=0.046), ferritin (29 vs 68 ng/mL, p<0.001), total cholesterol (5.4 vs 5.9 mmol/L, p<0.001), apolipoprotein A1 (1.40 vs 1.57 g/L, p<0.001) and apolipoprotein B (1.16 vs 1.21 g/L, p=0.009) compared to seronegative population. The groups did not differ in age (48 vs 51 years, p=0.159), sex (females 62% vs 56%, p=0.205), BMI (26 vs 26, p=0.567), blood pressure (131/81 mmHg vs 132/82 mmHg, p=0.230), or the presence of other gastrointestinal diseases, cardiovascular and psychiatric diseases, osteoporosis, malignancies, or smoking and alcohol consumption. No significant changes in cholesterol or apolipoprotein levels, mental health, or health care utilization were observed among CeD patients during the 11-year follow-up. The patients had a lower mortality rate compared to non-CeD individuals after 17 years with borderline significance (14.1% vs. 25.6%, p=0.059).

Conclusion

Population-representative individuals with screen-detected celiac disease exhibit a more favorable metabolic profile, but have lower hemoglobin and iron levels and a higher prevalence of pre-eclampsia at diagnosis. Gluten-free diet does not appear to cause adverse effects. Screen-detected patients may also have a reduced long-term mortality, although further research is needed.

Introduction

Current evidence suggests that joint complaints without any underlying rheumatic condition are common in patients with celiac disease. This important clinical aspect of non-rheumatic joint complaints has not systematically been investigated and the prevalence of joint complaints is not known.

Aims & Methods

The aim of this study was to estimate the prevalence of joint complaints in patients with celiac disease through a systematic review and meta-analysis of existing literature. We searched Medline, Embase, Cochrane, and Web of Science databases for studies reporting joint complaints in patients with celiac disease between January 1, 1990 and November 26, 2024. Search results were screened by two independent reviewers. The quality of included studies was appraised and meta-regression analysis performed. A study protocol was pre-registered in the PROSPERO database and results were reported according to the PRISMA guidelines.

Results

A total of 7,414 publications were identified in the search. Of these, 226 were reviewed in full-text and 27 included in the meta-analysis. Among 6,901 patients with celiac disease, 530 had joint complaints, yielding a weighted pooled prevalence of 10.7% (95 % CI 6.9-15.1). Stratified by adults (n=17 studies) vs. children (n=13 studies), the pooled prevalence was 16.8% (95% CI 9.0-26.3) in adults compared with 6.4% (95% CI 3.4-10.1) in children. In comparison by region, studies in South and North America (n=5) showed the highest weighted pooled estimate (12.9%; 95% CI 8.7-17.8). Europe (n=15) had the second highest (12.4%; 95% CI 6.8-19.4, and Asia (n=3) the lowest prevalence (5.2%; 95% CI 0.0-18.3). In meta-regression analysis, no association between the prevalence of joint complaints and study characteristics or demographics was found.

Conclusion

One in 10 patients with celiac disease suffers from joint complaints that are not directly associated with any specific rheumatic comorbidity. This indicates that joint complaints are extraintestinal manifestations in patients with celiac disease, occurring more frequently than commonly thought. Increased awareness of joint complaints is warranted to improve the clinical care of patients with celiac disease.

Disclosure

Drs. Poddighe, Galiyeva, Zhubanova and Mussina declare no conflicts of interest. Dr. Forss has served as a speaker and an advisory board member for Janssen Cilag AB and Tillotts Pharma.

Introduction

Nanoparticles containing gliadin (TAK-101) are under development to induce gliadin tolerance in patients with celiac disease (CeD). We assessed the immunomodulatory signature induced by TAK-101 treatment in a mouse model of CeD.

Aims & Methods

Human leukocyte antigen (HLA)-DQ8 transgenic mice were intravenously pretreated on Days −11 and −3 with 2.5 mg TAK-101 or were not pretreated (‘gliadin immunization-only’). Animals were then immunized with gliadin on Day 0 and boosted on Day 14. Mice from both groups were sacrificed after 1month. After sacrifice, spleen cells were cultured for 3 days with gliadin, and supernatant cytokine and antigliadin IgG2c antibody levels assessed. Single cell RNA-Seq was performed on cultured spleen cell samples from both groups (n=4).

Results

Production of complement-fixing anti-gliadin IgG2c and pro-inflammatory cytokines, including interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor α (TNFα), IL-17, IL-6 and IL-22 was reduced in splenic cells of TAK-101-treated relative to gliadin immunization-only mice. Differential expression of 1380 genes was demonstrated in B cells following TAK-101 treatment relative to gliadin immunization-only, confirming earlier results from bulk RNA-Seq, including of fractionated B cells. Transcriptomic changes in B cell activation, signaling, proliferation and apoptosis pathways (Gene Ontology) were significantly associated with TAK-101 treatment, while manually curated pathways for B cell anergy and regulatory B cells also matched the identified gene signature.

Conclusion

B cells appear to be important for the immunomodulation of the adaptive gliadin immune response by TAK-101.

Introduction

The synthetic peptide p31–43, derived from α-gliadin, is known to elicit innate immune responses and epithelial stress in the small intestine. In murine models, intragastric administration of p31–43 reproduces some of the key features of celiac disease (CeD), including reduced villus-to-crypt (V/C) ratio, intraepithelial lymphocyte (IEL) infiltration, production of proinflammatory mediators, inflammasome activation, and epithelial cell death. Previously, we reported that Saccharomyces boulardii CNCM I-745 (S.b.) pre-treated mice effectively prevented histological alterations and inflammation in the proximal small intestine triggered by a single intragastric administration of p31-43 peptide. To better replicate the chronic and progressive nature of small intestinal inflammation observed in human pathology, such as in CeD, we developed a more stringent and sustained model through repeated p31–43 exposure.

Aims & Methods

To evaluate whether the histological and inflammatory changes induced by a three-week intragastric administration of the gliadin peptide p31-43, could be alleviated by concomitant treatment with S.b.
Seven-week-old C57BL/6 mice received daily oral gavage of either S.b. (3 g/kg/day) or vehicle for three weeks. Concurrently, animals were challenged five times per week with 40 µg of the p31-43 gliadin peptide (LGQQQPFPPQQPY) via intragastric administration, either alone or in combination with S.b. (p31-43+S.b.). Sixteen hours after the final challenge, mice were euthanized, and the small intestine was collected for histological and molecular analyses. Histological assessments included V/C ratio, IEL, and Goblet cell count. Caspase-1 activation was evaluated by Western blot (WB) to assess inflammasome activation. Expression of genes related to inflammation and tissue repair was assessed by RT-qPCR. Statistical significance was determined using ANOVA.

Results

Histological analysis revealed that S.b. significantly prevented mucosal alterations induced by p31–43, restoring V/C ratio (p = 0.025) and reducing IEL infiltration (p = 0.08). No significant changes were observed in Goblet cell numbers; however, MUC2 mRNA expression was significantly upregulated after three weeks of p31-43 exposure independently of S.b. intervention (p=0.01). Markers related to epithelial cell proliferation and differentiation (ATOH1/HES1) suggested a trend toward enhanced differentiation of secretory epithelial cells in mice treated with S.b., either alone or in combination with p31-43.
RT-qPCR analysis of genes associated with barrier protection, including AREG, REG3g, and RELMB did not reveal significant changes. However, exposure to p31-43 led to upregulation of proinflammatory genes such as MX1, IFNβ, and CXCL10. Notably, S.b. treatment effectively blocked the p31-43-induced upregulation of CXCL10 (p=0.09). WB further demonstrated that S.b. attenuated caspase-1 activation, indicating suppression of p31-43-induced inflammasome activation (p=0.09).

Conclusion

This study demonstrates that treatment with S.b. effectively impedes the mucosal damage and inflammation induced by gliadin peptide p31-43. Although Goblet cell numbers remained unchanged, the upregulation of MUC2 expression suggests an enhanced mucosal defense response. S.b. also suppressed key inflammatory markers, including CXCL10 and caspase-1 activation. Collectively, these findings support the therapeutic potential of Saccharomyces boulardii CNCM I-745 in managing gliadin-induced intestinal damage and highlight its promise for preventing or alleviating intestinal pathology caused by sterile inflammation.

Disclosure

Biocodex (France) funded this study, but did not play a role in the experiment design or the results analysis

Introduction

Qualitative exit interviews provide key insights into patient experience and treatment expectations, which are particularly important in celiac disease (CeD) for which there are no current medications. Data relating to patients’ experiences are critical to understand what is considered a ‘meaningful change’ to patients when they participate in clinical trials. The objective of this study was to understand the clinical trial participants’ experience of CeD, their treatment expectations, and how they define meaningful changes in their symptoms as they exited from a phase 2 clinical trial.

Aims & Methods

Semi-structured telephone interviews of 60 minutes were conducted with eligible patients following a phase 2 double-blind, randomized, placebo-controlled trial in patients with moderate-to-severe CeD who maintained a gluten-free diet (GFD) for ≥ 12 months (NCT05353985).¹ Patients could provide more than one response to some questions. Interviews were blinded to treatment assignment and were audio recorded, transcribed and coded guided by an a priori coding dictionary and a qualitative analysis plan. Transcript analysis was facilitated by ATLAS.ti 9 software. This study was approved by the relevant Institutional Review Boards as part of the phase 2 trial.

Results

Overall, 29 English-speaking patients from 15 clinical sites in the USA were interviewed. Three patients exited the trial early. Most participants were female (23/29, 79.3%), the mean age was 50.6 years, and the mean duration of disease before study enrollment was 6.9 years. These characteristics were similar to the full clinical trial population in which most patients were female (115/153, 75.2%), the mean age was 46 years, and the average time to CeD diagnosis was 9 years. The most commonly reported symptoms were abdominal pain (27/29, 93.1%), bloating (26/29, 89.7%), and diarrhea (24/29, 82.8%). The most bothersome symptom reported was diarrhea (12/29, 41.4%).
Participants most often stated that they were hoping for an improvement in their CeD (25/29, 86.2%) providing descriptions that included the desire to be able to eat without the worry of potential gluten contamination.
Participants were asked if a ‘symptom-free day’ (SFD) (defined as a day with no diarrhea, abdominal pain, bloating, or nausea) would be meaningful. All participants agreed that the concept of SFD is important, with the majority stating that an increase of 1–2 SFDs per week would be meaningful (20/28, 71.4%).
Participants were also asked what improvements on the PGIS (Patient Global Impression of Severity) and PGIC (Patient Global Impression of Change) scales would be meaningful to them (participants could provide multiple responses). The majority (31 responses) reported that a 2-point decrease in severity would represent a meaningful improvement, followed by 21 responses for a 1-point decrease in PGIS. Regarding PGIC, most patients (15/25, 60.0%) stated that ‘much improved’ would indicate a meaningful change, followed by ‘a little improved’ (6/25, 24.0%).

Conclusion

Despite adhering to a GFD, patients experienced frequent and bothersome symptoms, particularly abdominal pain, bloating, and diarrhea, prior to enrolling in the study. This study identified potential thresholds for meaningful improvement in weekly SFDs and PGIS and PGIC scales. These data are important to inform the design and interpretation of future CeD clinical trials.

References

1. ClinicalTrials.gov. Available from: https://clinicaltrials.gov/study/NCT05353985 (Accessed April 1, 2025).

Disclosure

SG, MA, and DAL are employees of Takeda Development Center Americas, Inc. and receive stock or stock options. NH and SM are employees of RTI Health Solutions which received funding from Takeda for participation in this study.