Introduction

IBD is a global health problem. It is necessary to understand the evolution and treatment exposure in a cohort of newly diagnosed IBD patients in the biologic era in the South of Europe

Aims & Methods

Aims: 1) To describe the main epidemiological and clinical characteristics of patients at IBD diagnosis and the long-term outcomes; 2) to analyse the use of drugs for IBD, and the need of hospitalisations and surgeries; 3) to compare IBD management based on the type of disease and the resources of the hospitals.
Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD —Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified— during 2017 in the 17 Spanish regions were included. Patients who consented were followed-up for 5 years (yr) after diagnosis. Treatment was grouped into 5 categories: mesalamine (oral or topical), steroids (intravenous, oral, or topical), immunomodulators (thiopurines, methotrexate or cyclosporine), biologics (anti-TNF, vedolizumab, ustekinumab) or JAK inhibitors (JAKi), and surgery. Hospitals were classified into high resources and low resources ones. Cumulative incidence of exposure to each of the studied treatments was estimated by Kaplan-Meier curves; curves were compared with log-rank test.

Results

A total of 3,301 incident cases of IBD diagnosed during 2017 in 108 hospitals, covering over 22 million inhabitants in Spain (about 50% of the population), were enrolled into the follow-up study. Main characteristics of the cohort are summarised in table 1A and 1B. Median diagnosis delayed was 3.5 months (5.6 in CD and 2.7 in UC, p<0.001). During the 5-yr follow-up, 25% of UC patients progressed to more extensive involvement, while 8% of CD patients with inflammatory behaviour progressed to either stricturing or fistulising behaviour. Most of the patients who received mesalamine, corticosteroids, or immunomodulators initiated treatment within the first 2 years after diagnosis (figure 1). However, the cumulative incidence of biologics/JAKi usage steadily increased over time, reaching 49% by the 5-yr timepoint in CD. In terms of surgeries, a progressive increase in cumulative incidence was observed in CD; however, the incidence of colectomy remained stable in UC from the 2^nd year post-diagnosis. The management and progression of IBD unclassified were similar to that of UC. Regarding the type of hospital, a higher cumulative incidence of biologics/JAKi usage, hospitalisations, and surgeries was observed in CD at high resources hospitals. No differences were observed in the use of other therapeutic resources or the management of UC.

Conclusion

In the EpidemIBD large-scale epidemiological study, we have observed that the delay in diagnosing IBD is shorter than previously described. Approximately 50% of patients with CD and 20% of patients with UC end up receiving biologics/JAKi in the first 5 yrs following diagnosis. The percentage of patients undergoing surgery was lower than previously reported; in the case of UC, the majority of colectomies occurred within the first 2 yrs after diagnosis.

Disclosure

MDMA has received consulting and/or speaker fees from AbbVie, Pfizer, Takeda, Janssen, Tillotts Pharma and Galapagos; and has received research funding from Abbvie, Janssen and Pfizer.
RF-I has served as a speaker, advisory member or has received research funding from Takeda, MSD, Abbvie, Janssen, Pfizer, Palex, Shire Pharmaceuticals, TillottsPharma, Faes, Adacyte, Ferring and Casenrecordati.
R. Lorente has served as a speaker, or has received research or education funding from Abbvie, Pfizer, Takeda, Janssen and Galapagos.
IV has served as a Speaker, consultant and advisory member for and has received funding for: MSD, Abbvie, Pfizer, Ferring, Shire Pharmaceuticals, Takeda, Tillots, Jannsen y Galápagos.
EF-S Tillotts Pharma (speaker and travel grants), Ferring (speaker and travel grants) ), Faes (travel grants), MSD (speaker and travel grants), Abbvie (speaker and travel grants), Falk (travel grants), Shire (speaker and travel grants), Takeda (speaker and travel grants).
LAG has served as speaker or has received research or education funding from MSD; Abbvie; Kern Pharma; Ferring; Faes Farma; Shire Pharmaceuticals; Pfizer; Takeda; Janssen; Tillots Pharma and OtsuKa Pharmaceutical

Introduction

Individuals with coeliac disease (CeD) commonly complain of persistent symptoms despite adhering to a gluten free diet (GFD). We analysed baseline data from the prospective pseudonymized German CeD Registry to identify factors associated with ongoing complaints.

Aims & Methods

​​​​​​After written informed consent, participants self-reported demographic, clinical and healthcare related information at baseline and yearly thereafter. Symptoms before diagnosis and during the four weeks prior to completing the baseline questionnaire were retrospectively assessed. Factors associated with symptoms after at least one year of gluten-free diet (GFD) were evaluated by multivariate logistic regression.

Results

From 11/2019 to 10/2021, 2164 participants provided baseline data: 78% were female, median age 36 years (range 1.1 to 93.2), median time since diagnosis 6.3 years (0 to 58.7), and median diagnostic delay (time from first symptom to diagnosis) 2.2 years (0 to 64.8). Most common symptoms before diagnosis included abdominal pain (83%), bloating (82%), fatigue (78%), and diarrhoea (71%). Individuals diagnosed in adulthood were more symptomatic compared to paediatric patients. Although 93.4% of participants reported improvement after diagnosis, a substantial proportion of those keeping a GFD >1year (n=1861, 86% of cohort) had ongoing symptoms. Factors associated with regularly experiencing above symptoms included female gender, having the same symptom before diagnosis, feeling insufficiently informed by their physician about CeD and implications for their daily life, and age at diagnosis (per decade), but not time since diagnosis (table).

Conclusion

Our findings revealed deficits in awareness, the diagnostic process, and post-diagnostic care. In this large cohort of patients with CeD we identified factors associated with persistence of symptoms despite keeping a GFD for at least one years. Early diagnosis, providing comprehensive education after confirmed diagnosis, and ensuring strict dietary adherence are pivotal for symptom resolution. A population-based mass-screening for CeD in childhood should be further explored. Implementing a multifaceted approach will enhance care for individuals with CeD and ultimately improve long-term health and well-being.

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

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

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

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

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