Introduction

The microbiota of the small intestinal (SI) lumen is substantially different from that of the colon, and SI dysbiosis is associated with functional GI disorders and SI bacterial overgrowth [1]. However, sampling luminal content of SI requires invasive methods and is at high risk of contamination when collected at endoscopy. SIMBA is a novel ingestible capsule with a pH-dependent coating which dissolves once in the SI. SI content then enters the capsule through fenestrations, and the capsule self-seals using a passive time-sensitive mechanism prior to reaching the colon. The SIMBA chamber contains a preservant to maintain sample bioinformation. The capsule is then collected with feces for subsequent analysis.

Aims & Methods

Aim: 1) test performance characteristics of SIMBA in healthy and IBS patients, and 2) demonstrate the difference between fecal and SI microbiome and metabolome, as assessed by SIMBA capsules and endoscopic aspirates. Methods: 10 healthy, 10 IBS-C and 10 IBS-D volunteers (mean(±SD) age 44 ± 13, range 23-67 years; mean BMI 24.9 ± 4.2; 18 females) were recruited. Baseline Visit: Fasting subjects took 2 SIMBA capsules together with water and had abdominal X-rays every 30 mins up to 12 scans to assess capsule location and sampling. Subjects checked each feces after ingestion until the SIMBA capsules passed, then collected them with a fecal sample. Endoscopic Visit: One week later, 2 more SIMBA capsules were ingested followed by an endoscopic sterile aspiration and saliva collection the next day. Endpoints: Sampling time and location at baseline, capsule content analysis for 16s microbiome sequencing and metabolomic analysis with comparison to feces, aspirates and saliva, safety and usability assessment for both capsule sets (total 120 capsules in 60 ingestions).

Results

X-ray monitoring of baseline capsules showed 49/53 (92%) deployed in the SI, mostly in jejunum and ileum; 5 were indeterminate, 2 stopped sampling in the colon. Overall, 113/120 (94%) capsules were retrieved by subjects with total gut transit time median 47 hours (IQR 24-54) and no significant performance differences between healthy and IBS-C or -D (Table 1). SIMBA was well tolerated with no adverse events, and retrieval from stool was judged not difficult by participants. Multi-omic analysis using the same SIMBA samples showed significantly different microbiota and metabolomic composition between SIMBA contents and fecal samples within subjects. Microbiome profiles from the SIMBA samples are similar to those obtained through small intestine endoscopy aspirates but less affected by oral microbiota interference. The SIMBA samples also contain a large group of small molecules that are predictably up-regulated in the small intestine, such as amino acids, bile acids, and so on, which is similar to the endoscopic aspirates and complementing fecal samples from the same cohort of patients.

Conclusion

SIMBA samples are better proxies than fecal samples to depict the expressions of essential metabolites such as amino acids, short chain fatty acids and bile acids obtained using aspirates in small intestine. The SIMBA capsule appears safe and reliable to capture, seal, and preserve SI luminal fluid which is suitable for further multi-omics data analysis for interrogating and diagnosis of digestive conditions, complementing fecal sampling.

References

[1] Saffouri, G.B., Shields-Cutler, R.R., Chen, J. et al. Small intestinal microbial dysbiosis underlies symptoms associated with functional gastrointestinal disorders. Nat Commun 10, 2012 (2019).

Disclosure

G.W, S.B and S.M are employees of Nimble Science. G.W, S.B. and C.N.A. are shareholders and hold stock options of Nimble Science.

Introduction

Fatigue, defined as “an overwhelming sense of tiredness, lack of energy and feeling of exhaustion” [1] is a frequent complaint in celiac disease. A strict, lifelong gluten free diet is the only established treatment for celiac disease, however its long-term effect on fatigue is unknown.

Aims & Methods

Our aims were to investigate the course of fatigue severity and prevalence in celiac patients from diagnosis to five to seven years on a gluten free diet, and to investigate whether diet adherence, disease activity and selected biochemical markers are associated with fatigue.
We conducted a single-center prospective study in 45 patients with newly diagnosed celiac disease. The primary endpoints were fatigue severity, as measured by the Fatigue Severity Scale (FSS) [2], the fatigue Visual Analog Scale (fVAS) [3], and the Vitality subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36vs) [4]. SF-36vs scores were inverted (100 – SF-36vs = inverted SF-36vs) to ease comparison between the other scales, so that higher scores indicate more fatigue. Clinically relevant fatigue was defined by an FSS score of ≥4, a fVAS score of ≥50, and an inverted SF-36vs score of ≥65. Study visits were performed at the time of diagnosis (Visit 1), after adhering to a gluten free diet for one year (Visit 2) and for five to seven years (Visit 3). Diet adherence was evaluated through urinary gluten immunogenic peptides (GIP) and the Celiac Diet Adherence test (CDAT) [5]. Disease activity was assessed through Celiac Symptom Index (CSI) [6], celiac autoantibodies (anti tissue transglutaminase IgA and deamidated gliadin peptide IgG) and histologic evaluation (Marsh score). Nutritional status was assessed through BMI, hemoglobin, 25-hydroxy vitamin D, cobalamin, ferritin and folic acid levels.

Results

Fatigue severity was significantly reduced from time of diagnosis, for all three instruments (Table 1). Fatigue prevalence rates were significantly decreased from Visit 1 (40-53%) to Visit 3 (27-31%). Fatigue was significantly lower in patients with good adherence compared to patients with poor adherence according to CDAT scores (For FSS p=0.022, fVAS p=0.017, and for inverted SF-36vs p=0.033). There was however no difference in fatigue severity between adherent and nonadherent patients when evaluating adherence through urinary GIP. Fatigue was lower in patients in clinical remission according to CSI scores (for FSS p=0.002, fVAS p=0.004, and for inverted SF-36vs p=0.002), but not associated with autoantibodies or nutritional status. In multiple linear regression analysis, depression was the only independent variable significantly associated with all three fatigue measures at Visit 3, whereas pain was positively associated with inverted SF-36vs scores.

Table 1.

Conclusion

Fatigue remains a frequent complaint in celiac disease even after five to seven years on a gluten free diet. However, fatigue severity is reduced from time of diagnosis. Fatigue was associated with dietary adherence as assessed by CDAT. Disease activity according to CSI was associated with fatigue, whereas nutritional status, autoantibodies and histologic changes were not.

References

1. Krupp, L.B. and D.A. Pollina, Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol, 1996. 9(6): p. 456-60.
2. Krupp, L.B., et al., The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol, 1989. 46(10): p. 1121-3.
3. Wolfe, F., Michaud K, Pincus T, Preliminary evaluation of a visual analog function scale for use in rheumatoid arthritis. J Rheumatol, 2005. 32(7): p. 1261-6.
4. Ware, J.E., Jr. and C.D. Sherbourne, The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care, 1992. 30(6): p. 473-83.
5. Leffler, D.A., et al., A simple validated gluten-free diet adherence survey for adults with celiac disease. Clin Gastroenterol Hepatol, 2009. 7(5): p. 530-6, 536.e1-2.
6. Leffler, D.A., et al., A validated disease-specific symptom index for adults with celiac disease. Clin Gastroenterol Hepatol, 2009. 7(12): p. 1328-34, 1334.e1-3.

Disclosure

Berit Mære Skjellerudsveen: Received lecture honoraria from Takeda for lectures on IBD and pregnancy. This study is partly funded by a grant from the patient organization “The Norwegian Coeliac Society”.

Introduction

Coeliac disease (CeD) is a chronic immune-mediated enteropathy driven by dietary gluten proteins. Previous studies have indicated an increased risk of cardiovascular disease (CVD) in individuals with CeD [1-3]. However, results are inconsistent and specific guidelines on the management of CVD risk and comorbidities for individuals with CeD do not exist. In this study, we aimed to compare the distribution of traditional CVD risk factors in CeD patients and non-CeD controls from a population-based cohort.

Aims & Methods

We performed a CeD screening of 54,541 serum samples by anti-transglutaminase 2 immunoglobulin A and G serology from in total 56,042 adult participants in the fourth wave of the Norwegian Trøndelag Health Study (HUNT4) [4]. All seropositive participants were invited to upper endoscopy with duodenal biopsies to confirm a CeD diagnosis. Seronegative participants with previously diagnosed CeD were identified by linkage to hospital records and the Norwegian Patient Registry. We calculated SCORE2 and SCORE2-OP as predictors for 10-year risk of first-onset CVD [5, 6]. The groups “no CeD”, previously diagnosed CeD (“known CeD”) and CeD diagnosed in HUNT4 (“new CeD”), as well as “CeD” (known + new cases) were examined in this study. To compare group characteristics, we used the Wilcoxon rank sum test. Associations between groups and SCORE2(-OP) were assessed using ordinal logistic regression analysis.

Results

468 (0.80%) individuals received a CeD diagnosis in HUNT4, while 309 (0.57%) seronegative individuals had known CeD. Individuals with newly diagnosed CeD were younger, better educated, and had lower blood lipids compared to controls. Individuals with CeD smoked significantly less, had lower BMI and waist-hip-ratio, glycated hemoglobin levels, serum creatinine, and hsCRP levels compared to controls without CeD (n=52,438; p<0.05 for all variables mentioned, see table). We found a significantly lower SCORE2 for CeD cases (n=589) compared to controls (n=39,747; p<0.05). Adjustment for alcohol consumption did not affect group characteristics. A significantly lower SCORE2 was observed in CeD cases also after adjustment for level of education (OR .84, 95% CI .72-.98), high sensitivity C-reactive protein (hsCRP) and serum creatinine (OR .85, 95% CI .78-.99), but not for the combination of all three variables (OR .90, 95% CI .76-1.05).

Conclusion

Individuals with CeD appear to have a lower cardiovascular risk based on traditional risk factors like smoking habits, body fat, diabetes, renal function and inflammation compared to control individuals without CeD. In line with that, SCORE2 and SCORE2-OP as predictors for 10-year risk of first-onset CVD were lower in individuals with CeD.

References

1. Bathrellou, E., M.D. Kontogianni, and D.B. Panagiotakos, Celiac disease and non-celiac gluten or wheat sensitivity and health in later life: A review. Maturitas, 2018. 112: p. 29-33.
2. Ludvigsson, J.F., et al., Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease. Circulation, 2011. 123(5): p. 483-90.
3. Figtree, G.A., et al., Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data. Lancet, 2021. 397(10279): p. 1085-1094.
4. Asvold, B.O., et al., Cohort Profile Update: The HUNT Study, Norway. Int J Epidemiol, 2023. 52(1): p. e80-e91.
5. SCORE2 working group and ESC Cardiovascular risk collaboration, SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe. Eur Heart J, 2021. 42(25): p. 2439-2454.
6. SCORE2-OP working group and ESC Cardiovascular risk collaboration, SCORE2-OP risk prediction algorithms: estimating incident cardiovascular event risk in older persons in four geographical risk regions. European Heart Journal, 2021. 42(25): p. 2455-2467.

Disclosure

None.

Introduction

Infliximab (IFX) is a mainstay in the treatment of Crohn´s disease (CD) and ulcerative colitis (UC)^1,2. However, some patients do not respond to IFX; others develop antibodies to IFX (ATI), resulting in loss of response (LOR) over time^3,4. As second-line treatments for adults are not approved in pediatrics, current ECCO/ESPGHAN guidelines recommend combination therapy with an immunomodulator (IM) to improve response and prevent ATI development.^2,5 Recent studies suggested that combination therapy is not superior to IFX monotherapy if proactive therapeutic drug monitoring (TDM) is performed⁶.

Aims & Methods

We investigated whether recommended early combination therapy has an additional benefit in a proactively managed pediatric IBD cohort. Medical records from 01/2013 to 12/2022 were retrospectively reviewed and children (3-18 years) with at least four doses of IFX, 3-60 months (m) follow-up and proactive TDM were included. Patients were grouped in either early (IM^e: ≤3m since IFX start and duration of IM therapy >6m or until the end of observation) or late/never IM treatment (IM^l/n: >3m since IFX start/no IM combination therapy). Kaplan-Meier analysis and log-rank test (significance level p<0.05) were used to analyze time to LOR with IFX discontinuation or time to ATI development. Hazard ratio (HR) applying Cox regression represents the relative risk of LOR occurring in IM^l/n compared to IM^e.

Results

Of 315 reviewed IBD children, 127 patients were included (43% girls, median age at IFX start: 14 years, 77 CD, 50 UC including 5 IBD-u) and IFX treatment of 2855 visits was analysed. Sixty patients received IM^e (41 CD, 19 UC), 20 patients started IM >3m after IFX (13 CD, 7 UC) and 47 patients had IFX monotherapy (23 CD, 24 UC). Patient characteristics, previous therapies, IFX dosage and intervals were comparable between IM^e and IM^l/n groups (except E2 in UC). Proactive TDM was comparable in both IM^e and IM^l/n, i.e., duration from IFX start to first TL measurement (median of 6 weeks, p=0.9), median number of 4 TL measurements per follow-up year (p=0.6), and median TL of 10 and 11 μg/mL (p=0.6), respectively. Most patients (84%) had a median TL >5µg/ml over time. The median follow-up time was 29.6m for IM^e and 25.5m for IM^l/n.
IFX treatment persistence was 68% after 60m in the total cohort. LOR with IFX discontinuation was observed in 7 IM^e and 15 IM^l/n patients (p=0.2). Combining IFX infusions with IM^e significantly delayed the occurrence of LOR with IFX discontinuation (median LOR free interval IM^e 29.4m, IM^l/n 8.6m, p=0.01). The IM^l/n group was more likely to experience LOR than IM^e after 1, 2, 3, 4, and 5 years (HR₁=10.3, p₁=0.01; HR₂=4.1, p₂=0.02; HR₃=2.9, p₃=0.03; HR₄=2.9, p₄=0.03; HR₅=2.1, p₅=0.09). IM^l/n instead of IM^e increased the risk for LOR, especially in UC patients (HR 7.5, p=0.04).
Low ATI >10AU/ml were found in 76/106 IFX-treated patients, while high ATI >100AU/ml were detected in 10/52 IM^e and 15/54 IM^l/n patients, p=0.2. There was no significant difference regarding median ATI level (both 12AU/ml, p=0.7) and ATI-free interval (9m vs 8m, p=0.65) in the groups. Only in CD patients, IM^l/n showed a significantly higher risk of developing high ATI (HR 4.1, p=0.046) compared to IM^e.

Conclusion

Proactive TDM resulted in high IFX treatment persistence in pediatric IBD. Early combination therapy of IM with IFX showed a significant benefit with improved IFX treatment persistence during the first four years of therapy. This effect was partly explained by preventing high-titer ATI in CD patients.

References

1. van Rheenen, P. F. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J. Crohns Colitis 15, 171–194 (2021).
2. Turner, D. et al. Management of Paediatric Ulcerative Colitis, Part 1 and 2: Ambulatory Care-An Evidence-based Guideline from European Crohn’s and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J. Pediatr. Gastroenterol. Nutr. 67, 257–291 (2018).
3. Adedokun, O. J. et al. Pharmacokinetics of infliximab in children with moderate-to-severe ulcerative colitis: results from a randomized, multicenter, open-label, phase study. Inflamm. Bowel Dis. 19, 2753–2762 (2013).
4. Vande Casteele, N. et al. Antibody response to infliximab and its impact on pharmacokinetics can be transient. Am. J. Gastroenterol. 108, 962–971 (2013).
5. van Rheenen, P. F. et al. The Medical Management of Paediatric Crohn’s Disease: an ECCO-ESPGHAN Guideline Update. J Crohns Colitis (2020) doi:10.1093/ecco-jcc/jjaa161.
6. Sandborn, W. J. et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J. Crohns Colitis 8, 927–935 (2014).

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.