Introduction

IL-33/ST2 axis and gut microbiota are important factors in the pathogenesis of IBD with a potential reciprocal influence. IL-33/ST2 axis controls the mucosal healing process during intestinal inflammation. Restorative proctocolectomy with ileal pouch-anal anastomosis is a surgical procedure in patients with ulcerative colitis (UC) refractory to medical therapies. Pouchitis, the most common complication, is the inflammation of the pouch with a controversial etiology.

Aims & Methods

We aimed to explore the potential role of IL-33/ST2 and gut microbiota axis in the inflammatory process of pouchitis.
30 UC patients with ileal pouch-anal anastomosis were enrolled. After clinical, endoscopic and histological assessment 18 showed pouchitis and 12 a normal pouch. Mucosal samples were collected from the afferent ileal loop and from the pouch and processed for cytokines assessment, histological evaluation and gut microbiota analyses. Multiplex analysis for inflammatory and regulatory cytokines was performed. ELISA and western blot were run to assess IL-33/ST2 protein levels and to evaluate protein isoforms, respectively. IHC was done to evaluate mucosal IL-33/ST2 expression and localization. Microbiota was analyzed by 16S ribosomal RNA gene amplicon pyrosequencing. Pouchitis Disease Activity Index and Pouchitis Histological Score were calculated, and CRP and fecal calprotectin were obtained for each patient. Multivariate analyses were run to generate transcriptional interaction networks and identify biomarkers for patients with inflamed pouches.

Results

IL-1Ra, IL-6, IL-8, IL-17, IP-10, MCP-1, MIP-1a, MIP-1b resulted increased in inflamed pouch vs. normal pouch. No differences were registered between samples obtained from the afferent ileal loop. In pouchitis, IL-7 resulted reduced in the inflamed pouch vs. the afferent ileal loop. In pouchitis, IL-33 and ST2 protein levels were reduced in the pouch vs. the afferent ileal loop and resulted overall decreased vs. patients with normal pouch indicating a potential IL-33/ST2-mediated defective healing process. Full-length, bioactive IL33, ST2L and sST2 were expressed in all experimental groups; the cleaved, less active form of IL33 was increased in only patients with pouchitis. IHC confirmed these observations. IL-33 and ST2 staining was less intense within the inflamed and ulcerated mucosa of pouchitis patients compared to normal pouch, and in close proximity to areas of re-epithelialization. An overall decreased biodiversity in patients with pouchitis vs. patients with normal pouch (both at pouch and afferent ileal loop level) was shown. Lower levels of Verrucomicrobia and increased abundance of Actinobacteria were recorded in inflamed pouch vs normal pouch. In pouchitis, the afferent ileal loop and the pouch showed significantly decreased levels of Akkermansia muciniphila and augmented abundance of Collinsella vs. samples obtained from patients with normal pouch. In pouchitis, multivariate analyses evidenced a significant inverse correlation between Collinsella e Collinsella aereofaciens abundance and ST2 levels.

Conclusion

In patients with pouchitis vs patients with normal pouch divergent inflammatory molecular pathways and microbial populations distinctly characterize the pouch and the afferent ileal loop. Overall, our results suggest a potential role for IL-33/ST2 and gut microbiota axis in driving the gut mucosal wound healing in patients with ileal pouch-anal anastomosis. Further studies are underway to determine mechanisms of action that support these findings.

Introduction

Nowadays, Non-Alcoholic Fatty Liver Disease (NAFLD) is a leading cause of liver disease and liver transplantation. Although obesity is a well-recognized risk factor for NAFLD, there are data to support that not all patients with NAFLD are necessarily obese. However, the evidence on the prevalence and risk factors for NAFLD in lean individuals with Inflammatory Bowel Disease (IBD) is scarce.

Aims & Methods

The aim of the study was to assess the prevalence and risk factors for NAFLD in lean population with IBD. This is a cross-sectional, case control study including lean individuals with IBD (cases) and lean individuals without IBD (controls), matched for age and sex. Patients with risky alcohol consumption, previous diagnosis of chronic liver disease (immune, viral, genetic) and secondary causes of NAFLD were excluded. All included patients were performed a liver ultrasound, transient elastography and laboratory tests. Lean individuals were defined as Body Mass Index < 25 kg/m², and NAFLD as ultrasound steatosis and/or Controlled Attenuation Paremeter >248 dB/m. A descriptive analysis was carried out, and the relationship between variables was assessed using Chi square test/Fisher´s test (categorical variables) or T-student/Mann-Whitney U test (quantitative variables), as appropiate. In addition, a multivariate analysis was performed, presented as adjusted Odds Ratio (OR) and 95% Confidence Interval (95%CI).

Results

A total of 443 participants, 363 lean cases and 80 lean controls, were included in the study. No differences were observed in terms of age, sex and metabolic risk factors between both groups (Table 1). The prevalence of NAFLD in lean individuals with IBD was significantly higher compared to lean individuals without NAFLD (22% vs. 10%, p=0.015). Multivariate analysis confirmed that IBD was an independent risk factor for NAFLD in lean population (OR 2.75 95%CI (1.18-6.41)). In addition, male sex (OR 1.78 95%CI (1.04-3.05)) and older age (OR 1.03 95%CI (1.01-1.05)) were identified as risk factors for NAFLD in lean individuals.

Table 1. Baseline characteristics of cases and controls.

Conclusion

The prevalence of NAFLD is significantly higher in lean population with IBD, suggesting that IBD could play a role in the development of NAFLD in lean individuals.

Disclosure

This project has received funding from “Diputación General de Aragón” (code: DGACOVID-02).

Introduction

Immunomodulators and biologicals play an essential role in current IBD management, but are associated with increased risk of infections. In light of the growing number of treatment options, the benefit-risk balance of drugs is becoming increasingly important in clinical decision making. Post-marketing surveillance studies are pivotal to assess infection risk, yet mainly focus on severe infections. As a result, data on mild and moderate infections are scarce. However, mild and moderate infections take longer to clear in immunosuppressed patients, have been reported to be the most burdensome adverse drug reaction according to patients, and can negatively influence drug adherence.

Aims & Methods

Aim: To assess the incidence of all infections and identify risk factors for the development of infections in IBD patients.
Methods: We previously developed and validated a Patient-Reported Infections Questionnaire (PRIQ), with excellent diagnostic accuracy, covering 15 infection categories with a 3-month recall period. [1] The current prospective, multicentre, observational cohort study was performed between Jun, 1 2020 and Jul, 1 2021, enrolling consecutive IBD patients and using the PRIQ which was implemented in myIBDcoach, an established telemedicine platform. Infection severity was defined as mild (self-limiting or topical treatment), moderate (oral antibiotics, antivirals or antifungals) or severe (hospitalization or IV treatment). Incidence rates (IR) were calculated for all infections, stratified for severity and subtype. Multivariable logistic regression, adjusting for relevant confounders, was performed to identify risk factors for infections.

Results

In total, 629 IBD patients (n=346 CD, n=283 UC, 58.3% female, mean age at cohort entry 48.3 years [SD 14.8], mean disease duration 12.4 years [SD 10.8]) were included which completed 2391 PRIQs during 572 person-years (PY) of follow-up. This resulted in 990 reported infections, corresponding to IRs of 17.3, 11.8, 5.1, and 0.4 per 10PY for all, mild, moderate, and severe infections, respectively. Upper respiratory tract (IR 26.9/100PY) and urinary tract infections (IR 14.8/100PY) were the most commonly reported mild and moderate infections types, respectively (Table 1). Compared to patients without treatment, patients on immunosuppressive treatment more frequently experienced infections of any severity (mild vs. no treatment: IR ratio (IRR) 1.57 [95%CI 1.21-2.06] p<0.001, moderate vs. no treatment: IRR 1.42 [95%CI 1.20-1.69] p<0.001). On multivariable logistic regression, female sex (mild adjusted odds ratio [aOR] 1.96 [95%CI 1.38-2.79]; moderate aOR 1.71 [95%CI 1.15-2.54]), smoking status (mild aOR 1.66 [95%CI 1.15-2.41]; moderate aOR 1.86 [95%CI 1.05-3.28]), higher BMI (moderate aOR 1.05 [95%CI 1.02-2.00]), and more comorbidities (mild aOR 2.41 [95%CI 1.46-3.98]; moderate aOR 1.82 [95%CI 1.07-3.11]) were all significantly associated with the development of mild and moderate infections.

Conclusion

​In this real-world prospective study, immune suppressive therapy was associated with mild and moderate infections of any kind in IBD patients. These infections particularly occur in females, smokers, patients with higher BMI and more comorbidities. This information should be considered in personalised treatment selection.

References

[1] Rezazadeh Ardabili A, van Esser D, Wintjens D, et al. Development and validation of a remote monitoring tool for assessment of mild, moderate, and severe infections in Inflammatory Bowel Disease [published online ahead of print, 2023 Feb 16]. J Crohns Colitis. 2023;jjad023. doi:10.1093/ecco-jcc/jjad023

Disclosure

M.P. reports grants and non-financial support from Falk Pharma, grants from European commission, grants from ZonMw (Dutch national research fund), grants and non-financial support from Takeda, grants and non-financial support from Johnson and Johnson, grants and non-financial support from Abbvie, non-financial support from Ferring, non-financial support from Immunodiagnostics, non-financial support from MSD, all outside the submitted work. D.J. reports grants from Top Knowledge Institute (Well on Wheat), grants from Horizon 2020 DISCOvERIE, grants from NWO-CCC Partnership program (Carbokinetics), all outside the submitted work. Z.M. reports grants form MLDS, Niels Stensen Fellowship and Galapagos. A.v.B. has served as speaker, adviser and/or principal investigator for AbbVie, Arandal, Arena, Celgene, Ferring, Galapagos, Janssen, MSD, Pfizer, Roche, Takeda, TEVA, and received research grants from Pfizer, TEVA, Eurostars funding, ZonMw, all outside the submitted work.
The other authors have nothing to disclose relevant to this publication.

Introduction

The incidence of elderly-onset ulcerative colitis (EO-UC) and Crohn’s disease (EO-CD) is increasing globally. However, whether the initial disease presentation of EO-UC and EO-CD differs from that in adult-onset (AO) is currently poorly investigated.

Aims & Methods

The aims of this study were to explore the initial presentation, severity, and disease course of newly diagnosed EO-UC and EO-CD (age ≥60 years) in comparison to AO-UC and AO-CD (18–59 years). The study was conducted as an ongoing prospective population-based inception cohort, IBD Prognosis Study, with enrollment between May 2021 and April 15^th, 2023, within a catchment population of 1.050.000 citizens (~20% of the Danish population). We defined severe disease course as requiring surgery or initiation of biological therapies within six months of diagnosis.

Results

The cohort comprised 501 patients, including 398 (79.4%) with AO disease (AO-UC: 223 (56.0%), AO-CD: 145 (36.4%), AO-IBDU: 30 (7.5%)), and 99 (19.8%) with EO disease (EO-UC: 64 (64.6%), EO-CD: 35 (35.4%), EO-IBDU: 5 (5.1%)). A comparison of the clinical presentation, severity, and initial disease course is presented in Table 1. As shown, EO-UC and EO-CD did not differ significantly from AO-UC and AO-CD in terms of demographic factors, disease phenotype, severity, and initial therapy. However, a significantly higher proportion of patients with EO-UC had left-sided UC, and tended to be treated less frequently with biological therapies and immunomodulators.
In a Cox multivariable regression model with Bonferroni correction adjusting for disease type and gender, patients with EO-UC (adjusted hazard ratio (aHR)=1.9 (95% confidence interval (CI) 0.5-7.3)) and EO-CD (aHR =4.1 (95% CI 0.3-12.3)) were not at different risk of requiring surgery or initiation of biological therapies within six months of diagnosis than patients with adult-onset IBD.
Table 1: Pairwise comparison of newly diagnosed elderly-onset and adult-onset inflammatory bowel diseases

Conclusion

In this population-based study, we found no difference between EO-IBD and AO-IBD in terms of initial disease presentation, severity, and course. However, patients with EO-IBD tended to be treated with less biological therapies and immunomodulators.

Disclosure

Mohamed Attauabi: None
Gorm Roager Madsen: None
Flemming Bendtsen: Tillotts, Ferring
Klaus Theede: Ferring, Janssen, Takeda, Pfizer, and Tillotts
Jakob Benedict Seidelin: has received research grants from Takeda, Janssen and is national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. None of these pertain to the research submitted here.
Johan Burisch: reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos, outside the submitted work.

Introduction

Etiology of acute pancreatitis can be established in the majority of patients. However, in 25 % of cases it remains elusive. Biliary microlithiasis/sludge is detected in up to 75% of patients with idiopathic acute pancreatitis (IAP). As recurrent biliary pancreatitis can be prevented, the underlying etiology of IAP should be established. The aim of this multicentre retrospective study was to develop a machine learning-aided non-invasive prediction tool to guide clinicians in the selection of idiopathic acute pancreatitis patients to be referred to endosonography to establish etiology and allow treatment.

Aims & Methods

We retrospectively used routinely recorded clinical and laboratory parameters of 218 consecutive patients with confirmed acute pancreatitis admitted to our tertiary care hospital between 2015 and 2020. Patients who did not receive endosonography as part of the diagnostic work-up and whose pancreatitis episode could be adequately explained by other causes than biliary sludge and microlithiasis were excluded. We trained supervised machine learning classifiers using H2O.ai automatically selecting the best suitable predictor model to predict microlithiasis/sludge. The predictor model was validated in two independent retrospective cohorts from two tertiary care centers (TU Munich & University Medical Center Göttingen).

Results

28 categorized patients’ variables recorded at admission were identified to compute the predictor model with an accuracy of 0.84 [95% CI 0.791, 0.9185], positive predictive value of 0.84 and negative predictive value 0.80 in the identification cohort (218 patients). In the validation cohort, the robustness of the prediction model was confirmed with an accuracy of 0.76 [95% CI 0.673, 0.8347], positive predictive value of 0.76 and negative predictive value of 0.78 (117 patients).

Conclusion

We present a robust and validated machine learning-based predictor model consisting of routinely recorded lab work at admission that can predict biliary sludge and microlithiasis as cause of acute pancreatitis and select patients for EUS.

Introduction

Chronic fatigue is a debilitating symptom and has major impacts on the quality of life of patients with chronic inflammatory conditions. In IBD, an estimated 50% of patients suffer from persistent fatigue despite successful treatment of intestinal inflammation. During active disease flares, this number jumps to 80% (Borren et al. 2018). Tryptophan metabolites are not only associated with disease activity in UC and CD, but also with chronic fatigue (Kavyani et al. 2022). Thus, our aims are (1) to characterize the relationship between fatigue and tryptophan derivatives and (2) to understand the metabolic dynamics arising when fatigue symptoms improve following therapeutic intervention.

Aims & Methods

In a prospective open label cohort of patients with moderate-to-severe Crohn’s disease (CD, n = 71) and ulcerative colitis (UC, n = 94) assigned to biologics therapy or JAK inhibitors, fatigue was assessed by the fatigue subscale of the Functional Assessment of the Chronic Illness Therapy – Fatigue (FACIT-F) questionnaire at therapy induction and 2 and 14 weeks thereafter. A FACIT-F score of <30.1 was considered severe fatigue while a score of >40 was considered no relevant fatigue. Clinical response at week 14 was defined as Crohn’s Disease Activity Index (CDAI) <150 and reduction of Partial Mayo Clinical Score (PMCS) >50% vs. baseline, respectively. We used targeted mass spectrometry to quantify the levels of 13 tryptophan derivatives and neopterin in a subset of patient serum in the weeks following therapy induction (at 0, 2, and 14 weeks, n = 120 individuals).

Results

Half of the recruited patients had severe fatigue at baseline (50.3%). Of the 120 patients who reached week 14 and had FACIT-F scores available, severe fatigue was experienced by 45.9% of the patients who did not respond to therapy and the rate was reduced to 13.2% in therapy responders. We found 8 metabolites positively associated with FACIT-F: tryptophan, kynurenic acid, kynurenine, picolinic acid, xanthurenic acid, serotonin, indole-3-proprionic acid, and quinaldic acid, while neopterin was negatively associated (FDR < 0.05). Four of these metabolites changed dynamically as a function of the extent of fatigue improvement: tryptophan, kynurenine, xanthurenic acid, and serotonin (FDR < 0.05). In all cases, the rate of change of these metabolites increased as a function of fatigue improvement.

Conclusion

Fatigue is linked to a diverse array of tryptophan metabolites. Notably, all of the significantly associated tryptophan derivatives were positively associated with FACIT-F, meaning that as fatigue symptoms improve, tryptophan metabolite levels increase. Many of these metabolites have previously been linked to symptom severity in IBD: for example, tryptophan, kynurenic acid and xanthurenic acid all tend to increase with symptom alleviation (Nikolaus et al. 2017, Michaudel et al. 2022). While the kynurenine-to-tryptophan ratio is elevated in active IBD (Nikolaus et al. 2017), this ratio did not convey a specific, fatigue-related signature. Considering that some patients continue to suffer from persistent fatigue even during disease quiescence, further work is needed to disentangle the impact of tryptophan metabolism on therapy response from its role on fatigue improvement.

Disclosure

F. Tran receives scientific funding from Sanofi, received consulting fee's from LEK Consulting and speaker's fees from Lilly, Janssen, Falk, Abbvie, Celltrion, onkowissen.de, CED Service GmbH. S. Schreiber reports consulting fees from Abbvie, Arena, BMS, Biogen, Celltrion, Celgene, IMAB, Gilead, MSD, Mylan, Pfizer, Fresenius, Janssen, Takeda, Theravance, Prevention Bio, Protagonist and Falk.