Introduction

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with a high social and health care system burden. Despite recent advances in UC treatment with available drugs acting in different signalling pathways related to the disease, there is still a significant proportion of non-responders who end up being overtreated and exposed to treatment's secondary effects. Therefore, it would be helpful to know the activity of each inflammatory pathway involved in UC pathogenesis in order to tailor the best treatment for each patient.

Aims & Methods

The aim of our study was to measure the activation of JAK/STAT pathway and IL-6 levels in colonic biopsies from patients with UC.
Methods: A prospective, observational single-centre study was designed and it is currently on going. Adult UC patients with any endoscopic activity (Mayo Endoscopic Score (MES) > 0) in a routine colonoscopy were included. Biopsies from inflamed (endoscopically active) and non-inflamed (endoscopically inactive) colon of each patient were homogenised and processed by using RIPA buffer and ultrasounds to obtain cell lysates. Determination of the activation of JAK/STAT pathway was performed by detecting phosphorylated forms of JAK1, JAK2, JAK3, TYK2, STAT1, STAT3 and STAT4 by Western blot. Human Luminex discovery assay was used for IL-6 quantification. Data are shown as percentage, median, interquartile range (IQR) and mean ± standard deviation as appropriate.

Results

So far, 19 patients were consecutively included (median age 60.9 years (IQR 40.8-66.6), 58% female). About 47% had left-sided UC, 32% extensive UC and 21% had proctitis. Regarding endoscopic activity, 52.6% of patients showed MES-3, 42.1% MES-2 and 5.2% MES-1. IL-6 was increased in biopsies from inflamed colon, while no IL-6 was found in biopsies from non-inflamed colon (p=0.00). Median IL-6 in inflamed colonic biopsies from patients with MES-2 was 41.5pg/ml (IQR 7.4-106.7) and 51.9pg/ml (IQR 17.5-220.5) in patients with MES-3 (p=0.4). Every patient showed, at least, one phosphorylated JAK protein and one phosphorylated STAT protein from JAK/STAT pathway in inflamed colonic biopsies. Nevertheless, the pattern of activation of JAK/STAT pathway was different in all patients as shown in table 1.

Conclusion

Different activated forms of JAK and STAT kinases are detected in inflamed colonic biopsies from UC patients, even though the activation pattern of JAK/STAT pathway differs among them. IL-6 levels are increased in inflamed colonic biopsies from UC patients while it is not detected in non-inflamed mucosa.

Introduction

Filgotinib (FIL) is a once-daily, oral, Janus 1 kinase preferential inhibitor approved for the treatment of ulcerative colitis (UC) in Europe and Japan. The efficacy and safety of FIL in patients with moderately to severely active UC was evaluated in the phase 2b/3 randomized, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522).¹

Aims & Methods

This post hoc analysis aimed to identify characteristics of FIL-treated patients that were associated with achieving corticosteroid (CS)-free remission. Adults aged 18–75 years were randomized 2:2:1 to induction FIL 100 mg, FIL 200 mg or PBO once daily for 11 weeks in induction study A (biologic-naive) and B (biologic-experienced). At week 10, patients in clinical remission or with a Mayo Clinic Score (MCS) response were re-randomized 2:1 to continue their FIL regimen or PBO for 47 weeks in the maintenance study. This analysis included only data from patients receiving CSs at baseline. Using univariate logistic regression, we analysed characteristics associated with achieving clinical remission at week 58 without using CSs for UC over a continuous period of ≥6 months (CS-free remission). P values <0.05 were considered statistically significant.

Results

At baseline, 81, 37, 92 and 47 patients were receiving CSs in the maintenance FIL 100 mg (n=172), PBO-to-match (PTM) FIL 100 mg (n=89), FIL 200 mg (n=199) and PTM FIL 200 mg (n=98) groups, respectively. The rates of CS-free remission in the FIL 100 mg, PTM FIL 100 mg, FIL 200 mg and PTM FIL 200 mg groups were 13.6%, 5.4%, 27.2% and 6.4%, respectively. Age, body mass index, history of pancolitis, duration of UC, faecal calprotectin and C-reactive protein levels, MCS and concomitant use of systemic CSs, immunomodulators and aminosalicylates had no significant effect on CS-free remission in the FIL 200 mg group. Mean baseline Robarts Histopathology Index (RHI) (odds ratio [OR]=0.949, p=0.023) was significantly associated with 6-month CS-free remission in the FIL 200 mg group. A baseline Mayo endoscopic subscore (MES) of 2 (vs 3) was associated with significantly increased odds of 6-month CS-free remission in the FIL 200 mg and FIL 100 mg groups (Table). Being male, a former (vs current) smoker or biologic-experienced was associated with significantly reduced odds of 6-month CS-free remission in the FIL 200 mg group.

Table. Association between 6-month CS-free clinical remission (dependent variable) and baseline characteristics^a by treatment groups.

Conclusion

Most baseline characteristics analysed had no statistically significant effect on 6-month CS-free remission under FIL 200 mg treatment. Low baseline MES and RHI, female sex, being a current (vs former) smoker and biologic-naive may predict higher likelihood of sustained CS-free remission in patients receiving FIL 200 mg.

References

1. Feagan BG et al. Lancet 2021;397:2372–84.

Disclosure

TK has served as an advisory board member, consultant or speaker for AbbVie, Activaid, Ajinomoto Bio-Pharma, Alfresa Pharma, Astellas Pharma, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical, and has received research funding from AbbVie, Alfresa Pharma, EA Pharma, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Sekisui Medical, Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical.
AD reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Abivax, AbbVie, Arena Pharmaceuticals, Falk Foundation, Gilead/Galapagos, Janssen and Pfizer; consultancy fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Janssen, MSD, Pfizer, Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts, and Vifor Pharma; payment from lectures, including service on speakers bureaus from AbbVie, Biogen, Celltrion, the Falk Foundation, Ferring Pharmaceuticals, Gilead/Galapagos, High5ImmunoTV, Janssen Pharmaceuticals, MSD, Pfizer, Takeda, Tillotts Pharma and Vifor Pharma; and payment for manuscript preparation from the Falk Foundation, Takeda, Thieme Medical Publishers and UNI-MED Verlag.
XR has served as an advisory board member, consultant or speaker for AbbVie, Amgen, Biogen, Celltrion, Ferring Pharmaceuticals, Galapagos NV, Janssen Pharmaceuticals, MSD, Pfizer, Sandoz and Takeda.
YF is an employee of Gilead Sciences K.K.
AO is an employee and shareholder of Galapagos NV.
CJ is a contractor for Galapagos NV.
TH has received lecture fees from Aspen Japan K.K., Janssen Pharmaceuticals, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd., Pfizer and Takeda; research grants from AbbVie GK, Activaid, Alfresa Pharma Corporation, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Inc., Janssen Pharmaceutical K.K., JMDC Inc., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc. and Takeda; scholarship contributions from Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd. and Zeria Pharmaceutical Co., Ltd.; and study group sponsorship from AbbVie GK, EA Pharma Co., Ltd., JIMRO Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Otsuka Holdings and Zeria Pharmaceutical Co., Ltd.
This study was funded by Gilead Sciences K.K.
The SELECTION trial was sponsored by Gilead Sciences Inc (Foster City, CA, USA). Galapagos NV (Mechelen, Belgium) was a collaborator for the SELECTION trial.
Writing support for the development of this abstract was provided by Tamsyn Stanborough, PhD, and Georgii Filatov of Oxford PharmaGenesis, Melbourne, Australia, and funded by Gilead Sciences K.K.

Introduction

Filgotinib is an oral Janus kinase 1 selective inhibitor licensed for the treatment of moderate to severe ulcerative colitis (UC) following the successful UC-SELECTION registration trials.¹ However, no real-world data have been published since filgotinib first received marketing authorisation in November 2021.

Aims & Methods

The aim of this study was to assess the short-term safety and effectiveness of filgotinib for the treatment of UC. The primary outcome was post-induction clinical remission, defined as a Simple Clinical Colitis Activity Index (SCCAI) of ≤2. A retrospective, observational cohort study was conducted at a tertiary IBD referral centre using prospectively maintained records between August 2022 and February 2023. Clinical disease activity was assessed at baseline and following induction at week 10 using paired SCCAI scores, faecal calprotectin (FCAL), and C-reactive protein (CRP). Quality of life was assessed using the IBD-Control questionnaire. Non-responder imputation was used for analyses.

Results

Thirty-four patients were initiated on filgotinib during the study period, with post-induction outcome data available for 32 patients; 56% male, median age 38 (IQR range 26–53), 41% with prior biologic and/or tofacitinib exposure. Patients were treated for a median duration of 20 weeks (IQR 13–25) with treatment persistence of 69% at the time of analysis; eight patients were switched to alternative treatments due to non-response and two patients underwent colectomy.
At the end of induction, nine patients (28%) were in clinical remission; all patients were corticosteroid-free. Median SCCAI decreased significantly from a baseline of 7 (IQR 4-10) to 1 (IQR 0-6) at week 10, p<0.01, n=25. Median FCAL fell numerically from a baseline of 464 mcg/g (IQR 183-1245) to 125mcg/g (IQR 30-502) following induction, p=0.06, n=20. There was no significant change in CRP, haemoglobin, serum albumin, or lipid profile components following induction. There was a significant improvement in pre- and post-treatment quality of life scores from a median of 5 (IQR 2-9) to 16 (IQR 4-16), p<0.01.
Thirteen patients described a mild self-resolving coryzal illness, sore throat, or headaches during treatment. There was one reported case of oral herpes simplex infection requiring treatment interruption. There were no serious adverse events.

Conclusion

Filgotinib was well tolerated and clinically effective in the short term with improvements in quality of life but larger prospective cohorts with longer follow up are needed.

References

1. Feagan BG, Danese S, Loftus EV, et al. Filgotinib as induction and maintenance therapy for ulcerative colitis (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. The Lancet. 2021 Jun 19;397(10292):2372–84.

Disclosure

FD has received honoraria for educational meetings and speaker fees for Dr Falk. Received advisory board/nurse consultation fees for for Dr Falk, Galapagos, Pfizer and Takeda. Travel grants received from Pharmacosmos, Celtrion, and Tillotts.
KP has received honoraria for educational meetings and speaker fees from AbbVie, Janssen, Takeda, Pfizer, DrFalk, PredictImmune and Ferring and has received advisory board fees from AbbVie, Galapagos, Pfizer and Janssen.
SH served as a speaker, a consultant, and/or an advisory board member for Pfizer, Janssen, AbbVie, and Takeda. Travel grants received from Ferring, Falk Pharma, and Pharmacosmos.
RH, AA and SK have no disclosures.

Introduction

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a widespread chronic liver condition closely associated with obesity, insulin resistance, and dyslipidemia. Recent evidence points to gut microbiota dysbiosis as a key player in MASLD pathogenesis, affecting intestinal barrier function and systemic inflammation.

Aims & Methods

The aim was to investigate gut microbiota composition in patients with MASLD and assess its association with disease progression and gut barrier dysfunction. A total of 152 MASLD patients and 150 matched controls without liver pathology were examined. Diagnosis was confirmed by ultrasound and steatometry, alongside assessment of cardiometabolic risk factors. Gut microbiota composition was analyzed using real-time PCR, focusing on Bacteroidetes, Firmicutes, and Actinobacteria. Hydrogen breath testing was used to diagnose small intestinal bacterial overgrowth (SIBO), and the presence of Akkermansia muciniphila was evaluated as a marker of gut barrier integrity.

Results

MASLD patients demonstrated a significant increase in Firmicutes (50.3%) and Actinobacteria (15.3%) proportions compared to controls, with a higher Firmicutes/Bacteroidetes (F/B) ratio. SIBO was detected in 52% of MASLD patients versus 40.5% in controls (p<0.05). The presence of Akkermansia muciniphila was notably lower in MASLD patients (33%) compared to controls (63%), suggesting impaired gut barrier function. Strong positive correlations were observed between Actinobacteria abundance and the F/B index (r=0.75, p<0.05), while Akkermansia muciniphila presence negatively correlated with MASLD development (r=–0.69, p<0.05).

Conclusion

Gut microbiota dysbiosis, characterized by elevated Firmicutes and Actinobacteria and reduced Akkermansia muciniphila, is closely associated with MASLD pathogenesis. The findings highlight the potential of microbiota-targeted interventions for improving gut barrier function and modifying disease progression in MASLD patients.

Introduction

Fructans or fructooligosaccharides are included in the spectrum of FODMAP (fermented) sugars, which are relevant in the induction of symptoms in patients with disorders of gut-brain interaction (DGBI) and in non-coeliac gluten sensitivity (1). Fructans have been shown to induce visceral hypersensitivity, an increase in mucosal mast cells, and changes in the colonic mucosal barrier in mice, and hypersensitivity associated with an altered gut microbiome in humans (2-5). Breath tests are used in the assessment of intolerances to several FODMAPs, but the test is poorly standardised for fructans (6).

Aims & Methods

A standardised breath test with fructans (10g Orafti^®HSI) was performed afer a 24-hour low-FODMAP diet and >8-hour fast. Exhaled hydrogen and methane concentrations were measured every 30 minutes until 5h, and synchronised symptom assessments performed for 24h (composite symptom index score, SI, 7) in 600 successive male (33%) and female patients of average age 41 years referred to our gastroenterology practice with DGBI (irritable bowel syndrome and/or functional dyspepsia, Rome 4 criteria). Breath gas concentration thresholds of >20ppm and >8ppm above baseline were used for hydrogen and methane, respectively.

Results

The SI was positive in 61.2% (n=367) of patients within 24 hours of fructan ingestion. The SI peaked in the first 3 hours in 17.5% (n=105) and in the first 5 hours in 42.5% (n=255) of patients. Suprathreshold increases in hydrogen and methane concentrations within 5 hours were seen in 62.7% and 14.9% of patients, respectively. Discordant SI and breath gas results were obtained in 35.1% (hydrogen) and 57.8% (methane) of patients. A negative SI with a suprathreshold hydrogen or methane result occurred in 18.2% and 5.2%, respectively. A positive SI with a subthreshold hydrogen or methane result occurred in 16.9% and 52.6%, respectively. Suprathreshold concentrations in methane and not in hydrogen were apparent in 4.5%. Main symptoms during tests were excessive flatulence (58.8%), bloating (50.3%), abdominal fullness (49.3%), abdominal cramps (29.0%), nausea (26.7%), GORD (26.7%), diarrhoea (9%) and extra-GI symptoms (16.2%).

Conclusion

Standardised oral provocation with fructans resulted in familiar clinical symptoms in a majority of patients with DGBI, suggesting a high prevalence of fructan intolerance. Due to the slow fermentation of intestinal fructans and the associated delayed symptoms, prolonged data collection over at least 12, preferably 24 hours is recommended. The test duration of 3 hours currently commonly used in test centres is inadequate. Symptom and breath gas concentration results are often divergent, as is known from other FODMAP breath tests, and validation against clinical outcome results is required. Fructans are of interest in DGBI as the current literature suggests they have both protective as well as detrimental effects on intestinal physiology, which may be dependent on the resident microbiota.

References

1. Gry I et al. Gastroenterology 2018;154:529–539
2. Kamphuis JBJ et al. Gastroenterology 2020;158:652-663
3. Chen BR et al. World J Gastroenterol 2017;23:8321-8333
4. Kamphuis JBJ et al. FASEB J. 2022;36:e22297
5. Chumpitazi BP et al. Aliment Pharmacol Ther 2021;53:499-509
6. Fedewa A et al. Curr Gastroenterol Rep 2014;16:370
7. Wilder-Smith CH et al. Aliment Pharmacol Ther 2013;37:1074-83

Introduction

Patients with Disorders of Gut-Brain Interaction (DGBI) often experience meal-related symptoms, potentially due to carbohydrate intolerances like fructose and/or lactose. While breath tests are common for exploring carbohydrate malabsorption, assessing intolerances, defined by the onset of gastrointestinal (GI) symptoms after a defined load of carbohydrates, is valuable. The adult carbohydrate perception questionnaire (aCPQ) can be used for detecting carbohydrate intolerances (1).

Aims & Methods

We aimed to determine lactose and fructose intolerance prevalence in DGBI and characterize these patients. DGBI patients who underwent fructose (25g) and lactose (25g) breath tests alongside the aCPQ in our tertiary center between May 2022 and December 2023 were included. Carbohydrate intolerance was a 20 mm increase in any of the five Visual Analog Scales (VAS) scores (for abdominal pain, nausea, diarrhea, bloating, and flatulence) in aCPQ. An increase from baseline of ≥20 ppm in exhaled H2 or ≥10 ppm of CH4 (≥20 ppm for fructose) indicated malabsorption. Patients completed questionnaires on irritable bowel syndrome (IBS) symptom severity (IBS-SSS), somatic symptoms (PHQ-15), quality of life (QOL)(GIQLI), anxiety, and depression (HAD).

Results

We included 314 DGBI patients, among them, 124 were lactose intolerant, 138 were fructose intolerant, and 77 were intolerant to both carbohydrates. Lactose intolerant patients were younger (42± 15.9 vs 46 ± 15.3; p=0.022), and more likely to have lactose malabsorption and fructose intolerance, while fructose intolerant patients were more likely to have fructose malabsorption, lactose intolerance, and higher anxiety/depression levels. Both intolerant groups were more likely to be female (81.5% vs 61.6%; p<0.0001 for lactose, 77.5% vs 63.1%; p=0.006 for fructose), with 2 DGBI or more (63.1% vs 40.7%; p<0.0001 for lactose, 57.4% vs 43.5%; p=0.021 for fructose), to have a reduced QOL, higher levels of GI symptoms, and somatic symptoms (table). Logistic regressions showed independent associations of female sex, fructose intolerance, and lactose malabsorption with the lactose intolerance variable, and IBS symptom severity, lactose intolerance, and fructose malabsorption with the fructose intolerance variable.

Table: Comparison of DGBI patients with and without lactose and fructose intolerance

Conclusion

DGBI patients with lactose and fructose intolerance exhibit severe IBS symptoms and reduced QOL. Interestingly, intolerance to one carbohydrate is associated with malabsorption of this specific carbohydrate and the coexistence of intolerance to the other carbohydrate.

References

1. Hammer, Johann et al. European journal of gastroenterology & hepatology 2021, doi:10.1097/MEG.0000000000001880

Disclosure

CM has served as a consultant/advisory board member for KyowaKirin, Norgine, Biocodex, Mayoly Spindler, Tillots, Ipsen, Nestlé HealthScience and Viatris.
FM has served as a consultant/speaker for Laborie, Medtronic, Dr Falk Pharma.
GG has served as a consultant/speaker for Laborie, Medtronic, Kyowa Kirin, Lilly and Enterra medical.