Introduction

The gut microbiome has been implicated in inflammatory bowel disease (IBD), with functional defects leading to disturbances in important classes of metabolites, including bile acids. Bile acids are molecules produced by the liver that help aid in the digestion of dietary fats. While most are reabsorbed in the small intestine, approximately 5% escape into the colon and are metabolized by bacteria in the colon. Bile acids are important signalling molecules and have been implicated in both inflammation and colorectal cancer. More information is needed to understand how dysbiosis modifies bile acid profiles in patients with IBD.

Aims & Methods

This is a bioinformatic analysis of whole metagenomic sequences that searched for bacteria and genes involved in the transformation of primary bile acids into secondary bile acids. The population consisted of 215 IBD patients who were previously recruited from France. The faecal samples and metagenome sequences were obtained for each patient. The data was processed through a metagenomic pipeline using HUMAnN 3.0 and MetaPhlAn 3.

Results

Cluster analysis previously revealed 3 distinct patient groups based on their gut microbiome composition, one of which, cluster 3, was strongly associated with bile acid dysmetabolism. Firmicutes CAG:103 and Firmicutes CAG:83, previously uncultured co-abundance groups, most strongly positively correlated with secondary bile acid levels in the dataset. Firmicutes CAG:103 has previously been identified as a potential dominant secondary bile acid producer in metagenomic surveys. Notably, these bacterial groups were almost completely absent in cluster 3 subjects, implicating them as potential actors in secondary bile acid depletion in IBD patients.

Conclusion

This study suggest loss of Firmicutes CAG:103 and Firmicutes CAG:83 could be a driving factor for bile acid dysmetabolism in IBD patients. Further research is underway to validate these findings using metagenome-assembled genomes.

References

Lavelle, A., Nancey, S., Reimund, J. M., Laharie, D., Marteau, P., Treton, X., ... & Sokol, H. (2022). Fecal microbiota and bile acids in IBD patients undergoing screening for colorectal cancer. Gut Microbes, 14(1), 2078620.

Lavelle, A., & Sokol, H. (2020). Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nature reviews Gastroenterology & hepatology, 17(4), 223-237.

Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, has demonstrated efficacy and safety in moderately to severely active ulcerative colitis (UC) Phase 3 trials (LUCENT-1 and -2; NCT03518086, NCT03524092) among patients who had an inadequate response, loss of response, or intolerance to conventional or advanced therapy. At the LUCENT-1 induction baseline, 41% of the population had experienced a biologic/tofacitinib failure, and 36.3% experienced at least one anti-TNF failure. Among patients with one prior anti-TNF failure only, this analysis evaluated the clinical efficacy of miri compared to placebo (PBO) in induction and maintenance therapy and the efficacy of miri in extended induction.

Aims & Methods

In LUCENT-1, UC patients were randomized to receive 3 intravenous (IV) doses of 300mg miri or PBO every four weeks (Q4W) at W0, W4, and W8 (induction population). In LUCENT 2, responders to miri induction at W12 were re-randomized to subcutaneous (SC) 200mg miri or PBO Q4W through W52 of continuous therapy (maintenance population). Patients not achieving clinical response with miri 300mg IV at W12 received extended induction treatment with open-label 300mg miri IV at W12, W16, and W20 (extended induction population). Patients responding to extended induction at W24 entered open-label maintenance and received 200mg miri Q4W SC until W52 (extended induction responders). Endpoints evaluated were clinical response, clinical remission, symptomatic remission, endoscopic remission, corticosteroid (CS)-free remission, and histologic-endoscopic mucosal remission (HEMR). Efficacy in the subgroup of patients with failure of one anti-TNF only was assessed using Cochran-Mantel-Haenszel tests at W12 (induction population) and W52 (maintenance population).

Results

At LUCENT-1 baseline, of patients who experienced anti-TNF failure, 45% of patients (n=190) had one prior anti-TNF failure only. The one anti-TNF failure subgroup had a longer disease duration, higher rate of pancolitis, similar disease severity (MMS and ES) and slightly higher baseline CS and IMM use, compared to the overall LUCENT population. In the induction and maintenance population, a significantly greater proportion of miri-treated patients achieved the following efficacy endpoints compared with PBO [miri vs. PBO, p-value]: clinical response (W12: [64.4% vs. 34.1%, p=0.001]; W52: [67.2% vs. 44.8%, p=.03]), clinical remission (W52: [44.3% vs. 17.2%, p=.017]), symptomatic remission (W52: [63.9% vs. 34.5%, p=.005]) (Table). Among the extended induction population, 45.7% achieved clinical response at W24; 75% achieved clinical response, 30% achieved clinical remission and CS-free remission at W52 (Table).
Table: Efficacy of miri vs PBO for subjects with Only One Prior anti-TNF Failure^a

Conclusion

Mirikizumab is efficacious for induction and maintenance therapy in patients with moderately to severely active UC who have failed one prior anti-TNF.

Disclosure

• A. Hart has served as a speaker, consultant, and advisory board member for: AbbVie, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Pharmacosmos, Takeda, and Roche
• M. D. Martín-Arranz has served as a speaker or has received research or educational funding or advisory fees from: AbbVie, Eli Lilly and Company, Faes Farma, Ferring Pharmaceuticals, Janssen, Merck Sharp & Dohme, Pfizer, Shire Pharmaceuticals, Takeda, and Tillots Pharma
• D. Laharie has received consulting, boards, transports, or fees from: AbbVie, Amgen, Biogaran, Biogen, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Janssen, Merck Sharp & Dohme, Pfizer, Prometheus, Roche, Takeda, and Theradiag
• K. Matsuoka has received fees for grants and/or contracts from: AbbVie, EA Pharma, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, and Zeria Pharmaceutical; lecture fees from: AbbVie, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, JIMRO, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; and manuscript preparation fees from: Eli Lilly and Company
• E. Dhesi, I. Redondo, S. Baygani, and K. Samaan are employees and shareholders of: Eli Lilly and Company
• L. Zaremba-Pechmann is a contractor for: Eli Lilly and Company through HaaPACS
• S. Navabi has served as an advisor for: Eli Lilly and Company
• Medical writing assistance was provided by Estelle Sontag, PhD, and Alice Carruthers, PhD, of ProScribe – Envision Pharma Group, and was funded by Eli Lilly and Company
• Previously presented at the European Crohn's and Colitis Organisation - 2024 Congress

Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 describes etrasimod efficacy and safety in patients stratified according to baseline disease activity. In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg once daily or placebo.¹ ELEVATE UC 52 had a treat-through design comprising a 12-week (wk) induction period followed by a 40-wk maintenance period. ELEVATE UC 12 comprised a 12-wk induction period. In this analysis, data were pooled from both trials and patients’ baseline UC activity was stratified as moderately or severely active based on a Modified Mayo score (MMS) of 5–7 or 8–9, respectively. Efficacy endpoints were measured at Wk 12 and included mean percentage change from baseline in MMS and clinical response/remission according to MMS category. Efficacy data were analysed descriptively, and 95% confidence intervals (CIs) were calculated for all means or proportions using normal approximation or simultaneous estimation method, respectively. Safety was assessed up to Wk 52 in the pooled safety analysis set.

Results

Of the 743 patients in this analysis, 525 (70.7%) had a baseline MMS 5–7 and 218 (29.3%) had a baseline MMS 8–9. Baseline characteristics were broadly similar between subgroups, with the exception of lower rates of proctitis in patients with MMS 8–9 vs 5–7 (3.3% and 3.0% vs 9.3% and 9.4% in etrasimod and placebo groups, respectively). At Wk 12, patients treated with etrasimod showed larger mean percentage reductions (95% CI) in MMS, vs placebo, regardless of baseline disease activity (48.4% [52.3, 44.4] vs 27.0% [32.2, 21.7] for baseline MMS 5–7, and 46.4% [51.2, 41.5] vs 29.8% [37.2, 22.3] for baseline MMS 8–9). At Wk 12, more patients treated with etrasimod achieved clinical response, vs placebo, regardless of baseline disease activity, with an overall reduction from baseline disease activity as measured by MMS categorisation in both baseline MMS subgroups (Table). Generally, rates of treatment-emergent adverse events (TEAEs) were similar across treatment and baseline disease activity subgroups (proportion of patients with any TEAE: 59.0% vs 50.8% and 65.1% vs 56.1% for etrasimod vs placebo, in baseline MMS 5–7 and 8–9 groups, respectively).

Conclusion

Etrasimod showed greater reductions in disease severity and higher rates of clinical response, vs placebo, regardless of baseline disease activity. The safety profile of etrasimod was consistent with the overall trial population¹ and was not impacted by baseline disease activity.

References

1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171

Disclosure

BES has received consulting fees from AbbVie, Abivax, Alimentiv, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Morphic Therapeutics, MRM Health, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, Theravance Biopharma, TLL Pharmaceutical, Ventyx Biosciences; speaker fees from Abivax, Bristol Myers Squibb, Janssen, Lilly, Pfizer, Takeda; research grants from Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma; stock options from Ventyx Biopharma; and other support from Bristol Myers Squibb, Lilly, Janssen, Pfizer and Takeda. MCD is a consultant for AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer Inc, Prometheus Labs, Spyre and Takeda. PGK has received consulting and speaker fees from AbbVie, Janssen, Pfizer Inc, and Takeda and has received scientific grants from Pfizer Inc and Takeda. SV has received speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; and grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. RP has received consulting fees from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, UCB; speaker fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda; an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, Ventyx; and received research support from AbbVie, Janssen, Takeda and Pfizer. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, BMS, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr, Theravance; and has received research support from Pfizer Inc and Takeda. JCW, JW and EB are employees and shareholders of Pfizer Inc. AM is an employee of Pfizer Ltd and shareholder of Pfizer Inc. MG is an employee and shareholder of Pfizer AG. AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda, Bristol Myers Squibb; and speaker fees from Bristol Myers Squibb.

Introduction

Inflammatory Bowel Disease (IBD), encompassing Crohn's Disease (CD) and Ulcerative Colitis (UC), shares chronic and inflammatory characteristics with Non-Alcoholic Fatty Liver Disease (NAFLD). While their precise pathogenesis remains unclear, emerging evidence implicates dysbiosis and metabolic changes. This study aims to investigate the association between IBD and NAFLD, focusing on metabolic syndrome and its nutritional implications

Aims & Methods

Objective: To evaluate the nutritional status and body composition in IBD patients, comparing groups with and without NAFLD, and identifying the associated factors.
Methods: A cross-sectional study was conducted, assessing clinical data, metabolic syndrome presence, nutritional status, and biochemical markers. Patients were categorized into IBD+NAFLD and IBD-only groups based on hepatic ultrasound findings. Statistical analysis included descriptive statistics and logistic regression.

Results

127 patients were included, comprising 58 CD and 69 UC, with a mean age of 45.56 years. Most patients were female and did not engage in physical activity. Patients were mostly in clinical remission and endoscopic activity. 58 patients (45.67%) had hepatic steatosis on ultrasound, forming the IBD+NAFLD group. The IBD+NAFLD group had higher BMI, fat mass, and all circumference values, Table 1, as well as a higher prevalence of hypertension (p=0.0446) and dyslipidemia (p=0.0377). It is noteworthy that, although most of these patients were classified as overweight by BMI, considering anthropometric data, most IBD+NAFLD patients were classified as eutrophic. 86.21% of patients in the IBD+NAFLD group met the criteria for MAFLD. No difference was observed regarding medication in use. Regarding biochemical tests, the IBD+NAFLD group had higher values of hematocrit (p=0.0023), liver enzymes (AST, p=0.0141 and ALT, p<0.0001), fasting glucose (p=0.0107), glycated hemoglobin (p=0.0146), basal insulin (p=0.0003), and triglycerides (p=0.0001), with lower HDL cholesterol (p=0.0101)

Conclusion

The study highlights a significant association between nutritional status and NAFLD in IBD patients. Those categorized as eutrophic had a higher prevalence of hepatic steatosis, potentially linked to dietary factors.

References

Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and
natural history of non‐alcoholic fatty liver disease and non‐alcoholic
steatohepatitis in adults. Alimentary pharmacology & therapeutics.
2011;34(3):274-285./ Silva A.F; Schieferdecker M.H; Amarante M. B. Ingestão alimentar em pacientes
com doença inflamatória intestinal ABCD, arq. bras. cir. dig. 24 (3) • Set 2011/ Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA.
2015;313(22):2263-73

Clinical Case Summary

Celiac disease (CD) is one of the most common autoimmune disorders, affecting up to 1% of the population. The overlap of CD with other benign and malignant pathologies can make the diagnostic course complex.

We present the case of a 51-year-old man with no known medical history, who developed generalized edema. In this context, and after etiological investigation, CD was diagnosed with modified Marsh classification 3c. In the following 6 months, despite gluten avoidance, decreased anti-transglutaminase antibody titers and weekly albumin replacement, the patient developed progressive anasarca. Laboratory findings suggested nephrotic syndrome with proteinuria of 30g/24h. Renal biopsy confirmed membranous nephropathy (MN). At this point, the diagnosis of secondary MN due to CD was made, following the exclusion of other potential etiologies. The patient showed only partial remission of proteinuria which led to new studies revealing a surprising de novo positivity of anti-PLA2R. Immunosuppressive therapy was started, with full remission. After 3 months of stopping this therapy the patient again presented with generalized edema associated with inguinal, cervical, and axillary lymphadenopathy and lymphocytosis. Excisional lymph node biopsy revealed classical mantle cell lymphoma. Endoscopic studies showed diffusely infiltrative pseudonodules in the stomach, duodenum, ileum, and colon. Histological evaluation confirmed gastrointestinal involvement of the lymphoma. The patient is currently under R-CHOP chemotherapy. It is now believed that MN was a paraneoplastic glomerular presentation of an indolent neoplasm masked by immunosuppressants rather than a causal relationship with CD.

We highlight a case where the systemic presentation of CD made the diagnosis of refractory disease versus mimicking pathologies challenging, necessitating extensive etiological study. Despite the association of CD with T-cell lymphomas, other unrelated malignancies should be considered.