Lewis, James D.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder of the gastrointestinal tract whose genetic basis is only partly resolved because most risk variants identified by genome-wide association studies (GWAS) lie in non-coding regions, limiting direct gene assignment and biological interpretation 1,2 . Here we analysed whole-exome and whole-genome sequencing data from 86,213 IBD cases and 478,363 controls of European ancestry. We identified 68 IBD genes directly implicated by conditionally independent protein-coding associations across the allele frequency spectrum. Many newly implicated IBD genes are supported by orthogonal genomic or pleiotropic evidence, pointing to disease-related pathways and nominating targets with therapeutic relevance. We further identified allelic series and non-additive effects at key loci such as NOD2 and TYK2. These results show that large-scale sequencing can resolve disease genes and pathways that remain ambiguous from non-coding association alone, providing a more direct route from human genetics to biological insight and therapeutic hypotheses.

ABSTRACT Background Obesity has been linked to a more severe phenotype in patients with ulcerative colitis (UC). Aim To evaluate the impact of obesity on outcomes of advanced therapies in UC. Methods We conducted a retrospective cohort study utilising the TriNetX database comparing the composite score of corticosteroid use, change in advanced therapy or colectomy within two years between two cohorts of patients with UC—those with obesity (BMI ≥ 30 kg/m 2 ) and those without (BMI 18.5–24.9). The risk assessment was stratified to specific advanced therapies, including tumour necrosis factor α inhibitors (TNFi), vedolizumab, ustekinumab and Janus kinase inhibitors (JAKi). We performed 1:1 propensity score matching (PSM) for demographics, co‐morbid conditions, laboratory values and IBD medications including corticosteroids. Results There were 3904, 2025, 1150 and 477 patients on TNFi, vedolizumab, ustekinumab and JAKi, respectively, in the UC obesity cohort. After PSM, the UC obesity cohort was at an increased risk of the composite outcome of corticosteroid use, change in therapy and colectomy compared to the UC control cohort in patients on TNFi (aHR 1.37, 95% CI 1.29–1.49), vedolizumab (aHR 1.29, 95% CI 1.16–1.43), ustekinumab (aHR 1.1.26, 95% CI 1.10–1.44) and JAKi (aHR 1.38, 95% CI 1.13–1.69). Sub‐group analysis based on the specific TNFi also showed an increased risk of composite outcome for infliximab (aHR 1.36, 95% CI 1.22–1.52) and adalimumab (aHR 1.26, 95% CI 1.11–1.42) within 2 years. Conclusions Obesity is associated with lower efficacy of several advanced therapies in patients with UC.

Abstract Background Extraintestinal manifestations (EIMs) of inflammatory bowel diseases (IBDs) are a common and debilitating feature of disease, occurring in up to 40% of patients with IBD, yet predicting who may develop them is difficult. The goal of our study was to better characterize which patients may be at highest risk of developing not only 1 EIM, but also multiple EIMs, across both diseases. Methods A retrospective study of participants enrolled in the SPARC IBD (Study of Prospective Adult Research Cohort with IBD) registry was performed, and demographic and clinical data were analyzed. A total of 1211 patients with data available on EIMs were included, and differences among variables with vs without EIMs were assessed. Results A total of 329 participants with at least 1 EIM were identified, compared with 882 participants without any EIMs. Crohn’s disease patients and women were more likely to have 2 or more EIMs (P = .005 and P ≤ .001, respectively). Participants with ocular manifestations were likeliest to have at least 2 EIMs (P ≤ .001). Even when diagnosis was controlled for, involvement of the right colon (P = .021) was predictive of IBD-associated arthritis across both diseases in a multivariate generalized linear model. Conclusions This is the first comprehensive large-cohort assessment of how EIMs relate to one another at the individual vs systems levels. Further, our analysis is the first to recognize specific locations of colon involvement associated with EIMs of IBD, regardless of IBD type. These results are important in identifying patients at risk of developing future EIMs and may help with risk stratification when choosing treatments.

As medical management of inflammatory bowel disease makes great advances, most patients with inflammatory bowel disease will have long life expectancies without need for total colectomy. With prolonged disease duration, however, there is increased risk of dysplasia leading to colorectal cancer. Multiple consensus and guideline documents have been published over the last decade with recommendations to optimize early detection and management of dysplastic lesions. Endoscopic technology has improved tremendously, even over the past few years. Previously invisible dysplasia has become visible in most cases with advanced imaging technologies that now allow for much clearer and more detailed mucosal inspection. New tools to facilitate endoscopic resection of visible lesions have also enabled patients to avoid colectomy, with resulting need to continue colon surveillance. There are limited or conflicting data leading to inconsistent recommendations regarding the need for random biopsies, the preferred endoscopic imaging technique, and surveillance intervals after resection of dysplasia. Similarly, there remains significant variability in the application of guidelines into daily practice and availability of and training with advanced imaging technologies. Here, we present a narrative review of which patients are at highest risk for dysplasia, the current guidelines on surveillance colonoscopy, factors affecting optimal mucosal visualization, enhanced imaging techniques, standardized reporting terminologies for surveillance colonoscopy, endoscopic management of dysplasia, indications for colectomy, and briefly on future potential technologies to assist in dysplasia detection.

Abstract Background Entry criteria and outcome measures of Crohn’s disease (CD) clinical trials have evolved. Patients are now required to have active inflammation on screening endoscopy, with some studies requiring moderate-severe SES-CD scores. Recent trials have endoscopic response as a co-primary endpoint and endoscopic remission (ER) and deep remission (DR) as major secondary endpoints. Pivotal CD maintenance studies typically examine only responders to induction. The SEAVUE study required ≥1 ulceration of any size (SES-CD≥3) at baseline and had a treat-through design. To examine the results in the context of these trial design characteristics, we evaluated endoscopic outcomes at wk52 in the subgroup of pts with moderate-severe baseline SES-CD scores in SEAVUE, as well as those who were in clinical response after induction. Methods Biologic-naïve pts failing or intolerant to conventional therapy with CDAI≥220/≤450 and SES-CD≥3 were eligible. Pts were randomized, 1:1 to UST (~6mg/kg IV at wk0 then, 90mg SC q8w) or ADA (SC, 160mg at wk0, 80mg at wk2, then, 40mg q2w). Endoscopic outcomes were evaluated in all pts and the subgroup with moderate-severe endoscopic disease (baseline SES-CD≥6 for ileocolonic or colonic disease or SES-CD≥4 for isolated ileal disease). Endoscopic response was a ≥50% reduction from baseline in SES-CD, SES-CD≤3, or SES-CD=0 for pts with baseline SES-CD=3. ER was SES-CD≤3 or, 0 in pts with baseline SES-CD=3. DR was CDAI<150 and ER. Results Endoscopic outcomes for the subgroup with moderate-severe endoscopic disease were similar to those of the full cohort of pts. In UST-treated pts, endoscopic response was achieved at wk52 in, 41.9% in the full cohort and, 43.1% in the moderate-severe subgroup (Table, 1). In ADA-treated pts, endoscopic responses were, 36.9% and, 35.4%, respectively. For pts who were in clinical response after induction (Table, 1), endoscopic response rates were, 48.2% in the full cohort and, 49.5% in the moderate-severe subgroup for UST and, 44.8% and, 43.1%, respectively, for ADA. ER and DR rates were generally similar between the full cohort and the moderate-severe subgroup (Table, 2; eg, ERs were UST, 28.5% and ADA, 30.7% in full cohort; UST, 27.1% and, 27.8% ADA in subgroup). ER and DR rates were, 3%-7% higher in induction responders compared with the full cohort. Of note, even among wk16 nonresponders, some pts attained endoscopic outcomes at wk52 (eg, endoscopic responses in wk16 nonresponders were UST, 21.4% and ADA 13.3%). Conclusion In SEAVUE, both the UST and ADA treatment groups achieved high endoscopic response, ER, and DR rates at wk52. Results in pts with moderate-severe endoscopic disease were similar to those of the full cohort, but clinical responders after induction had higher rates than the full cohort.

Abstract Background and Aims Patient-reported outcomes are recommended endpoints in Crohn’s disease [CD] trials. The association between patient-reported general well-being relative to symptoms of diarrhoea and abdominal pain [AP] in patients with moderate to severe CD was explored. Methods Patients from three randomized, placebo-controlled, double-blind adalimumab or upadacitinib studies with average daily very soft/liquid stool frequency [SF] ≥4 and/or AP score ≥2 at baseline were included. Using electronic diaries, patients reported general well-being [seven-point Likert scale; 1 = worst; 7 = best] in item 10 of the Inflammatory Bowel Disease Questionnaire [IBDQ]. Changes in well-being and clinical outcomes of SF and AP from baseline to week 12 or 16, and the relationship between well-being and clinical outcomes were evaluated using cumulative distribution function and probability density function curves. Results In total, 858 patients with CD were included [adalimumab, n = 695; upadacitinib, n = 163]. Patients who achieved clinical remission [SF ≤2.8, AP score ≤1.0, neither worse than baseline] were more likely than those not in clinical remission to report IBDQ item 10 response in the 6–7 group category but not IBDQ categories ≤5. Higher IBDQ score for item 10 [6–7] was associated with lower SF and AP score. Greater point increases in IBDQ item 10 were associated with a greater percentage decrease in clinical parameters; a ≥25–30% decrease in SF or AP was associated with a ≥1-point improvement in IBDQ. Conclusions An association between improvements in patient-reported general well-being and clinical remission/response was observed using outcomes of SF and AP, supporting the clinical remission/response endpoint definitions used in clinical studies of CD. Clinical Trial Registrations [ClinicalTrials.gov]: NCT00077779 [CHARM]; NCT00348283 [EXTEND]; NCT02365649 [CELEST].