Sebastian, Shaji

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 Background and Aims Intestinal ultrasound (IUS) is increasingly used to monitor treatment efficacy in inflammatory bowel disease (IBD) trials. However, standardized definitions for response, remission, and optimal assessment timing remain undefined. An international expert consensus meeting was held to establish IUS endpoints for clinical trials. Methods A panel of 35 international gastroenterologists and radiologists participated in a modified Delphi process, reviewing the literature and developing consensus statements. Agreement was defined as at least 75% consensus. Results Consensus was reached on 150 statements across four domains: general IBD (30 statements), luminal Crohn’s disease (CD) (43), perianal CD (51), and ulcerative colitis (UC) (26). For luminal CD and UC, ultrasound response was defined by: (1) a ≥25% reduction in bowel wall thickness (BWT) from baseline, or (2) multifactorial improvement, combining BWT reduction with ≥1 grade decrease in color Doppler signal (CDS) or another IUS parameter. Assessments were set at weeks 4-8 for the colon and week 12 for the terminal ileum. Ultrasound remission in luminal CD was defined as: (1) BWT normalization (≤3 mm) or (2) normalization of multiple parameters, including BWT, CDS, and all other IUS parameters. Similar remission criteria were proposed for UC, but the sigmoid BWT normal range (3-4 mm) remained uncertain. The bowel ultrasound score (BUSS) for CD and the Milan ultrasound criteria (MUC) for UC were supported as standardized scoring systems for trials. Conclusion This consensus provides standardized IUS definitions to enhance consistency in IBD trials, supporting the integration of IUS in future research.

Abstract Background and Aims Perianal fistuliing Crohn’s disease [PFCD] is an aggressive phenotype of Crohn’s disease defined by frequent relapses and disabling symptoms. A novel consensus classification system was recently outlined by the TOpCLASS consortium, which seeks to unify disease severity with patient-centred goals but has not yet been validated. We aimed to apply this to a real-world cohort and to identify factors that predict transition between classes over time. Methods We identified all patients with PFCD and at least one baseline and one follow-up pelvic MRI [pMRI]. TOpCLASS classification, disease characteristics, and imaging indices were collected retrospectively at time periods corresponding with respective MRIs. Results We identified 100 patients with PFCD, of whom 96 were assigned TOpCLASS Classes 1–2c at baseline. Most patients [78.1%] started in Class 2b, but changes in classification were observed in 52.1% of all patients. Male sex [72.0%, 46.6%, 40.0%, p = 0.03] and prior perianal surgery [52.0% vs 44.6% vs 40.0%, p = 0.02] were more frequently observed in those with improved class compared to unchanged and worsened class. Baseline pMRI indices were not associated with changes in classification; however, greater improvements in mVAI, MODIFI-CD, and PEMPAC were seen among those who improved. Linear mixed effect modelling identified only male sex [-0.31, 95% CI -0.60 to -0.02] with improvement in class. Conclusion The TOpCLASS classification highlights the dynamic nature of PFCD over time. However, our ability to predict transitions between classes remains limited and requires prospective assessment. Improvement in MRI index scores over time was associated with a transition to lower TOpCLASS classification.