James Christopher Lee

Background & Aims: Patient-reported outcomes (PRO) are essential for monitoring disease activity and treatment response in inflammatory bowel disease (IBD). The conventional PRO-2 requires several days of prospective symptom recording, increasing participant burden and attrition in longitudinal research. We evaluated whether a “rapid PRO-2”, using 2 days of data collected retrospectively and prospectively in a single day, could serve as a reliable and pragmatic alternative to a 4-day PRO-2. Methods: Using data from the ongoing IBD-RESPONSE cohort (n = 684 Crohn’s disease [CD]; n = 548 ulcerative colitis [UC]), we compared 4-day PRO-2 and rapid PRO-2 scores at baseline and 14 weeks post-therapy to assess disease activity, clinical (non) response and remission. Results: At baseline, 87.1% (596/684) of CD and 88.7% (486/548) of UC patients remained in the same active/inactive disease activity category (Cohen’s kappa: CD 0.715; UC 0.762; both P < .001). At week 14, 77% (CD; 195/252) and 83.1% (UC; 193/232) remained in the same non-response/response/remission category (Cohen’s kappa: CD 0.653; UC 0.743; both P < .001). Discrepancies mainly involved adjacent category shifts (ie, between response and remission, or non-response and response), with minimal re-classification between remission and non-response (n = 7 CD and n = 2 UC). Greater symptom variability across the 4 days increased the likelihood of switching between remission and non-response (odds ratio [95% confidence interval], CD 5.0 [3.65–6.85]; UC 7.8 [5.6–11.0], both P < .001). Responsiveness to clinical change was comparable between instruments. Conclusions: The rapid PRO-2 retains essential symptom data and demonstrates strong agreement with the 4-day PRO-2, offering an alternative in longitudinal studies to minimize burden and attrition.

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.

Background: Ileo-colonoscopy provides accurate assessment of mucosal inflammation in Crohn’s disease. Magnetic resonance imaging (MRI) offers a non-invasive alternative. MRI-based scores such as the simplified MaRIA (sMaRIA) have been proposed for measuring treatment response in clinical trials, but systematic comparisons with endoscopic scoring systems in prospective datasets are lacking. Methods: PROFILE trial participants underwent ileo-colonoscopy and small bowel MRI at baseline and week 48 (end-of-trial). Using this dataset our primary objective was to assess the correlation between Simple Endoscopic Score for Crohn’s Disease (SES-CD) and sMaRIA scores using contemporaneous ileo-colonoscopy and MRI studies. We also assessed the utility of sMaRIA as a clinical trial endpoint, and correlation between baseline sMaRIA and need for future surgery. Endoscopic and MRI remission were defined as SES-CD and sMaRIA scores of 0. Ulcer subscores were also examined. Results: In total, :285 patients had paired baseline ileo-colonoscopy and MRI studies and 220 had paired end-of-trial studies—undertaken a median of 35 and 22 days apart respectively. Correlation between total SES-CD and sMaRIA scores on end-of-trial studies was moderate (Spearman’s ρ = 0.428). MRI/sMaRIA identified only 18/143 ulcerated segments seen on ileo-colonoscopy. While remission rates between PROFILE treatment arms were significantly different on ileo-colonoscopy/SES-CD (P = .005), this difference was not seen on MRI/sMaRIA (P = .564). Patients requiring abdominal surgery had higher baseline sMaRIA scores than those who did not (P = .015), while SES-CD scores were not different between these groups (P = .830). Conclusions: MRI should be considered as complementary to ileo-colonoscopy for assessing ileal Crohn’s disease. sMaRIA should not replace SES-CD in clinical trials.

Leading biomedical resources rely on genome variation in Britain ^1–3 , but the historical processes that shaped present-day fine-scale diversity remain debated ^4–13 . Here we sequenced 1039 ancient shotgun genomes from Britain (median 1.4-fold coverage), primarily dating to the first millennium CE. We imputed ∼660 million variants in the UK Biobank ^14–16 and employed genealogy-based ancestry reconstruction. We found an association between Iron Age consanguinity and matrilineal burial practices ¹⁷ , later disrupted following the Roman Conquest. Despite this societal impact, only 20% of Roman-period individuals carried detectable ancestry from outside Britain. In contrast, from the 6th century CE we detect widespread influx of ancestry in over 70% of individuals in southern’Anglo-Saxon’ Britain, with limited local admixture. We find previously underappreciated heterogeneity, with ancestries associated with Central and Southern Europe rising in prevalence from the 7th century CE. We demonstrate distinct Scandinavian-related ancestry in many Viking-associated contexts, but show that the population-level impact of the Viking Age in Britain was limited. Finally, we detect pre-medieval selection on variants linked with key immunity genes TLR10-TLR1 and IRF8 . These results identify population-level and selective processes that shape variation and disease risk in Britain today.

Inflammatory bowel disease (IBD) arises from a multifaceted interplay of genetic predisposition, environmental triggers, microbial dynamics, and immune dysregulation. This complex network of interacting factors disrupts gut homeostasis, leading to chronic relapsing inflammation in the gastrointestinal tract. This review synthesizes the current understanding of the multifactorial causes of IBD. Central to disease pathogenesis is the altered relationship between the host immune system and the intestinal microbiome, which culminates in a persistent cycle of tissue damage and inflammation, involving both innate and adaptive immunity as well as non-immune cells. Efforts to elucidate these integrated pathways have underscored the importance of both intrinsic host factors and extrinsic environmental triggers in IBD pathogenesis. Despite this, a better understanding of disease mechanisms is still needed, and will be essential to developing better therapies that can target relevant axes of the disease process and restore immune balance, facilitate tissue repair, and induce lasting remission.

B-1 cells are innate-like immune cells abundant in serosal cavities with antibodies enriched in bacterial recognition, yet their existence in humans has been controversial^1–3. The CD5⁺ B-1a subset expresses anti-inflammatory molecules including IL-10, PDL1 and CTLA4 and can be immunoregulatory^4–6. Unlike conventional B cells that are continuously replenished, B-1a cells are produced early in life and maintained through self-renewal⁷. Here we show that the transcription factors TCF1 and LEF1 are critical regulators of B-1a cells. LEF1 expression is highest in fetal and bone marrow B-1 progenitors, whereas the levels of TCF1 are higher in splenic and peritoneal B-1 cells than in B-1 progenitors. TCF1–LEF1 double deficient mice have reduced B-1a cells and defective B-1a cell maintenance. These transcription factors promote MYC-dependent metabolic pathways and induce a stem-like population upon activation, partly via IL-10 production. In the absence of TCF1 and LEF1, B-1 cells proliferate excessively and acquire an exhausted phenotype with reduced IL-10 and PDL1 expression. Furthermore, adoptive transfer of B-1 cells lacking TCF1 and LEF1 fails to suppress brain inflammation. These transcription factors are also expressed in human chronic lymphocytic leukaemia B cells and in a B-1-like population that is abundant in pleural fluid and circulation of some patients with pleural infection. Our findings define a TCF1–LEF1-driven transcriptional program that integrates stemness and regulatory function in B-1a cells.

Autoimmune and inflammatory diseases are rising globally yet widely effective therapies remain elusive. Most treatments have limited efficacy, significant potential side effects, or eventually lose response, underscoring the urgent need for new therapeutic approaches. We recently discovered that ETS2, a transcription factor, functions as a master regulator of macrophage-driven inflammation-and is causally linked to the pathogenesis of multiple inflammatory diseases via human genetics. The pleotropic inflammatory effects of ETS2 included upregulation of many cytokines that are individually targeted by current disease therapies, including TNFα, IL-23, IL1β, and TNF-like ligand 1A signaling. With the move toward combination treatment-to maximize efficacy-targeting ETS2 presents a unique opportunity to potentially induce a broad therapeutic effect. However, there will be multiple challenges to overcome since direct ETS2 inhibition is unlikely to be feasible. Here, we discuss these challenges and other unanswered questions about the central role that ETS2 plays in macrophage inflammation.