INTRODUCTION: Clinical trials are the key to research in inflammatory bowel disease therapeutics. However, their external validity has been poorly evaluated, as have the outcomes in patients who do not meet the inclusion criteria. METHODS: This retrospective observational study at Miguel Servet University Hospital, Zaragoza, Spain, included all consecutive patients diagnosed with Crohn's disease or ulcerative colitis who initiated biologic treatments between January 2017 and December 2022. Eligibility was assessed against the criteria of pivotal randomized clinical trials (RCTs) for adalimumab, infliximab, golimumab, ustekinumab, or vedolizumab. Clinical effectiveness and safety were evaluated at 14–16 weeks and 54 weeks, with treatment persistence assessed using survival analysis. Effectiveness and persistence were assessed to analyze whether patient selection has an impact on different clinical outcomes. RESULTS: A total of 631 biologic treatments were initiated in 477 patients. Only 16.9% met the RCT criteria according to pivotal RCTs and 8% with newer RCTs. Disease-related criteria were the most frequently unmet (57.3%). Patients with ulcerative colitis were less likely to meet the criteria compared with patients with Crohn's disease (23% vs 4%, P < 0.001). No significant differences were observed in response rates, remission rates, adverse events, or drug discontinuation between eligible and noneligible patients. Survival analysis showed no differences in treatment persistence between both groups (hazard ratio 1.01, 95% confidence interval 0.73–1.38). DISCUSSION: Only a minority of real-world patients with inflammatory bowel disease would qualify for corresponding RCTs, questioning the external validity of these trials. However, real-world use of biologics demonstrated similar effectiveness and safety in eligible and noneligible patients, underscoring the importance of practical clinical judgement in therapeutic decisions.

Background: Upadacitinib (UPA) is the first oral Janus kinase (JAK) inhibitor approved for the treatment of Crohn's disease (CD). Real‐world data, particularly from large nationwide cohorts, remain limited. This study aimed to evaluate the real‐world effectiveness, safety, and treatment persistence of UPA in patients with CD. Methods: Multicenter observational study including patients with CD who received UPA, using data from a nationwide registry. Patients were classified according to active luminal disease, extraintestinal manifestations (EIMs), or combination therapy with another biological therapy. Disease activity was assessed using the Harvey–Bradshaw Index (HBI), C‐reactive protein (CRP), and fecal calprotectin (FC) at baseline and weeks 12, 24, and 52. Endoscopic outcomes were evaluated when available. Adverse events (AEs), hospitalizations, and treatment discontinuations were recorded. Results: 300 patients were included, representing a highly treatment‐refractory population, with 98% previously exposed to anti‐TNF agents and 59% to three or more advanced therapies. In those treated for active luminal disease, corticosteroid‐free clinical remission was achieved in 60%–62% of patients at weeks 12, 24 and 52. CRP normalization increased from 64% at week 12%–74% at week 52, while FC normalization improved from 48% to 64%. Patients treated for EIMs achieved high and sustained remission rates with excellent treatment persistence. Early remission at week 12 was strongly associated with sustained remission and meaningful endoscopic improvement. UPA was discontinued in 98 patients (39%). AEs were reported in 71 patients (24%). Conclusions: In this large real‐world cohort, UPA demonstrated sustained clinical and biochemical effectiveness, meaningful endoscopic response, and a safety profile consistent with clinical trial data. Early response emerged as a key predictor of long‐term outcomes, supporting the clinical utility of UPA.

Crohn’s disease (CD) is a chronic immune-mediated inflammatory disorder characterized by transmural inflammation and a progressive course that frequently leads to structural complications such as intestinal fibrosis. Fibrostenosing disease represents a major clinical challenge, affecting up to 50% of patients over time and often requiring surgical intervention. Despite advances in anti-inflammatory therapies, no effective treatments currently exist to prevent or reverse established fibrosis. Intestinal fibrosis arises from a dysregulated tissue remodeling process driven by excessive extracellular matrix deposition and persistent activation of mesenchymal cells, particularly fibroblasts and myofibroblasts. This process is orchestrated through complex interactions between immune and non-immune cells and mediated by key signaling pathways, including transforming growth factor beta (TGF-β1) and the TL1A/DR3 axis. Genetic susceptibility, notably variants in NOD2 and other fibrosis-related genes, contributes not only to disease risk but also to phenotype progression. Epigenetic mechanisms, particularly microRNAs such as the miR-29 and miR-200 families, further modulate fibrogenesis and represent promising non-invasive biomarkers. Additionally, intestinal dysbiosis and specific microbial signatures, including reduced short-chain fatty acid-producing bacteria and the presence of adherent-invasive Escherichia coli, play a critical role in promoting fibrotic pathways. Mesenteric adipose tissue, especially creeping fat, also contributes to fibrosis through immune and metabolic signaling. Emerging biomarkers related to collagen metabolism and advances in molecular profiling are improving early detection strategies. Novel therapeutic approaches targeting fibrogenic pathways, including anti-TL1A agents, show promising preliminary results. A deeper understanding of these mechanisms is essential to develop effective antifibrotic therapies and improve long-term outcomes in CD.

Immunotherapy with immune checkpoint inhibitors (ICIs) has represented a major breakthrough in the treatment of multiple solid and hematological malignancies, significantly improving survival and tumor control. However, the blockade of immune regulatory pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) is associated with the development of immune-related adverse events, among which immune-mediated colitis (IMC) constitutes one of the most relevant gastrointestinal complications due to its frequency, potential severity, and impact on the continuation of oncologic treatment. IMC typically presents with diarrhea, abdominal pain, and gastrointestinal bleeding, and may progress to severe, life-threatening forms. Its incidence varies according to the type of ICI, and is higher with CTLA-4 inhibitors and particularly elevated with combination therapies. The pathophysiology is complex and multifactorial, involving dysregulated activation of proinflammatory T lymphocytes, impairment of immune regulatory mechanisms, disruption of the intestinal epithelial barrier, and a key modulatory role of the gut microbiota. Diagnosis requires a high index of clinical suspicion and relies on endoscopy with biopsies, given the poor correlation between clinical severity and endoscopic or histological findings. Fecal biomarkers, such as calprotectin and lactoferrin, are useful for risk stratification and disease monitoring. Treatment is based on a stepwise immunosuppressive approach, with corticosteroids as first-line therapy and biologic agents such as infliximab or vedolizumab in refractory cases. Emerging strategies, including fecal microbiota transplantation, offer new therapeutic perspectives. This article provides a comprehensive review of the current evidence on the epidemiology, pathophysiology, diagnosis, and management of IMC, as well as future challenges and opportunities in its clinical management.