Health Technology Assessment Volume: 26, Issue: 38, Published in September 2022

Most genetic variants associated with complex diseases lie in non-coding regions ¹ , complicating efforts to identify effector genes and relevant cell types. Here we map cis -expression quantitative trait loci (eQTLs) across 2.2 million single cells using intestinal biopsies and blood from 421 individuals, including 125 with inflammatory bowel disease (IBD). Cell-type-level eQTLs were more distal to transcription start sites, enriched in enhancers, less likely to regulate the nearest gene, and more than 3.5-fold more likely to colocalize with IBD loci detected in genome-wide association studies (GWASs) than eQTLs detected at tissue-level resolution. We nominate effector genes at more than half of known IBD loci, including MAML2 , PSEN2 and ZMIZ1 in myeloid cells, implicating reduced Notch signalling in intestinal immune dysfunction. We also identify Wnt-regulated genes, including MYC , in epithelial stem and progenitor cells, suggesting that impaired renewal contributes to barrier breakdown. Our results provide a mechanistic map that links genetic risk to specific genes and cell types in IBD, and a generalized framework for interpretation of GWAS loci using single-cell eQTL mapping of disease-relevant tissues in complex diseases.

Background/Objectives: The management of inflammatory bowel disease (IBD) varies due to differences in healthcare systems, treatment costs, access to diagnostics, and diverse clinical practices between specialists. Despite the frequent advocacy of a treat-to-target (T2T) approach, there is insufficient clarity on how clinicians implement T2T in real-world settings. We aim to conduct a large, global survey among IBD experts to identify current practices in management. Methods: A prospective, cross-sectional study was conducted using a 16-item survey divided into two sections—for ulcerative colitis (UC) and Crohn’s disease (CD)—and distributed to practicing IBD clinicians. Results: A total of 261 respondents from 88 countries participated in the survey, with the majority (253/261) being physicians and eight being IBD nurse specialists. Despite global guidance, only a quarter of the respondents routinely perform an endoscopy to assess the response after starting an advanced therapy (28.4% in UC vs. 23.5% in CD). Moreover, despite an increasing academic focus on intestinal ultrasound (IUS), 171 (66%) of respondents in UC and 132 (51%) in CD reported that they do not routinely undertake IUS to guide treatment decisions. Faecal calprotectin for monitoring treatment response was routinely used by 87% (90% in UC and 84% in CD) of the respondents. Forty-five percent reported use of therapeutic drug monitoring (TDM) both proactively and reactively and 35% reported only using TDM reactively. Conclusions: Our study shows considerable variation in IBD management across different countries and interpretation of the T2T approach. This highlights the need for standardised and pragmatic guidelines to help improve outcomes for patients with IBD globally.

Background: The ability to predict whether patients with a new diagnosis of Crohn’s disease will develop disabling disease is an unmet clinical need. Magnetic resonance enterography is a first-line investigation for Crohn’s disease, but its role in prognostication is unknown. Objective(s): To improve prediction of disabling Crohn’s disease within 5 years of diagnosis by developing and internally evaluating a multivariable prediction model comprising clinical predictors and adding magnetic resonance enterography scores (Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index). To estimate the healthcare costs incurred within 5 years of Crohn’s disease diagnosis and to explore factors driving costs. Design: A multicentre diagnostic inception cohort. Setting: Nine National Health Service hospitals. Participants: Aged ≥ 16 years with newly diagnosed Crohn’s disease. Main outcome measures: Comparative predictive ability of prognostic models, including magnetic resonance enterography scores (Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index) versus a model based on clinical predictors alone for the development of modified Beaugerie disabling Crohn’s disease within 5 years of diagnosis. Statistical analysis: We censored development of modified Beaugerie disabling disease ≤ 90 days from diagnosis, and utilised time-to-event models using Royston–Parmar flexible parametric models. Risk group definitions were prespecified; for risk group definition 1, the high-risk patients were the top 40% with the greatest predicted risk, and the high-risk patients had an absolute risk ≥ 10% for risk group definition 2. The absolute risk cut-off was calculated by sorting patients by predicted risk and using the risk of the eighth (10% of 81) patient who developed modified Beaugerie disabling disease. Results: We studied 194 patients, median age 29, interquartile range 22–44 years. Within 5 years from diagnosis, 42% (81/194) developed modified Beaugerie disabling disease. There was a univariable association between initial need for steroid therapy and developing modified Beaugerie disabling disease [hazard ratio 2.11 (95% confidence interval 1.36 to 3.26)]. Using risk group definition 1, the baseline clinical model had 49% (95% confidence interval 39 to 60) sensitivity and 66% (95% confidence interval 57 to 74) specificity for predicting the development of modified Beaugerie disabling disease. There was no difference in sensitivity and specificity between models incorporating Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index compared to the baseline clinical model. Using risk group definition 2, the model, including magnetic resonance enterography predictors, had 86% (95% confidence interval 77 to 92) sensitivity and 35% (95% confidence interval 27 to 45) specificity for predicting the development of modified Beaugerie disabling disease. There was no difference in sensitivity between the clinical model and models incorporating Magnetic resonance Enterography Global Score, Simplified Magnetic Resonance Index of Activity and Lémann Index, but specificity was significantly lower for models incorporating Magnetic resonance Enterography Global Score [29% (95% confidence interval 22 to 38)] and Lémann Index [29% (95% confidence interval 22 to 38)]. The mean total 5-year per-patient cost of health care was £24,267 (standard deviation £33,108). Mean 5-year costs were £29,763 (standard deviation £38,278) compared to £20,327 (standard deviation £28,368) for those with and without disabling disease, respectively. The largest contributor to costs was biologic use. Age under 40 years, presence of perianal disease and presence of severe endoscopic disease were associated with higher costs. Limitations: Liège and Montreal criteria for disabling disease could not be studied due to an insufficient event rate. Conclusions: Addition of magnetic resonance enterography scores to a multivariable model comprising existing clinical predictors did not improve prediction of modified Beaugerie disabling disease. Healthcare costs were increased in those aged under 40 years and patients with perianal and severe endoscopic disease. Future work: Testing the predictive ability of magnetic resonance enterography against alternative definitions for disabling Crohn’s disease. Trial registration: This trial is registered as ISRCTN76899103. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/59/17) and is published in full in Health Technology Assessment ; Vol. 30, No. 18. See the NIHR Funding and Awards website for further award information.

Crohn’s disease (CD) remains challenging to diagnose and classify accurately despite advances in endoscopy, cross-sectional imaging, intestinal ultrasound, and inflammatory biomarkers. Earlier diagnosis and treat-to-target strategies have improved outcomes but have also increased the risk of misdiagnosis, overdiagnosis, and misclassification of disease activity or severity. Misdiagnosis may expose patients without CD to unnecessary immunosuppressive therapy while delaying recognition and treatment of the true underlying condition, including drug-induced enteropathy, bile acid malabsorption, irritable bowel syndrome, and other disorders of gut–brain interaction. This is particularly relevant in tuberculosis (TB)-endemic regions, where intestinal TB remains one of the most challenging mimics of CD. Overdiagnosis commonly results from overinterpretation of nonspecific symptoms, incidental terminal ileitis, or isolated endoscopic and histological abnormalities. Elevated fecal calprotectin lacks specificity, whereas a low value provides stronger evidence against CD, although it does not reliably exclude isolated small-bowel disease. Misclassification most often reflects underestimation of disease severity, particularly when standard ileocolonoscopy fails to detect proximal small bowel or transmural disease or when discordant endoscopic and cross-sectional imaging findings are not appropriately reconciled. This review examines the major diagnostic and classification pitfalls in CD and proposes a practical, multidisciplinary approach based on integrating complementary investigations, longitudinal reassessment, and diagnostic reconsideration when uncertainty persists. Cite this article as: Bilican G, Brezina B, Sharip MT, et al. Pitfalls in the diagnosis and classification of Crohn’s disease: Misdiagnosis, overdiagnosis, and misclassification. Turk J Gastroenterol. Published online October 06, 2026. doi: 10.5152/tjg.2026.26534.

Despite significant advances in understanding the biology of inflammatory bowel diseases (IBD), the underlying etiology is still unknown, and currently available treatment options are not curative. Furthermore, even after the advent of multiple targeted “advanced” therapies, approximately one-third of patients do not respond to treatment, and approximately half of patients lose response over time. As a result, there have been efforts made to seek alternative treatment options. In recent years, there have been major advances made in the field of cellular therapy, involving administration of living cells to patients. Notably, the area with the most evidence base to date has been stem cell therapy, with data generated for both mesenchymal and hematopoietic stem cells. More recently, there have also been emerging data exploring the use of chimeric antigen receptor T cells and regulatory T cells. As the landscape for cellular therapy expands in the coming years, an important next step will be to understand which patients may or may not benefit from these therapies and at what point these treatment options might be considered in the disease course of IBD.