Clinical Case Summary

Coeliac disease is an autoimmune disorder triggered by gluten exposure. It often overlaps with microscopic colitis, particularly in refractory cases, posing treatment challenges. Upadacitinib, a Janus Kinase (JAK) 1 inhibitor, targets key inflammatory pathways by blocking JAK enzyme activity. We describe the efficacy of Upadacitinib in treating refractory coeliac disease with concomitant microscopic colitis, resulting in clinical and histological remission.
A 46-year-old woman diagnosed with coeliac disease in 2014, initially presenting with chronic diarrhea. Coeliac serology revealed markedly elevated anti-Gliadin IgG levels and Tissue Transglutaminase IgA. Duodenal biopsies demonstrated mild villous blunting, crypt hyperplasia, and increased number of intraepithelial lymphocytes (IELs). Following diagnosis, her symptoms resolved with strict adherence to gluten-free diet.
Despite continued dietary adherence, she experienced recurrent symptoms over subsequent years. In March 2021, repeat endoscopy appeared normal macroscopically, though histology revealed increased IELs and mild villous blunting. Concurrent colonoscopy identified features consistent with microscopic colitis.Two Budesonide courses yielded minimal improvement; coeliac serology remained elevated.
During this period, she was also initiated on Upadacitinib for psoriatic arthritis. Her symptoms subsequently resolved over several months of treatment. At approximately 12 months, serology showed normalization of coeliac antibodies, remaining negative since October 2022. Recent endoscopy in March 2025 revealed no evidence of active coeliac disease, and duodenal biopsies showed restoration of normal villous architecture and no significant increase in IELs.
This case supports the potential of JAK inhibitors in treating refractory coeliac disease with microscopic colitis, especially when standard therapies fail. Recognizing the frequent overlap of these conditions is crucial for effective management.

References

Figure 1 - Index endoscopy in March 2021. Endoscopic findings of normal duodenum examined under WLE, NBI or TXI
Figure 2 - Endoscopy findings part way through Upadacitinib therapy, demonstrating decreased folds found in duodenum with patchy, subtle changes best visualised under TXI
Figure 3 - Latest endoscopy findings in March 2025 whilst on Upadacitinib for 3 years, demonstrating normal duodenum without endoscopic evidence of coeliac disease

Introduction

The management of inflammatory bowel disease (IBD) often relies on colonoscopy to evaluate disease activity and detect complications. However, intestinal ultrasound (IUS) has emerged as a non-invasive, accurate alternative, endorsed by ECCO-ESGAR guidelines for use in both Crohn’s disease and ulcerative colitis. This study aimed to evaluate the impact of IUS implementation on the frequency of colonoscopies performed in IBD patients at a tertiary care hospital.

Aims & Methods

We conducted a retrospective analysis comparing two time periods: before IUS implementation (2021–2022) and after its introduction (2023–2024). The number of colonoscopies performed for IBD management in each period was recorded. Screening colonoscopies in IBD patients were not included in the analysis; therefore, the data reflect colonoscopies performed specifically for the clinical management of the disease. The percentage change in colonoscopy utilization was calculated to assess the effect of IUS integration into routine clinical practice.

Results

In the pre-IUS period (2021–2022), a total of 340 colonoscopies were performed for the management of patients with IBD. After the introduction of IUS in 2023, the number of colonoscopies over the subsequent two years decreased to 280, reflecting a 17.6% reduction. This decline suggests a meaningful shift towards non-invasive monitoring facilitated by IUS.

Conclusion

The integration of IUS into the endoscopic workflow was associated with a notable decrease in colonoscopy use among IBD patients. These findings reinforce the role of IUS as a valuable, non-invasive modality for disease monitoring, with the potential to optimize resource utilization and support faster clinical decision-making. Prospective studies are needed to further assess the long-term benefits and cost-effectiveness of widespread IUS adoption in IBD care.

References

1. Panés J, Bouzas R, Chaparro M, et al., Imaging techniques for assessment of inflammatory bowel disease: Joint ECCO and ESGAR evidence-based consensus guidelines. Journal of Crohn's and Colitis. 2013;7(7):556–585. doi: 10.1016/j.crohns.2013.01.206
2. Smith RL, Taylor SA, Horsthuis K, et al., Reduction in the use of endoscopy after implementing an intestinal ultrasound service: A retrospective single-centre study. Journal of Crohn’s and Colitis. 2024;18(Suppl 1):i1344. doi: 10.1093/ecco-jcc/jjad212.1124
3. Kucharzik T, Wittig BM, Helwig U, et al., Intestinal ultrasound for monitoring of Crohn's disease activity: A prospective multicenter study. Clinical Gastroenterology and Hepatology. 2023;21(6):1397–1406. doi: 10.1016/j.cgh.2022.12.005
4. Bryant RV, Jairath V, Kucharzik T, et al., AGA Clinical Practice Update on the Role of Intestinal Ultrasound in the Management of Inflammatory Bowel Disease: Expert Review. Clinical Gastroenterology and Hepatology. 2024. [In press] doi: 10.1016/j.cgh.2024.03.014
5. Zorzi F, Bezzio C, Mazza S, et al., The role of intestinal ultrasound in ulcerative colitis: A systematic review. World Journal of Gastrointestinal Endoscopy. 2023;12(3):97210. doi: 10.4253/wjge.v12.i3.97210

Introduction

IBS-D and microscopic colitis share overlapping symptoms like chronic diarrhea and abdominal pain, making clinical differentiation challenging. Microscopic colitis often remains undiagnosed without histological evaluation. Accurate identification allows for targeted treatment, resulting in superior symptom control compared to standard IBS management.

Aims & Methods

To evaluate the frequency of microscopic colitis in patients presenting with diarrhea-predominant irritable bowel syndrome (IBS-D) and to assess symptom response following targeted therapy in those diagnosed with microscopic colitis.
This prospective study was conducted at a tertiary care center from January 1, 2023, to January 1, 2025. A total of 120 patients fulfilling Rome IV criteria for IBS-D were enrolled (70 males, 50 females). All patients reported diarrhea, with associated symptoms including abdominal pain and bloating. Colonoscopic evaluation with random colonic biopsies was performed in all cases. Histopathological analysis identified patients with microscopic colitis. Symptom improvement was monitored following standard treatment for microscopic colitis and compared with patients managed as IBS-D alone.

Results

Among the 120 patients, 11 (9.2%) were found to have histologically confirmed microscopic colitis—7 males and 4 females—primarily from a younger age group. Patients diagnosed with microscopic colitis showed marked improvement in diarrheal symptoms when treated with standard therapies (e.g., budesonide) as opposed to those managed with conventional IBS treatment alone.

Conclusion

A significant minority of patients initially diagnosed with IBS-D may harbor microscopic colitis, particularly younger individuals. Routine biopsy during colonoscopy in IBS-D patients can aid in the identification of this subset, enabling specific therapy and leading to better clinical outcomes.

References

1. Irritable Bowel Syndrome and Microscopic Colitis: A Systematic Review and Meta-analysisKamp, Eline J.C.A. et al.
   Clinical Gastroenterology and Hepatology, Volume 14, Issue 5, 659 - 668.e1
2. Münch A, Sanders DS, Molloy-Bland M, et al
   Undiagnosed microscopic colitis: a hidden cause of chronic diarrhoea and a frequently missed treatment opportunity
   Frontline Gastroenterology 2020;11:228-234.
   
   

Introduction

The fecal immunochemical test (FIT) is the preferred non-endoscopic test in programmatic screening worldwide. Compared to other methods, FIT may be better accepted with higher participation rates, which may counteract its lower one-time sensitivities. We performed a systematic review and meta-analysis to ascertain participation patterns, participation rates, and FIT performance in organized multi-round FIT-based screening programs worldwide.

Aims & Methods

We performed a systematic search using Pubmed, Embase, and Cochrane databases. Participation patterns were categorized as “consistent screeners” (participation in 100% of rounds), “intermittent screeners” (including drop-outs, delayed entrants, and intermittent re-screeners), and “consistent non-screeners” (never screened). Data regarding positivity rates and detection rates for adenomas, advanced adenomas (AA), and colorectal cancer (CRC) across subsequent rounds were extracted and summary estimates were obtained. Yields were calculated for 2 populations: 1) Overall Population; 2) Consistent Screeners. A sensitivity analysis was performed including only programs with biennial screening with FIT cut-off of 20μg Hb/g feces.

Results

The literature search yielded 4,414 studies of which 25 were included. Across all studies, the fraction of the population behaving as “consistent screeners”, “consistent non-screeners”, and “intermittent screeners” was 47.1%, 30.3%, and 22.7%, respectively. For the overall population, FIT-positivity from the 1^st through 4^th rounds was 6.7%, 5.5%, 5.4%, and 5.3%; and detection rates were 5.8%, 3.3%, 2.9%, and 2.5% for CRC; 32.8%, 28.3%, 22.7% and 23% for AA; 48.6%, 46.2%, 48.7% and 44.6% for adenoma. For Consistent Screeners, FIT-positivity across studies from the 1^st through 4^th rounds was 6.4%, 4.8%, 4.1%, and 3.6%, respectively; and detection rates were 6.9%, 4.6%, 3.6%, and 3.1% for CRC; 38.7%, 30.6%, 28.2% and 24.9% for AA; 53.4%, 46.7%, 42.6% and 42.4% for adenoma. Similar trends were observed for biennial screening with FIT cut-off of 20μg Hb/g feces.

Conclusion

Organized multi-round FIT-based CRC screening programs achieve consistent participation in a minority of participants, and a sizeable proportion of the population do not initiate screening at all after multiple offers. Among those participating, FIT-positivity, and yields for CRC, AA, and adenoma are highest in the 1^st round, but may stabilize at a clinically relevant steady state at rounds 3+.

References

1. Doria-Rose VP, Lansdorp-Vogelaar I, McCarthy S, Puricelli-Perin DM, Butera V, Segnan N, et al. Measures of longitudinal adherence to fecal-based colorectal cancer screening: Literature review and recommended approaches. Int J Cancer. 2021 Jul 15;149(2):316–26.
2. Duncan A, Turnbull D, Wilson C, Osborne JM, Cole SR, Flight I, et al. Behavioural and demographic predictors of adherence to three consecutive faecal occult blood test screening opportunities: A population study. BMC Public Health. 2014 Mar 7;14(1).

Introduction

Until now, there have only been conflicting reports regarding whether adenomas located proximal to the splenic flexure have increased association with metachronous colorectal cancer (CRC) compared to distal adenomas, and whether adenoma location should affect surveillance practice.

Aims & Methods

To address this knowledge gap, we aimed to compare metachronous colorectal cancer (CRC) and advanced adenoma (AA) risk in patients with baseline proximal vs. distal adenomas, including consideration of metachronous CRC location, baseline proximal adenomas only vs. both proximal and distal adenomas, and baseline proximal non-advanced adenoma vs. AA.
We systematically searched Pubmed, EMBASE, and Cochrane for cohort studies and clinical trials describing CRC or AA incidence at surveillance stratified according to baseline adenoma’s location. Proximal adenomas were defined as those located from the cecum to the splenic flexure. We performed a meta-analysis by calculating pooled incidence rate ratios (IRR) and corresponding 95% confidence intervals (CI) for CRC and AA using a random-effects model. Heterogeneity was assessed with the I2 statistic.

Results

The literature search yielded 5,907 studies of which 13 were included, with a total of 205,207 patients (mean age 62.3 years, 63.8% males) and a mean duration of follow-up of 8.5 years. Compared with patients with only distal adenomas, patients with any proximal adenoma and only proximal adenomas had a significantly higher risk of metachronous CRC [1.70 (95%CI: 1.17-2.46; I2=73%), and 1.97 (95%CI: 1.41-2.75; I2=0%)], respectively. Patients with any proximal AA had also a higher risk of CRC compared to those with only distal AA [2.77 (95%CI 1.77-4.34; I²=38%)]. Also, patients with any proximal adenoma had an even higher risk of proximal CRC compared to patients with baseline only distal lesions [3.65 (95%CI 1.57-8.47; I2=86%)]. Finally, patients with any baseline proximal adenoma had also a higher risk of metachronous AA [1.82 (95%CI: 1.41-2.34; I2=59%)].

Conclusion

Our findings suggest that baseline adenoma proximal location is associated with future detection of CRC and AA. Better understanding of the reasons behind this increased CRC risk, and particularly whether these can be overcome with improved colonoscopic technique or technical innovations, will inform whether baseline adenoma location should be considered in future guidelines as an independent factor to tailor surveillance recommendations.

Introduction

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease characterized by inflammation, an influx of eosinophils and esophageal remodeling. Therapy for EoE includes proton-pump inhibitors, swallowed topical corticosteroids, dupilumab, and dietary elimination, but these are not always effective and have potential side effects.
EP-104GI is a long-acting fluticasone propionate (FP) injectable suspension being developed as a first-in-class treatment for EoE. EP-104GI consists of coated FP crystals that release at a pre-defined rate via diffusion at the injection site. Steady-state diffusion reduces peak concentrations while prolonging the therapeutic window.
RESOLVE (NCT05608681) is a Phase 1b/2a, multicenter, open-label, dose-escalation study to evaluate the safety, tolerability, feasibility, pharmacokinetics, and efficacy of EP-104GI in adults with symptomatic and histologically confirmed active eosinophilic esophagitis.

Aims & Methods

In this study, EP-104GI is injected at multiple sites in alternating quadrants at 2 cm intervals in the esophagus. Dose escalations increase the dose per injection site and/or number of sites, with the 6th cohort receiving 4 mg at 16 sites (64 mg total dose). After a single administration of EP-104GI, participants are followed for 24 weeks (cohorts 1-4) or 52 weeks (cohorts 5+). Safety assessments include adverse events and laboratory tests. Efficacy assessments include histological endpoints and patient-reported symptom outcomes, including the Straumann Dysphagia Index (SDI) and EoE Histologic Scoring System (EoEHSS). Esophageal biopsies are collected at baseline, Weeks 4, 12, and 36.

Results

Previously reported data from cohorts 3-5 (total doses 20-48 mg) showed symptom (SDI) reductions at Week 12 for 8/9 patients, the majority maintained to Week 24. Mean peak eosinophil count declined for 7/9 participants at Week 12, including one patient who achieved <6 eosinophils/hpf at all sites assessed, representing complete histological remission.
In Cohort 6, all three participants experienced a significant reduction in peak eosinophil count compared to baseline, ranging from 59 to 91% by Week 12. Symptoms (SDI) decreased for all 3 participants to Week 12, with a peak reduction of up to 6 points (0-9 scale). Histology scores have shown a progressively greater decrease from baseline with increasing EP-104GI dose. In Cohort 6 at Week 12, mean EoEHSS stage reduction was 66% or 0.40 points (composite score of 0-1) and mean EoEHSS grade reduction was 65% or 0.38 points (Table 1).
Plasma FP levels increased with dose and in Cohort 6 were stable at <25 pg/mL after the initial peak. Treatment-emergent adverse events were mild to moderate, most unlikely related to EP-104GI. Serum glucose and cortisol were stable post-dose with no adverse events such as candidiasis or adrenal suppression.

Table 1: Change from Baseline in EoEHSS, SDI, PEC, and mean plasma FP after a single dose of EP-104GI

Conclusion

These data support that local delivery of FP via EP-104GI has been feasible and safe in the ongoing study. Higher doses yield improved patient responses such as histological remission, enhanced patient-reported symptom scores, and favorable histology results, without the occurrence of corticosteroids-related side effects.

Disclosure

AM, JH, MMK, CD, VP: Employees of Eupraxia Pharmaceuticals. HHK, GH: Nothing to declare. WA: Speaker, advisory board member, and a clinical investigator for Abbvie, Amgen, Avir Pharma, Eli-Lilly, Eupraxia, Janssen, JAMP Pharma, Merck, Pfizer, Roche, Sandoz, Sanofi, Takeda. GH: TBD. ESD: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Sanfoi, Shire/Takeda, Uniquity; Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apogee, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Third Harmonic Bio, Upstream Bio Educational grant: Allakos, Aqilion, Holoclara, Invea. AJB: Research funding: Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt and AstraZeneca.

Introduction

Crohn’s Disease (CD), a subtype of Inflammatory Bowel Disease (IBD), is believed to arise from complex interactions between gut microbes, environment, and genetics. A significant proportion of patients develop fistulae, but unclear aetiopathogenesis impacts treatment outcomes, quality of life, and healthcare costs. Chronic granulomatous disease (CGD) is a monogenic condition caused by pathogenic variants in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complexes which can present as CD-like colitis, abscesses, and immunodeficiency. Given CD’s genetic and phenotypic similarities with CGD, we hypothesised that NADPH oxidases may contribute to CD phenotypes, specifically in relation to fistulating disease behaviour.

Aims & Methods

This study explores the role of genetic variation in NADPH oxidases in CD patients (Southampton IBD cohort) using a per-patient, per-gene deleteriousness score (GenePy) to determine whether CD fistulating disease behaviour can be predicted and establish any potential epistatic interactions between genetic variation of subunits of the NAPDH oxidase complexes relevant to CD. Key NADPH oxidase protein-coding genes involved in CD were identified via literature review. Protein-protein interaction databases were used to collate a comprehensive network of potentially implicated genes. To determine subgroups of patients with differing genetic variation in the NAPDH oxidase genes we employed a principal component analysis (PCA), followed by hierarchical clustering of patients using GenePy scores, with optimal cluster numbers determined by silhouette scores. Cluster enrichment for fistulating disease was explored using Fisher’s exact test. To identify genes driving separation between CD patients we assessed differences in GenePy scores for the top PCA gene drivers between fistulating and non-fistulating subgroups using a Mann-Whitney U-test. Mutational profile characterisation include potential gene-gene interactions were evaluated via Spearman correlations. Multiple test correction was applied.

Results

Twenty-nine protein-coding genes were analysed. Clustering patients by GenePy scores for these genes after PCA resulted in distinct clusters, but no significant association between fistulating phenotype and cluster assignments was observed. However, significant differences between the GenePy scores of the top 5% of fistulating and non-fistulating groups were found for NOX3 (p = 0.016) and DUOX2 (p = 0.001), with fistulating patients having lower GenePy score for these genes, indicating these genes may drive a proportion of inflammatory CD behaviour.
Four gene pairs were significantly correlated (Table 1), indicating potential epistasis within NADPH oxidase complexes for patients with CD. High deleteriousness scores in multiple genes within a complex may indicate oligogenic contribution to a disease phenotype within individuals.

Conclusion

NADPH oxidase genes, and epistatic interactions between them, may modify the risk of fistulating CD and drive disease phenotype in a proportion of patients.

Disclosure

JJA is a scientific advisory board member for Orchard Therapeutics