Introduction

Biologics are useful for the treatment of moderate to severe ulcerative colitis (UC) and can achieve mucosal healing (MH). Many papers have reported that relapse can be prevented by targeting MH. However, recurrences of UC is possible even in cases that MH was once obtained.

Aims & Methods

In this study, we investigated cases of relapse after MH was achieved with biologics, aiming to determine the predictors of recurrences.
Forty-five patients who were successfully treated with biologics (including Tofacitinib) at our hospital and confirmed MH were stratified into those who relapsed during the course of treatment and those who did not. Patient background (age, gender, extent of inflammation, severity, disease type, pre-treatment history, time to biologics introduction, Mayo Endoscopic Score (MES), smoking history), and clinical data (leukocyte count, hemoglobin level, albumin level, CRP level) at the time of biologics introduction were compared. For statistical analysis, χ-square and Mann-Whitney U tests were used for univariate analysis and logistic regression analysis was used for multivariate analysis, with p < 0.05 as a significant difference.

Results

Of the 45 eligible patients, 21 (47 %) relapsed during follow-up after the introduction of biologics (mean 28.6 months, range 8-95 months). Univariate analysis of the patients stratified into 21 patients with relapse and 24 patients without relapse showed that MES at the introduction of biologics was 3 (71 % vs. 29 %, p = 0.0047) and that those with history of smoking were significantly more frequent in the relapse group (8.3 % vs. 43 %, p = 0.0072). In addition, the relapse group had slightly higher CRP levels (mean 4.4 mg/dl vs. 2.3 mg/dl, p = 0.184), younger age (mean 39 vs 46 years, p = 0.10), severe disease activity (mild: moderate: severe 3: 19: 2 vs. 3: 11: 7, p = 0.094), and history of tacrolimus use (9.5 % vs 0 %, p = 0.12), although the differences were not significant. A multivariate analysis on these factors showed that MES 3 (OR 9.21, 95 % CI 1.18-72.0, p = 0.034) and smoking history (OR 25.2, 95 % CI 1.20-529.0, p = 0.038) were independent predictors of relapse.

Conclusion

In the present study conducted at our hospital, nearly half of the patients had relapsed even when MH was achieved with the use of biologics for UC. Furthermore, the severity of the endoscopic findings at the introduction of biologics was an important predictor of recurrence. In other words, patients with severe endoscopic findings at the time of introduction of biologics should be treated keeping in mind the high risk of relapse, even if MH is achieved. This fact is considered very important for the introduction of biologics with UC patients in future and the construction of treatment a strategy after the introduction.

Introduction

Ulcerative colitis (UC) is a chronic, relapsing-remitting inflammatory bowel disease (IBD) with increasing global prevalence. The FDA has emphasized the importance of histologic endpoints in clinical trials, noting mucosal healing claims should be supported by more than just endoscopic findings. However, there are many challenges to achieving a standardized assessment of histologic disease activity in a UC clinical trial, including: the heterogeneity in the collection of mucosal biopsies (number, location) from study to study, a lack of fully validated histology scoring systems and an absence of community standards for definitions of histologic improvement or histologic remission.

Aims & Methods

This work was conducted by the FNIH Biomarkers Consortium Mucosal Healing in UC Project, a collaborative initiative involving academic institutions, pharmaceutical companies, patient advocacy organizations, and regulatory agencies to foster consensus, encourage adoption of findings, and support regulatory decision-making.
Aim 1: McBride et al. analyzed 994 biopsies from UC colectomy specimens to determine optimal biopsy sampling strategies for histologic grading.
Aim 2: A prospective study enrolled 153 UC patients to compare targeted versus non-targeted biopsy strategies across four colonic segments, assessing both endoscopic and histologic remission.
Aim 3: Data from three clinical trials (NCT02840721, NCT02958865, NCT02065622) and four independent datasets were compiled, yielding 9,652 whole slide images (WSIs) were used to train two AI tools:
• AIM-HI UC: Multiple instance learning models for predicting Geboes Score (GS) subgrades directly from H&E-stained WSIs.
• IBD Explore: A suite of convolutional neural networks (CNNs) for segmentation and classification of histologic features, including tissue types, crypt architecture, and cells. Performance was evaluated using a held-out test set (N=578 WSIs) and inter-pathologist agreement metrics.

Results

Aim 1: Sampling 2–3 biopsies per colonic region most effectively captured histologic heterogeneity and improved grading reliability. Agreement across histologic indices increased with biopsy number, particularly after the second and third biopsies.
Aim 2: Rectal histologic remission was highly predictive of proximal colonic remission (93% endoscopic, 88% histologic concordance). Histologic scores showed high correlation between targeted and non-targeted biopsies (ρ = 0.80–0.86), especially in remission.
Aim 3: Most AIM-HI UC models outperformed individual pathologists in predicting GS subgrades. IBD Explore generated interpretable histologic features—such as epithelial-to-lamina propria ratio, crypt distortion, and lymphocyte density—supporting advanced spatial analysis beyond conventional scoring systems.

Conclusion

This consortium-based endeavor generated several key findings: 1) Up to 3 biopsy samples per region of interest are required to overcome microscopic heterogeneity and ensure accurate histological grading in active colitis; 2) Targeted and random biopsies provide comparable histologic information, supporting the use of random biopsies in future clinical trials and practice; 3) Rectal endoscopic and histologic remission are highly predictive of pancolonic remission in extensive UC, supporting assessment limited to rectum in stable disease. Development of a ML-based approach for predicting GS subgrades, combined with these sampling insights, has the potential to improve standardization and automation of GS histological assessment, enhancing measurement of histological treatment response and endpoints in clinical trials.

References

IBD Explore and AIM-HI UC are for Research Use Only. Not for use in diagnostic procedures
McBride, R. B., Suarez-Farinas, M., Ko, H. M., Chen, X., Liu, Q., & Harpaz, N. (2023). Density of Biopsy Sampling Required to Ensure Accurate Histological Assessment of Inflammation in Active Ulcerative Colitis. Inflammatory bowel diseases, 29(11), 1706–1712. https://doi.org/10.1093/ibd/izad063
Danese S, Klopocka M, Scherl EJ, et al. Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clin Gastroenterol Hepatol. 2021;19(11):2324-2332.e6. doi:10.1016/j.cgh.2021.06.011
Sandborn WJ, Danese S, Leszczyszyn J, et al. Oral Ritlecitinib and Brepocitinib for Moderate-to-Severe Ulcerative Colitis: Results From a Randomized, Phase 2b Study. Clin Gastroenterol Hepatol. 2023;21(10):2616-2628.e7. doi:10.1016/j.cgh.2022.12.029
Panés J, Colombel JF, D'Haens GR, et al. Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results. Gastroenterology. 2022;162(7):1891-1910. doi:10.1053/j.gastro.2022.02.033

Disclosure

Disclosures of Primary Authors
Autumn Jones: None
Russell McBride: None
Stephen Laroux: holds shares of stock in AbbVie
Christina Jayson: PathAI stock holder
Noam Harpaz: has served as an advisory board member or consultant for Lilly, Inc., Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.

All listed organizations are financially contributing partners and/or consulting partners of the Foundation for the National Institutes of Health Biomarkers Consortium project team.
PathAI employees, previous and current are PathAI stock holders.

Introduction

The therapeutic landscape of ulcerative colitis (UC) has expanded significantly in recent years, yet real-world data are still needed to guide optimal treatment sequencing and improve short and long-term outcomes. Mucosal healing (MH) is a well-established therapeutic goal in UC management, closely associated with improved long-term prognosis.

Aims & Methods

The aim of this study was to describe real-life treatment sequences in UC patients receiving biological therapies at a tertiary referral center. This retrospective analysis included UC patients treated with biological therapies between 2019 and 2023. Patients received infliximab, adalimumab, vedolizumab, ustekinumab, or other advanced therapies across up to six treatment lines. Biological treatment pathways prior to achieve MH were visualized using a Sankey diagram. Endoscopic outcomes were evaluated one year after each biological therapy. MH, the primary outcome, was defined as endoscopic remission (Mayo UC score 0–1).

Results

Among 98 patients treated with biologics, MH was achieved in 46% (n = 45). Infliximab was used as the first-line agent in 55 patients (56%), adalimumab in 12 (12%), vedolizumab in 25 (25%), and golimumab in 3 (3%). Thirty-five patients (36%) achieved MH after the first-line therapy (n = 20 with infliximab; n = 2 with adalimumab; n = 12 with vedolizumab; n = 2 with golimumab). MH rates declined with each additional line of therapy: 17.4% after second-line treatment and no patients beyond the third line. The median time to achieve MH was 24.5 months (range 6–180). Treatment sequencing analysis revealed a progressive shift toward vedolizumab and ustekinumab in later lines, with infliximab remaining the most frequent first-line agent.

Conclusion

This study highlights a progressive decline in MH rates with successive lines of biological therapy in UC in a real-life cohort of patients. These findings emphasize the need for predictive tools to personalize treatment strategies in routine clinical practice.

Introduction

The therapeutic landscape for ulcerative colitis (UC) is rapidly evolving, with an increasing number of biologic agents available.

Aims & Methods

This systematic review and meta-analysis synthesised randomised controlled trials (RCTs) data on biologic therapies for achieving key endoscopic and histologic endpoints in moderate to severe UC. A systematic search of MEDLINE, EMBASE, Cochrane Library, Web of Science and grey literature was conducted through November 2024. Separate meta-analyses were performed for induction and maintenance. A random-effects model was used to estimate relative risks (RR), with 95% confidence intervals (CI) and confidence in estimates was evaluated with the GRADE approach (Grading of Recommendation Assessment, Development and Evaluation).

Results

We included 40 RCTs (13 therapies , 14,369 patients). Thirty-two trials provided data in induction phase and twenty-eight in maintenance phase. During induction phase, all biologic therapies except for mirikizumab and filgotinib 100 mg demonstrated superiority over placebo (RR 2.02, 95% CI:1.76–2.31, I²=72%) for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 5.53, 95% CI: 3.78-8.09). In biologic-naive patients and in patients with no previous biologic failure status upadacitinib 30mg had the highest efficacy (RR 4.07, 95% CI:2.69-6.16). In biologic-exposed patients or those with previous biologic failure, upadacitinib 30mg also showed the greatest benefit (RR 10.52, 95% CI:4.55-24.34). For induction of mucosal healing, all interventions were superior to placebo (RR 2.95, 95% CI:2.11–4.13,I²=61%), except for filgotinib 100 mg. Risankizumab showed the highest efficacy (RR 10.25, 95% CI:2.49-42.11). In maintenance phase, all therapies showed superiority over placebo for endoscopic improvement. Upadacitinib showed the highest efficacy (RR 4.18, 95% CI: 2.79–6.27). In biologic-naïve patients or those without prior biologic failure, all interventions—except filgotinib 100 mg and vedolizumab—were significantly superior to placebo, with etrasimod showing the highest efficacy (RR 3.12, 95% CI: 1.79–5.43). Among biologic-exposed patients or those with prior biologic failure, upadacitinib, mirikizumab, ustekinumab, etrasimod, tofacitinib, and risankizumab 180 mg were significantly superior to placebo. Upadacitinib showed the highest efficacy (RR 7.58, 95% CI: 3.42–16.8). For mucosal healing all therapies were superior to placebo, except for risankizumab. Upadacitinib showed the highest efficacy (RR 4.01 ,95% CI: 1.81–8.87). In biologic-naïve patients or those without prior biologic failure, only etrasimod, mirikizumab, upadacitinib 30 mg and subcutaneous infliximab were significantly superior to placebo, with upadacitinib showing the highest efficacy (RR 3.02, 95% CI: 1.18–7.71). Among biologic-exposed patients or those with prior biologic failure, only etrasimod, mirikizumab, and upadacitinib were significantly superior to placebo, with etrasimod demonstrating the highest efficacy (RR 9.45, 95% CI: 1.31–68.36).

Conclusion

Biologic and small-molecule therapies demonstrated substantial efficacy in achieving key endoscopic and histologic endpoints in moderate to severe UC. Upadacitinib consistently showed the highest efficacy across both induction and maintenance phases. Stratified analyses revealed enhanced response rates in biologic-naïve patients, supporting early initiation of advanced therapies. Our findings highlight the importance of individualised treatment strategies and the urgent need for standardised endpoint definitions to enhance comparability across future trials.

Introduction

Metaplasia refers to the emergence of cells not normally present in a given organ, typically as a result of chronic inflammation. While often linked to cancer development, its role in inflamed epithelium remains unclear. Paneth cell metaplasia (PCM) is a phenomenon in which Paneth cells, normally restricted to the small intestine, appear ectopically in the inflamed colonic epithelium of patients with ulcerative colitis (UC). However, the roles and characteristics of PCM in the inflamed colonic mucosa remain poorly understood. This study aimed to characterize the clinical and molecular features of colonic PCM and investigate its functional role in the inflamed epithelium.

Aims & Methods

We first analyzed the clinical characteristics of PCM using biopsy samples and clinical data from UC patients who underwent endoscopic evaluation at our institution. To elucidate the molecular features of colonic PCM, we employed spatial transcriptomics to compare PCM in the colon with Paneth cells in the small intestine from the same individuals. These findings were validated in a knockout mouse model, murine colonic organoids, and patient-derived human colonic organoids. This multi-model approach allowed us to investigate the mechanisms underlying PCM formation and assess its functional relevance in intestinal epithelial biology.

Results

PCM was predominantly observed in the left-sided colon and was associated with longer disease duration and the presence of pathological inflammation. Spatial transcriptomic HD analysis suggested that colonic PCM emerges within an inflammatory microenvironment distinct from that of the small intestine. Notably, the expression of the Wnt target genes HD5 and HD6, which are typically required for Paneth cell differentiation in the mouse small intestine, was reduced in colonic PCM. In contrast, expression of REG3A, a gene known to be induced by the inflammation-associated cytokine IL-22, was maintained. Consistent with previous reports highlighting the role of IL-22 in the differentiation and maturation of human Paneth cells, these findings suggest that IL-22 may contribute to the induction of PCM under inflammatory conditions. Mechanistically, IL-22 was shown to suppress Notch signaling in human colonic organoids, thereby promoting PCM formation and inducing REG3A expression in metaplastic cells. In vitro experiments using mouse colonic organoids demonstrated that Reg3a enhances epithelial cell proliferation and promotes wound healing. In vivo, Reg3a^ΔIEC mice exhibited impaired wound healing in both acute and chronic DSS-induced colitis models. Furthermore, REG3A treatment of human colonic organoids derived from UC patients stimulated epithelial proliferation and accelerated wound closure.

Conclusion

PCM contributes to epithelial protection in UC by promoting REG3A-mediated regeneration. These findings suggest that PCM may play a compensatory role in mucosal healing during colonic inflammation.

Clinical Case Summary

Introduction. Differential diagnosis between extra-intestinal manifestations of inflammatory bowel disease and side effects of biologics is challenge. Even in the known setting of anti-tumor necrosis factor α agents (anti TNF α), cutaneous T-cell lymphoma (CTCL) carries potential risk to be missed due to indefinite early features mimicking psoriasis or eczema.
Case presentation. Thirty-two years non-smoker female had ulcerative colitis for 13 years. In September 2015, she suffered severe relapse followed by Infliximab introduction (the first dose was administrated on 10 October in 2015). She was good responder, disease remission confirmed on histology. In September 2018, patient reports frequent dermatology visits due to itchy skin lesion on her left earlobe (erythema, erosion, crust, squams) that progressed infiltrating almost half auricle despite local application of steroids and antibiotics. Skin biopsy was performed twice, and acquired samples were examined by two pathologists. First sample is considered for psoriasis. Second sample (acquired afterward) combined with revision of the first sample imposed multiple skin CTCL differentials due to indeterminate histology and biological behavior.
Our patient had her last infliximab administration on 25 February 2019. Since infliximab dismissal, we have followed up patient for 5 years and 2 months. Complete spontaneous regression, absence of CTCL recurrence implied that CTCL was biologics side effect.
Conclusion. Despite multidisciplinary approach diagnosing among justified differentials was a challenge, as follows: extra-intestinal manifestations of ulcerative colitis (Sweet syndrome) versus dermatological side effects of infliximab (eczema, anti TNF induced psoriasis and CTCL). Furthermore, indeterminate histology followed by unpredictable evolution of CTCL created slippery diagnostic path, that could be only hacked through afterward biopsy combined with revision of initial sample.

References

Mariette X, Tubach F, Bagheri H et al. Lymphoma in patients treated with anti-TNF: results of the 3-year prospective French RATIO registry. Ann Rheum Dis. 2010;69(2):400-408.
Mercer LK, Galloway JB, Lunt M et al. Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis. 2016
Rojas-Feria M, Eslam M, Castro- Fernandez M, et al. Cutaneous lymphoma in a patient with ulcerative colitis after immunosuppressive therapy. J Crohns Colitis 2011; 5: 608–11