BACKGROUND AND AIMS:Vedolizumab has become the preferred first-line advanced therapy in ulcerative colitis (UC). However, the optimal second-line treatment following vedolizumab failure remains unclear. We aimed to evaluate the effectiveness and safety of second-line therapies after first-line vedolizumab. METHODS:We conducted a multicenter retrospective study including UC patients from 31 centers who received infliximab (IFX), subcutaneous (SC) anti-TNFs, or ustekinumab after vedolizumab failure. The primary endpoint was steroid-free clinical remission (SFCR) at week 14. Predictors of remission were identified using multivariate logistic regression. RESULTS:Among 196 patients, 99 received IFX, 27 anti-TNF SC, and 70 ustekinumab. At week 14, SFCR was achieved in 78 patients (39.8%): 38 (38.4%) with IFX, 8 (29.6%) with anti-TNF SC, and 32 (45.7%) with ustekinumab, with no significant difference between groups (p = 0.32). Median treatment persistence ranged from 8 to 9.2 months. Baseline corticosteroid use was associated with lower odds of SFCR (OR = 0.37, 95% CI [0.18-0.73]). Adverse events occurred in 15.8% of patients, including 12.2% serious events. Overall adverse events were less frequent with ustekinumab than with IFX (10.0% vs. 24.2%, p = 0.02), while serious events were comparable (5.7% vs. 16.1%, p = 0.08). Discontinuation due to adverse events was more frequent with IFX (12.1%) and anti-TNF SC (14.8%) than with ustekinumab (2.9%, p = 0.045 and 0.049). CONCLUSION:In UC patients failing vedolizumab, second-line IFX, anti-TNF SC, and ustekinumab showed similar effectiveness and persistence. Infliximab remains a robust option for rapid control in high inflammatory burden, whereas ustekinumab may be preferred for its superior safety profile in high-risk patients.

This is the second of two articles presenting the European Crohn's and Colitis Organisation [ECCO] evidence‑based consensus guidelines on the management of adult patients with ulcerative colitis [UC]. The first article covers the medical management of UC, including acute severe colitis. The present article addresses the surgical management of medically refractory UC, including the general surgical approach and perioperative optimisation, surgical strategies and techniques, and recommended levels of centre expertise and surgical specialisation. Together, these two articles aim to inform shared decision‑making and to guide clinicians and healthcare professionals involved in the care of patients with UC, drawing on the best available evidence.

BACKGROUND & AIMS:Despite recent advances, refractory celiac disease (RCD) poses challenging questions. In type 2 RCD (RCD2), the lack of response to the gluten-free diet is attributed to an intestinal intraepithelial lymphoma-carrying driver JAK1 or STAT3 mutations. However, it remains unclear whether these can be safely targeted for therapy. In RCD1, pathogenic insights are still lacking. METHODS:Duodenal biopsy specimens and peripheral blood mononuclear cells from patients with RCD1, RCD2, active celiac disease (CeD), CeD in remission, and controls were analyzed. Lymphocyte populations were characterized using single-cell transcriptomic, genomic, and T cell receptor (TCR) repertoire profiling. Functional and exome sequencing analyses were performed on patient-derived RCD2 cell lines exposed to JAK inhibitors. RESULTS:We show that clonal malignant RCD2 lymphocytes exhibit interpatient similarities but substantial intratumoral heterogeneity, and provide in vitro evidence that JAK inhibitors can select drug-resistant tumor cells, arguing against their use as monotherapy. In RCD1, we identified clonal T-cell expansions harboring mutations that enhance the JAK-STAT pathway. The detection of both RCD2 and a CD4+ lymphoproliferation in a patient initially diagnosed with RCD1 further illustrates the diversity of lymphoproliferative outcomes in CeD. CONCLUSIONS:These findings suggest that RCD subtypes may share underlying mechanisms driven by clonal evolution and JAK-STAT dysregulation. They also highlight the potential limitations of JAK inhibitor monotherapy and the importance of molecularly informed therapeutic strategies.

BACKGROUND AND AIMS:The impact of Physical activity (PA) on the activity of inflammatory bowel disease (IBD) remains unclear. PATIENTS AND METHODS:A descriptive cross-sectional study included consecutive patients with Crohn's disease (CD), ulcerative colitis (UC). PA was assessed using the short International Physical Activity Questionnaire. PA was classified as low, medium or high PA. PA was also assessed according to WHO recommendations. IBD activity was evaluated using PRO-2, while IBD-related disability was assessed with the IBD-disk questionnaire. RESULTS:Among a total of 2514 patients (1715 CD), only 28.8% met the WHO recommendations on PA (49.8% had low PA, 35.2% had medium PA, and 15.0% had high PA). Medium and high PA levels were associated with a higher rate of patient-reported clinical remission in patients with CD (OR 1.30 [1.08-1.57] for medium PA, and 1.33 [1.03-1.72] for high PA vs. low PA; p-trend=0.02) but not in those with UC. Higher PA levels were associated with less IBD-related disability in both CD, and UC. CONCLUSION:In a large cohort of IBD patients, moderate and high PA was associated with higher rates of clinical remission in patients with CD and lower IBD-related disability in both CD and UC patients.

Investigator-initiated studies that include information collected by patients are rising, but limited data is available on patient and investigator experience in this setting. The I-CARE cohort included patients with inflammatory bowel disease (IBD) monthly collecting clinical information in 15 countries for up to 6 years. We describe patients and investigators' involvement in I-CARE and identify predictors of early withdrawal due to patient non-engagement. Patients' characteristics according to the number of electronic Patient-reported outcomes (ePRO) completed during follow-up were assessed. Predictors of early withdrawal due to patient non-engagement were identified using logistic regression. The coding of outcomes reported by patients and corrections by investigators on patients' ePROs were assessed. Among 12,846 patients included by 502 investigators, 79.3% and 77.3% filled more than one ePRO and at least one ePRO within 6 months before the study end date, respectively. All ePROs were completed in 72.8% and 56.4% of patients during year 1 and 3, respectively. Male gender, younger age (< 20), being unemployed or a student, and no previous history of abdominal surgery were associated with early withdrawal. Investigators corrected 52.5% of cancer or dysplasia reported by patients compared to 10% of serious infections. Investigators added or removed a treatment sequence in 19.6% of the 6708 patients treated with biologics. These results highlight the implication of patients in research and the importance of data validation by investigators alongside the challenge and potential of collecting medical data from patients. These findings can inform similar future initiatives in other diseases. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

BACKGROUND & AIMS:About 50% to 75% of patients with Crohn's disease (CD) need bowel resection. Postoperative recurrence of CD is frequent. Here, we investigate the evolution of the mucosa-associated microbiota along the Rutgeerts score measuring endoscopic recurrence after surgery. METHODS:We used 16S ribosomal RNA and ITS2 sequencing to profile the mucosa-associated microbiota of biopsies from patients with CD at the time of surgery (M0, n = 139) and later, at the time of endoscopic assessment of recurrence (M6, n = 125). RESULTS:Although the effect of surgery and recurrence were moderate on the overall microbiota composition, we identified specific microbial signatures displaying differential relative abundance when accounting for clinical covariates. The relative abundance of certain species, notably a decrease of Faecalibacterium prausnitzii, or increase of Akkermansia muciniphila, was differentially associated with a whole range of Rutgeerts score or with more specific scores characterizing the inflammation of the anastomosis or the ileum. In addition, machine learning performances were impacted by the consideration of the Rutgeerts score as a multilevel prediction instead of a binary classification, further confirming the need to consider its full range. Finally, we investigated the community dynamics, which highlighted a denser network organization after surgery and in the absence of recurrence, along with changes in keystone species. CONCLUSIONS:Altogether, these results provide further understanding of the effects of ileal resection in patients with CD and show that disease recurrence is a dynamic process characterized by several waves of changes in the microbiota composition.

Background and Aims: Pancreatic hyperenzymemia in inflammatory bowel disease (IBD) is an under-recognized and challenging condition, as elevated pancreatic enzymes may arise from heterogeneous mechanisms and do not necessarily reflect true pancreatic disorder. This multicenter study aimed to characterize the clinical spectrum, diagnostic work-up, and outcomes of hyperenzymemia in IBD. Methods: This retrospective multicenter study was conducted within the PANDORA network, including 34 international IBD centers. For the present analysis, only centers providing patient-level data on pancreatic hyperenzymemia were considered. Collected variables included demographic, clinical, biochemical, imaging, and therapeutic data. Cases were categorized into three predefined phenotypes: chronic asymptomatic pancreatic hyperenzymemia (CAPH), reclassified acute pancreatitis not meeting Atlanta criteria (recAP), and autoimmune pancreatitis (AIP). Results: A total of 148 IBD patients with elevated pancreatic enzymes were included (CAPH 54.7%, RecAP 35.1%, AIP 10.1%). Ulcerative colitis (UC) accounted for 56.8% of cases and Crohn’s disease (CD) for 43.2%. Overall, 73.6% of patients were asymptomatic at the time of enzyme elevation. Marked hyperenzymemia (≥3× ULN) occurred in 22.3% of patients and was more frequent in RecAP than in CAPH or AIP (50.0%, 6.2%, and 13.3%, respectively). IBD was clinically active in 48.6% of patients, with higher rates in CD. Notably, the clinical meaning of hyperenzymemia differed across IBD phenotypes: in CD it was more often associated with active inflammation, whereas in UC it more frequently prompted advanced imaging and led to the identification of AIP. Imaging strategies differed significantly across phenotypes, and drug withdrawal was common in CAPH and RecAP but unnecessary in AIP. Only two rechallenges confirmed a drug-related mechanism. Conclusions: Pancreatic hyperenzymemia in IBD encompasses a spectrum of conditions with different implications. A phenotype-oriented diagnostic approach is essential to avoid misclassification and unnecessary treatment changes.

ABSTRACT A recent New England Journal of Medicine report described the first successful use of anti‐CD19 CAR‐T cell therapy in a patient with multirefractory ulcerative colitis (UC). This exceptional case provides striking proof of concept that B cells and plasma cells can act as key pathogenic drivers in UC. In that case, the rationale for B‐cell targeting was the presence of autoantibodies against colonic αvβ6‐integrin, which disrupt activation of the anti‐inflammatory TGF‐β pathway. In other immune‐mediated diseases, although monoclonal antibodies against CD19 or CD20 have shown limited efficacy—largely due to incomplete depletion of tissue‐resident B cells and plasma cells within mucosal niches—CAR‐T cells demonstrate superior tissue penetration and more profound depletion. Although the procedure remains intensive, costly, and associated with potentially severe adverse effects, its success rekindles interest in the humoral axis of UC pathogenesis. Beyond this singular case, it encourages the exploration of safer, more scalable B‐cell–directed strategies, for patients with antibody‐driven disease. This viewpoint discusses the implications of the NEJM report and outlines future directions for therapeutic developments in inflammatory bowel diseases.

INTRODUCTION:Upadacitinib (UPA) is effective for treating luminal Crohn's disease (CD), but data on perianal CD (pCD) remain limited. METHODS:All consecutive patients with active pCD (primary and/or secondary lesions) treated with UPA across 13 French centres between September 2022 and August 2025 were included in a retrospective cohort study. Clinical remission was defined as absence of fistula drainage (spontaneous or on gentle pressure) and healing of anal ulcerations without initiation of new therapy. Clinical response was defined as ≥ 50% improvement in fistulas and/or ulcerations based on physician assessment. Clinical outcomes were analysed using non-responder imputation, and magnetic resonance imaging (MRI) outcomes as observed. RESULTS:Among the 59 patients included, 43 (73%) had fistulizing pCD and 16 (27%) isolated anal ulcerations. All patients were previously exposed to at least one biologic and 79% of those with fistulizing pCD underwent prior perianal surgery. In patients with fistulizing pCD, clinical remission was achieved in 11/43 (26%) and 11/43 (26%) patients at 6 and 12 months, respectively, clinical response in 21/43 (49%) and 13/43 (30%) patients. At 12 months, MRI response was documented in 9/13 (69%) and MRI remission in 1/13 (8%) patients with fistulizing pCD. Among patients with fistulizing pCD, no factors predicted clinical remission. Among patients with isolated anal ulcerations, complete healing occurred in 5/16 (31%) at 3 months, 4/16 (25%) at 6 months and 4/16 (25%) at 12 months. CONCLUSION:In this real-world cohort of refractory pCD, UPA achieved clinical remission in one-quarter of patients at 1 year.

BACKGROUND AND AIM:Methotrexate has demonstrated efficacy in Crohn's disease (CD) as monotherapy and is increasingly used in combination therapy. We investigated for the first time the use of methotrexate in a very large cohort of patients with inflammatory bowel disease (IBD) in a real-world setting. METHODS:This was an observational, retrospective, multicenter study including consecutive adult IBD patients treated with methotrexate in monotherapy or combination therapy between January 2015 and December 2022 in 15 French centers. RESULTS:Among the 1115 patients included, 77% had CD and 34.5% had at least one extra-intestinal manifestation (EIM). Regarding prior treatments, 44.0% of patients had been exposed to azathioprine and 75.1% to anti-tumor necrosis factor agents. The primary indication for methotrexate was IBD (81.5%), followed by EIM (rheumatological [11.9%] or dermatological [3.9%]). Methotrexate was prescribed in combination therapy in 90.6% of cases. The most frequent induction and maintenance dose was 15 mg/week (47.5% and 51.1% respectively). The persistence rate of methotrexate was 27.7 months in CD and 22.4 months in ulcerative colitis (UC). For CD, factors associated with persistence were female gender (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.51) and the presence of EIM (HR 0.71; 95% CI 0.58-0.86), and for UC, the presence of EIM (HR 0.63; 95% CI 0.42-0.94). Among the 344 (31.7%) patients who experienced an adverse event related to methotrexate, nine experienced a serious adverse event. CONCLUSION:The French multicenter MICI-METHO study is the first to provide a comprehensive overview of the real-world use, persistence, and safety of methotrexate in patients with IBD.

Most pivotal trials for advanced therapies in ulcerative colitis (UC) exclude patients with isolated rectal disease. This study compares treatment effectiveness between E1 (rectal) and E2/E3 (left-sided or extensive) UC. This analysis pooled individual-level data from several multicentre, retrospective, real-world comparative studies. All consecutive patients with active disease (partial Mayo score (PMS) > 2) who initiated an advanced therapy after failure of at least one biologic were included. The primary outcome was steroid-free symptomatic remission, defined as a PMS ≤ 2 at week 14 (W14). The comparison for the primary outcome was adjusted for potential confounders, including concomitant medications. The secondary outcome was discontinuation-free survival. A subgroup analysis of the primary outcome was performed within each therapeutic class. A total of 608 patients were included: 73 were E1 and 535 E2/E3. Among them, 48% were female, the median age was 39 years [interquartile range: 27–54], and the median disease duration was 6 years [3–10]. Overall, 38% of patients were initiating a second-line advanced therapy, 35% a third-line, 17% a fourth-line, and 4% a fifth-line treatment. The initiated drug was vedolizumab in 28% of cases, ustekinumab in 24%, and a JAK inhibitor (tofacitinib, filgotinib, or upadacitinib) in 48%. A concomitant treatment was prescribed in 256 patients (42%): 76 (13%) with 5-aminosalicylates, 55 (9%) an immunomodulator and 166 (27%) corticosteroids. E1 disease was not significantly associated with a different rate of symptomatic remission at week 14 in univariate analysis (OR = 1.50 [95% CI: 0.94–2.89], p = 0.09). In the multivariate analysis adjusted for age, disease duration, baseline PMS, elevated baseline CRP, concomitant therapy, and number of prior treatment lines, disease extent was not associated with remission (OR = 1.75 [0.87–3.70], p = 0.13). Conversely, an elevated PMS was independently associated with lower rates of remission (OR = 0.84 [0.75–0.95], p = 0.004). Survival analysis showed no difference between the two groups in time to treatment discontinuation for failure (HR = 0.78 [0.56–1.10], p = 0.20), Figure. Subgroup analyses by therapeutic class found no difference in efficacy according to disease extent, whether for vedolizumab (OR = 0.91 [0.30–2.84]), ustekinumab (OR = 1.81 [0.32–14.32]), or JAK inhibitors (OR = 2.63 [0.94–10.0]) (all non-significant). In this large multicenter real-world cohort, advanced therapies demonstrated similar efficacy in patients with isolated rectal UC compared with those with more extensive disease, underscoring the need to adequately treat this disease location. Conflict of interest: Dr. Hupé, Marianne: Abbvie, Takeda, Celltrion Healthcare, Pfizer, Johnson & Johnson, Lilly, Amgen Uzzan, Mathieu: Grant: ECCO-IOIBD, Fondation pour la Recherche Medicale (FRM), SNFGE Personal Fees: Abbvie, Takeda, Celltrion, Janssen, Amgen, Alfasigma, Pfizer Altwegg, Romain: Advisory boards from Abbvie, Takeda, Johnson and Johnson, Lilly, Alphasigma, Celltrion, Pfizer, Amgen, Biogen, Sandoz, Ferring Bouguen, Guillaume: Grant: Abbvie, Ferisinus Personal Fees: Abbvie, Takeda, Fresinus, Amgen, Biogène, Arena, Ferring, Gilead, Janssen, MSD, Pfizer, Sandoz, Takeda, Tillots, Vifor pharma Nachury, Maria: Abbvie, Alfa Sigma, Biosynex, Celltrion, Galapagos, Janssen, Lilly, MSD, Pfizer, Takeda Domas, Quentin: No conflict of interest Fumery, Mathurin: Grant: Pfizer Personal Fees: Abbvie, Janssen, Takeda, MSD, Biogen, Amgen, Sandoz, Fresenius, Gilead, Celgene, Galapagos, Mylan, Tillots, Ferring, Pfizer, Hospira, CTMA, Boehringer, Lilly, Arena Non-financial Support: Abbvie, Janssen, Takeda, MSD, Galapagos, Ferring, Pfizer Tretón, Xavier: Personal Fees: Lectures and advisory board : Abbvie, Celltrion, MSD, Johnson & Johnson, Takeda, Amgen, Alphasigma, Lilly, Pfizer Other: participations: Thabor Therapeutics Amiot, Aurelien: Personal Fees: Abbvie, Fresenius-Kabi, Adacyte, Tillotts pharma, Janssen, Pfizer, Biogen, AMgen, Sandoz, Takeda, Galapagos, Eli Lilly Vuitton, Lucine: Abbvie, Amgen, Viatris, Celltrion, Janssen, Takeda, Lilly, Pfizer, Dr Falk Pharma, MSD, Ferring, Galapagos Caillo, Ludovic: Abbvie, Amgen, Celltrion, Ferring, Fresenius, Lilly, Jonhson & Jonhson, MSD, Pfizer, Takeda, Sandoz Gilletta de Saint Joseph, Cyrielle: Speaker/ consultant fees from Abbvie, AlfaSigma, Amgen, Celltrion, Ferring, Fresenius, Janssen, Lilly, Pfizer, Takeda and Tillots Pereira, Bruno: No conflict of interest Buisson, Anthony: Grant: Abbvie, Celltrion, Pfizer and Takeda Personal Fees: Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Janssen, MSD, Pfizer, Roche, Sanofi-Aventis, Takeda, Tillotts, Vifor Pharma,

Background Head-to-head trials comparing advanced therapies as second-line treatment in ulcerative colitis (UC) are lacking. The EFFICACI trial compared two strategies, switching to infliximab or swapping to vedolizumab, after failure of a first sub-cutaneous anti-tumor necrosis factor (TNF) therapy (ClinicalTrial: 35RC17_8841_EFFICACI). Patients and Methods EFFICACI was a double-blind multicenter randomised controlled trial (1:1) comparing infliximab 5 mg/kg to vedolizumab 300 mg administered intravenously at weeks 0-2-6. Eligible patients had moderate-to-severe UC (total Mayo score ≥ 6 with an endoscopy subscore ≥ 2), who failed to at least 8 weeks of treatment with adalimumab or golimumab as first line of advanced therapy. The primary endpoint was steroid-free clinical remission at W14 (total Mayo score ≤2 without subscore >1). At week 14, patients were unblinded and open-label treatment were administered until week 54. Secondary endpoints included clinical response and endoscopic improvement at week 14, and steroid-free clinical remission at week 54 Findings Among the 151 patients included, 73 were randomised in the infliximab arm and 78 in the vedolizumab arm. Thiopurines or methotrexate were used as concomitant immunosuppressive therapy with infliximab (43/78; 55·1%) and vedolizumab (37/72; 51·4%). At week 14, proportions of patients in steroid-free clinical remission were 17·8% (13/73) with infliximab and 33·3% (26/78) with vedolizumab (RR: 2·31; 95%CI [1·08 ; 4·95], p=0·02). At week 14, clinical response was achieved in 36/73 (49·3%) patients treated with infliximab and 46/78 (59·0%) with vedolizumab (p=0·23) while endoscopic improvement was observed in 21/73 (28·8%) and 36/78 (46·2%) (p=0·02), respectively. At week 54, rates of steroid-free clinical remission were 24/73 (32·9%) in the infliximab group and 31/77 (40·3%) in the vedolizumab group (p=0·31). Rates of adverse event rates were similar across groups. Interpretation Induction therapy with vedolizumab was more effective than infliximab in patients with moderate-to-severe UC who had failed to a first subcutaneous anti-TNF. ​

BACKGROUND AND AIMS:Bowel urgency is one of the most distressing symptoms experienced by patients with inflammatory bowel disease (IBD). The relationship between bowel urgency and multidimensional IBD-related disability has not been well characterised. PATIENTS AND METHODS:We conducted a multicentre cross‑sectional study including adult patients with Crohn's disease (CD) and ulcerative colitis (UC). Patients completed self-administered questionnaires evaluating bowel urgency and IBD-related disability using the IBD-Disk questionnaire. Severe bowel urgency was defined as an IBD-disk bowel urgency subscore ≥6. RESULTS:A total of 2,514 patients (1,715 with CD) were included. Severe bowel urgency was observed in 17.1% of patients with UC and in 20.4% of patients with CD, compared to 3.6% and 7.6%, respectively, in those in clinical remission according to PRO-2 criteria. In multivariate analysis in patients with UC, factors associated with severe bowel urgency were general well-being subscore ≥2 and abdominal pain subscore ≥2 while treatment with advanced therapy, clinical remission according to PRO-2, fatigue subscore <5, work productivity subscore <3 and sexual life subscore <2 were negatively associated. In patients with CD, factors were rectal bleeding subscore ≥2, abdominal pain subscore ≥2 and history of intestinal resection while clinical remission, fatigue subscore <5, work productivity subscore <3 and sexual life subscore <2 were negatively associated. CONCLUSION:Severe bowel urgency is frequent in both patients with CD and UC beyond IBD activity and is strongly associated with various dimensions of IBD-related disability. These findings emphasise the importance of systematically assessing urgency in routine clinical practice.

We compared the effectiveness of ustekinumab (UST) and upadacitinib (UPA) in patients with ulcerative colitis (UC) previously exposed to at least one anti-TNF agent. This was a multicenter retrospective study that consecutively included all patients aged ≥18 years-old with symptomatic UC (partial Mayo score >2) who initiated UST or UPA after exposure to at least one anti-TNF. UST was initiated with an intravenous infusion followed by SC injections of 90 mg every 8 weeks, with the option of intensification to 90 mg every 4 weeks from week 4 at the clinician’s discretion. UPA was prescribed at 45 mg once daily for 8 weeks, followed by 45 mg, 30 mg, or 15 mg at the physician’s discretion. The primary endpoint was symptomatic remission (partial Mayo score ≤2) without corticosteroids (CFREM) at week 16 (W16). Secondary endpoints were clinical remission per modified Mayo score, and histological and endoscopic improvement (HEMI). Comparisons were made using propensity-score analyses adjusted on the usual potential confounders. A total of 226 patients were included (165 and 61 in UST and UPA groups, respectively). Except for higher proportion of prior exposure to more than two biologics (46.6% vs 82.0%; p < 0.001) in UPA group, the populations were comparable (UST vs UPA). After propensity score adjustment, CFREM at W16 was 35.1% and 37.2% in UST and UPA groups, respectively (p = 0.91). Subgroup analyses (after propensity adjustment) did not show any difference in CFREM at W16 after failure to only one biologic, whereas UPA was significantly more effective than UST (OR = 6.05 [1.10–33.42]; p = 0.039), after exposure to ≥ 2 advanced therapies, as well as in patients with primary failure to ≥ 2 prior biologics (OR = 4.25 [1.11–16.28]; p = 0.035). However, no difference was observed between the two treatments according to UC severity. No predictor of UPA effectiveness was identified. Factors associated with absence of CFREM at W16 under UST were: failure of ≥ 3 biologics (p = 0.013) and primary failure to at least one biologic (p = 0.013). No difference was observed between the two treatments regarding clinical remission and HEMI (p = 0.48 and 0.68, respectively). After a median follow-up > 12 months, we did not see any difference regarding treatment discontinuation, UC-related hospitalization, or colectomy. In this study, UST and UPA appeared to have comparable effectiveness in the overall population of UC patients previously exposed to at least one anti-TNF. However, UPA was more effective than UST in patients exposed to at least two biologics and/or with at least two prior primary failures. These results may help physicians to personalize therapeutic decision-making in UC. Conflict of interest: Prof. Dr. Buisson, Anthony: Consulting fees from: Abbvie, AlfaSigma, Amgen, Arena, Biogen, Celltrion, CTMA, Ferring, Galapagos, Guty Care, Janssen, Hikma, Lilly, Mylan, Nexbiome, Pfizer, Roche, Takeda, Tillotts Lecture fees from: Abbvie, AlfaSigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Hikma, Janssen, Lilly, Mayoli-Spindler, MSD, Pfizer, Roche, Sanofi-Aventis, Takeda, Tillotts, Vifor-Pharma Research fundings from: Abbvie, AlfaSigma, Celltrion, Janssen, Lessaffre, Lilly, Pfizer, Takeda Serrero, Melanie: fees from Pfizer, Abbvie, Takeda, Janssen, MSD, Amgen, Ferring, Tillotts, Celltrion Altwegg, Romain: Advisory boards from Abbvie, Takeda, Johnson and Johnson, Lilly, Alphasigma, Celltrion, Pfizer, Amgen, Biogen, Sandoz, Ferring Vuitton, Lucine: No conflict of interest Uzzan, Mathieu: Grant: ECCO-IOIBD, Fondation pour la Recherche Medicale (FRM), SNFGE Personal Fees: Abbvie, Takeda, Celltrion, Janssen, Amgen, Alfasigma, Pfizer Domas, Quentin: No conflict of interest Tretón, Xavier: Personal Fees: Lectures and advisory board : Abbvie, Celltrion, MSD, johnson&Johnson, Takeda, Amgen, Alphasigma, Lilly, Pfizer Other: participations: Thabor Therapeutics Nachury, Maria: Abbvie, Alfa Sigma, Biosynex, Celltrion, Galapagos, Janssen, Lilly, MSD, Pfizer, Takeda Amiot, Aurelien: Personal Fees: Abbvie, Fresenius-Kabi, Adacyte, Tillotts pharma, Janssen, Pfizer, Biogen, AMgen, Sandoz, Takeda, Galapagos, Eli Lilly Caillo, Ludovic: Abbvie, Amgen, Celltrion, Ferring, Fresenius, Lilly, Jonhson&Jonhson, MSD, Pfizer, Takeda, Sandoz Hupé, Marianne: No conflict of interest Pereira, Bruno: No conflict of interest Fumery, Mathurin: Grant: Pfizer Personal Fees: Abbvie, Janssen, Takeda, MSD, Biogen, Amgen, Sandoz, Fresenius, Gilead, Celgene, Galapagos, Mylan, Tillots, Ferring, Pfizer, Hospira, CTMA, Boehringer, Lilly, Arena Non-financial Support: Abbvie, Janssen, Takeda, MSD, Galapagos, Ferring, Pfizer

BACKGROUND AND AIMS:Evidence from rheumatology supports a within-class treatment switch for JAK-inhibitors (JAKi), but data in ulcerative colitis (UC) remain limited. We aimed to assess the effectiveness and safety of initiating a second JAKi in patients with UC previously treated with another JAKi. METHODS:We conducted a multicenter retrospective study, including patients with UC starting a second JAKi after prior JAKi exposure. The primary endpoint was Week 12 steroid-free clinical remission (SFCR-rectal bleeding subscore = 0, stool frequency subscore ≤ 1, and no steroids). RESULTS:We included 243 patients (median follow-up: 38 [21-57] weeks). At Weeks 12, 26, and 52, SFCR was achieved in 116/243 (48%), 120/243 (49%), and 69/243 (28%), respectively. Secondary loss of response to the first JAKi was associated with higher SFCR at Week 12 compared to primary failure (odds ratio [OR] = 1.92, 95% confidence interval [CI] = 1.11-3.30, P = 0.02). Higher baseline disease activity (OR = 0.68, 95% CI = 0.68-0.55, P < 0.01) and steroid use (OR = 0.23, 95% CI = 0.13-0.42, P < 0.01) had lower odds of Week 12 SFCR. Endoscopic remission occurred in 22/243 (9%) (<Week 26) and 27/243 (11%) (26-78 weeks), and endoscopic improvement in 53/243 (22%) and 45/243 (19%), respectively. Sixty-seven (28%) patients discontinued the second JAKi, mostly due to primary (36/67) or secondary failure (22/67). Sixty-six adverse events (mostly acne and infections) occurred in 56 (23%) patients, without major thromboembolic or cardiovascular events. CONCLUSION:Treatment with a second JAKi is effective and safe in patients with UC already exposed to JAKi. Primary failure to a first JAKi and steroid use at initiation of the second JAKi might reduce the likelihood of success with the second JAKi.

INTRODUCTION:The exact positioning of granulocyte and monocyte adsorptive apheresis (GMA) using the ADACOLUMN® system (JIMRO, Takasaki, Japan) remains unclear in the era of advanced therapy. PATIENTS AND METHODS:We conducted a retrospective multi-centre cohort study which included all patients with active Crohn's disease (CD) or ulcerative colitis (UC) who were treated with GMA alone or in combination with advanced therapy at 15 French tertiary care centres between 2007 and 2024. RESULTS:A total of 129 patients with IBD (median age: 40.9 years; IQR: 29.3-58.1; 79% with UC; IBD duration: 7.0 [2.9-13.1] years; 97 (75%) had been previously exposed to advanced therapies) were included. In patients with UC, the rates of clinical remission, steroid-free clinical remission, and response at week 14 were 33.3%, 27.5%, and 52.0%, respectively. In patients with CD, the corresponding rates were 33.3%, 29.6% and 66.7%, respectively. At week 54, 33 patients (26%) were still receiving maintenance GMA therapy, including 12 with CD and 21 with UC. Among these patients, the rates of steroid-free clinical remission were 71.4% for those with UC and 41.7% for those with CD. A total of 26 adverse events were reported, 16 of which were an exacerbation of IBD activity. CONCLUSION:In this real-world cohort of patients with refractory IBD, GMA induced steroid-free clinical remission in one-third of patients with CD and UC by week 14. A significant proportion of patients who continued GMA therapy beyond week 14 experienced ongoing clinical benefits.

We aimed to demonstrate the non-inferiority of subcutaneous infliximab monotherapy (SC IFX mono) compared with combination therapy (SC IFX + IS) in patients with Crohn’s disease (CD). In this multicenter (22 centers) retrospective study, we consecutively included all patients ≥18 years-old with symptomatic CD according to PRO-2 (abdominal pain subscore >1 or stool frequency >3) who started SC infliximab 120 mg every 2 weeks, from week 6 or W10 after an IV induction regimen (2 or 3 IV infusions at 5 mg/kg at week 0, W2 ± W6). The primary endpoint was clinical remission (abdominal pain subscore ≤1 and stool frequency ≤3) without steroid (CFREM) and is expressed as % of months (4-week periods) spent in CFREM (month being the statistical unit). The non-inferiority margin was predefined at -10% according to IOIBD recommendations. A priori sample-size calculation (considering hypothesis of 55% of months spent in CFREM in reference group, 90% power, one-sided 95% confidence interval due to non-inferiority design, and imbalance between groups), indicated that 2,160 months were required, i.e 210 patients. We present here the results of an interim analysis while data from half of participating centers have been collected. Secondary endpoints considered the patient as the statistical unit. All comparisons were performed using propensity-score adjustment (IPTW) To date, 196 patients (1,954 months) have been included (SC IFX mono = 62 and SC IFX +IS = 134 patients). The two groups were comparable except for higher complicated phenotypes and shorter disease duration in SC IFX+IS group (Table 1), which has been taken into account in propensity score analyses. Analysis on primary endpoint including 1,954 months, showed that 73.6% and 61.5% of months were spent in CFREM in SC IFX and SC IFX + IS groups, respectively, giving an absolute difference of + 12.1% [lower bound = +8.4%, upper bound = +15.6%], confirming the non-inferiority of SC IFX mono. After IPTW (N = 196 patients), no difference of CFREM at W12 (67.1% vs 59.8%;p=0.32), W24 (71.5% vs 64.2%;p=0.28), and W52 (65.4% vs 61.9%;p=0.66) was seen between SC IFX mono and SC IFX + IS, respectively, (Table 2) with no difference in subgroups such as bio-exposed, B2/B3 phenotypes, and prior exposure to IS. SC IFX mono was not associated with a higher risk of SC IFX dose optimization (HR = 0.81 [0.41–1.60], p = 0.55), IFX discontinuation (HR = 1.87 [0.96-3.65], progression of bowel damage (HR = 0.66[0.15–2.96]), bowel resection (HR = 0.15[0.02–1.15]), or hospitalization (HR = 0.80[0.30–2.10]) (median follow-up=19.4 months). In this real-world multicenter study, SC infliximab monotherapy appeared non-inferior to combination therapy in CD at both short and mid-terms. Conflict of interest: Prof. Dr. Buisson, Anthony: Consulting fees from : Abbvie, AlfaSigma, Amgen, Arena, Biogen, Celltrion, CTMA, Ferring, Galapagos, Guty Care, Janssen, Hikma, Lilly, Mylan, Nexbiome, Pfizer, Roche, Takeda, Tillotts Lecture fees from: Abbvie, AlfaSigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Hikma, Janssen, Lilly, Mayoli-Spindler, MSD, Pfizer, Roche, Sanofi-Aventis, Takeda, Tillotts, Vifor-Pharma Research fundings from: Abbvie, AlfaSigma, Celltrion, Janssen, Lessaffre, Lilly, Pfizer, Takeda Caron, Bénédicte: No conflict of interest Le Berre, Catherine: Abbvie, Amgen, Celltrion, Ferring, Fresenius Kabi, Galapagos, Gielad, Janssen, Lilly, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda. Le Cosquer, Guillaume: consultant/lecture, transport fees from AbbVie, Amgen, Johnson & Johnson, Lilly, Takeda, Fresenius Kabi, Celltrion, and Pfizer. Serrero, Melanie: fees from Pfizer, Abbvie, Takeda, Janssen, MSD, Amgen, Ferring, Tillotts, Celltrion Nachury, Maria: Abbvie, Alfa Sigma, Biosynex, Celltrion, Galapagos, Janssen, Lilly, MSD, Pfizer, Takeda Altwegg, Romain: Advisory boards from Abbvie, Takeda, Johnson and Johnson, Lilly, Alphasigma, Celltrion, Pfizer, Amgen, Biogen, Sandoz, Ferring Boschetti, Gilles: No conflict of interest Vuitton, Lucine: No conflict of interest Uzzan, Mathieu: Grant: ECCO-IOIBD, Fondation pour la Recherche Medicale (FRM), SNFGE Personal Fees: Abbvie, Takeda, Celltrion, Janssen, Amgen, Alfasigma, Pfizer Tretón, Xavier: Personal Fees: Lectures and advisory board : Abbvie, Celltrion, MSD, johnson & Johnson, Takeda, Amgen, Alphasigma, Lilly, Pfizer Other: participations: Thabor Therapeutics Fumery, Mathurin: Grant: Pfizer Personal Fees: Abbvie, Janssen, Takeda, MSD, Biogen, Amgen, Sandoz, Fresenius, Gilead, Celgene, Galapagos, Mylan, Tillots, Ferring, Pfizer, Hospira, CTMA, Boehringer, Lilly, Arena Non-financial Support: Abbvie, Janssen, Takeda, MSD, Galapagos, Ferring, Pfizer Peyrin-Biroulet, Laurent: CONSULTING Abbvie, Abivax, Adacyte, Alimentiv, Alfasigma, Amgen, Apini, Banook, BMS, Celltrion, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Lilly, LifeMine, Medac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Par’ Immune, Pfizer, Prometheus, Roche, Roivant, Samsung, Sandoz, Sanofi, Sorriso, Spyre, Takeda, Teva, ThirtyfiveBio, Tillots, Vectivbio, Vedanta, Ventyx. LECTURE Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Iterative Health, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots Gilletta de Saint Joseph, Cyrielle: Speaker/ consultant fees from Abbvie, AlfaSigma, Amgen, Celltrion, Ferring, Fresenius, Janssen, Lilly, Pfizer, Takeda and Tillots Guillo, Lucas: No conflict of interest Nancey, Stéphane: board membership and lecturing fees from Abbvie, Takeda, Celltrion Healthcare, Pfizer, Galapagos, Johnson & Jonshon, Lilly, Fresenius, Amgen, Medac, MSD. Domas, Quentin: No conflict of interest Pereira, Bruno: No conflict of interest

Upadacitinib has demonstrated efficacy for induction and maintenance therapy in luminal Crohn’s disease (CD) (1). According to a post-hoc analysis of a phase 3 randomized controlled trial, upadacitinib also showed benefit in the treatment of fistulizing perianal CD (2). However, its real-world effectiveness in this specific phenotype has not yet been evaluated. All consecutive patients with active perianal CD (primary and/or secondary lesions) treated with upadacitinib across 13 French centres between September 2022 and August 2025 were included in a retrospective cohort study. Clinical remission was defined as the absence of draining pus including with pressure and healing of anal ulcers and/or fissures, without the addition of new dedicated treatment for perianal lesions (antibiotics and/or topics). Clinical response was defined as improvement of at least 50% of fistulas and/or ulcers by physician’s assessment. MRI-based response and remission were also assessed. Treatment failure was defined as upadacitinib discontinuation, initiation of a new advanced therapy, or need for additional perianal surgery. Patients lost to follow-up were considered as treatment failures. Fifty-nine patients were included: 43/59 (73%) with fistulizing perianal CD and 16/59 (27%) with isolated primary anal ulcerations. Median age was 38 years (interquartile range [29–47]); 29 (49%) were male and 11 (19%) were active smokers. All patients had previously been exposed to at least two biologics (median 4 [3–5]), and 40 (68%) had a history of perianal surgery, including 34/43 (79%) in the fistulizing subgroup. Among patients with fistulizing perianal CD, clinical remission was achieved in 5/43 (12%), 11/43 (26%), and 11/43 (26%) patients at 3, 6, and 12 months, respectively, while clinical response was observed in 27/43 (63%), 21/43 (49%), and 13/43 (30%) patients (Figure 1). At 12 months, MRI response was documented in 9/14 (64%) and MRI remission in 1/14 (7%) patients with fistulizing perianal CD. Among those with isolated anal ulcerations, complete ulcer healing was observed in 4/16 (25%) at 12 months (Figure 1). No clinical or demographic factors were associated with clinical remission at 12 months in univariate analysis. Sixteen adverse events (AEs) were reported in 14 patients (27%), including three (5%) serious AEs corresponding to CD exacerbations. At 12 months, 10 patients (17%) underwent perianal drainage surgery, and 16 (27%) discontinued upadacitinib, all due to lack of efficacy. In this real-world multicentre cohort of patients with refractory perianal CD, treatment with upadacitinib achieved clinical remission in approximately one-quarter of patients at one year. References: (1) Loftus EV, Panés J, Lacerda AP, et al. Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease. N Engl J Med. 2023;388(21):1966-1980. (2) Colombel JF, Lacerda AP, Irving PM, et al. Efficacy and Safety of Upadacitinib for Perianal Fistulizing Crohn’s Disease: A Post Hoc Analysis of 3 Phase 3 Trials. Clin Gastroenterol Hepatol. 2024;0(0). Conflict of interest: Dr. Richard, Nicolas: Lecture/consultant fees from AbbVie, Amgen, Celltrion, Ferring, Janssen, Lilly, Sandoz and Takeda. Seksik, Philippe: I received personal fees from Takeda, Janssen, Merck MSD, Biocodex, Ferring, Fresenius Kabi, Astellas, Amgen, Pfizer, Pilege and Abbvie Altwegg, Romain: Advisory boards from Abbvie, Takeda, Johnson and Johnson, Lilly, Alphasigma, Celltrion, Pfizer, Amgen, Biogen, Sandoz, Ferring Nachury, Maria: Abbvie, Alfa Sigma, Biosynex, Celltrion, Galapagos, Janssen, Lilly, MSD, Pfizer, Takeda Laharie, David: Personal Fees: Board, consulting and lecture fees from Abbvie, Alfasigma, Amgen, Biocon, Celltrion, Ferring, Fresenius-Kabi, Johnson & Johnson, Lilly, MSD, Pfizer, Sandoz and Takeda Nancey, Stéphane: board membership and lecturing fees from Abbvie, Takeda, Celltrion Healthcare, Pfizer, Galapagos, Johnson & Jonshon, Lilly, Fresenius, Amgen, Medac, MSD. Coffin, Benoît: No conflict of interest Pelletier, Anne-Laure: •ALP has received lecture/consultant fees from Janssen, Pfizer, and Novartis. Uzzan, Mathieu: Grant: ECCO-IOIBD, Fondation pour la Recherche Medicale (FRM), SNFGE Personal Fees: Abbvie, Takeda, Celltrion, Janssen, Amgen, Alfasigma, Pfizer Amiot, Aurelien: Personal Fees: Abbvie, Fresenius-Kabi, Adacyte, Tillotts pharma, Janssen, Pfizer, Biogen, AMgen, Sandoz, Takeda, Galapagos, Eli Lilly Amil, Morgane: No conflict of interest Vuitton, Lucine: •LV has received fees for lectures and/or consulting fees from Abbvie, Amgen, Johnson & Johnson, Celltrion, Takeda, Pfizer, Lilly, Ferring, MSD, Dr Falk Pharma, Nordic Pharma, Alpha sigma. Fumery, Mathurin: •M.F. has received lecture/consultant fees from AbbVie, Ferring, Tillotts, MSD, Biogen, Amgen, Fresenius, Hospira, Sandoz, Pfizer, Celgene, Gilead, Boehringer, Galapagos, Janssen, and Takeda. N.R. has received lecture/consultant fees from AbbVie, Janssen and Takeda. Bozon, Anne: No conflict of interest

INTRODUCTION:Women with endometriosis have a higher risk of developing inflammatory bowel diseases (IBDs). This study aimed to better understanding the impact of endometriosis on the course of IBD. METHODS:We conducted a retrospective cohort study in 18 French and Belgian IBD centers between June 2022 and March 2023. Any patient with both conditions was eligible for inclusion. They were randomly matched to 1 or 2 patients with IBD without endometriosis. The impact on IBD progression was assessed using a composite severity criterion including intestinal damage or need for bowel surgery. RESULTS:Overall, 207 patients with both conditions (149 Crohn's disease [CD]; 58 ulcerative colitis [UC]) were matched to 409 patients with IBD alone. The median follow-up duration for IBD was 10 years (5.75-17). No difference was observed between the 2 groups regarding CD location, disease phenotype, and anoperineal involvement. Proctitis were more frequent in patients with UC and endometriosis. Patients with IBD with endometriosis were significantly less exposed to immunosuppressants (UC P < 0.01; CD P < 0.001) and biologics (UC P < 0.01; CD P < 0.001). Patients with CD with endometriosis had a less severe disease course compared with patients without endometriosis (hazard ratio 0.68, 95% confidence interval 0.50-0.92, P = 0.011). Patients with UC with endometriosis had not a significant different disease course compared with patients without endometriosis (hazard ratio 1.73, 95% confidence interval 0.74-4.00, P = 0.20). These results were similar in the subgroup of patients with endometriosis treated surgically. DISCUSSION:Endometriosis does not negatively influence the course of IBD, patients with CD even have a less severe progression. Patients were significantly less exposed to immunosuppressants and biologics.