BACKGROUND & AIMS:Secondary loss of response to ustekinumab is observed in patients with Crohn's disease (CD). Multiple dose-intensification regimens have been proposed. We aimed to test prospectively 2 different dose-intensification regimens with ustekinumab in patients with CD experiencing secondary loss of response. METHODS:This was an investigator-initiated, multicenter, randomized, placebo-controlled trial conducted at 15 hospitals in Belgium. Eligible patients were adults with CD treated with ustekinumab on maintenance dosing of 90 mg subcutaneous every 8 weeks and experiencing a secondary loss of response (Patient-Reported Outcomes 2: abdominal pain score >1 and liquid or very soft stool frequency >3 and an objective documentation of disease). Patients were randomized 1:1 to receiving a single intravenous reinduction with ustekinumab ≈6 mg/kg followed by either subcutaneous ustekinumab 90 mg every 4 weeks or every 8 weeks until week 48. The primary endpoint was the proportion of patients with steroid-free clinical remission at week 48, defined as Patient-Reported Outcomes 2 remission: (abdominal pain ≤ 1 and stool frequency ≤3) and fecal calprotectin <250 μg/g and no steroids in the 90 days before week 48. RESULTS:Between March 2020 and October 2023, 108 patients were randomized. Steroid-free clinical remission at week 48 was reached in 15% vs 19% of patients in the every 4 weeks vs the every 8 weeks group (difference 4%; P = 0.5). Serious adverse events occurred in 17% vs 13% of patients. CONCLUSIONS:In patients with CD and secondary loss of response to ustekinumab, dose intensification with a single intravenous administration and followed by 4 weekly subcutaneous dosing of ustekinumab was not more effective than 1 intravenous administration followed by 8 weekly subcutaneous dosing of ustekinumab. (ClinicalTrials.gov, Number: NCT04245215).

BACKGROUND AND AIMS:Restoration of intestinal barrier integrity and function in inflammatory bowel disease (IBD) has been associated not only with a reduced burden of persistent symptoms but also with improved long-term outcomes, prompting growing interest in intestinal barrier healing as a potential new therapeutic target. To date, no clinical trials have specifically evaluated therapies aimed at restoring intestinal barrier function in IBD, and there is currently no consensus on how such trials should be designed or how the intestinal barrier should be assessed. The aim of this initiative was to develop consensus recommendations on the optimal design of clinical trials and the selection of tools to evaluate therapies targeting the intestinal barrier in IBD. METHODS:A panel of 12 international specialists with recognised expertise in the intestinal barrier and/or IBD clinical trials evaluated statements developed from a systematic literature review. Statements were discussed and anonymously voted on using a modified Delphi methodology. Consensus was predefined as at least 75% agreement among participants. The study was conducted and reported in accordance with the Conducting and REporting of DElphi Studies framework. RESULTS:Fourteen statements reached consensus and were approved. These statements addressed key aspects of clinical trial design, including the role of intestinal barrier assessment as an endpoint, timing of reassessment, protocol requirements and disease-specific considerations. Additional statements focused on the selection and standardisation of tools for intestinal barrier assessment, encompassing imaging-based techniques, functional permeability assays and endogenous biomarkers, as well as considerations for implementation and future research directions. CONCLUSIONS:This international consensus provides a structured framework to guide the design of future clinical trials evaluating efficacies of therapies in restoring intestinal barrier integrity and/or function in IBD.

Off-label ustekinumab benefits patients with chronic pouchitis, yet its pharmacokinetics (PK) and target concentrations remain unclear. We aimed to characterize its population PK in chronic pouchitis, identify concentration thresholds predicting clinical remission (modified pouchitis disease activity index <5 and a reduction by ≥ 2 points), and propose optimized dosing regimens. Twenty-two patients with chronic pouchitis were included.1 All received standard ustekinumab intravenous induction dosing (∼6 mg/kg), followed by 90mg subcutaneous maintenance dosing every eight weeks. Serum samples were collected at week (w)4, w8, w16, and w24. A popPK model was developed to characterize ustekinumab PK. A population pharmacodynamics (popPD) model using logistic regression was used to link drug concentrations and clinical remission and to identify the cutoff. Monte Carlo simulations (n = 1000) were conducted for the 22 patients comparing four induction dosing strategies: (1) standard label dosing, (2) exact 6 mg/kg, (3) 6 mg/kg rounded to the nearest 130 mg vial size, and (4) increased fixed-dose regimen (390 mg <55 kg, 520 mg 55–85 kg, 650 mg >85 kg). For each strategy, the rate of target attainment was calculated based on the identified cutoff. The PopPK model well captured the time course of ustekinumab concentrations (Figure 1a). Standardized to a 70-kg patient with albumin level 44 g/L, clearance (CL) was estimated at 0.348 L/day. The popPD model identified w4 drug concentrations as a predictor of clinical remission at w16, with a threshold of 15.0 mg/L (AUC 0.84; 95% CI 0.62–1.00) (Figure 1b). Simulations revealed that standard dosing achieved this target exposure in only 46.6% of patients (95% CI 46.0–47.3). An exact 6 mg/kg dosing improved this to 57.0% (95% CI 56.4–57.7), while vial-rounded dosing further increased target attainment to 60.9% (95% CI 60.3–61.6). The increased fixed-dose regimen achieved the highest target rate at 80.2% (95% CI 79.6–80.7). Notably, the vial-rounded dosing strategy provided consistent exposure across weight bands (58.6% <55 kg; 61.4% 55–85 kg; 60.4% >85 kg), mitigating underexposure in lighter patients (<55 kg), who had a target rate of only 10.4% under the standard regimen (Figure 2). Clearance of ustekinumab in patients with chronic pouchitis is 1.5–2 times higher than that in Crohn’s disease and ulcerative colitis. W4 concentrations were predictive of clinical remission at w16, with a cutoff of 15.0 mg/L. The vial-rounded induction strategy substantially improves target attainment, particularly in the lighter patients. Reference: [1] Outtier et al. Clin Gastroenterol Hepatol. 2024;22(12):2468-2474.e1 Conflict of interest: Ms. Zhang, Wei: No conflict of interest Outtier, An: No conflict of interest Dewit, Olivier: Consulting, lectures fees or travel accommodations: Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, Janssen, MSD, Mylan, Pfizer and Sandoz. Louis, Edouard: Education and Reserach Grants for my department: Abbvie, Takeda, Johnson and Johnson, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Johnson and Johnson, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Ferrante, Marc: Research grants from AbbVie, EG Pharma, Celltrion, Janssen, Pfizer, Takeda and Viatris Consultancy fees from AbbVie, AgomAb Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, MRM Health, Merck Sharp and Dohme, Pfizer, Takeda and ThermoFisher Speakers’ fees from AbbVie, Biogen, Boehringer Ingelheim, Dr Falk Pharma, Ferring, Janssen-Cilag, Merck Sharp and Dohme, Pfizer, Takeda, Truvion Healthcare and Viatris Dreesen, Erwin: Erwin Dreesen received consultancy fees from Alimentiv and argenx, lecture fees from Celltrion and Galapagos, and financial support from Celltrion, Janssen, Pfizer, Prometheus Biosciences, R-Biopharm, and Sandoz, outside the submitted work, with all honoraria/fees being paid to KU Leuven and not to any personal account of Erwin Dreesen.

The intestinal epithelium is a key component of the intestinal barrier, which is the largest and most complex barrier of the human body, regulating nutrient absorption while restricting the entry of harmful antigens. Breakdown of this barrier facilitates microbial and dietary antigenic translocation, triggering local immune system activation and inflammation. Although barrier alteration alone may not be sufficient to initiate disease, accumulating evidence highlights its critical role in the pathogenesis and progression of a wide range of gastrointestinal and systemic disorders. Early identification of intestinal epithelium and barrier alterations could enable timely therapeutic approaches. This systematic review provides an overview of current in vivo (both noninvasive and invasive) and ex vivo/in vitro approaches used to assess intestinal epithelial barrier alterations. Noninvasive in vivo approaches rely mainly on urinary detection of orally ingested probes, but their clinical utility is limited by lack of standardization and specificity. Circulating and fecal constitutive markers derived from the intestinal barrier, which reflect epithelial alterations, together with indicators of microbial translocation, provide complementary insights but remain insufficiently validated. Advanced invasive endoscopic modalities such as confocal laser endomicroscopy enable near-histological, real-time visualization but are costly and largely used as research tools in specialist centers. In vitro, transepithelial electrical resistance assessment remains the reference standard, though novel technologies (including impedance spectroscopy and organic electrochemical transistors) offer enhanced sensitivity and resolution. Despite progress, major gaps remain, including the absence of a standardized definition of epithelial barrier breakdown, the lack of a practical diagnostic tool, methodological heterogeneity, unvalidated thresholds, and limited prospective validation.

IMPORTANCE AND OBJECTIVE:Upadacitinib, an oral, reversible Janus kinase inhibitor, is approved for the treatment of moderate-to-severe Crohn's disease (CD). Limiting corticosteroid exposure is an important goal in treating CD. This posthoc analysis evaluated the corticosteroid-sparing effects of upadacitinib in patients with CD. DESIGN AND SETTING:This study included pooled data from two phase 3, multicenter, double-blind induction trials and one maintenance trial. Randomization was stratified by corticosteroid use at induction baseline, with a mandatory corticosteroid taper starting at induction week 4. Efficacy was evaluated by baseline corticosteroid use and by achieving corticosteroid-free outcomes through year 2 of maintenance therapy. Safety was also assessed. RESULTS:At baseline, 34.7% (234/674) and 35.7% (124/347) of upadacitinib 45 mg and placebo-treated patients were taking corticosteroids, respectively. At induction week 12 and maintenance week 52, higher rates of upadacitinib-treated patients were corticosteroid-free among all patients and among patients with baseline corticosteroid use compared with placebo; upadacitinib-treated patients achieved higher rates of corticosteroid-free outcomes, compared with placebo, including corticosteroid-free clinical remission (stool frequency/abdominal pain score [SF/APS]: 42.7% vs 16.1%; CD activity index [CDAI]: 41.2% vs 23.4%) and corticosteroid-free endoscopic response (37.0% vs 8.1%), with similar results observed among responders to upadacitinib induction therapy at maintenance week 52. Corticosteroid-free outcomes were sustained through year 2 of maintenance therapy. The safety profile was similar to the overall population, with no new safety risks identified. CONCLUSIONS AND RELEVANCE:The results from pivotal studies demonstrated that upadacitinib effectively induced early and sustainable corticosteroid-free clinical remission with a manageable safety profile in patients with moderate-to-severe CD. CLINICAL TRIAL IDENTIFIERS:U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.

Abstract Background In Crohn’s disease (CD), an exposure-response relationship exists for ustekinumab, with higher serum levels associated with better outcomes. Although several retrospective and observational studies demonstrate dose-escalation of ustekinumab can be effective in case of secondary loss of response (LOR), prospective placebo-controlled data are lacking. The aim of the REScUE study (NCT04245215) was to investigate the effect of 2 different re-induction regimens with ustekinumab on clinical, endoscopic, biological and pharmacological outcomes in patients with CD. Methods This Belgian multicentre prospective double-blind randomized placebo-controlled trial included adult patients with CD treated with ustekinumab who presented with secondary LOR to ustekinumab after documented primary response. Secondary LOR was defined by PRO-2 (AP> 1 AND SF> 3) and confirmed by either an elevated biomarker (CRP >5 mg/L or faecal calprotectin >250 µg/mg) or endoscopic signs of inflammation. All patients received a single IV re-induction with ustekinumab (≈6mg/kg) and were then randomized 1:1 to blinded maintenance ustekinumab 90 mg SC Q4W (intervention) or 90 mg SC Q8W (control) for 48 weeks. Primary endpoint was proportion of patients with steroid-free clinical remission (definition in fig 1) at week 48, with missing data were handled using non-responder imputation. Results In total, 132 patients were screened, and 108 patients were included: 67% female, median [IQR] age 41 [32-54] year, median disease duration 14 [7-22] years. Prior anti-TNF exposure was reported in 92% of patients, while ustekinumab was the first-line advanced treatment in 7% of patients. The primary endpoint of steroid-free clinical remission at week 48 was achieved by 9/54 (17%) patients in the q4w regimen vs 8/54 (16%) in the q8w regimen (p=0.96) (fig 1). Endoscopic remission (SES-CD <3) was achieved in 5/54 (10%) vs 3/54 (6%) (p=0.52), endoscopic response (≥50% decrease in SES-CD from baseline) was achieved in 11/54 (22%) vs 6/54 (12%) (p=0.23) and 0.52biomarker remission was achieved in 20/54 (38%) vs 13/54 (26%) (p=0.19) in the q4w regimen vs the q8w regimen, respectively. Time to first clinical remission was similar between groups (fig 2). Association with ustekinumab serum levels will be reported. No new safety signals were observed. Conclusion In patients with CD experiencing secondary LOR to ustekinumab, dose optimization with a single IV re-induction followed by intensified maintenance dosing (90 mg SC q4W) was not superior to a single IV re-induction followed by conventional maintenance dosing (90 mg SC q8W) in achieving steroid-free clinical remission. The secondary endpoints were numerically higher but not significant in the intensified regimen.

BACKGROUND AND AIMS:While this strategy is frequently used for other biologics, real-world evidence on subcutaneous (SC) vedolizumab (VDZ) dose intensification in inflammatory bowel disease (IBD) is lacking. This study aimed to assess the effectiveness and safety of SC VDZ intensification. METHODS:We conducted a retrospective study in 25 centers including all patients with active ulcerative colitis (UC) or Crohn's disease (CD) (defined by PRO2), and incomplete or loss of response to SC VDZ 108 mg every other week (EOW) when the drug was intensified. The primary outcome was steroid-free clinical response (SFCr) defined by at least 50% of PRO2 improvement, no treatment change, no surgery, and SC VDZ persistence at 3 months. RESULTS:Of the 154 included patients (66% UC, 34% CD), prior anti-tumor necrosis factor (anti-TNF) exposure was reported in 85% of CD and 50% of UC patients. SC VDZ was intensified for an incomplete response in 73% of CD and 53% of UC patients, mostly at 108 mg weekly (95%). At 3 months, SFCr was achieved in 35% of CD and 43% of UC patients. In multivariate analysis, factors associated with response were secondary loss of response in CD, and prior anti-TNF exposure in UC. At 12 months, 51% of CD and 37% of UC patients maintained SC VDZ. Adverse events occurred in 10 patients including one severe pneumonia and one angioedema. CONCLUSIONS:In this real-world study evaluating SC VDZ intensification, an SFCr was observed in at least one-third of IBD patients at 3 months, suggesting the benefit of this strategy in clinical practice.

Abstract Background The therapeutic options for Inflammatory Bowel Disease (IBD) have expanded with the introduction of JAK inhibitors. However, real-world data on upadacitinib (UPA) in patients with moderate to severe Crohn’s disease (CD) are scarce. Our aim was to assess the long-term effectiveness and safety of UPA in multi-refractory Belgian patients. Methods Data from all patients with active CD initiating UPA between September 2022 and January 2024 were retrospectively collected from 17 Belgian centres. Effectiveness endpoints were evaluated at week 24 and 52. Steroid-free clinical response and remission were defined using the two-component patient-reported outcome. Endoscopic response was defined as a decrease in baseline Simple Endoscopic Score (SES-CD) with ≥50%, and endoscopic remission as SES- CD ≤ 4 or absence of ulcers. Adverse events (AE), treatment discontinuation, CD-related hospitalization and surgery were assessed throughout follow-up. Non-response imputation was applied for clinical evaluation. Results A total of 140 patients were included (Table 1) with a median follow-up of 33 weeks (IQR: 3-97). The majority of patients (89%) were exposed to at least 3 biologics. At week 24, 53% and 40% of patients achieved steroid-free clinical response and remission, respectively (Figure 1). At week 52, these numbers were 37% and 29%. Endoscopic data were available in 48/140 patients at week 24, of whom 52% and 27% reached endoscopic response and remission. At week 52, these numbers were 63% and 37%. Of patients with active articular extra-intestinal manifestations at baseline 37% and 34% had a quiescent articular disease by week 24 and 52, respectively. 5 out of 9 patients with active perianal disease at baseline and on UPA by week 52, had persistent perianal active disease. Overall, 66 patients (47%) discontinued UPA during follow-up: 23 due to primary non response, 13 due to secondary loss of response, 16 due to AE, 3 due to patient’s choice and 11 due to CD-related surgery. 16 patients required CD-related hospitalization within 52 weeks. AE occurred in 60% of patients (84/140). Of these patients, 11% experienced serious AE of which 2 cardiovascular events: 1 transit ischemic attack and 1 deep venous thrombosis. The most common reported AE were herpes simplex reactivation (5/140), respiratory tract infection (7/140), cutaneous reactions (7/140) and acne (17/140). Only 3 patients had reactivation of herpes zoster infection. Conclusion In this real-world cohort of highly refractory CD patients, UPA effectively induced both steroid-free clinical remission and endoscopic remission by week 52. UPA was relatively well tolerated with respect to adverse events.

Abstract Background Subcutaneous (SC) vedolizumab (VDZ) has demonstrated its efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD). This study aimed to evaluate the effectiveness and safety of SC VDZ dose intensification in IBD patients with an incomplete clinical response or loss of response. Methods We conducted a retrospective international study in 25 IBD centers from August 2023 to April 2024. All patients with active CD or UC, as defined by patient-reported outcomes (PRO2), who had incomplete response or lost response and required intensified SC VDZ at 108 mg weekly or 216 mg every other week, were included. The endpoints at 3 months post-intensification were steroid-free (SF) clinical response (defined as at least a 50% PRO2 improvement, no treatment change, no surgery, and SC VDZ persistence) and SF clinical remission (CD: abdominal pain≤1 and liquid stool frequency≤3; UC: rectal bleeding=0 and stool frequency=0). Results 154 patients (66% UC, 34% CD) were included. Among the 52 CD patients (median age 36 years, disease duration 14 years), 85% had already been exposed to anti-TNF; among the 102 UC patients (median age 40 years, disease duration 7 years), 50% had prior anti-TNF exposure. The reason for SC VDZ intensification was an incomplete response in 73% of CD and 53% of UC patients, and a secondary loss of response in 27% of CD and 47% of UC patients. Intensification had been done at 108 mg weekly in 95% of patients. At 3 months, SF clinical response was observed in 18/52 (35%) CD and 44/102 (43%) UC patients. Clinical response occurred in 9/14 (64%) of CD patients and 23/48 (48%) of UC patients who had been intensified due to loss of response, and in 9/38 (24%) of CD patients and 21/54 (39%) of UC patients who were in incomplete clinical response. Among responders, all CD patients and 72% of UC patients achieved SF clinical remission. In multivariate analysis, factors associated with SC VDZ response after dose escalation were secondary loss of response (vs incomplete response) (OR=5.8(95%CI: 1.54-21.8);p=0.01) in CD patients, and prior anti-TNF exposure (OR=2.66(95%CI: 1.19-5.98);p=0.02) in UC patients. In survival analysis, 50% of patients had discontinued SC VDZ within 12 months for CD and within 8 months for UC following dose intensification. Adverse effects were reported in 11 patients (7%), including one severe case (pneumonia) and one systemic allergic reaction. Four patients underwent surgery (1 UC and 3 CD patients). Conclusion This first real-world study evaluating SC VDZ intensification demonstrated a SF clinical response at 3 months in more than one third of IBD patients, suggesting the interest of this strategy in clinical practice. Acknowledgment Takeda

It is with great sadness that we learned of the death of Professor René Fiasse on the 26th of February 2024, at the age of 87. Born in Quiévrain in 1936 in the Borinage region, to two teachers, he was the eldest of four children. From an early age, he developed a quality that would mark him throughout his life: a committed humanism. Struck by the horrors of war, he became interested in international politics and then became actively involved in the pacifist movements and Amnesty International. Having received a pluralist education and thanks to his open-mindedness, he was always ahead of his time when it came to major ethical issues.

BACKGROUND & AIMS:Seventeen percent of patients with ulcerative colitis that undergo proctocolectomy with pouch surgery will develop chronic pouchitis. We evaluated the efficacy of ustekinumab for these patients. METHODS:We performed a prospective study of patients with chronic pouchitis receiving ustekinumab intravenously at baseline (∼6 mg/kg) and 90 mg ustekinumab subcutaneously every 8 weeks thereafter. The Modified Pouchitis Disease Activity Index (mPDAI) was assessed at baseline and weeks 16 and 48. The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points) at week 16. Secondary endpoints included the proportion of patients achieving remission at week 48, the proportion of patients achieving response (reduction of mPDAI by ≥2 points) at weeks 16 and 48, and change in mPDAI. RESULTS:We enrolled 22 patients (59% male; median age, 42.2 years). Remission was achieved in 27.3% at week 16 and 36.4% at week 48. Response was achieved in 54.5% both at weeks 16 and 48. The median mPDAI decreased from 8 (interquartile range [IQR], 7-10) to 7 (IQR, 4-9) at week 16 (P = .007) and 4 (IQR, 1.75-7.25) at week 48 (P < .001). The clinical mPDAI subscore decreased from 3.5 (IQR, 2-4) to 2 (IQR, 1-3) at week 16 (P = .009) and 1 (IQR, 0-2.25) at week 48 (P = .001). The endoscopic mPDAI subscore decreased from 5.5 (IQR, 4-6) to 4 (IQR, 3-6) at week 16 (P = .032) and 3 (IQR, 1.75-4.25) at week 48 (P = .001). CONCLUSION:Ustekinumab was efficacious in one-half of the patients suffering from chronic pouchitis. Ustekinumab should therefore be positioned in the treatment algorithm of chronic pouchitis. (ClinicalTrials.gov Number NCT04089345).

Introduction: Long-term use of corticosteroids (CS) in Crohn’s disease (CD) is limited by toxicities. The CS-sparing effect of upadacitinib (UPA) was evaluated among all patients with active CD in phase 3 clinical trials. Methods: In U-EXCEL (NCT03345849) and U-EXCEED (NCT03345836), patients with moderate-to-severe CD were randomized to 12-week induction with UPA 45 mg once daily (QD) or placebo (PBO). Patients who achieved clinical response to UPA 45 mg were re-randomized in U-ENDURE (NCT03345823) to UPA 30 mg QD, UPA 15 mg QD, or PBO for a 52-week maintenance period. Patients taking CS at baseline began a CS taper at induction week 4 and continued the taper during maintenance; those who initiated CS during the study started the CS taper on symptom improvement. Endpoints included the proportion of patients without CS use (CS-free) at week 12 or for ≥ 90 days before week 52 who achieved clinical remission by stool frequency/abdominal pain score (SF/APS) or by CD Activity Index (CDAI), enhanced clinical response, decrease of ≥ 100 points in CDAI from baseline (CR-100), endoscopic remission, and endoscopic response at week 12 and week 52. CS daily dose (in prednisone-equivalent doses) was recorded. Results: Of 1021 patients evaluated, the mean (SD) cumulative CS exposure over 12 weeks was 16.0 (19.0) mg daily of prednisone equivalent for UPA 45 mg and 24.0 (34.0) mg for PBO, and during maintenance, 13.7 (16.3) mg for UPA 15 mg, 13.5 (27.3) mg for UPA 30 mg, and 13.7 (9.9) mg for PBO. A significantly higher proportion of patients who received UPA vs PBO were CS-free and achieved clinical remission (by SF/APS and CDAI), enhanced clinical response, CR-100, endoscopic remission, and endoscopic response at week 12 (Figure 1A). At week 52, response rates across all assessed endpoints were generally maintained in patients who received UPA 15 or 30 mg, with significantly higher response rates in patients who received either UPA dose vs PBO (Figure 1B). Safety was as expected for UPA or CS.1 Conclusion: During induction, higher proportions of patients treated with UPA were CS-free and experienced greater clinical and endoscopic improvements vs those receiving PBO. CS-free response rates were generally sustained through week 52, suggesting that UPA may have an enduring steroid-sparing effect. 1. Loftus EV Jr, et al. N Engl J Med. 2023;388:1966–1980.Figure 1.: Proportion of Patients Who Were CS-Free and Achieved Clinical and Endoscopic Endpoints at Induction Week 12 (A) and Maintenance Week 52 (B) Among All Patients APS, abdominal pain score; CDAI, Crohn’s Disease Activity Index; CR-100, clinical response 100; CS, corticosteroids; NRI-C, non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19; PBO, placebo; SES-CD, Simplified Endoscopic Score for Crohn’s Disease; SF, stool frequency; UPA, upadacitinib. Only patients with clinical response (≥ 30% decrease in average daily very soft or liquid SF and/or ≥ 30% decrease in average daily APS and both not worse than baseline) in the induction studies were eligible to enter the maintenance study. For all assessments, NRI-C was used for incorporating multiple imputation to handle missing data due to COVID-19. Data are percent of patients (95% CI). Values above bars are percent of patients and n/N. CS-free in the induction studies: Patients not taking CS at week 12. CS-free in the maintenance study: Patients not taking CS within 90 days before week 52. SF/APS clinical remission: Average daily very soft or liquid SF ≤ 2.8 and average daily APS ≤ 1.0 and both not greater than baseline. CDAI clinical remission: CDAI < 150. Enhanced clinical response: ≥ 60% decrease in average daily very soft or liquid SF and/or ≥ 35% decrease in average daily APS and both not greater than baseline, or clinical remission. CR-100: Decrease of ≥ 100 points in CDAI from baseline. Endoscopic remission: SES-CD ≤ 4 and ≥ 2-point reduction from baseline and no subscore > 1 in any individual variable. Endoscopic response: Decrease in SES-CD > 50% from baseline of the induction period (or at least a 2-point reduction from baseline for patients with an SES-CD of 4 at baseline). ***P < .001 vs PBO.

Background Fatigue is commonly reported by patients with inflammatory bowel disease [IBD], but the determinants of IBD-related fatigue have yet to be determined. Aims To identify the factors associated with fatigue in a large population of patients with IBD. Patients and Methods Fatigue and nine other IBD-related disability dimensions were assessed in a cohort of 1704 consecutive patients with IBD using the IBD-disk questionnaire in a cross-sectional survey of 42 French and Belgian centres. Fatigue and severe fatigue were defined as energy subscores >5 and >7, respectively. Determinants of fatigue were assessed using univariate and multivariate analyses (odds ratios [ORs] are provided with 95% confidence intervals). Results The prevalence rates of fatigue and severe fatigue were 54.1% and 37.1%, respectively. Both fatigue and severe fatigue were significantly higher in patients with active disease than in patients with inactive disease [64.9% vs 44.7% and 47.4% vs 28.6%, respectively; p < 0.001 for both comparisons]. In the multivariate analysis stratified by age, sex, type of IBD and IBD activity, fatigue was associated with age >40 years (OR = 0.71 [0.54-0.93]), female sex (OR = 1.48 [1.13-1.93]) and IBD-related sick leave (OR = 1.61 [1.19-2.16]), and joint pain (OR = 1.60 [1.17-2.18]), abdominal pain (OR = 1.78 [1.29-2.45]), regulating defecation (OR = 1.67 [1.20-2.32]), education and work (OR = 1.96 [1.40-2.75]), body image (OR = 1.38 [1.02-1.86]), sleep (OR = 3.60 [2.66-4.88]) and emotions (OR = 3.60 [2.66-4.88]) subscores >5. Conclusion Determinants of fatigue are not restricted to IBD-related factors but also include social factors, sleep and emotional disturbances, thus supporting a holistic approach to IBD patient care.

Abstract Background Up to 10% of patients with ulcerative colitis who undergo a proctocolectomy with ileal pouch-anal anastomosis, will develop chronic antibiotic refractory pouchitis (CARP). As there is a large unmet need in the management of these patients, we evaluated the efficacy and safety of induction and maintenance therapy with ustekinumab (UST). Methods We performed a prospective, multicentre, open-label study of patients with CARP (mPDAI ≥5 with an endoscopic subscore ≥2) . Patients received a weight-range-based infusion of UST at baseline (~6mg/kg) and subcutaneous injections of 90mg UST every 8 weeks thereafter until week 48. Patients underwent a pouchoscopy at baseline, week 16 and week 48, with assessment of the modified pouchitis disease activity index (mPDAI). The primary endpoint was the proportion of patients achieving steroid-free remission (mPDAI <5 and reduction by ≥2 points from baseline) at week 16. For this abstract we focus on the secondary endpoints at week 48 including the proportion of patients achieving steroid-free remission and response (reduction of mPDAI by ≥2 points from baseline) using a non-responder imputation. For patients still continuing UST at week 48, we evaluated the change in symptomatic and endoscopic mPDAI subscore, C-reactive protein (CRP) and faecal calprotectin levels compared to baseline. Descriptive statistics and paired nonparametric tests (Wilcoxon signed-rank) of changes from baseline were performed. Results We enrolled 22 patients (59% male, median age 42.2 years, median time after surgery 8.2 years). Twelve (54.5%) patients had previously been treated with biologics for CARP (table 1). At week 16, steroid-free remission was achieved in 27.3% of patients. At week 48, steroid-free remission was achieved in 36.4% and response in 54.5% of patients. In the 14 patients continuing UST at week 48, a significant decrease in total mPDAI (4 (1.8-7.3) vs. 8 (8-10), p<0.001), clinical subscore (1 (0-2.3) vs. 3 (2-4), p=0.001), and endoscopic subscore (3 (1.8-4.3) vs. 6 (4.8-6), p=0.001) was observed compared to baseline (figure 1). Faecal calprotectin (129 (80-344) vs. 229 (139-541) mg/kg, p=0.17) and CRP (2.5 (1.3-4.4) vs. 3.8 (1.6-9.3) mg/L, p=0.09) levels did however not decrease significantly (figure 2 and 3). Three serious adverse events (hospitalization for subobstruction, worsening pouchitis and choledocholithiasis) were recorded, but were not considered related to UST. Conclusion In this open-label pilot study in patients with CARP, maintenance therapy with UST showed a clinical and endoscopic effect in half of the patients, but was not associated with changes in inflammatory biomarkers. These promising results warrant confirmation in a placebo-controlled study with UST for the treatment of CARP.

Abstract Background Anti-tumor necrosis factor (TNF)-α agents are a therapy of choice in the induction and maintenance treatment of inflammatory bowel disease (IBD). Unfortunately, their efficacy varies. Some IBD patients are primary non-responders and many will experience a secondary loss of response. However, we do not yet have good predictors of their efficacy. Obesity, which prevalence increases worldwide, is also increasingly found in IBD population. Some studies suggest an association between obesity and poorer response to anti-TNFα therapy in IBD patients, although with conflicting results. The aim of this study is to assess the impact of patients’ body mass index (BMI) on the efficacy of anti-TNFα agents in IBD and if there is difference according to the route of administration (intravenous (IV) vs subcutaneous (SC)) or the type of disease (Crohn’s disease (CD) vs ulcerative colitis (UC)). Methods We retrospectively collected data from 188 patients with IBD, aged ≥ 18 years, treated with a first anti-TNFα agent started in our center between January 2002 and December 2020 to avoid missing data. A lack or loss of response to anti-TNFα therapy was defined by the need to optimize or change the treatment or by the initiation of any intercurrent treatment (steroid therapy, hospitalization, or surgery). Frequency of the event and time to its occurrence were analyzed and compared according to BMI using uni- and multivariate logistic regression models and survival curves (Kaplan-Meier), represented by BMI categories (<18.5; 18.5-25; 25-30 and ≥ 30 kg/m²). Results In this cohort of 188 patients (143 CD, 43 UC, 2 Indeterminate Colitis), 8% were obese. We observed that the higher the patient’s BMI, the earlier the risk of optimization or change of treatment (HR=1.043, p=0.045). Association was even stronger for obese patients (HR=2.13, p=0.018). After adjustment for IBD type and administration route, association with obesity persisted. Two other characteristics - female gender (HR=1.56, p=0.012) and higher CRP (HR=1.14, p=0.021) – were associated with earlier optimization or treatment change. Similarly, analysis of survival curves showed a significant difference in time to optimization or change of treatment between BMI categories in patients with CD (p=0.02) but not in those with UC (p=0.87). No association was found between BMI and need for intercurrent treatment. Conclusion This study confirms an association between higher BMI – specifically obesity - and an earlier loss of efficacy of a first anti-TNFα treatment, regardless of IBD type or route of drug administration. Prospective studies with analysis of trough levels are required for a better understanding of the mechanisms involved in the response to anti-TNFα therapy in IBD obese patient.

BACKGROUND:In recent years, an increasing prevalence of obesity in inflammatory bowel disease (IBD) has been observed. However, only a few studies have focused on the impact of overweight and obesity on IBD-related disability. AIMS:To identify the factors associated with obese and overweight patients with IBD, including IBD-related disability. PATIENTS AND METHODS:In this cross-sectional study, we included 1704 consecutive patients with IBD in 42 centres affiliated with the Groupe d'Etude Therapeutique des Affections Inflammatoires du tube Digestif (GETAID) using a 4-page questionnaire. Factors associated with obesity and overweight were assessed using univariate and multivariate analyses (odds ratios (ORs) are provided with 95% confidence intervals). RESULTS:The prevalence rates of overweight and obesity were 24.1% and 12.2%, respectively. Multivariable analyses were stratified by age, sex, type of IBD, clinical remission and age at diagnosis of IBD. Overweight was significantly associated with male sex (OR = 0.52, 95% CI [0.39-0.68], p < 0.001), age (OR = 1.02, 95% CI [1.01-1.03], p < 0.001) and body image subscore (OR = 1.15, 95% CI [1.10-1.20], p < 0.001) (Table 2). Obesity was significantly associated with age (OR = 1.03, 95% CI [1.02-1.04], p < 0.001), joint pain subscore (OR = 1.08, 95% CI [1.02-1.14], p < 0.001) and body image subscore (OR = 1.25, 95% CI [1.19-1.32], p < 0.001) (Table 3). CONCLUSION:The increasing prevalence of overweight and obesity in patients with IBD is associated with age and poorer body image. A holistic approach to IBD patient care should be encouraged to improve IBD-related disability and to prevent rheumatological and cardiovascular complications.

BACKGROUND:Recent data regarding the impact of biologics and new surgical techniques on the indications and outcomes of colectomy for ulcerative colitis (UC) are limited. AIMS:The present study aimed at determining the trend of colectomy in UC by comparing colectomy indications and outcomes between 2000 and 2010 and 2011-2020. METHODS:This observational retrospective study was conducted in two tertiary hospitals, including consecutive patients who underwent colectomy between 2000 and 2020. All data concerning UC history, treatment and surgeries were collected. RESULTS:Among the 286 patients included, 87 underwent colectomy in 2001-2010 and 199 in 2011-2020. Patients' characteristics were similar between groups, except for prior biologic exposure (50.6 % vs. 74.9%; p<0.001). The indications of colectomy significantly decreased for refractory UC (50.6 % vs. 37.7%; p = 0.042), but were similar for acute severe UC (36.8 % vs. 42.2%; p = 0.390) and (pre)neoplastic lesions (12.6 % vs. 20.1%; p = 0.130). A widespread use of laparoscopy (47.7 % vs. 81.4%; p<0.001) was associated with fewer early complications (12.6 % vs. 5.5%; p = 0.038). CONCLUSION:Over the last two decades, the proportion of surgery for refractory UC significantly decreased compared to other surgical indications while surgical outcomes improved despite larger exposure to biologics.

Background and Aims Optimal management of patients with inflammatory bowel disease [IBD] after anti-tumour necrosis factor [TNF] discontinuation due to severe induced skin lesions is unclear. Our study aimed to describe dermatological and IBD evolution after anti-TNF discontinuation for this side effect. Methods We conducted a multicentre retrospective study including consecutive IBD patients who discontinued anti-TNF due to severe induced skin lesions. Our objectives were to determine factors associated with dermatological remission [complete disappearance of skin lesions] and with IBD relapse in patients with inactive disease at inclusion, notably the impact of an early switch to another biological agent within 3 months of anti-TNF discontinuation. Results Among the 181 patients [134 women, 160 Crohn's disease] included in the 13 participating centres, dermatological remission occurred in 110 [62%] patients with a median [interquartile range, IQR] interval of 8.0 [6.8-11.0] months. Scalp location was independently associated with less remission of skin lesions (hazard ratio [HR] = 0.64 [95% CI 0.43-0.94], p = 0.02) while early switch was independently associated with a higher probability of remission of skin lesions (HR = 1.64 [95% CI 1.1-2.5], p = 0.02). Among the 148 patients with inactive IBD at inclusion, disease relapse occurred in 75 [51%] patients with a median [IQR] interval of 26.0 [23.0-39.1] months. Survival rates without IBD relapse at 1 year were 85.8% [95% CI 77.5-94.9] in the early switch group and 59.3% [95% CI 48.9-71.9] in the other group [p Conclusions Early switch to a new biological is associated with a higher probability of healing of anti-TNF-induced skin lesions and significantly reduces the risk of IBD relapse.

Abstract Background The management of ulcerative colitis (UC) has been improved due to progresses in medical and surgical practices during the past twenty years. Yet the impact of new therapies on the evolution of the three colectomy’s indications in UC (severe acute colitis, refractory ulcerative colitis and (pre-)neoplastic complication) is still not well established. The aim of this study was to compare the evolution of the surgical indications within the last two decades. Methods This was an observational retrospective study carried out in two tertiary hospitals. All patients with UC who underwent total or segmental colectomy between 2001 and 2020 were included, without age restriction. Two periods were compared: 2001–2010 and 2011–2020. Endpoints were to compare the colectomy indications, patients’ characteristics, surgical procedures, and rates of postoperative complication between the two cohorts. Results Among the 286 patients included (57% were men; median age of 40 years; 60.5% of extensive and 35.7% of distal colitis), 87 (30.4%) underwent colectomy in 2001–2010 and 199 patients (69.6%) in 2011–2020. Patients’ characteristics were similar between the two periods, including duration of UC and the severity according to the global Mayo score. Colectomy rate for refractory UC significantly decreased over time (n=119) (50.6% vs. 37.7%; p=0.042), while it increased for acute severe colitis (n=116) (36.8% vs. 42.2%; p=0.390) and (pre-)neoplastic indication (n=51) (12.6% vs. 20.1%; p=0.130) (Figure 1). Regarding surgery, there was an increased use of laparoscopic colectomy (47.7% vs. 81.4%; p<0.001) during the latter period and the median length of stay in hospital after surgery has decreased from 13 to 10 days (p=0,098). There were less early (12.6% vs. 5.5%; p=0.038) and late severe complications (1.6% vs. 0.8%; p< 0.001) and less surgical revisions (38.6% vs. 19.5%; p<0.001) without change on 30-day mortality rate (2.3% vs. 1%; p=0.391). The rate of extraintestinal postoperative infections (especially urinary, pulmonary and catheters infections) increased during the second period (27% vs; 45.7%; p=0.018). As expected, the mean number of past biotherapies was higher during the second period (1.2 versus 0.6; p<0.001), as well as the rate of pre-operative exposition to TNFα antagonists (68.4% vs. 50.6%; p=0.016). Conclusion The rate of surgery for refractory colitis has significantly decreased while the rate of colectomy for cancer and acute severe colitis has risen during the last twenty years. In the same time, surgical technics have changed with more laparoscopic surgeries associated with a reduction of postoperative morbidity despite the larger use of biotherapies.