Objective Risankizumab is an interleukin-23 p19 subunit inhibitor which received approval for Crohn's disease (CD) by UK licensing authorities in May 2023. Our aim was to evaluate the real-world outcomes of risankizumab in the UK. Design We conducted a retrospective, multicentre, cohort study of patients with CD treated with risankizumab across 25 health boards in the UK between 1 January 2021 and 1 November 2024. Our primary outcome was treatment persistence at 6 months. Our secondary endpoints were steroid-free clinical remission (Harvey-Bradshaw index <5), C-reactive protein (CRP) remission (CRP <= 5 mg) and faecal calprotectin (FCAL) remission (FCAL <250 mu g/g). Results We included 763 patients with a median follow-up time of 27 weeks (IQR 18-41 weeks) with a total of 432 and 110 patients having 6-month and 12-month data available. The median number of advanced therapy exposures was 3 (2-4), with 92% (704/763) having failed anti-tumour necrosis factor therapy and 72% (548/763) having failed ustekinumab. Treatment persistence at 6 and 12 months was 95.4% and 89.2%, respectively. Unadjusted persistence rates for ustekinumab-naive versus ustekinumab-exposed patients were 92.7% vs 95.3% and 89.0% vs 74.2% at 6 and 12 months, respectively (p=0.62). Rates of clinical, CRP and FCAL remission were 52% (123/236), 53% (169/319) and 44% (69/156) at 6 months. Rates of clinical remission for ustekinumab naive versus exposed were 57% (29/51) vs 51% (94/185) (p=0.54) 6 months. Adverse events occurred in 17% (n=127) of the cohort, of which 12% (n=92) were serious. Conclusion Risankizumab was effective in a large, real-world, medically refractory CD cohort with excellent persistence and good clinical and biochemical remission rates.

INTRODUCTION:We evaluated guselkumab efficacy and safety through week 92 of the ongoing QUASAR (NCT04033445) long-term extension (LTE). METHODS:Intravenous guselkumab induction responders were randomized (1:1:1) at QUASAR maintenance study week 0 (M-0) to receive subcutaneous guselkumab 100 mg every 8 weeks (q8w) or 200 mg every 4 weeks (q4w) or placebo. Participants completing the maintenance week 44 (M-44) visit could enter the LTE, continuing the treatment they were receiving. Participants receiving placebo discontinued at unblinding after week M-44 analyses and were excluded from LTE efficacy analyses. Clinical remission at week M-92 was a key efficacy endpoint. Safety was evaluated from weeks M-44 through M-92. RESULTS:Overall, 87% (329/378) of participants randomized to guselkumab at week M-0 entered the LTE. Among the 303 participants who had not received a maintenance dose adjustment (guselkumab 100 mg q8w, n = 155; guselkumab 200 mg q4w, n = 148), 95% (287/303) completed treatment through week M-92. At week M-92, among participants receiving guselkumab 100 mg q8w or 200 mg q4w, 71% (110/155) and 74% (109/148), respectively, achieved clinical remission (analyzed using nonresponder imputation). Among participants receiving guselkumab 100 mg q8w or 200 mg q4w with available data at week M-92 (as observed analysis), 75% (110/147) and 83% (109/132), respectively, achieved clinical remission. Nearly 100% (218/219) of participants in clinical remission at week M-92 were corticosteroid free for ≥8 weeks prior. Safety findings were consistent with the known safety profile. DISCUSSION:Sustained and durable corticosteroid-free efficacy and safety were observed among participants receiving up to 2 years of guselkumab maintenance treatment.

Background:Mirikizumab, a selective IL-23p19 monoclonal antibody, has demonstrated efficacy in moderate-to-severe ulcerative colitis (UC) although real-world data are limited. In addition, registrational trials excluded patients previously treated with ustekinumab, which targets the IL-12/23 p40 subunit. We aimed to evaluate the real-world effectiveness and safety of mirikizumab in a multicenter UK cohort of patients with UC, including those with prior ustekinumab exposure. Methods:A retrospective observational study was conducted across 3 tertiary UK centers. Adults with confirmed UC who received mirikizumab and had ≥12 weeks of follow-up were included. Data on demographics, disease activity (SCCAI, UCEIS), biomarkers (CRP, fecal calprotectin), and treatment persistence were analyzed at 3 and 6 months. Outcomes were compared between ustekinumab-exposed and ustekinumab-naïve patients. Results:Among 100 patients (36 ustekinumab-exposed), treatment persistence at 3 months was 72% with no significant difference between groups. SCCAI scores decreased from 5.8 to 3.3 at 3 months (P < .00001), and fecal calprotectin decreased from 1094 µg/g to 586 µg/g (p = 0.006). UCEIS scores (n = 36) improved significantly post-induction (mean 4.4 to 2.7, P < .000001). Multivariable logistic regression did not reveal any factors associated with treatment persistence, including prior ustekinumab exposure. Adverse events were infrequent and mild. Conclusion:Mirikizumab is effective and well tolerated in a real-world UC population, including patients with prior ustekinumab exposure. These findings support the use of IL-23p19 inhibition regardless of previous IL-12/23 blockade.

Sphingosine 1 phosphate receptor (S1PR) modulators are the latest drug class to have received approval for the treatment of ulcerative colitis, and have brought a new mechanism of action to this landscape. They target immune cell trafficking, specifically the egress of lymphocytes from lymph nodes to the bloodstream, and have proven to be an efficacious and safe anti-inflammatory mechanism. This narrative review aims to distil the key trial data on the efficacy and safety of ozanimod and etrasimod, the two S1PR modulators currently licensed for use in UC. We discuss the higher response rates in the advanced therapy naive versus exposed subgroups. We summarise their safety profiles, taking into consideration open label extension data. Finally, we consider where this class of drugs may be best placed in the treatment landscape and also provide a practical guide for their use in clinical practice.

BACKGROUND & AIMS:No fully validated indices to measure pouchitis activity exist. We aimed to develop and externally validate a novel endoscopic and histologic index. METHODS:Endoscopists and pathologists used 11 (4 endoscopic, 4 histologic, 3 composite) existing indices and items from a prior Research and Development/University of California Los Angeles appropriateness exercise to assess pouchitis disease activity in videos and images from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomized placebo-controlled alicaforsen trial. Reliability was assessed with the intraclass correlation coefficient (ICC). Responsiveness was quantified by the area under the receiver operating characteristic curve (AUROC). A novel index was developed using linear regression with a visual analog scale (VAS) of pouchitis endoscopic and histologic disease activity as the dependent variable and was externally validated with the EARNEST vedolizumab trial data. RESULTS:The Atlantic Pouchitis Index (API) (range, 0-69) comprises the Simple Endoscopic Score for Crohn's Disease and Robarts Histopathology Index. The API exhibited almost perfect intra-rater (ICC, 0.88; 95% confidence interval [CI], 0.81-0.92) and substantial inter-rater reliability (ICC, 0.72; 95% CI, 0.60-0.79). A high degree of responsiveness (AUROC, 0.95; 95% CI, 0.89-0.98), greater than existing endoscopic indices (ΔAUROC, 0.09-0.24; P ≤ .005), was observed when the change criterion was a decrease in the VAS of one-half of the standard deviation. Good responsiveness was observed in external validation when vedolizumab was the change criterion (AUROC, 0.63; 95% CI, 0.51-0.73). CONCLUSIONS:Development and validation of the API advances pouchitis disease assessment. Integration of endoscopy and histopathology results in an objective, reliable, and responsive instrument to evaluate therapy effectiveness in research and clinical settings.

Therapeutic drug monitoring is important for optimizing anti-tumor necrosis factor-α (TNF-α) therapy in inflammatory bowel disease. However, the exposure–response relationship has never been assessed in pouchitis. To explore associations between anti-TNF-α drug concentration and pouchitis disease activity in patients with a background of ulcerative colitis. A retrospective, multicenter, cross-sectional study was conducted in adult patients with pouchitis requiring anti-TNF-α treatment. Rates of clinical and endoscopic remission were calculated, and drug concentrations during maintenance therapy were compared between remission and non-remission cohorts. Sixty-three patients were included: median age, 48 years (IQR 36–59) and median time since pouchitis diagnosis, 7 years (IQR 2–13). Patients received infliximab, n = 27 (43

BACKGROUND & AIMS:Assessing endoscopic activity is integral in the management of postoperative Crohn's disease (CD). We aimed to comprehensively characterize the reliability and responsiveness of different endoscopic instruments when used to assess postoperative CD activity. METHODS:Ileocolonoscopy videos (n = 70) from the PREVENT (Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Comparing REMICADE ® [infliximab] and Placebo in the Prevention of Recurrence in Crohn's Disease Patients Undergoing Surgical Resection Who Are at an Increased Risk of Recurrence) trial were reviewed by 3 blinded central readers. Disease activity was assessed using the Rutgeerts and modified Rutgeerts scores, POCER (postoperative Crohn's endoscopic recurrence) index, REMIND (groupe de REcherche sur les Maladies INflammatoires Digestives) score, Simple Endoscopic Score for Crohn's Disease (SES-CD), and the Crohn's Disease Endoscopic Index of Severity (CDEIS). Reliability was quantified by the intraclass correlation coefficient (ICC). Responsiveness was quantified using the win probability (WinP) defined as the probability that a patient in the treatment (infliximab) group had a better score than a patient in the placebo group. The neoterminal ileum, anastomosis, and distal colon were scored separately. RESULTS:Interrater reliability was substantial for the Rutgeerts and modified Rutgeerts scores, ileal REMIND score, SES-CD, and CDEIS (ICC 0.74-0.80), moderate for the POCER index (ICC 0.49), and fair for the anastomotic REMIND score (ICC 0.30). A large degree of responsiveness was observed for the Rutgeerts and modified Rutgeerts scores, ileal REMIND score, SES-CD, and CDEIS (WinP 0.75-0.83). The degree of responsiveness for the POCER index and the anastomotic REMIND score was small (WinP 0.54 and 0.53, respectively). Estimates of index reliability and responsiveness were consistently lower when assessed at the anastomosis or distal colonic segment compared with the neoterminal ileum. CONCLUSIONS:Existing endoscopic indices are reliable and responsive for assessing postoperative CD activity in the neoterminal ileum, although are suboptimal for evaluation in the anastomosis or distal colonic segment.

BACKGROUND AND AIMS:We conducted a prospective study (FAVOUR) of patients with ulcerative colitis (UC) commencing vedolizumab to investigate fecal vedolizumab loss and its impact on serum levels and treatment outcomes. METHODS:FAVOUR recruited patients with moderate-to-severe UC commencing vedolizumab. Fecal vedolizumab levels (FVL) were measured at days 1, 4, and 7 and at weeks 2, 6, and 14. Trough serum vedolizumab levels (SVL) were measured at weeks 2, 6, and 14. RESULTS:In total, 36 patients were recruited, of whom 33 completed induction therapy. Fecal vedolizumab was detectable in 80/203 (39%) samples. Statistically significant, positive correlations were observed between FVL and clinical, biochemical, baseline endoscopic, and histologic disease activity at day 1, 4, and 7 as well as weeks 2 and 6. Week 14 clinical non-responders had higher FVL than responders at that timepoint (median 1.0 vs 0.0 µg/g, P = .004) but not at other timepoints. Area-under-the-curve analysis of FVL was used to quantify cumulative vedolizumab stool loss. This demonstrated significant differences between week 14 clinical responders and non-responders (44 µg/g/day, 95% CI: 0-128 vs 233 µg/g/day, 95% CI 0-1139, P < .0001), as well as between endoscopic responders and non-responders (48 µg/g/day, 95% CI 0-142 vs 179 µg/g/day, 95% CI 0-142, P = .0017), with non-responders having a higher rate of cumulative loss. CONCLUSIONS:Active UC results in fecal loss of vedolizumab. This correlates with lower SVL and decreased response to treatment. Fecal loss of vedolizumab may be a marker of disease activity and/or result in lower rates of drug exposure at a tissue level, negatively impacting response.

Children and young people with severe neurodisabling conditions (CYPSND)experience severe functional gastrointestinal symptoms and dependence on artificial nutrition. 'Gastrointestinal dystonia' (GID) has been applied by clinicians when symptoms become debilitating and potentially life-limiting. Evidence is lacking regarding the definition and appropriate management of GID. We therefore assembled a RAND appropriateness panel. We performed a systematic review, created an online survey and distributed this to a panel of 27 experts from five stakeholder groups from 13 UK specialist centres across the British Isles (gastroenterology, neurology/neurodisability, surgery, palliative care and allied health professionals). A Disagreement Index ≥1 indicated disagreement. The panel rated the appropriateness of 250 statements covering the following in GID: definition, clinical evaluation, nutritional assessment/feeding strategies, investigations, medications and prescribing, surgical interventions, safeguarding, palliative care and ethics. Agreement was reached except in selected statements regarding uncommon diagnostic features. There was uncertainty in specific clinical scenarios regarding: investigation, the use of blenderised diet, certain pharmacological agents and surgical interventions. The only intervention deemed inappropriate was antireflux surgery in the context of GID and gastrointestinal dysmotility without reflux disease. The remaining statements (198) were considered appropriate. We present a comprehensive review, agreement on the definition of GID and recommendations on management pathways agreed by a selected panel of multidisciplinary experts. Clear diagnostic criteria will enable important epidemiological work to record outcomes for this complex patient group. Identifying the associated morbidity, burden of care and mortality will help advocate for appropriate health resources and support to carers and families.

OBJECTIVE:To evaluate real-world patient-reported experience with subcutaneous (SC) risankizumab administered by on-body device (OBD) in patients with Crohn's disease (CD). METHODS:Uncontrolled observational cross-sectional study in five UK units between October 2023 and May 2024. Patients who had received maintenance risankizumab via SC injection of four pre-filled syringes (PFS) self-administered in hospital were switched to OBD self-injection. Self-Injection Assessment Questionnaires (SIAQ) were completed pre- and post-first OBD use. The primary end-point was "Overall, how satisfied are you with your current way of taking your medication (self-injection)?" from post-injection SIAQ. Baseline patient data were collected retrospectively from medical records. RESULTS:The study recruited 50 patients with moderate-to-severe CD, 48 completed the study. Most (81%) were satisfied/very satisfied with self-injection using OBD vs only 54% with PFS. Satisfaction with the OBD was highest with home use (90% vs 65%). Confidence was high with the OBD; numerically higher rates of patients were confident in giving themselves an injection in the right way (83% vs 64%), in a clean and sterile way (90% vs 74%) and safely (85% vs 72%) post-OBD than before using OBD. Self-injection using the OBD was reported as easy by 92% and convenient by 83% of participants. Most participants reported that they would continue to use the OBD (82%) and be confident to self-inject at home (81%). The OBD was well tolerated. CONCLUSION:The OBD provides a safe, easy to use and convenient way to self-administer risankizumab at home using one injection with improved satisfaction and confidence vs self-administration of four PFS in hospital.

Abstract Background Infliximab is detectable in the faeces of patients with active UC and faecal loss is associated with more severe disease and with primary non-response. Detection of vedolizumab (VED) in faeces and its importance in patients with UC has not been investigated. We conducted a prospective, observational study of patients with UC commencing VED to investigate faecal VED loss as well as its impact on serum VED levels (SVL) and association with treatment outcomes. Methods The FAVOUR study recruited UC patients with moderate to severe UC commencing vedolizumab between April 2019 and May 2022. Patients were treated with 300mg VED IV at weeks 0, 2, 6 and 14. Trough SVL were measured at weeks 2, 6 and 14. Faecal samples at days 1, 4, 7 and at weeks 2, 6 and 14 were homogenised and centrifuged to produce supernatants which were analysed for faecal VED levels (FVL) using a commercially available ELISA (LISA TRACKER, Theradiag, France). Clinical (SCCAI) and biochemical disease activity (CRP and faecal calprotectin) were measured at each infusion. Endoscopy was performed at baseline and week 14 to measure endoscopic (UCEIS/Mayo) and histologic activity (NHI). Correlations were calculated using the Spearman correlation coefficient (r). Categorical variables were compared using Mann-Whitney U. Results 36 patients (median age 34 (range 18-73); 13 Female) were recruited, of whom 33 completed induction therapy (3 withdrew early and were considered non-responders). 26/36 (72%) achieved a clinical response (SCCAI≤5 and reduction of ≥2) and 18/36 (50%) achieved endoscopic remission (UCEIS≤2). Faecal VED was detectable in 80/203 (39%) samples. Statistically significant correlations were observed between FVL and markers of clinical, biochemical, baseline endoscopic and histologic disease activity at day 1, and weeks 2 and 6 (table 1). Week 14 clinical non-responders had higher FVL than responders at that time point (median 1.0 vs 0.0ug/mL, p=0.004) but not at other timepoints. A statistically significant negative correlation was observed between week 2 FVL and SVL measured at weeks 6 and 14 (table 1). SVL did not differ significantly between week 14 responders and non-responders at any time point. Conclusion Active colonic inflammation results in faecal loss of vedolizumab. This appears to correlate with lower SVL and rates of response to treatment. However, SVL were not observed to directly influence rates of response. It is possible that FVL may be a marker of disease activity or that faecal loss results in lower rates of drug exposure at a tissue level and negatively impacts rates of response by this mechanism.

Background Heterogeneity in demographic and outcomes data with corresponding measurement instruments [MIs] creates barriers to data pooling and analysis. Several core outcome sets have been developed in inflammatory bowel disease [IBD] to homogenize outcomes data. A parallel Minimum Data Set [MDS] for baseline characteristics is lacking. We conducted a systematic review to develop the first MDS.Methods A systematic review was made of observational studies from three databases [2000-2021]. Titles and abstracts were screened, full-text articles were reviewed, and data were extracted by two reviewers. Baseline data were grouped into ten domains: demographics, clinical features, disease behaviour/complications, biomarkers, endoscopy, histology, radiology, healthcare utilization and patient-reported data. Frequency of baseline data and MIs within respective domains are reported.Results From 315 included studies [600 552 subjects], most originated from Europe [196; 62%] and North America [59; 19%], and were published between 2011 and 2021 [251; 80%]. The most frequent domains were demographics [311; 98.7%] and clinical [289; 91.7%]; 224 [71.1%] studies reported on the triad of sex [306; 97.1%], age [289; 91.7%], and disease phenotype [231; 73.3%]. Few included baseline data for radiology [19; 6%], healthcare utilization [19; 6%], and histology [17; 5.4%]. Ethnicity [19; 6%], race [17; 5.4%], and alcohol/drug consumption [6; 1.9%] were the least reported demographics. From 25 MIs for clinical disease activity, the Harvey-Bradshaw Index [n = 53] and Mayo score [n = 37] were most frequently used.Conclusions Substantial variability exists in baseline population data reporting. These findings will inform a future consensus for MDS in IBD to enhance data harmonization and credibility of real-world evidence.

Abstract Background The increase in licensed therapies for ulcerative colitis (UC) is revolutionizing its treatment but making first line choice more challenging. Adalimumab (ADA) is inexpensive but, anecdotally, is sometimes regarded as less effective than other first line advanced therapies. We aimed to evaluate the results of first line ADA in UC. Methods We performed a single centre retrospective analysis of UC patients started on ADA between January 15 and March 2022 in an IBD referral hospital. Clinical remission was defined as SCCAI <2 points, endoscopic remission as a UCEIS <2 points and treatment failure as the need for colectomy or second biological line Results A total of 79 patients were included (Table 1). Median follow-up was 19 months (2-91); 78.5% were followed >6 months. At 6 months, 80.3% (61/76) and 37.3% (22/59) of the patients were in clinical and endoscopic remission, respectively. 54.3% received combination treatment with immunomodulators (50.6% thiopurines, 3.7% methotrexate). Dose intensification to weekly treatment occurred in 27.8% after median 9 months (4-48 months). During follow-up 51% received corticosteroids at some point (26% topically-acting oral corticosteroids, 10% oral corticosteroids, 15% both). Of patients who received steroids, 55% (22/40) were able to continue adalimumab therapy. 2.5% of patients were hospitalised for a disease flare. 5.1% had an infection recorded during follow up, none discontinued the treatment. No other major adverse events were recorded. In 22.8% (18/79) of patients, ADA was stopped due to treatment failure, mean 15 months after starting the drug (4-56 months), (Figure 1). None of these patients underwent colectomy at the time of stopping the drug; in 17/18 a second biological therapy was started (10 tofacitinib, 1 filgotinib, 1 upadacitinib, 2 ustekinumab, 2 vedolizumab, 1 golimumab). TDM was performed using a drug-sensitive ELISA, which is only able to detect antidrug antibodies when drug levels are low or absent. Drug levels at the time of stopping the drug were <5 µg/mL in 22% of patients (in 2 antibodies were detected), 5-8 µg/mL in 11% and >8 µg/mL in 67%. Conclusion In a real-world UC cohort, ADA appears to be an effective well tolerated first-line advanced therapy with the vast majority of patients reaching clinical remission and a significant proportion achieving mucosal healing. Table 1. Cohort characteristics (N 79, frequency and %). Figure 1: Kaplan-Meier survival analysis of time to ADA discontinuation.

Objective Since approval in Crohn’s disease (CD) of risankizumab, there has been widespread use. Real-world data are, however, limited and our aim is to address that gap. Design/method We performed a retrospective, observational study of risankizumab use in patients with CD starting treatment between January 2021 and January 2023 at two UK centres. Clinical activity, biochemical and faecal biomarkers were measured at baseline, weeks 4, 12, 28 and 52. The primary outcome was clinical response at weeks 12, 28 and 52. Results 53 patients (51% women); median (range) age 40 years (20–70); median disease duration 15 years (6–52). Clinical response was observed in 33% (n=14/42), 45% (n=17/38) and 52% (n=13/25), and clinical remission in 31% (n=13/42), 40% (n=15/38) and 44% (n=11/25) at weeks 12, 28 and 52, respectively. Median C reactive protein decreased from 12 mg/L (IQR: 4–30; n=50) at baseline to 6 mg/L (IQR: 2–16; p=0.03 vs baseline; n=49) at week 12, 3 mg/L (IQR: 2–8, p=0.003; n=44) at week 28 and 3 mg/L (IQR 1–4, p=0.007; n=31) at week 52. Median faecal calprotectin concentration was 668 µg/g (IQR: 246–1098; n=32) at baseline, 298 µg/g (IQR: 176–546, p=NS; n=21) at week 12, 358 µg/g (IQR: 133–622, p=0.03; n=14) at week 28 and 63 µg/g (IQR: 38–120, p=0.007; n=12) at week 52. 12 out of 18 patients discontinued corticosteroids at week 12, 16 by week 28 and 18 by week 52. Four major adverse events—three elective and one emergency surgery—were recorded. Conclusion Risankizumab is effective in a refractory real-world population with CD.