Perianal pouch fistula can significantly affect quality of life, yet no disease-specific patient reported outcome measure (PROM) exists. We have developed and validated a 14-item PROM—the Pouch Anal and Vaginal Fistula Quality of Life scale (PAVF-QoL-14). COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidance for PROM development was used to develop and validate PAVF-QoL-14. A systematic literature review and semi-structured patient interviews (n = 14) identified key domains. Cognitive interviews and item-level content validity index with experts refined the draft questionnaire. Psychometric evaluation included principal component analysis (PCA), internal consistency testing, and construct validity assessment against Hospital Anxiety and Depression Scale (HADS) and Short-Form 12 (SF-12). Test–retest analysis was performed on 76 patients. An initial 34-item draft scale was generated and refined through cognitive interviews (n = 10) and psychometric testing (n = 76). Flesch readability score was 63

Perianal fistulising Crohn’s disease (pfCD) is a challenging phenotype that markedly affects quality of life. Anti-TNF therapy, particularly infliximab, is commonly used first-line, yet primary non-response and secondary loss of response remain frequent. Adalimumab is often used second-line despite limited evidence. This study evaluated real-world outcomes of first- versus second-line adalimumab in pfCD to inform therapeutic sequencing. A multicentre retrospective cohort study included adult pfCD patients treated between 2005 and 2024. The primary outcome compared adalimumab second-line (after infliximab) versus first-line using changes in the Perianal Disease Activity Index (PDAI). Secondary outcomes were hospitalisation and antibiotic use. Response was assessed at early (£24 weeks) and late (>24 weeks) time points. Analyses used Mann–Whitney U for continuous and Fisher’s exact for categorical variables. Of 167 patients, 107 received adalimumab first-line and 60 second-line. Among those previously exposed to infliximab, 45% stopped due to loss of response after initial response, 16% had non-response despite adequate levels, 25% ceased due to intolerance or adverse effects, and 11% due to patient preference. Second-line patients were older, had higher BMI, fewer smokers, and more stricturing disease, with similar immunomodulator use. PDAI pain improvement was greater with first-line therapy early (46% vs 4%, p < 0.01) but not late (50% vs 9%, p = 0.07). Hospitalisations, including for surgical management, were higher second-line (13% vs 11%, p = 0.04) at > 24 weeks. No differences were observed in PDAI discharge sub scores, clinical healing or response, or antibiotic use. More first-line patients remained on adalimumab (77% vs 28%, p < 0.01) over follow-up (median 82 months, IQR 73), although treatment duration before cessation was similar (40 vs 40 months, p = 0.47). Dose escalation was comparable (54% vs 37%, p = 0.71). The distinction between true non-response and secondary loss of response was limited by the absence of pharmacokinetic data and incomplete documentation. In pfCD, first-line adalimumab delivers greater improvements in PDAI pain sub scores and fewer hospitalisations on late outcomes assessment compared with second-line use. Adalimumab is effective after infliximab failure despite its similar mechanism of action, positioning it as a viable second-line option. Future studies incorporating standardised clinical and patient-reported outcome measures with radiological endpoints are needed to refine therapeutic sequencing in this high-risk population. Conflict of interest: Dr. Hartley, Imogen: Scholarship to attend conference- Celltrion Tassone, Daniel: No conflict of interest Winata, Leon Shin-ha: No conflict of interest Sy, Meredith: No conflict of interest Chow, Jocelyn Hui Ching: No conflict of interest McCurdy, Jeffrey: No conflict of interest Ravikulan, Abhimati: No conflict of interest Gabrielson, Stefan: No conflict of interest Su, Heidi: Advisory Board - Takeda, Johnson & Johnson Speaker fees - Takeda, Johnson & Johnson, GSK Xia, Bowen: No conflict of interest Keung, Charlotte: No conflict of interest Lai, Karen Hei-Tung: No conflict of interest Mak, Joyce Wing Yan: No conflict of interest Welman, Christopher J: No conflict of interest Thin, Lena: Pfizer- advisory board fees, research grants Takeda- research grant, advisory board fees JNJ- advisory board fees Abbvie- advisory board fees Neuroscientific - advisory committee Celltriom- advisory board fees Chen, Lynna: No conflict of interest Nguyen, Andrew: No conflict of interest Srinivasan, Ashish: AS has served as a speaker for Arrotex Pharmaceuticals and has received advisory fees or conference support from AstraZeneca, AbbVie, Takeda Pharmaceuticals, and Dr Falk Pharma. Wu, Hsin-Yun: No conflict of interest Wei, Shu Chen: Consultancy fees: AbbVie, Bristol Myers Squibb, Cornerstones, Ferring Pharmaceuticals Inc., Janssen/J & J, Pfizer, Sanofi, SPYRE, Takeda, ThermoFisher. Lectures and/or speakers’ bureau payments: AbbVie, Bristol Myers Squibb, Celltrion, CornerStones, Excelisior, Ferring Pharmaceuticals Inc., Janssen/J & J, Pfizer, Takeda, ThermoFisher. Van Wees, Jacoba: No conflict of interest Sparrow, Miles P.: Educational grants or research support – Gilead, Celltrion Speaker’s fees – Janssen, Abbvie, Ferring, Takeda, Pfizer, Celltrion, Eli Lilly, Dr. Falk Pharma Advisory boards or consultancy fees – Janssen, Takeda, Pfizer, Celgene, Abbvie, MSD, Emerge Health, Gilead, BMS, Celltrion, Eli Lilly, Alimentiv Lai, Mark: No conflict of interest Kalasabail, Sanjna: No conflict of interest Borok, Nira: No conflict of interest Connor, Susan Jane: Grant: Research Support: Abbvie, Agency for Clinical Innovation, Amgen, BMS, Chiesi, Celltrion, DrFalk, Ferring, Janssen, Medical Research Future Fund, Pfizer, South Western Sydney Local Health District, Sydney Partnership for Health, Research and Enterprise, Takeda and The Leona M and Harry B Helmsley Charitable Trust Personal Fees: Ad Boards: Abbvie, Amgen, BMS, Celltrion, Eli Lilly, Ferring, GSK, Janssen, Organon, Pfizer, Takeda Speaker Fees: Abbvie, Cornerstones Health, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Sydney IBD School, Takeda Educational Support: DrFalk, Sandoz, Takeda Chen, Cheng-Yu: No conflict of interest Shibu, Roney: No conflict of interest Mohsen, Waled: No conflict of interest An, Yoon-Kyo: Yoon-Kyo An has received speaking and consulting fees from Abbvie, Bristol Myers Squibb, Celltrion, Chiesi, Dr Falk, Ferring, Janssen, Pfizer, Sandoz, Shire and Takeda served on advisory boards member for Abbvie, Bristol Myers Squibb, Chiesi, Janssen, NPS Medicine wise, Microba received research and educational funding from Abbvie, Celltrion, Dr Falk, Janssen, Pfizer, Sandoz and Takeda. Tan, Ethan: No conflict of interest Xu, Ziheng: No conflict of interest Garg, Mayur: No conflict of interest Lo, Sheng Wei: No conflict of interest De Cruz, Peter: No conflict of interest Pelly, Theo: No conflict of interest Hart, Ailsa: Grant: Takeda Personal Fees: Abbvie, Amgen, Arena, AZ, Falk, Celltrion, Eli Lilly, Ferring, Genentech/ Roche, GSK, Pfizer, Takeda, Napp, Pharmacosmos, Janssen (J & J), Bristol-Myers Squibb, Gilead, Galapagos, Alfasigma Ding, Nik John Sheng: Grant: Forcrohn’s, ECCO, GESA Personal Fees: Abbvie, Pfizer, Ferring ANZIBD Consortium, ANZIBD Consortium: No conflict of interest

BACKGROUND:Perianal fistulising Crohn's disease (pfCD) remains a therapeutic challenge, with a limited sustained response to biological therapy. Although higher serum anti-tumour necrosis factor (TNF) levels are associated with improved fistula healing, tissue pharmacokinetics in pfCD are poorly understood. This proof-of-concept study aimed to establish the feasibility of quantifying anti-TNF concentrations within fistula tissue and evaluate their relationship with serum levels and treatment outcomes. METHODS:Paired blood and fistula tract biopsies were obtained from 14 patients (infliximab, seven; adalimumab, seven) with active pfCD on established anti-TNF therapy (>14 weeks post-induction). The serum was processed by centrifugation within 8 h and stored at -80°C. Fistula tract biopsies were snap-frozen, homogenised, and extracted using an ELISA buffer proportional to tissue weight. Anti-TNF levels in the serum and tissue supernatants were quantified using standard and high-sensitivity ELISA assays, respectively. RESULTS:All patients had detectable anti-TNF concentrations in both serum and fistula tissues. Tissue and serum levels showed a moderate positive correlation ( r  = 0.45, P  = 0.09), with a stronger and statistically significant association in the infliximab subgroup ( r  = 0.81, P  = 0.01). Higher fistula-to-serum ratios, reflecting enhanced tissue penetration, tended towards improved clinical and radiological outcomes and lower perianal disease activity index scores, although the difference was not statistically significant. CONCLUSION:Anti-TNF levels in perianal fistula tissue are measurable and correlated with serum concentrations, supporting a mechanistic link between systemic exposure and local drug penetration. These findings highlight the feasibility of tissue-level pharmacokinetic assessments and warrant validation in larger prospective cohorts.

Perianal Crohn’s disease (pCD) is a distinct and debilitating phenotype of Crohn’s disease and an independent predictor of long-term adverse outcomes. Traditionally, outcome measurement has focused on fistula healing to assess treatment success; however, as we recognise distinct classes of patients and shift towards shared decision making, healthcare professionals are increasingly acknowledging the importance of assessing more nuanced outcomes such as downstaging, quality of life, sex and intimacy and the impact on family, education or work. Current challenges in outcome measurement include substantial heterogeneity in definitions, measurement tools and time points used. This review will cover the current landscape, reporting on historical measurement instruments, such as the fistula drainage assessment (FDA), perianal disease activity index (PDAI) and the collective move towards patient-centred and patient-developed tools, such as the Crohn’s anal fistula quality of life scale (CAF-QoL). It will also assess the value of core outcome measurement sets, which provide a uniform but flexible framework to standardise outcome reporting across studies and support comparison of interventions in clinical practice. Importantly, the incorporation of patient perspectives within their methodology ensures that their recommendations reflect outcomes that truly matter to those with pCD. The contemporary need is for novel clinical and radiological tools to monitor perianal disease activity that are predictive, preventative and provide treatment thresholds, so that patients can live well with their fistulising disease, if it cannot be eradicated. There will no doubt also be a role for digital applications and artificial intelligence in enhancing outcome measurement further for perianal Crohn’s disease.

BACKGROUND:Mirikizumab demonstrated efficacy in moderately-to-severely active ulcerative colitis, including in patients with prior advanced therapy failure (PATF) (Phase 3: LUCENT-1 [NCT03518086], LUCENT-2 [NCT03524092]). This post hoc analysis evaluates mirikizumab efficacy by number/mechanism of PATF. METHODS:LUCENT-1 patients received 300 mg mirikizumab or placebo; mirikizumab induction responders entered LUCENT-2 and received 200 mg mirikizumab or placebo until week (W)52. Mirikizumab induction non-responders received extended induction with open-label 300 mg mirikizumab between W12 and W24. Extended induction responders received open-label 200 mg mirikizumab between W24 and W52. In each population, efficacy was analyzed by subgroups based on PATF number (0, 1, ≥ 2 [2-3]) and mechanism (including difficult-to-treat [DTT]: anti-TNF plus tofacitinib and/or vedolizumab). RESULTS:At baseline, 479/1162 patients (41.2%) had (≥ 1) PATF, of which 177 (37.0%) had DTT. Among mirikizumab-treated patients (n = 868), W12 clinical response was achieved by 69.8%, 63.9%, 45.3%, and 41.9% of the 0-PATF, 1-PATF, ≥ 2-PATF, and DTT subgroups, respectively. 42.1% (365/868) continued with maintenance treatment. Among W12 responders, 51.9% (0-PATF), 44.2% (1-PATF), 49.0% (≥ 2-PATF), and 42.9% (DTT) achieved clinical remission at W52. Over half of the patients (54.0% [147/272]) in the extended induction population had PATF; 51.0% (75/147) were DTT. At W24, clinical response was achieved by 62.4%, 41.4%, 49.5%, and 49.3% of the 0-PATF, 1-PATF, ≥ 2-PATF, and DTT subgroups. Of this 49.3% of the DTT subgroup (extended induction responders), 38.9% (14/36) achieved W52 clinical remission. CONCLUSIONS:Mirikizumab induction and maintenance is efficacious in moderately-to-severely active ulcerative colitis with or without prior failure of advanced therapy, including difficult-to-treat disease. TRAIL REGISTRATION:LUCENT-1: NCT03518086; LUCENT-2: NCT03524092.

Objective Patients with inflammatory bowel disease (IBD) receiving immunosuppressive therapy are at increased infection risk. Although many infections are vaccine-preventable, immunisation uptake in IBD remains suboptimal, and hesitancy has increased since the COVID-19 pandemic. We assessed adherence to vaccination recommendations and barriers to uptake among immunosuppressed patients with IBD in North West London.Methods A paper-based survey was completed by 209 patients with IBD attending St Mark's Hospital and Imperial College Healthcare NHS Trust between 19 February and 19 April 2024. Data on demographics, vaccination history and prior counselling were collected. The primary composite outcome was receipt of pneumococcal, influenza and SARS-CoV-2 vaccines within recommended timeframes, according to UK guidelines for immunosuppressed patients. Univariate and multivariate analyses identified factors associated with uptake, and adherence to national guidance on pre-treatment vaccine counselling was evaluated.Results Of 194 patients on immunosuppressive medication, only 22.2% were fully vaccinated. Uptake was low for pneumococcal (30.9%), COVID-19 booster (56.7%) and influenza (64.4%) vaccines. Older age and receiving vaccine recommendations from healthcare professionals were significantly associated with uptake (OR=1.03 (95% CI 1.00 to 1.07) and OR=3.43 (95% CI 1.73 to 6.92), respectively). Common barriers included uncertainty about necessity, limited awareness and safety concerns. Over 40% reported inadequate counselling before starting immunosuppression. Vaccine recommendations from healthcare professionals were infrequent (66.8% for influenza, 59.1% for COVID-19 booster, 22.4% for Shingrix).Conclusion Vaccination uptake among immunosuppressed patients with IBD remains low in the post pandemic era. Clinicians and the wider multidisciplinary team should actively promote vaccination, given the strong association between healthcare professional-led counselling and improved uptake.

Background Inflammatory bowel disease (IBD) adversely impacts the quality of life. Healthcare professionals target treatment at controlling gut inflammation. However, patients report troublesome symptoms of fatigue, abdominal pain and urgency or faecal incontinence in the absence of inflammation. Objectives To address the symptoms of fatigue, pain and urgency/faecal incontinence in people living with inflammatory bowel disease. Research questions: Identifying the burden of symptoms: 1a. What proportion of people with inflammatory bowel disease have fatigue, pain or urgency/faecal incontinence and want help for them? 1b. Which symptoms could benefit from optimisation of medical treatment? Addressing symptoms: 2a. To develop and test a supported tailored online self-management programme (IBD-BOOST) for these symptoms in inflammatory bowel disease to improve the quality of life and reduce symptoms. 2b. Does better symptom control reduce healthcare and personal costs and is the intervention cost-effective? Design and methods Qualitative interviews with patients and nurses. Questionnaire to identify the inter-relationship of symptoms and the desire for intervention. Feasibility study of a checklist and algorithm (‘Optimise’) to manage medically reversible causes of symptoms. Multicentre, two-arm, parallel-group, randomised controlled trial of the IBD-BOOST intervention with qualitative and quantitative process evaluation. Target population: 740 people with inflammatory bowel disease recruited from the questionnaire survey. Six months of access to IBD-BOOST was compared with care as usual. Setting and participants United Kingdom inflammatory bowel disease clinics and online. Interventions Randomised controlled trial – a 12-session online self-management IBD-BOOST intervention, developed jointly with patients. Main outcome measures Primary outcomes for randomised controlled trial: United Kingdom Inflammatory Bowel Disease Questionnaire (inflammatory bowel disease-related quality of life) and Global Rating of Symptom Relief at 6 months. Cost-effectiveness of IBD-BOOST was assessed: incremental cost per quality-adjusted life-year 1 year following randomisation from healthcare service and societal perspectives. Results Interviews People with inflammatory bowel disease told us that they wanted help to self-manage their symptoms. Inflammatory bowel disease nurses wanted to be supportive but reported limited capacity to help. Survey There were 8486 responses: 3281 men and 4883 women. In the previous week, 2550 (30%) reported fatigue; 1766 (21%) pain and 4565 (54%) reported faecal incontinence; 925 (10.9%) reported all three; 56% of all respondents ‘definitely’ wanted help for fatigue; 42% wanted help for pain; 53% wanted help for incontinence and 29% ‘definitely’ wanted help for all three symptoms. Feasibility study of the optimise checklist and algorithm The 201/515 (39%) individuals reporting symptoms consented and 194/201 (97%) returned the symptom checklist; 157 (81%) returned a postal faecal calprotectin sample. The algorithm suggested at least one clinical test or intervention for fatigue, pain or incontinence in 67/157 (43%) participants, of whom 25 (37%) declined intervention for reasons unknown. Of those for whom clinical actions were indicated, 66% completed 3-month follow-up. Randomised controlled trial of the IBD-BOOST intervention Participants (N = 780) were randomised to the intervention (n = 391) or care as usual (n = 389). At 6 months, there were no statistically significant between-arm differences for United Kingdom Inflammatory Bowel Disease Questionnaire [mean difference = −1.67 (95% confidence interval = −4.17 to 0.83), p = 0.19] and Global Rating of Symptom Relief [mean difference = 0.44 (95% confidence interval = −0.56 to 1.43), p = 0.39]. Complier-averaged causal effects analysis demonstrated that participants who complied with the intervention reported better United Kingdom-Inflammatory Bowel Disease Questionnaire scores than ‘would-be’ compliers receiving care as usual (p = 0.03). Subgroup analyses did not identify any statistically significant treatment effect modifiers; 57% completed four sessions or more. Serious adverse events were similar between groups. Process evaluation suggested high facilitator fidelity but low overall participant compliance with the programme. Cost-effectiveness of the IBD-BOOST intervention Per participant cost for the development and delivery of intervention was £151.19. Allocation to inflammatory bowel disease-BOOST intervention resulted in additional 0.016 quality-adjusted life-years (95% confidence interval = 0.002 to 0.030) per participant over 12 months and cost savings of −£304.66 (−803.51; 194.18) for healthcare costs and −£39.48 (−388.09; 309.12) for out-of-pocket costs and time off work over months 3–6 and 9–12. Over the 12-month follow-up, there were cost savings of −£28,633 (95% confidence interval = −51,555 to 18,764) and −£33,568 (−64,421; 26,198) per quality-adjusted life-year gained with inflammatory bowel disease-BOOST from health services and societal perspectives, respectively. Limitations Our samples were predominantly White and English-speaking. Conclusions People with inflammatory bowel disease want help with their symptoms, but health professionals lack capacity. Over half of people with inflammatory bowel disease have faecal incontinence, and 1 in 10 have fatigue, pain and incontinence. Nearly a third want help for all three. Screening using a checklist and algorithm was feasible, and we identified around 40% who could benefit from optimisation of their medical treatment. Inflammatory bowel disease-BOOST had low compliance and did not improve disease-specific quality of life or Global Rating of Symptom Relief in inflammatory bowel disease patients with fatigue, pain and/or incontinence compared with care as usual, but it may help symptoms in people who comply with the programme. The economic evaluation indicated that the inflammatory bowel disease-BOOST intervention improves quality-adjusted life-years, and could be cost-effective, but economic results did not reach statistical significance. Future work Research should explore targeting the intervention to specific subgroups within inflammatory bowel disease and improving adherence to digital interventions. Study registration This study is registered as Optimising medical management ISRCTN15380317 and the RCT as ISRCTN71618461. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0216-20001) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 19. See the NIHR Funding and Awards website for further award information. Plain language summary Our programme addresses the common problems of fatigue, pain and urgent need for a toilet in inflammatory bowel disease. We worked closely with people with inflammatory bowel disease throughout our research. People we interviewed told us that they wanted to try online self-management and to avoid more clinic appointments. Inflammatory bowel disease nurses told us they wanted to help but had limited time. We conducted a survey in 8486 people with inflammatory bowel disease. Over half reported experiencing bowel incontinence in the past week, one in four reported experiencing fatigue and one in five reported pain. Nearly one in three (29%) ‘definitely’ wanted help for all three symptoms. There is a large unmet need for help with fatigue, pain and incontinence. We also developed a checklist and a flow chart to help inflammatory bowel disease nurses manage these symptoms (‘Optimise’). For two in five patients (43%), a test or intervention was indicated that might improve symptoms. Optimise was easy to use, and we are training inflammatory bowel disease nurses to use it. We designed a 12-session online-supported self-management programme (inflammatory bowel disease-BOOST) that people could follow at home, with one phone call from a ‘facilitator’ and online messaging. We recruited and randomly allocated (e.g. tossing a coin) 391 people to try inflammatory bowel disease-BOOST and 389 who had their usual care. After 6 and 12 months, inflammatory bowel disease quality of life, rating of symptom relief, fatigue and pain were not different between these groups. Incontinence and general health-related quality of life were a little better in the inflammatory bowel disease-BOOST group. Most people did not complete as many sessions as we had planned. So, we cannot conclude that inflammatory bowel disease-BOOST is generally helpful in its current format. However, economic evaluation suggested possible cost savings with the intervention and together with the improvement in general health-related quality of life, and it indicated that the inflammatory bowel disease-BOOST intervention could be cost-effective for the self-management of pain, fatigue and faecal incontinence in people with inflammatory bowel disease. We hope that our programme raises awareness of these troublesome symptoms and encourages future work to help fatigue, pain and urgency in inflammatory bowel disease. Scientific summary Background Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a lifelong illness. Prevalence is approaching 1% of the population and increasing worldwide. The primary aim of medical management is control of inflammation using medications. However, patients are burdened by symptoms, including fatigue, pain, urgency/faecal incontinence (FI), even when inflammation appears to be under control. These symptoms limit people’s quality of life (QoL) and ability to work and socialise. Patients report that these symptoms are not taken seriously by health professionals and that little help is given. Objectives/research questions Identifying the burden of medically treatable symptoms: 1a. What proportion of people with IBD have troublesome fatigue, pain or urgency/FI? 1b. Of people with these symptoms, what proportion have identifiable pathophysiological contributors which are potentially medically treatable? Addressing symptoms which persist after optimal medical treatment: 2a. Does a nurse-supported, tailored, online self-management programme for fatigue, pain and urgency/FI in IBD (IBD-BOOST) improves the QoL and rating of symptom relief 6 months after randomisation when compared with care as usual (CAU)? 2b. Does IBD-BOOST reduce healthcare costs and personal costs and is the intervention cost-effective? 2c. What factors impact on the completion and effect of the intervention? Design and methods Focus groups and individual interviews: with 40 people living with IBD and focus groups with 45 IBD nurse specialists. Interviews were recorded, transcribed and analysed thematically, with the input of eight people with IBD. A national online and postal questionnaire survey: asking about symptoms of fatigue, pain and urgency/FI and desire for help with these symptoms. Using validated Patient Reported Outcomes Measurement Information System (PROMIS) tools, we defined presence of symptoms as: fatigue: PROMIS fatigue T-score of ≥ 60; pain: PROMIS pain intensity ≥ T-score of 60; PROMIS bowel incontinence: raw score of ≥ 50. Participants also reported disease activity using the relevant PRO-2 score, IBD-Control, anxiety (Generalised Anxiety Disorder-7), depression [Patient Health Questionnaire-9 items (PHQ-9)] and generic QoL [EuroQol-5 Dimension, five-level version (EQ-5D-5L)]. We continued to invite participants until the randomised controlled trial (RCT) (below) was fully recruited. From the survey responses, we conducted a separate analysis to assess the impact of fatigue, pain and FI on generic health-related QoL (measured by the EQ-5D-5L questionnaire), with QoL utility calculated on a scale ranging from 1 (perfect health) to −0.594 (worst health). Linear regression models assessed the associations of these symptoms with QoL controlling for IBD type, sociodemographic characteristics, comorbidities and, in further analysis, for IBD activity and IBD control. We developed a checklist and algorithm (‘Optimise’) to manage medically reversible causes of fatigue, pain and urgency/FI in IBD and conducted a multisite, non-randomised feasibility study of its use in NHS clinics and interviewed nurses implementing the algorithm. We developed IBD-BOOST, a digital interactive facilitator-supported self-management intervention, to address fatigue, pain and urgency/FI in IBD, using theory, evidence and extensive stakeholder input. A trans-symptomatic cognitive behavioural (CB) framework of symptom perpetuation was developed, and a logic model was used to define the intervention techniques. Intervention facilitators (IBD nurse specialists and psychology graduates) were trained and supervised to deliver a 30-minute phone call and 12 weeks of in-site messaging during the intervention. A RCT comparing IBD-BOOST with CAU in relieving symptoms and improving QoL in people with IBD experiencing fatigue, pain and/or urgency/FI: a multicentre, two-arm, parallel-group, RCT; 4449 patients with IBD who rated the impact of fatigue, pain and/or FI as ≥ 5/10 on our previous survey were invited. The intervention was 6 months access to the online IBD-BOOST programme and the control group received CAU. Primary outcomes were UK Inflammatory Bowel Disease Questionnaire (UK-IBDQ) and Global Rating of Symptom Relief (GRSR) at 6 months post randomisation. Subgroup and complier-averaged causal effects (CACE) analyses were pre-specified. Cost-effectiveness analysis of the RCT: healthcare and other resource use and QoL data were collected at randomisation and at 6- and 12-month follow-ups. A cost–utility analysis from health and social care services and societal perspectives was conducted over the 1-year RCT follow-up. Total costs and quality-adjusted life-years (QALYs) were estimated and compared between trial arms using mixed-effects models, adjusting for pre-specified baseline factors. Process evaluation of the RCT: we conducted a mixed-methods process evaluation incorporating quantitative data for patient engagement and intervention fidelity, and we collected qualitative interview data from patient and intervention facilitator perspectives. A blinded randomised study within a trial in the RCT comparing a standard-length participant information leaflet (PIL) with a shortened one. Potential RCT participants were randomised to receive a standard length or shortened PIL electronically for recruitment to the RCT. We evaluated a suicide risk assessment protocol for people who report suicidal ideation on the PHQ-9 depression scale. Latent profile analysis was conducted on pre-randomisation RCT baseline measures of fatigue, pain and incontinence. Multinominal logistic regression, adjusted for inverse probability sample weights, examined associations between profile membership and clinical including inflammatory [faecal calprotectin (FCP)], demographic and psychological factors. Results Interviews People with IBD told us that they wanted help to self-manage their symptoms of fatigue, pain and urgency/FI. The persistent, often stark impact of multiple coexisting symptoms on physical and emotional well-being could force unwanted adjustments and limitations in working, social and intimate arenas of life. Unpredictable symptoms were challenging and impacted each other in negative vicious cycles. People told us what was helpful in self-managing symptoms and about their ways of coping and desired intervention functionality and content. Participants attempt to manage all three symptoms simultaneously. They wanted an accessible online intervention, with symptom management and activity-tracking features. Inflammatory bowel disease nurses told us that they had very limited capacity to assist patients with these symptoms. Most were positive about facilitating our intervention, but they were concerned about finding the time within already overloaded clinical workloads. They were keen to receive adequate training and support if undertaking facilitation. Survey Of 8486 useable responses (7716 online, 770 postal), 4176 reported CD, 4255 UC or other form of IBD; 3281 identified as male and 4883 as female. Median age was 51 years (range 18–92 years); 2550 (30%) reported fatigue, 1766 (21%) pain and 4565 (54%) FI; 925 (10.9%) reported having all three symptoms in the past week. Participants scored severity and impact a mean between 3.3 and 4.8 on a 0–10 scale, with a wide variation; 56% of all respondents ‘definitely’ wanted help for fatigue; 42% wanted help for pain; 53% wanted help for FI and 29% reported ‘definitely’ wanting help for all three symptoms. The mean QoL across all participants was 0.76 (standard deviation 0.23). From the three symptoms, pain was associated with the largest QoL decrement (−0.159), then fatigue (−0.140) and incontinence (−0.048). Co-occurrence of pain and fatigue further reduced QoL. Clear, graded associations were observed between symptom severity and QoL decrements (p < 0.001). Depression and anxiety were associated with further significant QoL decrements (−0.102 and −0.110 for moderate-to-severe anxiety and moderately severe depression, respectively). Worse IBD control and higher IBD activity were associated with lower QoL. Feasibility of Optimise checklist and algorithm About 515 individuals reporting IBD-related symptoms were invited to participate, and 201 (39%) consented; 194/201 (97%) returned the symptom checklist, of whom 157 (81%) returned a postal FCP sample. Five (3%) participants reported ‘red flags’, and 31/157 (20%) participants had a FCP result ≥ 200 μg/g, of whom 12 (8%) were judged to have likely active inflammation when clinical symptoms and disease history were reviewed. The algorithm suggested at least one clinical test or intervention for fatigue, pain or urgency/FI in 67 (43%) participants, of whom 25 (37%) declined. Among 87 participants for whom clinical actions were indicated, 57 (66%) completed follow-up outcomes 3 months after algorithm implementation. Three nurses interviewed found the Optimise algorithm easy to administer. Co-design of the intervention Patient feedback and qualitative interviews refined the website content and functionalities, including the use of visual aids, e-mail reminders and graphical tracking of symptoms. The IBD-BOOST intervention comprised 12 45- to 60-minute sessions. Accessibility was scored as 9.43/10 and ease of use as 8.07/10. Randomised controlled trial of the IBD-BOOST intervention Participants (N = 780) were randomised to the IBD-BOOST intervention (n = 391) or CAU (n = 389). At 6 months, there were no statistically significant between-arm differences for UK-IBDQ (mean difference = −1.67 [95% confidence interval (CI) = −4.17 to 0.83), p = 0.19] and GRSR [mean difference = 0.44 (95% CI = −0.56 to 1.43), p = 0.39]. CACE analysis demonstrated that participants who complied with the intervention reported better UK-IBDQ scores than ‘would-be’ compliers receiving CAU [mean difference = −2.36 (95% CI = −4.44 to −0.28), p = 0.03]. Subgroup analyses did not identify any statistically significant treatment effect modifiers. Serious adverse events were similar between the intervention (n = 55, 14%) and CAU (n = 79, 20%). Economic evaluation of IBD-BOOST intervention Development, maintenance, facilitators’ training and delivery of the IBD-BOOST intervention over the 12 months in the trial were estimated to cost £59,114 or £151.19 per participant allocated to the intervention. The IBD-BOOST intervention resulted in additional per participant 0.016 QALYs (95% CI 0.002 to 0.030) over the 12 months in the study and cost savings of −£304.66 (−803.51; 194.18) for healthcare costs and −£39.48 (−388.09; 309.12) for out-of-pocket costs and time off work over months 3–6 and 9–12. The cost-effectiveness analysis indicated that allocation to IBD-BOOST intervention resulted in cost savings of −£28,633 (95% CI −51,555 to 18,764) per QALY gained from the health services’ perspective and −£33,568 (95% CI −64,421 to 26,198) per QALY gained from the wider societal perspective. The IBD-BOOST intervention had a probability of being cost-effective compared to CAU above 74% at the threshold of £0/QALY and above 95% across willingness-to-pay thresholds of £20,000–30,000 per QALY from both healthcare and societal perspectives. Process evaluation Quantitative analysis found that participants completed a variable number of sessions with a mean of 5/12 sessions completed; 57% completed our pre-defined ‘dose’ of four or more sessions. Time spent was generally less than that recommended. Before the intervention, 30 patient participants were interviewed; 28 patient participants were interviewed after the intervention. They felt that the IBD-BOOST intervention significantly enhanced their symptom management and QoL. They expressed high satisfaction with the programme’s content and structure and hoped that the intervention will be freely available to all IBD patients. Facilitator fidelity was high (87–100% across elements of adherence to in-site messaging and 85.5–92.8% for CB content of messages). Nineteen facilitators were interviewed before and/or after the intervention. They found the training and the manual to be helpful. All were positive about IBD-BOOST, as they felt the content and format addressed patients’ needs. This process evaluation demonstrated that, although the intervention trial outcomes were unsuccessful overall, this was not due to a lack of facilitator intervention fidelity or their level of support for the programme. Study within a trial About 4201 participants were randomised to the standard length (n = 2099) and shortened (n = 2102) PIL arms; 34 e-mail queries were received about the PILs – 18 from those who received the standard and 16 from those receiving the shortened; 708 study within a trial (SWAT) participants were recruited to the RCT – 333 (15.86%) who received the standard length PIL and 375 (17.84%) who received the shortened PIL [odds ratio 1.15, (95% CI 0.98 to 1.35), p = 0.09]. Retention rates in the RCT were not statistically different between groups. Patient Health Questionnaire-9 items suicide risk assessment Overall, there were 58 risk alerts during the trial, 41 of which required risk assessment. All were assessed as low risk or medium risk; none were high risk. We found that the protocol was feasible to use. A refined version is available via our website. Additional randomised controlled trial baseline data analysis A three-profile model was the most appropriate, with moderate symptoms (n = 366, 50%), high symptoms (n = 296, 40.4%) and severe symptoms (n = 70, 9.6%). IBD diagnosis (UC or CD) and inflammation (FCP level) were not associated with profile membership, but comorbidity, time since diagnosis and irritable bowel syndrome were. Men were less at risk of severe symptoms than women. Depression, anxiety, negative illness perceptions, all-or-nothing behaviours and avoidance, all significantly increased the relative risk of being in the high and severe symptoms’ profiles compared with moderate symptoms. Higher self-efficacy was associated with risk reduction. Conclusions Fatigue, pain and urgency/FI are common, troublesome and coexist. People want help for these symptoms. Some people have underlying medical issues which have not been adequately previously addressed. The IBD-BOOST intervention did not improve disease-specific QoL or GRSR in IBD patients with fatigue, pain and/or urgency/FI compared to CAU. People who complied with the intervention appeared to derive benefit and future work should target improving engagement with the intervention. Only 57% completed a ‘dose’ of four or more sessions. However, health economic evaluations found that the IBD-BOOST intervention improves generic health-related QoL and is likely to be cost-effective in IBD patients with fatigue, pain and/or urgency/FI compared to CAU. Implications for health care It is important for healthcare professionals managing patients with IBD to recognise the huge unmet need presented by entangled symptoms of fatigue, pain, urgency and FI, as well as by anxiety and depression. These significantly influence QoL and are not fully explained by disease activity. These symptoms should be proactively enquired about and systematically assessed (and periodically re-assessed) routinely. There is a need for increased capacity, training and access to specialist nurses for people living with IBD to enable addressing symptoms early and effectively. Early intervention may have a role in preventing symptoms becoming chronic and vicious cycles of symptoms becoming established. Clinical systems need an auditable way of flagging the need for assessment and the resulting outcomes and actions. Staff need training and support to achieve this. Research questions to be prioritised How can the online IBD-BOOST self-management programme be optimised to encourage engagement and adherence? What are the biopsychosocial predictors of the presence and progression of symptoms of fatigue, pain and FI? Can these be prevented at an earlier stage after IBD disease onset? Test Optimise for clinical effectiveness. Further research to develop evidence-based information for IBD patients to self-manage symptoms. Is there a role for Artificial Intelligence-operated programmes aimed at individual educational level and learning styles? Study the causes and subtypes of FI and urgency which affect the majority of people with IBD yet very little is known about causes, subtypes and how to manage these symptoms. Study registration This study is registered as Optimising medical management ISRCTN15380317 and the RCT as ISRCTN71618461. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research Programme (NIHR award ref: RP-PG-0216-20001) and is published in full in Programme Grants for Applied Research; Vol. 14, No. 19. See the NIHR Funding and Awards website for further award information.

This case series describes striking clinical and radiological responses in 3 Crohn's disease patients with persistent perineal complications following proctectomy treated with upadacitinib. It highlights the potential of advanced therapies for this refractory inflammatory bowel disease phenotype with limited treatment options.

There is a growing body of evidence supporting the value of multidisciplinary teams in delivering comprehensive, holistic care for individuals with inflammatory bowel disease (IBD). Members of this team often include gastroenterologists, psychologists, nurses, dieticians, and other specialists and allied healthcare professionals, each of whom have a significant role in the treatment of IBD and its associated complications. Common symptoms that impact quality of life include persistent abdominal pain, fatigue, urgency, sleep disturbances, and mood disorders. Holistic care models are particularly well-suited to address these challenges, offering targeted symptom-based interventions. Further, holistic care models can modify broader health behaviors that can influence disease activity, such as nutrition, smoking cessation, and stress management. The implementation of holistic care can take various forms, ranging from fully integrated medical homes embedded within IBD centers to partially integrated or community-based programs. Antidepressant medications can help to restore the gut-brain axis, thereby improving mental health and physical symptoms concurrently, and we provide practical guidance in their dosing, side-effect profiles, and appropriate combination therapies. Additionally, digital health technologies have provided diagnostic and therapeutic insights into advancing IBD care, enhancing the delivery of longitudinal, patient-centered care. To improve long-term outcomes and enhance quality of life for individuals with IBD, clinicians and healthcare systems must prioritize the development and integration of holistic, multidisciplinary care models into routine practice.

Radiological healing on MRI is the ultimate therapeutic goal in Class 2a perianal fistulising Crohn’s disease (pfCD). The TOpClass consortium recently defined a radiologically healed fistula (TOpClass-RH). This study aimed to validate this definition in real-world practice. VALIDATE-PERIANAL was a retrospective, multi-centre, international study across three expert centres. pfCD patients with MRI evidence of a radiologically healed fistula between 2021–2023 were identified. Paired scans (baseline active and follow-up radiologically healed) were independently reviewed by three gastrointestinal radiologists using TOpClass-RH criteria, followed by consensus adjudication. At least 12 months of clinical follow-up was required. The primary outcome was sustained clinical remission; secondary outcomes included proctectomy, hospitalization, stoma formation. Reliability was assessed using Cohen’s kappa. Of 977 patients screened, 40 met the inclusion criteria of a radiologically healed fistula in pfCD with a baseline MR scan showing active disease. Of these, 14/40 (35%) fulfilled TOpClass-RH criteria. Clinical recurrence occurred in 1/14 (7%) of TOpClass-RH patients versus 8/26 (30.8%) in the non-RH group (relative risk 4.3 [0.60–31.0], p = 0.12). Sustained clinical remission was achieved in 93% of TOpClass-RH cases, with a trend towards lower rates of proctectomy, hospitalization, and stoma formation compared to non-RH patients. Inter-rater agreement for TOpClass-RH was excellent (κ 0.89 –0.95). TOpClass-RH predicted sustained clinical remission in 93% of patients and showed excellent reproducibility. These findings support TOpClass-RH as a robust and clinically meaningful radiological endpoint, providing a reliable benchmark for international trials and diagnostic stratification in pfCD. Patients not meeting TOpClass-RH criteria trended towards a fourfold rate of recurrence compared to existing standards, although limited sample size restricted statistical power.

Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.

Abstract Objectives Radiological healing on MRI is the ultimate therapeutic goal in Class 2a perianal fistulising Crohn’s disease (pfCD). The TOpClass consortium recently defined radiological healing (TOpClass-RH) by the absence of T2 hyperintensity, a completely fibrotic fistula tract, and the absence of contrast enhancement when used. This study aimed to validate TOpClass-RH in real-world clinical practice. Materials and methods VALIDATE-PERIANAL was a retrospective, multi-centre international study. Patients with pfCD with a baseline MRI scan showing active disease and follow-up MRI evidence of radiological fistula healing between 2021 and 2023 were identified. Paired scans were independently reviewed by three gastrointestinal radiologists using TOpClass-RH criteria, with consensus adjudication. A minimum of 12 months of clinical follow-up was required. The primary outcome was sustained clinical remission; secondary outcomes included inter-rater reliability (Cohen’s kappa) and rates of proctectomy and stoma formation. Results Of 977 patients screened, 40 with pfCD met the inclusion criteria;14/40 (35%) fulfilled TOpClass-RH criteria. Sustained clinical remission was achieved in 93% of TOpClass-RH patients. Clinical recurrence occurred in 1/14 (7%) of TOpClass-RH patients versus 8/26 (30.8%) in the non-RH group (RR 4.3 [0.60–31.0], p = 0.12), with a median follow-up of 28 months. Inter-rater reliability was excellent (κ 0.89–0.95). There was a trend toward lower rates of proctectomy and stoma formation in the TOpClass-RH group. Conclusion TOpClass-RH was associated with sustained clinical remission, although the study was underpowered to detect statistically significant differences. The definition demonstrated excellent inter-rater reliability, supporting TOpClass-RH as a clinically meaningful radiological endpoint for trials and diagnostic stratification in pfCD. Larger prospective studies are required. Critical relevance statement This study validates the TOpClass criteria for defining a radiologically healed fistula in perianal Crohn’s disease, providing radiologists with practical pearls, pitfalls, and illustrative figures that advance clinical radiology practice and research application in MRI interpretation and trial standardisation. Key Points The TOpClass definition provides an internationally agreed and standardised MRI-based criteria for identifying a radiologically healed fistula in perianal Crohn’s disease. 93% of patients who met the TOpClass criteria for a radiologically healed fistula achieved sustained clinical remission, with excellent inter-rater reliability. The TOpClass criteria offer a potential benchmark for clinical trials, where a radiologically healed fistula represents the aspirational gold standard, associated with long-term remission in perianal fistulising Crohn’s disease. Graphical Abstract

The International Organization for the Study of Inflammatory Bowel Disease (IOIBD) is an international scientific organization that has shaped the framework for inflammatory bowel disease (IBD) research, clinical management strategy, therapeutic development, and clinical trial methodology for more than four decades. Formally constituted in April 1981 in Lyon, France, IOIBD was created to address fundamental barriers to scientific and clinical progress in IBD, including inconsistent definitions of disease activity and outcomes across studies and countries. Since the establishment of the IOIBD Foundation for Research and Education in 1997, IOIBD has combined a highly engaged global membership of experts with structured governance, continuously active thematic clusters, and an annual rotating international meeting to deliver consensus frameworks and collaborative initiatives that translate directly to clinical practice and regulatory and translational science. Key outputs include studies of global epidemiology of IBD, the Selecting Therapeutic Targets in IBD (Selecting Therapeutic Targets in Inflammatory Bowel Disease, STRIDE) treat-to-target programs; the SPIRIT consensus initiative addressing long-term disease impact and endpoints for disease-modification trials; validated approaches to capturing disability and patient-reported outcomes; consensus guidance on nutrition and diet as modifiable and potentially disease-modifying factors; recommendations to optimize IBD clinical trial design and endpoints; reclassification of IBD initiative; rapid international guidance during the COVID-19 pandemic; and educational initiatives including topic-focused satellite symposia, the Helmsley-IOIBD Clinical Experience Exchange Program, and the Empowering Women in IBD Leadership Program (EMPOWHER). This manuscript reviews IOIBD's history, operational model, selected scientific contributions, educational mission, and evolving strategy as the field moves toward precision medicine, globalization of care, and data-intensive approaches, including artificial intelligence.

ABSTRACT Background The surgical journey of patients diagnosed with ulcerative colitis (UC) typically begins with an index colectomy, which may be followed by restorative procedures or further operations due to complications. Variation in surgical strategies exists, impacting patient outcomes. This study aims to comprehensively map the surgical trajectory of UC patients, providing insights into complications, morbidity and optimal operative strategies. Methods This is the protocol for a retrospective multi‐centre pan‐European cohort study. Data will be collected from 2010 to 2024, including all adult UC patients undergoing an index colectomy. Subsequent procedures, including ileo‐anal pouch formation, ileorectal anastomosis, Kock pouch and operations for complications will be analysed. Postoperative outcomes, morbidity (Clavien–Dindo III–V), and the frequency of subsequent surgeries will be documented. Data entry will occur via the REDCap platform, with appropriate data governance agreements in place, and the data will be analysed by a central team, with statistical support. Ethics and Peer Review The study has received full ethics approval in the United Kingdom (UK) (IRAS number 342922). It has been peer‐reviewed, through the European Crohn's and Colitis Organisation (ECCO) Clinical Research Committee (ClinCom) (2024) and the Association of Coloproctology of Great Britain and Ireland (ACPGBI) Research MDT (2025). Dissemination The study is being actively disseminated by ECCO and features on the ACPGBI/BRUK (Bowel Research UK) research application. Other explored avenues include professional networks, national representatives and social media channels to maximise recruitment. Conclusion This collaborative study establishes a pragmatic scalable framework for capturing real‐world UC surgical data across Europe, fostering meaningful collaboration and greater standardisation in reporting. By highlighting variation in practice and outcomes, it supports targeted quality improvement and strengthens the evidence base guiding surgical management. Future Perspectives By examining a 15‐year period, this work will deliver a uniquely representative snapshot of UC surgical practice across diverse centres and countries, enabling an overview of operative strategies and complication profiles, and identifying priorities for future prospective research. It also lays the groundwork to explore collaboration for an international prospectively maintained UC surgery registry.