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Background The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms on patients with moderate to severe UC and Crohn’s disease and to investigate gaps in communication with healthcare professionals (HCPs) in the United States (US), Europe (EUR), and Japan. Purpose This report focuses on patients with moderate to severe UC and HCPs from the US and EUR. Method Online, quantitative, cross-sectional surveys of patients with UC and HCPs were conducted in the US and EUR (France, Germany, Italy, Spain, and UK). HCP surveys included physicians and non-physician HCPs responsible for making prescribing decisions. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Data collected included perspectives on the experience of patients with UC. Result(s) A total of 200 US (62% male, mean age 40.4 years) and 556 EUR patients (57% male, mean age 38.9 years), and 200 US and 503 EUR HCPs completed the survey. According to US and EUR patients, the top 3 symptoms currently (past month) experienced were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). Blood in stool was reported as currently experienced by 27% and 24% of US and EUR patients, respectively. Among patients currently experiencing bowel urgency, 47% of US and 27% of EUR patients discuss this symptom at every appointment. Among those who do not discuss bowel urgency at every appointment, 74% and 75% of US and EUR patients would like to discuss this symptom more frequently with their HCP. A total of 30% and 43% of US and EUR patients that ever experienced bowel urgency were not comfortable reporting it to their HCP, with 62% and 58% of these US and EUR patients feeling embarrassed talking about this symptom (Table). HCPs in both the US and EUR ranked diarrhoea (74% and 65%), blood in stool (69% and 65%) and increased stool frequency (38% and 34%) as the top 3 symptoms most reported by patients. According to US and EUR HCPs, the top 4 symptoms proactively discussed in routine appointments were blood in stool (93% and 94%), diarrhoea (90% and 91%), increased stool frequency (82% and 82%) and bowel urgency (76% and 82%). Among HCPs who did not proactively discuss bowel urgency, 47% of US and 40% of EUR HCPs expect patients to bring this up if it is an issue. Image Conclusion(s) Communication gaps were similar between US and EUR patients and HCPs. Bowel urgency is the second-most reported symptom by patients with moderate to severe UC. However, this symptom is not among the HCP-perceived top 3 most reported symptoms. Although a substantial proportion of patients reported a desire to discuss bowel urgency more frequently with their HCP, some patients reported feeling embarrassed talking about it. Many HCPs who do not proactively discuss this symptom expect patients to bring this up. A communication gap was identified and highlights the under-appreciation of bowel urgency as an important symptom of UC. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest S. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, A. Bleakman Employee of: Eli Lilly and Company, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared

Background Risankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks. Aims FORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZB Methods Week 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time. Results Rates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P Conclusions In pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated. Funding Agencies AbbVie

Background The inflammatory bowel disease questionnaire (IBDQ) is a measure of health-related quality of life (QoL), with higher scores indicating greater QoL. In a prior phase 2 study (NCT02589665), mirikizumab, an anti-IL23p19 antibody, demonstrated efficacy and improvement in IBDQ scores in participants with moderately to severely active ulcerative colitis (UC). Purpose This analysis evaluated effect of mirikizumab (miri) vs placebo (PBO) on IBDQ scores in patients (pts) with moderately to severely active ulcerative colitis (UC) who had failed prior conventional or biologic therapy in a Phase 3, double-blind, 12-week (W) induction study (LUCENT-1) followed by a 40W maintenance study (LUCENT-2) for a total of 52W continuous therapy. Method Pts (N=1162) in LUCENT-1 were randomized 3:1 to receive 300mg miri or PBO intravenously once every four weeks (Q4W). 544 pts who achieved Modified Mayo Score Clinical Response to miri by W12 of induction were rerandomized 2:1 in LUCENT-2 to subcutaneous miri 200mg or PBO Q4W in maintenance period. Randomization was stratified by previous biologic therapy failure, baseline corticosteroid use, and region. LUCENT-1 stratification included baseline (BL) disease activity, and LUCENT-2 included LUCENT-1 clinical remission status. The least squares mean change from BL in IBDQ scores at W12 of induction and W40 of maintenance was determined using analysis of covariance models. BL was W0 of therapy and stratification factors and BL scores were used as covariates. The Minimal Clinically Important Difference (MCID) was defined as an improvement of ≥16 points in total IBDQ score (IBDQ response) and IBDQ remission as a total score ≥170 points. IBDQ response and remission were calculated using non-responder imputations. Treatments were compared using the common risk difference (risk diff). Result(s) Miri treatment resulted in significantly greater improvement from BL in IBDQ total and domain scores vs PBO at both W12 of induction and W40 of maintenance (52W treatment) (Table). The proportions of pts who achieved an IBDQ response was significantly greater for miri treated pts vs PBO at W12 (risk diff =17.1[95%CI:10.7, 23.5]) and W40 (29.5 [21.0, 37.9]). Significantly greater proportions of pts receiving miri achieved IBDQ remission at W12 (18.1 [11.8, 24.4]) and W40 (28.5 [20.1, 37.0]) vs PBO (all evaluations and timepoints: p Image Conclusion(s) Pts reported significantly greater improvements in IBDQ scores at induction and maintenance with miri compared to PBO. Over 75% of pts achieved a clinically meaningful improvement in QoL, as measured by IBDQ response, at the end of the 52 weeks of miri treatment. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest B. Sands Consultant of: Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Eli Lilly and Company, Enthera, Evommune, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutic, MRM Health, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio, B. Feagan Shareholder of: Gossamer Bio, Consultant of: AbbVie, AdMIRx, AgomAb Therapeutics, Akebia Therapeutics, Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avir Pharma, Azora Therapeutics, Boehringer Ingelheim, Boston Scientific, Celgene/Bristol Myers Squibb, Connect BioPharma, Cytoki Pharma, Disc Medicine, Ecor1 Capital, Eli Lilly and Company, Equillium, Everest Clinical Research, F. Hoffmann-La Roche, Ferring Pharmaceuticals, Galapagos NV, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Gossamer Bio, HotSpot Therapeutics, Imhotex, ImmuNext, InDex Pharmaceuticals, Intact Therapeutics, Janssen, Japan Tobacco, Kaleido Biosciences, Leadiant Biosciences, Millennium Pharmaceuticals, MiroBio, Morphic Therapeutics, Mylan, Novartis, OM Pharma, Origo Biopharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, PTM Therapeutics, Q32 Bio, Rebiotix, RedHill, Biopharma, Redx Pharma, Sandoz, Sanofi, Seres Therapeutics, Surrozen, Takeda, Teva, Thelium Therapeutics, Theravance Biopharma, TiGenix, Tillotts Pharma AG, UCB Pharma, VHsquared, Viatris, Ysios Capital, and Zealand Pharma, T. Gibble Employee of: Eli Lilly and Company, K. Traxler Employee of: Eli Lilly and Company, N. Morris Employee of: Eli Lilly and Company, X. Li Employee of: Eli Lilly and Company, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, V. Jairath Consultant of: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Shire, Takeda, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics, A. Armuzzi Consultant of: AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and TiGenix, J. Jones: None Declared

Background Moderate to severe ulcerative colitis (UC) exerts a significant burden on patients’ lives. Patients with UC report that bowel urgency has a substantial negative impact on their quality of life and psychosocial functioning, however, this symptom is missing from most disease activity indices. Purpose The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms, including bowel urgency, on the lives of patients (pts) with moderate to severe UC and Crohn’s disease in the United States (US), Europe (EUR), and Japan. These data focus on pts in the US and EUR. Method Online, quantitative, cross-sectional surveys of pts with moderate to severe UC were conducted in the US and EUR (France, Germany, Italy, Spain, and UK). Data included pt perspectives on their UC symptoms and the impact on their daily lives. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Descriptive statistics summarise the data. Result(s) 200 US pts (62% male, mean age 40.4 years) and 556 EUR pts (57% male, mean age 38.9 years) completed the survey, with 77% and 54% currently receiving advanced therapies (biologic or novel oral therapy), respectively. The top 3 symptoms currently (past month) experienced by US and EUR pts were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). In past 3 months, pts who have ever experienced bowel urgency or urge incontinence reported bowel urgency (93% US, 89% EUR) and urge incontinence (86% US, 71% EUR) at least once a month (Table). 69% and 65% of all US and EUR pts, respectively, reported wearing a diaper/pad/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. For pts receiving advanced therapies, similar patterns were observed. Among both US and EUR pts, the most common UC-related reasons for declining participation in social events were bowel urgency (43% and 30%) and fear of urge incontinence (40% and 32%). Similarly, the most common reasons for declining participation in work/school and sports/physical exercise were bowel urgency and fear of urge incontinence. Image Conclusion(s) Bowel urgency, which was the second-most frequently reported symptom, has an extensive impact on the lives of pts with moderate to severe UC. In this younger pt population, including pts receiving advanced therapies, almost two thirds of US and EUR pts reported wearing diapers/pads/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. Both US and EUR pts reported bowel urgency and fear of urge incontinence as the top reasons for declining participation in social events, work/school, and sports/physical exercise. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, A. Bleakman Employee of: Eli Lilly and Company, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, J. Jones: None Declared

Background Ulcerative colitis (UC) can result in a high prevalence of bowel movement urgency (BU), significantly reducing patient quality of life. Purpose Early BU improvement association with later clinical endpoint improvements was examined in moderately-to-severely active UC patients (pts) treated with mirikizumab (miri). Method BU was evaluated in Phase 3 randomized placebo (PBO)-controlled 12-week induction (LUCENT-1, NCT03518086) and 40-week maintenance (LUCENT-2, NCT03524092) trials with miri. Pts received IV miri 300mg or PBO during induction. Week (W)12 miri responders were rerandomized at LUCENT-2 baseline (BL) to subcutaneous miri 200mg or PBO. BU was measured with 11-point Urgency Numeric Rating Scale (UNRS) from 0 (no urgency) to 10 (worst possible). Pts’ UNRS scores were an average from 7 consecutive days prior to visit. Association of pts with BU Clinically Meaningful Improvement (CMI) or BU remission between BL and W4 with the proportion of pts achieving clinical response, and clinical, endoscopic, or symptomatic remission at end of W12 was assessed. For pts who achieved clinical response at W12, the analyses were repeated for the end of maintenance based on W12 BU status. Logistic regression models with treatment, urgency (BU CMI or BU Remission), treatment-by-urgency group interaction, and stratification factors were fitted to examine the association between early urgency improvement and later clinical endpoints. Result(s) Treatment-by-urgency group interactions were not statistically significant across clinical outcomes for induction and maintenance. For induction, treatment and urgency status were statistically significant. Pts experiencing BU CMI or BU remission at W4 were consistently more likely to achieve clinical response, and clinical, endoscopic, or symptomatic remission at W12 for both treatment groups. For remission, only treatment main effect was statistically significant. Among miri induction clinical responders (an enriched population), BU CMI or BU Remission at end of induction (W12) was not associated with later maintenance efficacy outcomes (W52). Miri-treated pts achieved higher rates of clinical response, and clinical, endoscopic, or symptomatic remission at W52 than with PBO regardless of BU CMI or BU Remission at W12 (Table). Image Conclusion(s) Early BU Improvement, CMI or Remission, was associated with better clinical outcomes during induction for miri and PBO pts, showing BU is a sensitive predictor of early clinical outcomes. Among miri induction responders, miri consistently provided better maintenance of response and remission rates than PBO. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding; Eli Lilly and Company Disclosure of Interest D. Clemow Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, T. Hibi Grant / Research support from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, S. Vermeire Consultant of: AbbVie, Arena Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, ProDigest, Progenity, Prometheus Therapeutics and Diagnostics, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance Biopharma, and Tillots Pharma AG, Speakers bureau of: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Janssen, Pfizer, Robarts Clinical Trials, and Takeda, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, L. Peyrin-Biroulet Grant / Research support from: AbbVie, Fresenius Kabi, Merck Sharp & Dohme, and Takeda, Consultant of: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillots Pharma AG, Viatris, and Vifor Pharma, M. Watanabe Grant / Research support from: AbbVie, Alfresa Pharma, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical, Consultant of: AbbVie, Boehringer Ingelheim, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Nippon, and Takeda, Speakers bureau of: EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Janssen, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Japan, Takeda, and Zeria Pharmaceutical, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared

Background With a growing prevalence of inflammatory bowel disease (IBD) in elderly patients, there is a clinical requirement to understand the impact of treatment in this population.1 Filgotinib (FIL) is an oral Janus kinase 1 preferential inhibitor. This post hoc analysis of data collected in the phase 2b/3 SELECTION programme evaluated the efficacy and safety of FIL in patients with ulcerative colitis (UC) stratified by age. Methods The SELECTION programme includes two Induction Studies, a Maintenance Study (NCT02914522) and a long-term extension (LTE) study (NCT02914535). Adults aged 18–75 years with moderately to severely active UC were randomized 2:2:1 to receive FIL 200 mg or 100 mg or placebo once daily for 11 weeks. Responders at week 10 were re-randomized 2:1 to continue assigned FIL treatment or placebo from week 11–58. In LTE, patients with disease worsening and those completing week 58 continued assigned treatment before receiving open-label FIL. We assessed the efficacy and safety of FIL at any dose in the overall cohort of SELECTION and LTE, stratified into five age groups: Results Baseline disease activity and previous and concomitant treatments were comparable across age groups in each treatment arm. While there were fewer patients in the ≥60 years group, patient distribution was similar in all other age groups. FIL induced clinical (~16%) and pMCS (~36%) remission in similar proportions of patients across all age groups at week 10 (Figure 1). At week 58, pMCS remission was achieved in ~53% of FIL-treated patients across age groups (Figure 2). In LTE, the proportion of FIL-treated patients in pMCS remission generally increased with time and remained similar across all age groups (Figure 3). FIL-treated patients aged ≥60 years had higher EAIRs of any AE, infections, herpes zoster, malignancies, NMSC and MACE than younger patients (Table). One thromboembolic event occurred in a FIL-treated patient aged Conclusion These findings suggest FIL is efficacious in inducing and maintaining symptomatic remission and could have an acceptable safety profile in adults with UC of all ages, including ≥60 years old. Age-related increases in incidences of certain AEs might be expected in patients with IBD; however, the number of patients ≥60 years limits comparison of these data with reported rates. Reference 1Zammarchi et al. BMC Gastroenterol 2020;20;147

Nature 603, 58 - 62 (2022). doi:10.1038/s41586-021-04348-8, The interaction of intense particle bunches with plasma can give rise to plasma wakes capable of sustaining gigavolt-per-metre electric fields, which are orders of magnitude higher than provided by state-of-the-art radio-frequency technology. Plasma wakefields can, therefore, strongly accelerate charged particles and offer the opportunity to reach higher particle energies with smaller and hence more widely available accelerator facilities. However, the luminosity and brilliance demands of high-energy physics and photon science require particle bunches to be accelerated at repetition rates of thousands or even millions per second, which are orders of magnitude higher than demonstrated with plasma-wakefield technology. Here we investigate the upper limit on repetition rates of beam-driven plasma accelerators by measuring the time it takes for the plasma to recover to its initial state after perturbation by a wakefield. The many-nanosecond-level recovery time measured establishes the in-principle attainability of megahertz rates of acceleration in plasmas. The experimental signatures of the perturbation are well described by simulations of a temporally evolving parabolic ion channel, transferring energy from the collapsing wake to the surrounding media. This result establishes that plasma-wakefield modules could be developed as feasible high-repetition-rate energy boosters at current and future particle-physics and photon-science facilities., Published by Nature Publ. Group, London [u.a.]

Being installed as close as 5.5 mm to the beam axis, the Micro Vertex Detector (mvd) of the cbm experiment will be exposed to a sizable flow of heavy beam ions and nuclear fragments. The cmos Monolithic Active Pixel Sensor for the mvd, mimosis, must resist the related heavy ion impacts without permanent damage or frequent interrupt of operation as caused by single event effects (see). We motivate the requirements on the sensor and introduce our concept for protecting the device against sees. Moreover, we report the results of a related test campaign carried out with the first full size sensor prototype, mimosis-1, and different heavy ion beams at gsi.

BACKGROUND AND PURPOSE: Cerebral small vessel disease contributes to stroke and cognitive impairment and interacts with Alzheimer disease pathology. Because of the small dimensions of the affected vessels, in vivo characterization of blood flow properties is challenging but important to unravel the underlying mechanisms of the disease. MATERIALS AND METHODS: A 2D phase-contrast sequence at 7T MR imaging was used to assess blood flow velocity and the pulsatility index of the perforating basal ganglia arteries. We included patients with cerebral amyloid angiopathy (n = 8; identified through the modified Boston criteria), hypertensive arteriopathy (n = 12; identified through the presence of strictly deep or mixed cerebral microbleeds), and age- and sex-matched controls (n = 28; no cerebral microbleeds). RESULTS: Older age was related to a greater pulsatility index, irrespective of cerebral small vessel disease. In hypertensive arteriopathy, there was an association between lower blood flow velocity of the basal ganglia and the presence of peri-basal ganglia WM hyperintensities. CONCLUSIONS: Our results suggest that age might be the driving factor for altered cerebral small vessel hemodynamics. Furthermore, this study puts cerebral small vessel disease downstream pathologies in the basal ganglia region in relation to blood flow characteristics of the basal ganglia microvasculature.

Aims The SELECTION (NCT02914522) Induction Studies evaluated the efficacy/safety of filgotinib (FIL), a preferential JAK1 inhibitor, as induction therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who were biologic-naïve but failed conventional therapy (Induction Study A) or failed prior biologics (Induction Study B). Methods Pts were randomized 2:2:1 to once–daily FIL 200mg, FIL 100mg or placebo (PBO). The primary (clinical remission), key secondary (Mayo Clinic Score [MCS] remission, endoscopic remission, and histologic remission), and exploratory endpoints (MCS response and endoscopic improvement) were assessed at Week 10. Results In both studies, baseline demographics and disease characteristics were similar across treatment groups. In Study A, 659 pts were randomized and treated. Baseline mean MCS was 8.6 and 56% had a Mayo endoscopic subscore (ES)=3. A significantly higher proportion of biologic-naïve pts on FIL 200mg achieved clinical remission vs PBO and all key secondary endpoints (Table). In Study B, 689 pts were randomized and treated. Baseline mean MCS was 9.3 and 78% had ES=3. Prior treatment failures were: anti-TNF (86%), vedolizumab (52%) and both (dual-refractory; 43%). A significantly higher proportion of biologic-experienced pts on FIL 200mg achieved clinical remission vs PBO. In Studies A and B, a greater proportion of pts on FIL 200 mg achieved an MCS response and endoscopic improvement vs PBO. The rates of AEs, serious AEs and discontinuations due to AEs were similar across FIL and PBO groups during induction. In the PBO, FIL 100mg and FIL 200mg groups, serious infections occurred in 0.7%, 0.7% and 0.4% pts in Study A and 1.4%, 1.4% and 0.8% pts in Study B; H Zoster occurred in Conclusions SELECTION included a high proportion of dual-refractory pts, and pts with severe endoscopic disease. Both doses of FIL were well tolerated. Filgotinib 200mg was effective induction therapy for both biologic-naïve/-experienced pts with moderately to severely active UC. Funding Agencies None

Bond-order potentials (BOPs) provide a local and physically transparent description of the interatomic interaction. Here we describe the efficient implementation of analytic BOPs in the BOPfox program and library. We discuss the integration of the underlying non-magnetic, collinear-magnetic and noncollinear-magnetic tight-binding models that are evaluated by the analytic BOPs. We summarise the flow of an analytic BOP calculation including the determination of self-returning paths for computing the moments, the self-consistency cycle, the estimation of the band-width from the recursion coefficients, and the termination of the BOP expansion. We discuss the implementation of the calculations of forces, stresses and magnetic torques with analytic BOPs. We show the scaling of analytic BOP calculations with the number of atoms and moments, present options for speeding up the calculations and outline different concepts of parallelisation. In the appendix we compile the implemented equations of the analytic BOP methodology and comments on the implementation. This description should be relevant for other implementations and further developments of analytic bond-order potentials.

The interaction of intense particle bunches with plasma can give rise to plasma wakes

Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]

Background Tyrosine kinase 2 (TYK2) is an intracellular kinase that mediates the signalling of key cytokines involved in ulcerative colitis (UC) pathophysiology. Deucravacitinib (DEUC) is a novel, oral, selective TYK2 inhibitor that binds to the TYK2 regulatory domain. The safety and efficacy of DEUC were evaluated in patients (pts) with moderately-to-severely active UC. Methods LATTICE-UC (NCT03934216), a randomised, double-blind, placebo (PBO)-controlled, multicentre, Phase 2 trial, enrolled pts with moderately-to-severely active UC (modified Mayo score of 5 to 9 [endoscopic {ES} subscore ≥2, rectal bleeding {RB} subscore ≥1, stool frequency {SF} subscore ≥2) with inadequate response, loss of response, or intolerance to ≥1 conventional or biologic therapy. Pts were randomised 2:1 to oral DEUC 6 mg or PBO twice daily (BID) and stratified by baseline (BL) corticosteroid use and prior exposure to biologics. The primary endpoint was clinical remission (modified Mayo score with subscores of SF ≤1 with ≥1-point decrease from BL, RB=0, and ES ≤1 [modified, excludes friability]) at Week (Wk) 12; endoscopic response (ES ≤1) at Wk 12 was a secondary endpoint. Results Demographic and BL characteristics were generally similar across groups, except for BL disease activity as measured by the modified Mayo score and ES subscore. Most pts (63.4%) were biologic naïve, and 40.5% were receiving concomitant oral corticosteroids (Table 1). Of 131 pts randomised, 104 (79.4%) completed 12 wks of treatment (DEUC, 69/87 [79.3%]; PBO, 35/42 [83.3%]). At Wk 12, clinical remission rates were 14.8% and 16.3% in the DEUC and PBO arms, respectively, in the overall population (P=0.59); 14.0% and 25.9% in biologic-naïve pts; and 16.1% and 0.0% in biologic-experienced pts (Figure 1). At Wk 12, endoscopic response rates were 19.3% and 27.9% in the DEUC and PBO arms, respectively, in the overall population (P=0.88); 15.8% and 37.0% in biologic-naïve pts; and 25.8% and 12.5% in biologic-experienced pts (Figure 2). Pharmacodynamic data suggest insufficient inhibition of TYK2 pathways with DEUC 6 mg BID. Incidence of adverse events (AEs) was 70.1% in the DEUC arm and 47.6% with PBO; rates of serious AEs were 9.2% (n=8) and 4.8% (n=2), respectively. Rash, acne, and worsening of UC were the most common AEs in the DEUC arm. No meaningful changes from BL in mean values of laboratory parameters were observed with DEUC treatment. Conclusion This Phase 2 study of DEUC 6 mg BID in moderately-to-severely active UC did not meet its primary or secondary efficacy endpoints at Wk 12. In biologic-experienced pts, response rates were numerically higher with DEUC compared with PBO. The safety profile was consistent with DEUC trials in psoriasis and psoriatic arthritis.

Background T cells, as part of the adaptive immune system, are a significant driver of inflammation in Crohn’s disease (CD), yet specific T-cell targets are largely unknown. Genetic factors contribute to a small portion of CD risk including several HLA alleles, such as DRB1*07:01 and HLA-DRB1*01:03, associated with CD. The involvement of HLAs suggests that studying specific T cells could lead to new insights into CD development and progression. In this study, we use established immunoSEQ® technology to profile T-cell receptors (TCRs) and identify TCRs associated with CD and CD characteristics. Methods We analyzed TCRs from blood of 1,738 CD cases and 4,970 healthy controls. TCRs that were statistically enriched in cases, but not healthy controls (p Results We identified 1,121 CD-associated ES in the exploratory cohort. These were also enriched in CD cases in our validation cohort (Fig 1A). Using intestinal tissue samples from a subset of cases, we found that a median of 14% ES from individual cases were shared between blood and tissue samples (Fig. 1B). ES breadth (ES diversity relative to total TCR diversity) was significantly associated with history of CD-related surgery (Fig 1C, p < 1x10-15), with stricturing or fistulizing phenotypes (Fig 1D, p < 1x10-5 for B1 versus B2 or B3), and with ileal or ileocolonic location (Fig 1E, p < 1x10-7 for L2 versus L1 or L3). We found that 202 ES formed clusters of similar sequences consisting of 2–23 members (Fig. 2A). We confidently (p < 0.0001) associated 398 ES to a specific HLA allele (Fig 2B), including 134 of the ES assigned to clusters (Fig 2A). Some clusters, including the largest, had no members that could be assigned to an HLA allele, raising the possibility that these ES clusters bind non-canonical HLAs. Conclusion Our discovery set of public TCRs associated with CD indicates that the immune system of CD patients responds to a consistent set of antigens. Importantly, CD ES were present in both tissue and blood, demonstrating that evaluating TCRs in blood may be a surrogate of TCRs in tissue. The HLA allele associations of these ES potentially point to new risk factors and disease insights, such as the involvement of DP and DQ alleles. The association of ES frequency with CD characteristics strongly suggested that further examination of these TCRs may impact CD patient care and advance understanding of the pathophysiology of the disease.

Background Ambitious therapeutic goals in the therapy of inflammatory bowel disease need more stringent individual endpoints. Several definitions for composite endpoints are under evaluation to describe disease control. Most commonly symptomatic (PRO2) remission is combined with endoscopic response, histology and/or biomarker remission. Here we explore the addition of fatigues as a lead problem reported by patients with IBD as part of a composite endpoint. Methods We have conducted an interim analysis of an ongoing open label study of patients with Crohn’s disease (CD) and ulcerative colitis (UC) assigned to anti-TNF therapy, vedolizumab, ustekinumab or tofacitinib. Patients are scheduled for evaluations at start of the respective therapy and at weeks 2, 6, 14, 26 and 52. Endoscopies are conducted before therapy and at weeks 14 and 52. Clinical remission (CR) was defined as CDAI < 150 and reduction of partial Mayo score (pMayo) > 50% vs. baseline at week 14. All patients who are not in CR and/or no improvement in endoscopy at week 14 are assessed for a switch in the mechanism of action and observation schedules after a switch are reset to week 0. FACIT-F scores Results Fatigue was present in 52% patients (39/75) at baseline. 54% (25/46) of the patients achieved CR at week 14 while 46% (21/46) did not meet CR criteria (non-responder). Fatigue at baseline was persistent at week 14 in 12% (3/25) of CR responders, in contrast to 43 % (9/21) of non-responders. 64% (21/33) of all patients reached a combined endpoint of CR and absence of fatigue. If fatigue was present at baseline (n = 25), fatigue response was observed in 52% (13/25) of the patients, while CR was only reached in 40% (10/25) and the combined endpoint of CR and fatigue response in 24% (6/25) of the patients at week 14. In contrast, 71% (15/21) of patients without fatigue at baseline reached CR at week 14. Absence of fatigue at baseline thus increased the chance of CR at week 14, with an OR of 3.75 [1.031 – 11.50] (p = 0.0422 in Fisher’s exact test). Conclusion Fatigue is an important complaint strongly impacting the patients’ quality of life. A composite endpoint including fatigue and clinical remission (based on pMayo and CDAI) can be reached in a significant percentage of patients treated with biological therapies. Presence of fatigue at baseline might serve as a strong marker for clinical non-response at week 14. Further evaluation and replication of this novel composite endpoint will be conducted in our ongoing trial with a particular focus on inclusion of endoscopies and long-term outcome.

Background Control of endoscopic inflammation like endoscopic remission is an important treatment target in Crohn’s disease (CD), as suggested in the STRIDE II guidelines. This study evaluated the relationship of early improvement in endoscopic outcomes on hospitalisation and surgery rates at, 52 wks in patients with CD treated with risankizumab (RZB). Methods This post-hoc analysis uses data from three double-blind, randomised Phase, 3 induction (ADVANCE and MOTIVATE) and maintenance (FORTIFY) trials evaluating the efficacy and safety of RZB in patients with moderate to severe CD. Patients who responded to, 12-wk induction therapy with RZB IV (600 mg or, 1200mg) in ADVANCE or MOTIVATE and received up to, 52 wks of maintenance therapy with RZB SC (180 mg or, 360 mg) in FORTIFY were analysed. Incidence rates (events/100 person-years) of CD-related hospitalisation, CD-related surgery (surgical procedures due to adverse events or complications related to CD), all-cause hospitalisation, and all-cause surgery were evaluated from the beginning of maintenance to wk, 52 and compared between patients who achieved endoscopic outcomes at end of induction (wk, 12) and those who did not. Endoscopic response, endoscopic remission and ulcer-free endoscopy (absence of ulceration) were defined using the Simple Endoscopic Score for CD (SES-CD) (Figure, 1–3), as scored by a blinded central reviewer. Results A total of, 298 patients were included in the analyses. Patients who achieved endoscopic response (n=121) at wk, 12 had a significantly reduced incidence rate of CD-related hospitalisation, CD-related surgery, and all-cause hospitalisation by wk, 52 compared to those who did not achieve an endoscopic response (n=177) at wk, 12 (Figure, 1). Additionally, patients who achieved endoscopic remission at wk, 12 (n=83) had a significantly reduced incidence rate of CD-related hospitalisation, CD-related surgery, and all-cause hospitalisation by wk, 52, compared to those not achieving endoscopic remission at wk, 12 (n=215) (Figure, 2). Though not statistically significant, numerically lower rates of all-cause surgery were observed for patients who achieved endoscopic remission or endoscopic response at wk, 12. Significantly lower rates of CD-related hospitalisation, CD-related surgery, all-cause hospitalisation, and all-cause surgery by wk, 52 were observed among patients who achieved ulcer-free endoscopy (absence of ulceration) (n=70) vs those who did not (n=228) at wk, 12 (Figure 3). Conclusion Early improvement of endoscopic outcomes at wk, 12 is associated with significant reductions in hospitalisations and surgeries through, 52 wks for patients receiving RZB therapy.

Background To gain insight into vedolizumab (VDZ) use as a first-line biologic in Crohn′s Disease (CD), this real-world study aimed to assess, within the maintenance phase, the 1-year comparative effectiveness and persistence of VDZ vs anti-TNF therapy in biologic-naïve CD-patients. Methods Between 2017–2020, 1200 consecutively enrolled biologic-naïve and biologic-experienced patients with ulcerative colitis (UC) and CD were prospectively included in the VEDOIBD-Registry from 45 IBD-experienced centres across Germany. 294 biologic-naïve CD-patients starting a new therapy with VDZ or anti-TNF (adalimumab: ADA or infliximab: IFX) were included in this real-world evidence (RWE) study. The Kaplan-Meier was used to summarize the treatment persistence from the start of therapy through week-52. The primary outcome was week-52 clinical remission (HBI ≤ 4). Patients were analyzed on a modified intent-to-treat basis (mITT; switchers considered as outcome failure) and on a per-protocol (PP) basis (excluding switchers). To reduce selection bias in the estimation of treatment effects, the inverse probability of treatment weighting propensity score (PS) was implemented. A weighted logistic regression was used to evaluate the effectiveness. The results were reported as odds ratio (OR) and 95% confidence interval (CI). Results 71 VDZ and 223 anti-TNF (ADA: 59.6%, IFX: 40.4%) biologic-naïve CD-patients were evaluated. 52-weeks after treatment initiation approximately 94% of VDZ patients were still in continuous treatment vs 75% of ADA and 78% of IFX (Figure 1). The mITT 1-year clinical remission rate was 76.1% for VDZ vs 63.8% for anti-TNF (OR: 1.80, 95% CI: 0.86–3.76). Similar results were observed for VDZ vs IFX (Table 1). In contrast, the clinical remission was significantly higher in the VDZ group than in the ADA group (OR: 2.24, 95% CI: 1.04–4.85). The PP analysis suggested comparative effectiveness, having excluded more anti-TNF switchers. 91.7% of week-14 responders VDZ patients were in clinical remission from week 14 through 52 vs 66.1% of anti-TNF patients (OR: 5.69, 95% CI: 1.66–19.5). Similar, significant, results were observed for VDZ vs ADA and for VDZ vs IFX (Table 2). Conclusion In this real-world setting comparing VDZ and anti-TNF in biologic-naïve patients via PS weighted analysis, VDZ showed especially in week-14 responders higher clinical remission rates in comparison to anti-TNF. The higher treatment persistence observed for VDZ, perhaps due to a more favourable safety profile vs anti-TNF, may be considered the main driver for the better effectiveness of VDZ at one year. These findings may aid physicians’ decision-making on the choice of VDZ as the first-line biologic for CD.

Background ORM1-like protein 3 (ORMDL3) is an endoplasmic reticulum (ER)-resident protein that has been implicated in ER homeostasis and sphingolipid biosynthesis. Genome-wide association studies identified susceptibility loci around the ORMDL3 gene for inflammatory diseases, including asthma and IBD. Preliminary studies suggested a role of ORMDL proteins within the ER stress-induced unfolded protein response (UPR). Here, we set out to investigate the role of ORMDL proteins in intestinal inflammation. Methods Mice with constitutive and conditional knockouts (KO) of Ormdl1, Ormdl2 and Ormdl3 in intestinal epithelial cells were generated. From these, intestinal organoids were generated to perform functional assessment of ER stress, autophagy, and inflammatory responses. We performed 3’-single cell RNA sequencing (scRNAseq) of small intestine tissue of animals with triple conditional knockout of Ormdl1/Ormdl2/Ormdl3 (“Ormdl123-VilCre”) vs. wildtype to identify cell type-specific effects of epithelial ablation of ORMDL proteins. 16S rDNA sequencing was performed on stool samples from these animals. Results Mice deficient for ORMDL displayed reduced body weight dependent on the number of knockouts. Ormdl1/2/3-KO mice are embryonically lethal while Ormdl1/2/3-VilCre animals were viable without signs of spontaneous inflammation. Ormdl1- and Ormdl3-KO animals displayed reduced number of Paneth and goblet cells in the small intestine, accompanied by massive dilation/ballooning of the ER. This phenotype was strongly pronounced in Ormdl1/3-KO and Ormdl1/2/3-VilCre animals. ORMDL3 co-localises and co-precipitates with LC3, indicating a direct interaction with autophagy proteins, while loss of ORMDL proteins impaired autophagic flux. Interestingly, UPR and Cxcl1 expression were insufficiently induced in intestinal organoids from Ormdl1/2/3-VilCre animals treated with tunicamycin. scRNAseq analysis of small intestine tissue surprisingly revealed compensatory induction of antimicrobial peptides in non-Paneth cells and vice versa downregulation of apoptosis regulating gene in Ormdl1/2/3-VilCre mice. We observed an expansion of myeloid and plasma cells in Ormdl1/2/3-VilCre mice, while no changes in epithelial cell proportions can be identified. These findings were accompanied by dysbiosis of the stool microbiome (β-diversity, Bray-Curtis dissimilarity) of Ormdl1/2/3-VilCre animals. Conclusion Our data suggest a critical regulatory role of the IBD risk gene ORMDL3 in the ER-autophagy axis in intestinal epithelial cells, shaping the mucosa homeostasis on cellular and microbiome level. Functional assessment of inflammation in Ormdl1/2/3-VilCre animals (e.g., DSS colitis model) will be performed to understand the role of ORMDL in intestinal inflammation.

Background Observational real world studies are required in addition to RCTs which typically represent selected patients not reflecting everyday clinical practice. Between 2017–2020 patients with Crohn’s disease (CD) receiving a newly initiated biologics therapy were consecutively enrolled into the prospective, observational RUN-CD registry from 44 IBD-experienced German centres to assess effectiveness and safety of ustekinumab (UST) with a 3 years follow-up. Here, the results on the effectiveness of the maintenance therapy over 12 months are presented as a real world evidence (RWE) comparison of UST vs anti-TNF. Methods After exclusion of other biologics than UST and anti-TNF and missing outcomes, the final sample consisted of 607 CD-patients. Clinical remission (HBI ≤ 4) was the predefined endpoint at month 12. Patients were analyzed on a modified intent-to-treat basis (mITT; switchers considered as outcome failure). To reduce the effect of confounders, propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Results 343 UST (naïve: 35) and 264 anti-TNF (naïve: 175) (ADA 61%, IFX 39%) CD-patients were included. PS removed systematic differences between both groups (mean of both groups: 15% perianal disease, 36% surgical resection, 41% EIM). Overall, the number of switches was lower in the UST group than in the anti-TNF group (Tab. 1). However, the number of switches within 12 months was significantly lower in the UST group only when compared to the IFX group (16.3% vs 27.2%; p=0.045) (Fig. 1). Clinical remission rates at 1 year (Tab. 2) were not statistically different for the overall UST vs. anti-TNF groups (65.8% vs 60.0%). Remission rates were similar for UST vs ADA, while these were significantly higher for UST vs. IFX (61.6% vs 41.8%; p=0.009). Looking at clinical remission in the week 16 responder group (Tab. 3), a statistically significantly higher remission rate was found in the overall group for UST (77.6%) vs anti-TNF (65.4%) (p=0.041), which was mainly driven by the higher UST remission rate in biologic-naïve CD patients (p=0.026). Conclusion This 1-year maintenance phase RWE-comparison with UST vs anti-TNF showed remarkably high clinical remission rates in both groups. Also due to a more frequent switching within the IFX group, the clinical remission rate at 1 year was significantly higher with UST than with IFX and higher with UST vs anti-TNF in the biologic-naïve groups. These results support together with the known favorable safety profile consideration of UST as a first-line targeted therapy for CD.

Background For patients with ulcerative colitis (UC), both subjectively and objectively reported measures are equally important treatment goals. We explored clinical, biological, HRQoL remission and endoscopic improvements as a combined endpoint (CE) from SELECTION (NCT02914522), a phase 2b/3 double-blind trial which assessed the efficacy and safety of filgotinib, a once-daily, oral, Janus 1 kinase preferential inhibitor, for the treatment of UC. Methods In SELECTION, patients with moderately to severely active UC were randomized 2:2:1 to 200mg filgotinib (FIL200), 100mg filgotinib, or placebo (PBO) for an 11-week induction phase followed by a 47-week maintenance period in patients who achieved clinical remission or response.1 We defined a CE as achieving all of the following: 1) clinical remission defined as partial Mayo Score (excluding endoscopy domain) ≤2 and no sub-score >1), 2) biological remission defined as faecal calprotectin 170 and 4) endoscopic improvement defined as Mayo endoscopic sub-score ≤1). We evaluated the CE among patients treated with FIL200 vs placebo in induction (week 10) and maintenance (week 58) phases. Among those achieving the CE, we analysed MCID improvement during induction and decline during maintenance on generic QoL instruments (36-item short-form questionnaire and EuroQol 5-dimension [EQ5D]).2,3,4 Results Overall population included 381 biologic-naïve and 401 biologic-experienced patients undergoing induction, of which 297 subsequently entered maintenance. A higher proportion of patients receiving FIL200 achieved CE than PBO by week 10 in the biologic-naïve induction cohort (17.6% vs 4.41%, p Conclusion Treatment with filgotinib resulted in a higher proportion of patients with combined clinical, biological, HRQoL remission and endoscopic improvements. Among patients achieving this combined composite endpoint, clinically meaningful improvements were observed in their overall quality of life. Holistic assessment of several subjective and objective measures may help achieve better outcomes in UC. References 1. Feagan BF, et al. Lancet 2021;397:2372–84. 2. User’s manual for the sf-36v2 health survey. Quality Metric, Inc; 2009. 3. Stark RG, et al. Inflamm Bowel Dis. 2010 Jan;16(1):42–51. 4. Irvine EJ. J Pediatr Gastroenterol Nutr. 1999 Apr;28(4):S23–27.

Background Upadacitinib (UPA) is an oral, once-daily (QD), selective Janus kinase inhibitor that has demonstrated efficacy in the induction and maintenance treatment of Ulcerative Colitis (UC). This analysis aimed to assess the impact of baseline UC characteristics on clinical outcomes following UPA therapy. Methods Patients (pts) with moderately to severely active UC who had failed conventional or biological treatment were enrolled in two randomised, double-blind (DB), placebo (PBO)-controlled, Phase 3, 8-week induction studies of UPA 45 mg QD vs PBO. Pts achieving a clinical response (decrease from baseline in Adapted Mayo score ≥2 points and ≥30% from baseline, plus a decrease in rectal bleeding score [RBS] ≥1 or an absolute RBS ≤1) at Week (Wk) 8 entered a 52-week, randomised, DB, PBO-controlled, Phase 3 maintenance study, and received UPA 15 mg QD, UPA 30 mg QD, or PBO. The primary efficacy endpoint was clinical remission per Adapted Mayo score at Wk 8 (induction) and at Wk 52 (maintenance). Pre-specified (PS) and post hoc (PH) analyses were conducted by baseline disease activity (full Mayo score ≤9 or >9) (PS), extent (PS), duration (5–10, >10 years [yrs]) (PH), and high-sensitivity C-reactive protein (hs-CRP) level (≤5 or >5 mg/L) (PH). Results 988 pts were included in the induction studies, and 451 in the maintenance study. The treatment difference between UPA 45 mg QD and PBO excluded zero for all subgroups at Wk 8 (Figure 1). Wk 8 remission rates were lower for full Mayo score >9 vs ≤9, and for CRP >5 vs ≤5 mg/dL, with minimal effects of disease extent or duration. Wk 52 maintenance of remission rates were greater with UPA 15 mg and 30 mg QD vs PBO (16–44% and 30–50% difference, respectively), and with UPA 30 vs UPA 15 mg QD. This incremental benefit of the 30 mg dose was greater in pts with severely (full Mayo score >9) vs moderately active disease (Figure 2); 15 mg and 30 mg demonstrated similar efficacy in pts with Mayo score 5 mg/L. Conclusion UPA 45 mg QD is an effective induction treatment for UC, regardless of baseline disease characteristics. Both 15 and 30 mg UPA doses are effective maintenance regimens, regardless of baseline disease characteristics. However, the 30 mg dose shows a trend towards increased benefit vs 15 mg in pts with Mayo score >9 and extensive disease. This analysis suggests that while UPA 15 mg may be most appropriate for patients with UC with a low inflammatory burden (per full Mayo score and extent), the 30 mg dose may be more appropriate for those with a high one.

Background In this real-world-evidence (RWE) study we aimed to analyse the persistence of biologic therapy in biologic-naïve ulcerative colitis (UC) patients and to compare 1-year effectiveness of vedolizumab (VDZ) and anti-TNF. Methods Between 2017 and 2020, 1200 consecutively enrolled biologic-naïve and biologic- experienced patients with UC and Crohn′s disease (CD) were prospectively included in the VEDOIBD-Registry from 45 IBD-experienced centres across Germany. After exclusion of bio-experienced patients, CD and missing outcomes, the final sample consisted of 274 biologic-naïve UC-patients with 1-year follow-up data. Switchers of a drug were considered as treatment failure (modified intention-to-treat analysis; mITT) while switchers were excluded from per protocol analysis (PP). Clinical response modified (reduction of partial Mayo score (pMayo) from baseline to 1-year by >3 points or a reduction of at least 30% compared to baseline or reaching remission at 1-year) and (steroid-free) remission rates (pMayo ≤1 plus a bleeding subscore=0 (and no systemic use of steroids or budesonide at 1-year)) were predefined as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Results 158 VDZ and 116 anti-TNF (ADA: 27.6%, IFX: 57.8%, GOL: 14.7%) biologic-naïve UC-patients were included in this prospective RWE comparing the effectiveness of VDZ vs anti-TNF. Until week 52 significantly more patients switched to another biologic-drug in the anti-TNF group than in the VDZ group (40.5% vs 16.5%; p Conclusion The 1-year maintenance findings suggested, in line with our previous induction phase data, only moderate long-term effectiveness in both groups. However, besides the significant response data, VDZ showed numerically higher remission rates compared to anti-TNF though only borderline significant. The higher treatment persistence of VDZ vs anti-TNF, along with the higher effectiveness, may suggest VDZ as a first-line biologic therapy option in UC patients.

Background Use of inflammatory biomarkers is common practice in ulcerative colitis (UC) management1. This study examined the utility of faecal calprotectin (FCP), C-reactive protein (CRP), and albumin biomarkers and their combination, for predicting outcomes of clinical remission and disease control (composite of clinical, endoscopic and histologic disease activity measures2) in patients (pts) with UC under therapy with vedolizumab (VDZ) or adalimumab (ADA) in the VARSITY study. Methods VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-control trial evaluating VDZ (anti-α 4β 7 integrin) vs ADA (anti-tumour necrosis factor-α) treatment in pts aged 18–85 years with moderate-to-severe UC (NCT02497469; EudraCT:2015-000939-33). Pts received either VDZ IV infusions (300 mg) on Day 1 and at Weeks (WKs) 2, 6, 14, 22, 30, 38, and 46 or ADA SC injections (40 mg), total dose 160 mg at WK1, 80 mg at WK2, and 40 mg every 2 weeks thereafter until WK50. In this post hoc analysis of data from 769 pts, the probability of clinical remission (total Mayo score ≤2, no subscore >1) and disease control (pt-reported outcome-2 [PRO2, Mayo subscores of stool frequency and rectal bleeding]; Mayo endoscopic subscore ≤1 [endoscopic improvement], and Robarts Histopathology Index score Results In comparison with biomarkers measured at baseline, FCP at WK14 was the most predictive of WK52 clinical remission after VDZ or ADA treatment3; WK14 FCP was also predictive of disease control using a combined endpoint of PRO2, endoscopy and histologic remission/response. VDZ-treated pts with low-risk FCP ( Conclusion The addition of CRP to FCP as a composite biomarker of IB at WK14 after treatment initiation can be a useful negative predictor of pts who are likely to achieve significant long-term benefits, including remission and disease control, with VDZ or ADA treatment. References 1. Turner D, et al. Gastroenterology 2021;160(5):1570-38. 2. Danese S, et al. J Crohn’s Colitis 2021;15(Suppl1):S305–S305. 3. Dulai PS, et al. Gastroenterology 2021;160(6):S-46–7.

Background Currently available disease activity indices for IBD (e.g., CDAI and Mayo score) focus on symptoms directly related to intestinal function, while other relevant health consequences of disease activity including quality of life, neuropsychiatric symptoms like depression, and social functionality, are not captured. With better therapies more stringent definitions of patient health have come into focus. One of the most common patient reported outcomes (PROs) in IBD is fatigue, which can be unrelated to endoscopic disease activity. We have shown earlier a strong degradation of tryptophan in active IBD (Nikolaus et al, 2017, Gastroenterology) and low tryptophan levels have been linked in various chronic disease to high fatigue levels. Here, we aim to study the relationship of fatigue with disease activity in the context of therapy response to a biological treatment. Methods Patients with Crohn’s disease and ulcerative colitis with high disease activity (Mayo score ≥ 6, CDAI ≥ 220) and planned new therapy with a biologic agent were included into a prospective observational protocol. After informed consent, clinical disease activity, inflammatory biomarkers, tryptophan levels in serum and fatigue levels were assessed longitudinally at week 0, 2, 6 and 14 after start of induction therapy. Complete assessments including week 14 were available for 38 patients for this interim analysis of the ingoing study. For fatigue assessment we used the validated German version of the fatigue subscale of the FACIT-F questionnaire. Patients were stratified into therapy responder (clinical remission (CR), reduction of partal Mayo score (pMayo) > 50%, CDAI < 150), non-responders (reduction of Mayo Results In the cross-sectional analysis of all patients (n = 76), the fatigue score strongly (inversely) correlated with pMayo and CDAI and correlated positively with tryptophan levels in serum. In receiver operating characteristic (ROC) analysis, FACIT-F score were able distinguish active vs. non-active disease (p < 0.0001, AUC = 0.7619) with specificity of 0.7103 and sensitivity of 0.7160. We did not observe significant differences in fatigue scores between males and females. In the longitudinal analysis, fatigue score only improved in the CR group (n = 25, median FACIT score 30 at baseline vs. 44 at week 14, p = 0.0221), and was significantly higher in CR vs. non-responder (n = 16, median FACIT score 44 vs. 31.5, p = 0.007). Conclusion Fatigue is strongly related but not completely overlapping with disease activity. Fatigue will be evaluated as a a patient-oriented indicator for therapeutic response. This observation will be extended by increasing the cohort size and independent validation.

Background Chronic endoplasmic reticulum stress (ER) in the intestinal epithelium is a pathophysiological hallmark of IBD. cGAS/STING is an innate immune pathway involved in the detection of double stranded DNA fragments leading to the subsequent induction of type I IFN responses. We here tested the hypothesis that chronic ER stress impairs cGAS/STING signalling in the intestinal epithelium. Methods Mice with a conditional intestinal epithelial deletion of Xbp1 (Xbp1 ΔIEC, Xbp1fl/fl) were used to assess intestinal epithelial STING expression in-vivo. Small intestinal organoids (Xbp1ΔIEC, Xbp1fl/fl) and cell lines (Mode K, iCtrl and iXbp1) were used to assess cGAS/STING signalling in-vitro using STING agonist (dsDNA, DMXAA). Murine cytomegalovirus (mCMV) infection assays were performed in iCtrl and iXbp1cells and Xbp1ΔIEC, Xbp1fl/fl mice to functionally link impaired cGAS/STING to pathogen response. LC-MS profiling was performed in iCtrl and iXbp1cells to identify underlying metabolic programs affecting cGAS/STING responses in ER-stressed cells. IBD biopsy samples (cross-sectional, longitudinal therapy response cohort) were used to validate key molecular phenotypes in human IBD. Results Compared to Xbp1 fl/fl mice, Xbp1ΔIEC show completely abrogated STING expression in the basal crypt compartment of the small intestinal epithelium. In line with that iXbp1 ModeK cells displayed impaired pathway activation (TBK1) and interferon inducible gene expression (Cxcl10) in response to cGAS/STING stimulation and towards mCMV infection, leading to increased viral replication compared to iCtrl cells. In-vivo mCMV infection led to augmented small intestinal histopathological disease activity in Xbp1ΔIEC, but not Xbp1fl/fl mice. Using LC-MS, we show that ER-stress induces a metabolic adaptation towards increased serin/glycin metabolism, which is used to counterbalance reactive oxygen species (ROS) via glutathione (GSH) synthesis. Pharmacological interception of key pathways of GSH synthesis of deprivation of serin/glycin phenocopies ER-stress in abrogating STING signalling in IECs. Lastly, we show that key aspects of metabolic adaptation to ER-stress are present in intestinal biopsies of IBD patients. Conclusion Our data describe a novel mechanism of metabolic adaptation to compensate ER-stress and maintain intestinal epithelial cGAS/STING signalling. We therefore put forward a model of ER-stress driven immunodeficiency via cGAS/STING signalling which renders the intestinal mucosa susceptible towards CMV infection in the context of IBD.

Background Independent assessments of histologic and endoscopic scores are two commonly used parameters as therapeutic endpoints in ulcerative colitis. However, our individual goal for patients is to achieve (long-term) disease-control. It has been recently shown that the individual combination of histologic and endoscopic remission is related to favorable long-term outcomes1. However, real world evidence for the benefit of using combined endoscopic and histologic remission endpoints is scarce. Methods We collected data from a retrospective cohort study of n=398 patients with active UC who underwent clinical assessment and routine colonoscopy. All patients donated data and biomaterials at the University Hospital Schleswig-Holstein (Kiel) using the broad consent2. The patients were observed over a minimum of 6 months and three individual outcomes were pre-defined as outcome-endpoints: i) therapy escalation (systemic steroids/new targeted MoA), ii) long-term hospitalization and iii) IBD-related surgery. Results 398 UC patients (female: n=166, 41.7%, male: n=232, 58.29% with a median age of 47 years at time of routine colonoscopy) were analyzed. We observed therapy escalation in 134 cases (42.27%), hospitalization in 70 cases (21.21%) and IBD-related surgery in 34 cases (10.66%). Remission at the time of colonoscopy was assessed by endoscopic Mayo (eMayo=0) or Nancy-Index (=0) and used for prediction of long-term outcome.We investigated the benefit of combined endoscopic and histologic remission on long-term outcome by comparing a combination of both eMayo=0 and Nancy=0 against eMayo=0 and Nancy>0. Patients with combined histologic and endoscopic remission show a significantly reduced hazard ratio for all three outcome endpoints, such as therapy escalation (HR 0.20, CI 0.10–0.39, p Conclusion We show that the combined assessment of endoscopic and histologic remission substantially increases the identification of patients with favorable long-term outcome in UC. However, even in patients with combined endoscopic and histologic remission approx. 20% underwent therapy escalation within 6-month period. These data highlight the need of combined endpoints using histology, endoscopy and probably other parameters (e.g. inflammatory biomarkers, patient reported outcomes) to define disease control and predict favorable disease trajectories in the future course of patients with UC.

Background Bowel urgency is the symptom described by patients as having the most impact on quality of life but is missing from most disease activity indices (Carpio et al., 2016). The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of patients’ experiences and the impact of IBD on their lives in the United States (US), Europe, and Japan. These data focus on US patients with moderately-to-severely active ulcerative colitis (UC). Methods An online, quantitative, cross-sectional survey was conducted with patients with moderately-to-severely active UC in the US in July 2021. Data included patient perspectives on their UC symptoms and the impact on their social life, work/school life, and ability to participate in sports/physical activities. Moderately-to-severely active UC was defined based on treatment, steroid use, and/or hospitalization history. Descriptive statistics (frequencies, percentages) summarise the data. Results 200 (of 756 total contacted) patients (61.5% male, mean age 40.4, mean disease duration 7.9 years) completed the survey in the US, with 77% (n=153) of patients receiving advanced therapies (biologic or novel oral therapy). Patients declined participation in social events due to bowel urgency (43%), fear of urge incontinence (40%), increased stool frequency (29%), and blood in stool (15%) in the last three months (Fig. 1). Patients declined participation in sports/physical exercise due to bowel urgency (38%), fear of urge incontinence (36%), increased stool frequency (24%), and blood in stool (10%) in the last three months (Fig. 2). Patients declined participation in work/school due to bowel urgency (37%), fear of urge incontinence (42%), increased stool frequency (25%), and blood in stool (16%) in the last three months (Fig. 3). Out of 123 patients who have ever suffered from bowel urgency, in the last three months 42% stopped working for the day sooner than planned and 41% worked fewer hours. Notably, 76% of patients reported wearing a diaper/pad/protection at least once in the last three months due to fear of urge incontinence. Bowel urgency had no impact on work/school for 22% (n=27) of patients who had ever experienced bowel urgency (Fig. 4). Conclusion Bowel urgency and fear of urge incontinence are the most reported symptoms leading to patients with UC declining participation in work/school, social events, and sports/physical exercise. Over three quarters of the surveyed patients reported wearing diapers/pads/protection in the past three months due to fear of urge incontinence and only 22% of patients who had ever suffered from bowel urgency reported that it had no impact on work or school.

Aims SELECTION (NCT02914522) Maintenance evaluated filgotinib (FIL), a preferential JAK1 inhibitor, as maintenance therapy for patients (pts) with moderately to severely active ulcerative colitis (UC) who achieved clinical remission or Mayo Clinic Score (MCS) response after 10 weeks of FIL 200mg QD, FIL 100mg QD or placebo (PBO) induction. Methods Pts randomized to FIL induction were rerandomized 2:1 to their induction FIL dose or PBO; pts randomized to PBO induction continued PBO maintenance. Steroid tapering was mandatory. The primary endpoint was clinical remission at Week 58. Key secondary endpoints and exploratory endpoints were assessed at Week 58. Results 664 pts were treated in the Maintenance Study (n=93, 270, and 301 from induction with PBO, FIL 100mg and FIL 200mg); efficacy analyses included only FIL induction pts. Baseline demographics and disease characteristics were generally balanced across treatment arms; 40% were biologic experienced. Significantly higher proportion of pts on FIL 200mg or FIL 100mg were in clinical remission vs PBO. Significantly higher proportions of pts achieved key secondary endpoints with FIL 200mg vs PBO. More pts on FIL 200 mg or FIL 100mg achieved an MCS response and endoscopic improvement vs PBO. Incidences of adverse events (AEs), serious AEs and discontinuations due to AEs were similar across arms. Serious infection ( Conclusions FIL 200mg and FIL 100mg were effective as maintenance treatment for pts with moderately to severely active UC who had achieved clinical response to FIL induction treatment. FIL 200 mg met all key secondary endpoints including endoscopic, histologic and 6-month corticosteroid-free remission. FIL was well tolerated in pts with moderate to severely active UC. Funding Agencies None

Disruption of the Heparan sulfate (HS)-biosynthetic gene N-acetylglucosamine N-Deacetylase/N-sulfotransferase 1 (Ndst1) during nervous system development causes malformations that are composites of those caused by mutations of multiple HS binding growth factors and morphogens. However, the role of Ndst function in adult brain physiology is less explored. Therefore, we generated mice bearing a Purkinje-cell-specific deletion in Ndst1 gene function by using Cre/loxP technology under the control of the Purkinje cell protein 2 (Pcp2/L7) promotor, which results in HS undersulfation. We observed that mutant mice did not show overt changes in the density or organization of Purkinje cells in the adult cerebellum, and behavioral tests also demonstrated normal cerebellar function. This suggested that postnatal Purkinje cell development and homeostasis are independent of Ndst1 function, or that impaired HS sulfation upon deletion of Ndst1 function may be compensated for by other Purkinje cell-expressed Ndst isoforms. To test the latter possibility, we additionally deleted the second Purkinje-cell expressed Ndst family member, Ndst2. This selectively abolished reproductive capacity of compound mutant female, but not male, mice, suggesting that ovulation, gestation, or female reproductive behavior specifically depends on Ndst-dependent HS sulfation in cells types that express Cre under Pcp2/L7 promotor control.