Manuscript Doi: 10.1093/ecco-jcc/jjab070 Effectiveness and safety of ustekinumab in ulcerative colitis: Real-world evidence from the ENEIDA registry María Chaparro1 M.D., Ph.D., Ana Garre1 Sc., Marisa Iborra2 M.D., Ph.D., Mónica Sierra 3, Manuel Barreiro-de Acosta4 M.D., Ph.D., Agnés Fernández-Clotet5 M.D., Luisa de Castro6 M.D., Ph.D., Maia Boscá-Watts7 M.D., María José Casanova1 M.D., Ph.D., Alicia López- García8 M.D., Rufo Lorente9 M.D., Cristina Rodríguez10 M.D., Ana Y Carbajo11 M.D., Maria Teresa Arroyo12 M.D., Ph.D., Ana Gutiérrez13 M.D., Ph.D., Joaquín Hinojosa14, Teresa t Martínez-Pérez15 M.D., Albert Villoria16 M.D., Fernando Bermejo17 M.D., Ph.D., David ip Busquets18 M.D., Blau Camps19 M.D., Fiorella Cañete20 M.D., Noemí Manceñido21 M.D., Ph.D., David Monfort22 M.D., Mercè Navarro-Llavat23 M.D., José Lázaro Pérez-Calle24 M.D., cr Laura Ramos25 M.D., Montserrat Rivero26 M.D., Ph.D., Teresa Angueira27 M.D., Patricia Camo28 M.D., Daniel Carpio29 M.D., Irene García-de-la-Filia30 M.D., Carlos González- us Muñoza31 M.D., Luis Hernández32 M.D., José M. Huguet33 M.D., Víctor J Morales34 M.D., Beatriz Sicilia35 M.D., Ph.D., Pablo Vega36 M.D., Isabel Vera37 M.D., Ph.D., Yamile Zabana38 an M.D., Ph.D., Pilar Nos2 M.D., Ph.D., Patricia Suárez Álvarez3 M.D., Cristina Calviño-Suarez4 M.D., Elena Ricart5 M.D., Ph.D., Vicent Hernández6 M.D., Ph.D., Miguel Mínguez7 M.D., M Lucía Márquez8 M.D., Daniel Hervías Cruz9 M.D., Saioa Rubio Iturria10 M.D., Jesús Barrio11, M.D., Carla Gargayo-Puyuelo12 M.D., Rubén Francés39 M.D., Ph.D., Esther Hinojosa14 Sc., María del Moral15 M.D., Xavier Calvet16 M.D, Ph.D., Alicia Algaba17 PhD, Xavier Aldeguer18 d M.D, Ph.D., Jordi Guardiola19 M.D, Ph.D., Miriam Mañosa20 M.D., Ph.D., Ramón Pajares21 e M.D., Marta Piqueras22 M.D., Orlando García-Bosch23,M.D., Pilar Lopez Serrano24 M.D., pt Ph.D., Beatriz Castro26 M.D., Alfredo J Lucendo27 M.D., Ph.D., Miguel Montoro28 M.D, Ph.D., Elena Castro Ortiz29 M.D., Francisco Mesonero30 M.D., Esther García-Planella31 M.D, Ph.D., ce David A. Fuentes32 M.D., Inmaculada Bort33 M.D., Pedro Delgado-Guillena34 MD., Lara Arias35 M.D., Agueda Iglesias36 Study nurse, Marta Calvo37 M.D., Maria Esteve38 M.D., Ph.D., Eugeni Domènech20 M.D., Ph.D. and Javier P. Gisbert1 M.D., Ph.D. Ac © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com Manuscript Doi: 10.1093/ecco-jcc/jjab070 Gastroenterology Departments of: Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid. Spain; 2Hospital Universitario y Politécnico La Fe and CIBERehd, Valencia, Spain; 3 Complejo Asistencial Universitario de León, León, Spain; 4Hospital Clínico Universitario de Santiago, Santiago de Compostela, Spain; 5Hospital Clìnic i Provincial and CIBERehd, IDIBAPS, Barcelona, Spain; 6Xerencia Xestion Integrada de Vigo, SERGAS. Vigo. Research Group in Digestive Diseases, Galicia Sur Health Research Institute (IIS Galicia Sur). SERGAS-UVIGO. Spain; 7Hospital Clinico de Valencia. Universitat de València, Valencia, t Spain; 8Hospital del Mar and Institut Hospital del Mar d’Investigacions Mèdiques, Barcelona, ip Spain; 9Hospital General Universitario de Ciudad Real, Ciudad Real, Spain; 10 Complejo cr 11 Hospitalario de Navarra, Navarra, Spain; Hospital Universitario Río Hortega. Gerencia 12 Regional de Salud de Castilla y León (SACYL). Valladolid, Spain; HCU Lozano Blesa, IIS us 13 Aragón and CIBERehd, Zaragoza, Spain; Hospital General Universitario de Alicante and 14 15 CIBERehd, IIS ISABIAL Alicante, Spain; Hospital de Manises, Valencia, Spain; Hospital 16 an Virgen de la Luz, Cuenca, Spain; Hospital Parc Taulí, Sabadell. Depàrtament de Medicina. 17 Universitat Autònoma de Barcelona and CIBERehd, Spain; Hospital Universitario Fuenlabrada and Instituto de Investigación Sanitaria del Hospital La Paz (IdiPAZ), Madrid, M 18 19 Spain; Hospital Universitario de Girona Dr. Josep Trueta, Girona, Spain; Hospital 20 Universitario de Bellvitge, Barcelona, Spain; Hospital Universitari Germans Trials i Pujol 21 d and CIBERehd, Badalona, Spain; Hospital Infanta Sofía, San Sebastián de los Reyes, 22 23 Spain; Consorci Sanitari de Terrassa, Terrassa, Spain; Hospital de Sant Joan Despí e 24 Moisès Broggi, Barcelona, Spain; Hospital Universitario Fundación Alcorcón, Madrid, pt 25 26 Spain; Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain; Hospital 27 Universitario Marqués de Valdecilla and IDIVAL, Santander, Spain; Hospital General de ce 28 Tomelloso and CIBERehd, Ciudad Real, Spain; Hospital General San Jorge, Huesca, 29 30 Spain; Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain; Hospital Ac 31 Universitario Ramon y Cajal, Madrid, Spain; Hospital de la Santa Creu i Sant Pau, 32 33 Barcelona, Spain; Hospital Santos Reyes, Burgos, Spain; Hospital General Universitario 34 35 de Valencia, Valencia, Spain; Hospital General de Granollers, Barcelona, Spain; Hospital 36 Universitario de Burgos, Burgos, Spain; Complejo Hospitalario Universitario de Ourense, 37 Ourense, Spain; Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; 38 39 Hospital Universitario Mútua Terrassa and CIBERehd, Terrassa, Spain; Hepatic and intestinal Immunobiology group Clinical Medicina, Department Miguel Hernández University, IIS ISABIAL, Hospital General Universitario de Alicante and CIBERehd, Alicante, Spain. 2 Manuscript Doi: 10.1093/ecco-jcc/jjab070 ABBREVIATIONS: Ulcerative colitis (UC), Crohn’s disease (CD), Partial Mayo Score (PMS), C-reactive protein (CRP), standard deviation (SD), interquartile range (IQR), Odds ratio (OR). AUTHOR CONTRIBUTIONS María Chaparro and Javier P. Gisbert: Study design, data collection, data analysis, data interpretation, writing the manuscript. t Ana Garre: Data monitoring. ip Rest of Patient inclusion. cr All authors approved the final version of the manuscript. us María Chaparro and Javier P. Gisbert are the guarantors of the article. an DATA AVAILABILITY: The data underlying this article will be shared on reasonable request to the corresponding autor. M FUNDING: The ENEIDA registry of GETECCU is supported by Biogen, Janssen, Takeda and Pfizer. e d CORRESPONDENCE pt María Chaparro, M.D., Ph.D. ce Inflammatory Bowel Disease Unit Ac Department of Gastroenterology Hospital Universitario de La Princesa Diego de León, 62. 28006 Madrid, Spain Tel.: 34-913093911; Fax: 34-915204013 e-mail: mariachs2005@gmail.com 3 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Conflict of interest Dra. María Chaparro has served as a speaker, as consultant or has received research or education funding from MSD, Abbvie, Hospira, Pfizer, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Biogen and Gilead. Dr M. Barreiro-de Acosta has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, t Takeda, Gillead, Pfizer, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, ip Chiesi, Gebro Pharma, Adacyte and Vifor Pharma. cr us Dra María José Casanova has received research or education funding from Pfizer, Takeda, Shire Pharmaceuticals, Janssen, MSD, Ferring, Biogen and Abbvie. an Fiorella Cañete has served as a speaker, or has received research or education funding or M advisory fees from Takeda, Janssen, MSD, Pfizer, and Ferring. d Jesús Barrio has served as a speaker, as consultant or has received research or education e funding from MSD, Abbvie, Takeda, Janssen and Ferring. pt ce Vicent Hernandez has served as speaker, has received travel support or research funding from MSD, AbbVie, Ferring, FAES Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Ac Pharma, Otsuka Pharmaceutical, Pfizer, Takeda, Jansen, KernPharma Biologics, Gebro Pharma, Adacyte, Sandoz, and Fresenius-Kabi. Elena Ricart has served as a speaker, or has received research or education funding or advisory fees MSD, Abbvie, Takeda, Ferring, Pfizer, Janssen, Fresenius Kabi. 4 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Míriam Mañosa has served as a speaker, or has received research or education funding or advisory fees from FAES, Ferring MSD, AbbVie, Takeda, Pfizer and Janssen. Montserrat Rivero has served as a speaker, a consultant and advisory member for Merck Sharp and Dohme, Abbvie, Pfizer and Janssen. Eugeni Domènech has served as a speaker and has received research and educational t ip funding and advisory fees from MSD, AbbVie, Takeda, Kern Pharma, Pfizer, Janssen, Celgene, Adacyte Therapeutics, Otsuka Pharmaceuticals, Ferring, Shire Pharmaceuticals, cr Tillots, Thermofisher, Grifols, and Gebro. us Dr. Javier P. Gisbert has served as a speaker, a consultant and advisory member for or has an received research funding from MSD, Abbvie, Pfizer, Kern Pharma, Biogen, Mylan, Takeda, Janssen, Roche, Sandoz, Celgene, Gilead, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, M and Vifor Pharma. e d pt ce Ac 5 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Abstract Background: The development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice. Aims: To evaluate the durability, effectiveness and safety of ustekinumab in UC in real-life. t Methods: Patients included in the prospectively maintained ENEIDA registry who received ip at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS. Short- cr term response was assessed at week 16. us Results: A total of 95 patients were included. At week 16, 53% of patients had response an (including 35% of patients in remission). In the multivariate analysis, elevated serum C- reactive protein was the only variable significantly associated with lower likelihood of M achieving remission. Remission was achieved in 39% and 33% of patients at weeks 24 and 52, respectively. Thirty-six percent of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab d treatment was 87% at week 16, 63% at week 56, and 59% at week 72; primary failure was e the main reason for ustekinumab discontinuation. No variable was associated with risk of pt discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. ce Ac Conclusions: Ustekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab. KEYWORDS: ustekinumab, ulcerative colitis, response, remission, durability, real-world evidence. 6 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Introduction The UNIFI trial has demonstrated the superiority of ustekinumab over placebo in inducing and maintaining remission in patients with active ulcerative colitis (UC), not only in naïve patients but also in those who failed previous biological agents with a good safety profile1. These promising results should be confirmed in clinical practice, where the experience with ustekinumab in clinical practice, in terms of both effectiveness and safety, is still limited2,3. t ip We performed the present study aiming to evaluate the durability of ustekinumab cr treatment in UC patients in clinical practice. Our secondary aims were to assess the short- us term response (at week 16) and the long-term effectiveness (at maximum follow-up), to identify predictive factors of response, to describe the schedules of ustekinumab an administration in UC in real-life and the need for dose adjustments, and finally, to assess the safety of ustekinumab in clinical practice. M Case report d Methods e pt Study design ce This was an observational multicentre study carried out with data from ENEIDA project 4. Patients 18 years of age or older, who received at least one intravenous dose of Ac ustekinumab at least 16 weeks before data analysis due to active UC [Partial Mayo Score (PMS)>2] were included. Patients who received ustekinumab for an indication other than UC while in remission or with a previous colonic resection were excluded. Patients were followed-up until last ustekinumab administration or last visit, whichever came first. Data were remotely monitored to assess data quality. ENEIDA project was approved by Research Ethic Committees in all participating centres. Written informed consent to be enrolled in ENEIDA registry was obtained from all patients. 7 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Variables collected and definitions used in the study are described in Supplemental material (Annex 1 and 2). Evaluation of effectiveness The assessment of ustekinumab effectiveness was based on the PMS. For the short-term efficacy analysis, the proportion of patients achieving remission or response after the t ip induction (week 16) was calculated. In the long-term, the proportion of patients in remission cr and steroid-free remission at weeks 24 and 52 were calculated. Patients who discontinued ustekinumab owing to lack of therapeutic effect, an adverse event or worsening of UC before us their last visit were considered as not having achieved the endpoint (remission or response) at subsequent time points, and therefore, they were considered failures. Dose adjustment an was considered to be part of the treatment regimen (i.e., not included in treatment failure M rules) unless otherwise indicated for dichotomous endpoints (remission vs. no remission at a certain time point). e d pt Statistical analysis ce The statistical analysis is described in Annex 3 in Supplementary Material. Results Ac Patient characteristics A total of 95 patients were included, with a median time of exposure to ustekinumab of 31 weeks (IQR=18-59 weeks). The main characteristics of the study population are summarised in table 1. 8 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Short-term effectiveness After the induction (week 16), 33 patients (35%) reached clinical remission and 50 (53%) reached clinical response (including patients with response) (Figure 1). The schedule for the induction varied widely between patients. All of them received a first intravenous dose of approximately 6 mg/kg. Ninety-one patients received a second dose of ustekinumab while 4 interrupted the treatment before administration of the second dose; 51 t ip of them (56%) received the second dose between weeks 6 and 10, 8 (9%) before week 6, 21 patients (23%) at week 11, 5 (5%) at week 12 and 6 (6%) after week 12. cr Eighty-four patients received a third dose of ustekinumab. In most of the cases (80%) us administration was between weeks 16 and 20. Fourteen patients (17%) received the third dose before week 16, and 3 patients (3.5%) after week 20. an At baseline, the proportion of patients with elevated CRP (above the normal range limit) M and the proportion of patients with severe endoscopic activity were significantly lower in patients who achieved remission at week 16 than in those who did not achieve remission, d (52% vs. 75% p<0.05) and (50 vs. 74%, p<0.05), respectively (table 2). In the multivariate e analysis, CRP above the normal range limit at baseline was the only variable associated with pt lower probability of achieving remission at week 16 [odds ratio (OR)=0.3, 95%CI=0.1-0.7]. ce Ac Ustekinumab durability A total of 34 patients (36%) discontinued ustekinumab over time; median time of exposure to ustekinumab was 31 weeks (IQR=18-59). The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72 (Figure 2). The reasons for ustekinumab discontinuation were: primary non-response in 21 patients (22%), loss of response in 12 patients (13%) and adverse event in 1 patient (1%). Neither 9 Manuscript Doi: 10.1093/ecco-jcc/jjab070 the univariate nor the multivariate analysis found any variable associated with ustekinumab discontinuation. Fifty-three patients were under steroids at baseline, and 35 (66%) were able to stop them. Long-term effectiveness and dose adjustments Of 83 patients who started ustekinumab at least 24 weeks before data analysis, 32 (39%) t ip were in remission at week 24, and 25 (30%) in steroid-free remission. Fifty-four patients cr started ustekinumab at least 52 weeks before data analysis; at week 52, 18 (33%) of them were in remission, and 17 (32%) in steroid-free remission (Figure 3). us Eighty-one patients started the maintenance phase (at week 16). Thirty patients were in an remission at that moment. Three patients (10%) started the maintenance phase with every- 12-week schedule, 24 patients (80%) with every-8-weeks schedule, and 3 (10%) with M intensified schedule (every-6-weeks or every-4-weeks). Two patients had to interrupt the treatment due to loss of response and one patient due to clinician’s choice during follow-up. d Ten patients relapsed during follow-up: 4 intensified the dose (2 reached remission again), 2 e interrupted the treatment, and in 4 the change in treatment was unknown. pt On the other hand, 51 patients started the maintenance phase despite having active ce disease at week 16. Three patients (6%) started with every-12-weeks schedule, 36 (71%) with every-8-weeks, and 12 (23%) with intensified schedule. Of those patients who were not Ac in remission at week 16, 21 (41%) ended-up stopping the treatment during follow-up, 13 (25%) maintained the treatment during follow-up despite never reaching remission, and 17 (34%) reached remission later on during follow-up. A total of 66 patients started the maintenance phase with the standard dose (either every- 12-weeks or every-8-weeks schedule); of them, 18 patients intensified the treatment 10 (55%) due to primary failure, 3 (17%) due to partial response and 5 (28%) due to loss of 10 Manuscript Doi: 10.1093/ecco-jcc/jjab070 response. One among 10 patients with primary failure and 2 among 5 patients with loss of response achieved remission after dose intensification. None of the 3 patients who intensified the dose due to partial response reached remission. Finally, 1 patient escalated the dose from every-12-weeks to every-8-weeks due to loss of response and reached remission after dose optimization. A total of 9 patients (9.5%) needed to undergo colectomy due to ustekinumab failure. t Median time from ustekinumab start to surgery was 14 weeks (IQR=7.5-18). ip cr Adverse events us Three adverse events were reported in our cohort. A patient developed dry skin and an itching probably related with ustekinumab. The symptoms were mild and did not lead to treatment discontinuation. Another patient had pneumonia probably not related to M ustekinumab treatment which did not cause treatment discontinuation. Finally, a 54-year-old male with extensive UC and no comorbidities, who had been exposed to ustekinumab for 43 d weeks, developed severe SARS-Cov-2 pneumonia and died. At the time of infection, the e patient had been treated with ustekinumab 90 mg every-6-weeks for 43 weeks without pt steroids or immunomodulators, after previously failing infliximab, adalimumab, golimumab, ce vedolizumab and tofacitinib. Discussion Ac To our knowledge this is the largest study to date providing real-life evidence on the long- term benefit of ustekinumab treatment in UC patients. In our cohort, one-third of patients were able to achieve remission after the induction (week 16), despite being highly refractory patients (80% had failed both anti-TNF agents and vedolizumab, and 30% anti-TNF agents, vedolizumab and tofacitinib). In addition, one third of patients achieved steroid-free remission during follow-up (week 24 and week 52). 11 Manuscript Doi: 10.1093/ecco-jcc/jjab070 To date, only one previous real-life study has assessed the short-term effectiveness of ustekinumab in UC patients2. In this study, at weeks 12-16, 39.8% of patients had clinical remission. This figure is quite similar to ours: 34.7% of patients were in remission at week 16. We found that CRP serum concentration over the normal range upper limit was the only factor significantly associated with lower probability of achieving remission. Similarly, Amiot t et al observed that patients with PMS>6 had significantly lower chance of achieving ip remission in the short-term2. Those findings suggest that the inflammatory burden has a cr significant impact on ustekinumab effectiveness during the induction in UC patients. Other factors, such as concomitant treatment with immunomodulators or the number of previous us biologics do not seem to have an impact on treatment response. an The long-term effectiveness of ustekinumab in UC in real life has hardly been studied. Ochsekühn et al. published a retrospective series of 19 UC patients treated with M ustekinumab3. The main aim was to know the proportion of patients in clinical remission at one year; 53% of patients (10/19) had clinical remission after 12 months of treatment. e d Our study provides some relevant findings on the long-term real-life effectiveness of pt ustekinumab treatment in UC. With respect to drug survival, we observed that the proportion of patients maintained under ustekinumab treatment was over 60% at 12 months, being ce primary failure the main reason for ustekinumab discontinuation. These results are similar to Ac those reported for other drugs in particularly refractory patient populations5–7. We acknowledge that ustekinumab might have been maintained in some patients, despite not reaching clinical remission, as the last medical option to avoid surgery. However, ustekinumab might have exerted some effect even in those patients avoiding colectomy (less than 10% of our patients ended-up undergoing surgery). Approximately one-third of patients who were in remission at week 16 in our cohort, relapsed during follow-up (median time of exposure to ustekinumab was 31 weeks). Dose 12 Manuscript Doi: 10.1093/ecco-jcc/jjab070 was optimized in 4 patients, and 2 of them regained remission. Ustekinumab dose intensification seems to be useful to regain remission in CD patients8,9; however, data in UC patients are lacking. The role of dose intensification in UC patients losing response to ustekinumab needs to be further studied. Finally, the potential role of concomitant therapy with immunomodulators is of great interest to optimize the treatment in clinical practice. Evidence from CD studies supports that t combo treatment with thiopurines does not increase either the short or the long-term ip effectiveness of ustekinumab10. In our cohort, combo treatment was not associated either cr with the probability of achieving short-term remission or with the durability of ustekinumab treatment in the long-term. us With respect to the safety profile, our results are consistent with those previously reported an for ustekinumab11. M In conclusion, ustekinumab is effective in inducing remission in up to one-third of UC patients, even in a highly refractory population. Patients with higher inflammatory burden are d less likely to achieve short-term remission. Over 60% of patients maintained ustekinumab e treatment at 12 months, suggesting that it also provides benefit in the long-term. The safety pt profile is similar to the previously described for ustekinumab. ce Ac 13 Manuscript Doi: 10.1093/ecco-jcc/jjab070 REFERENCES 1. Sands BE., Sandborn WJ., Panaccione R., O’Brien CD., Zhang H., Johanns J., et al. Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med 2019. Doi: 10.1056/nejmoa1900750. 2. Amiot A., Filippi J., Abitbol V., Cadiot G., Laharie D., Serrero M., et al. Effectiveness t and safety of ustekinumab induction therapy for 103 patients with ulcerative colitis: a ip GETAID multicentre real-world cohort study. Aliment Pharmacol Ther 2020. Doi: cr 10.1111/apt.15717. us 3. Ochsenkühn T., Tillack C., Szokodi D., Janelidze S., Schnitzler F. Clinical outcomes with ustekinumab as rescue treatment in therapy-refractory or therapy-intolerant an ulcerative colitis. United Eur Gastroenterol J 2020. Doi: 10.1177/2050640619895361. M 4. Zabana Y., Panés J., Nos P., Gomollón F., Esteve M., García-Sánchez V., et al. The ENEIDA registry (Nationwide study on genetic and environmental determinants of d inflammatory bowel disease) by GETECCU: Design, monitoring and functions. e Gastroenterol Hepatol 2020. Doi: 10.1016/j.gastrohep.2020.05.007. pt 5. Chaparro M., Garre A., Mesonero F., Rodríguez C., Barreiro-de Acosta M., Martínez- ce Cadilla J., et al. Tofacitinib in Ulcerative Colitis: Real-world Evidence From the ENEIDA Registry. J Crohns Colitis 2020. Doi: 10.1093/ecco-jcc/jjaa145. Ac 6. Chaparro M., Garre A., Ricart E., Iborra M., Mesonero F., Vera I., et al. Short and long-term effectiveness and safety of vedolizumab in inflammatory bowel disease: results from the ENEIDA registry. Aliment Pharmacol Ther 2018;48(8):839–51. Doi: 10.1111/apt.14930. 7. Gisbert JP., Chaparro M. Use of a third anti-TNF after failure of two previous anti- TNFs in patients with inflammatory bowel disease: is it worth it? Scand J 14 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Gastroenterol 2015;50(4):379–86. Doi: 10.3109/00365521.2014.928901. 8. Fumery M., Peyrin-Biroulet L., Nancey S., Altwegg R., Gilletta C., Veyrard P., et al. Effectiveness and Safety of Ustekinumab Intensification at 90 mg Every 4 Weeks in Crohn’s Disease: A Multicentre Study. J Crohn’s Colitis 2020. Doi: 10.1093/ecco- jcc/jjaa177. 9. Kopylov U., Hanzel J., Liefferinckx C., De Marco D., Imperatore N., Plevris N., et al. t Effectiveness of ustekinumab dose escalation in Crohn’s disease patients with ip insufficient response to standard-dose subcutaneous maintenance therapy. Aliment cr Pharmacol Ther 2020;52(1):135–42. Doi: 10.1111/apt.15784. 10. us Yzet C., Diouf M., Singh S., Brazier F., Turpin J., Nguyen-Khac E., et al. No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor an Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta- M Analysis. Clin Gastroenterol Hepatol 2020. Doi: 10.1016/j.cgh.2020.06.071. 11. Sandborn WJ., Feagan BG., Danese S., O’Brien CD., Ott E., Marano C., et al. Safety d of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results e from Phase 2/3 Studies. Inflamm Bowel Dis 2020. Doi: 10.1093/ibd/izaa236. pt ce Ac 15 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Table 1. Characteristics of the study population. Characteristics Mean age (SD) (years) 47 (16) Median time of follow-up (IQR) (weeks) 82 (41- 153) Female gender, n (%) 53 t (56) ip UC extent cr Extensive colitis, n (%) 55 (58) us Left-sided colitis, n (%) 37 Proctitis, n (%) (39) an 3 (3) Extraintestinal manifestations, n (%) 27 M (28) Smokers, n (%) 4 (4) d Family history, n (%) 7 (8) e Median partial Mayo score at baseline (IQR) 6 (4- pt 8) Endoscopic assessment at baseline, n (%) 68 ce (72) Mild, n (%) 3 (4) Ac Moderate, n (%) 20 (30) Severe, n (%) 45 (66) Baseline CRP over the upper limit of normal range, n (%) 61 (64) Anaemia at baseline, n (%) 38 (40) 16 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Median faecal calprotectin at baseline (IQR) (g/g) 1,56 4 (795- 2,99 8) Prior biological treatment or tofacitinib, n (%) 95 (100) Anti-TNF, n (%) 93 Vedolizumab, n (%) (98) Tofacitinib, n (%) t 78 ip Anti-TNF and vedolizumab, n (%) (82) 28 cr Anti-TNF, vedolizumab and tofacitinib, n (%) (30) us 76 (80) 27 an (28) Prior number of biological agents M 1-2 previous biologics, n (%) 40 (42) d 3 previous biologics, n (%) 55 (58) e Concomitant immunosuppresants, n (%) 16 pt (17) ce Steroids during induction, n (%) 53 (56) Ac Ulcerative colitis, UC; standard deviation, SD: interquartile range, IQR; C-reactive protein, CRP; tumour necrosis factor, TNF. 17 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Table 2. Distribution of different variables according to achievement of remission at week 16. Variable No Remis p remiss sion ion t N=33 ip N=62 Mean age (years) (SD) 46.5 47 (3) n.s. cr (2) us Female gender, n (%) 34 (55) 19 n.s. (59.4) Extensive colitis, n (%) 32 (52) 22 (69) n.s. an Extraintestinal manifestations, n (%) 17 (27) 10 (30) n.s. M Smokers, n (%) 1 (1.7) 3 (10) n.s. Family history, n (%) 4 (6.9) 3 (10.7) n.s. d Median partial Mayo score at baseline (months) (IQR) 6 (5-8) 6 (3-6) n.s. e Endoscopic assessment at baseline, n (%) 46 (74) 22 (67) pt Mild, n (%) 0 (0) 3 (14) Moderate, n (%) 12 (26) 8 (36) <0. ce 05 Severe (%) 34 (74) 11 (50) Ac Baseline CRP over the upper limit of normal range, n (%) 45 (79) 16 (52) <0. 05 Anaemia at baseline, n (%) 25 (42) 13 (43) n.s. Median faecal calprotectin at baseline (g/g) 1,625 1,281 n.s. Prior biological treatment or tofacitinib Anti-TNF, n (%) 61 (98) 32 (97) n.s. Vedolizumab, n (%) 53 (86) 25 (76) n.s. 18 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Tofacitinib, n (%) 19 (31) 9 (27) n.s. Median prior number of biologic agents (IQR) 3 (2-3) 2 (2-3) n.s. Concomitant immunosuppresants, n (%) 11 (18) 5 (15) n.s. Steroids during induction, n (%) 36 (58) 17 (52) n.s. t Standard deviation, SD: interquartile range, IQR; C-reactive protein, CRP; tumour necrosis ip factor, TNF. cr us an M e d pt ce Ac 19 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Figure 1. Effectiveness of ustekinumab for the induction of clinical remission in ulcerative colitis (week 16). 100 75 t ip 53% Proportion of patients (%) 50 cr 35% us 25 50/95 33/95 an 0 Response Clinical response (including remission) Remission Clinical remission M e d pt ce Ac 20 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Figure 2. Survival curve of the durability of ustekinumab treatment in patients with ulcerative colitis. Proportion of patients (%) t ip cr us an M e d pt ce Ac 21 Manuscript Doi: 10.1093/ecco-jcc/jjab070 Figure 3. Proportion of ulcerative colitis patients under ustekinumab treatment with clinical remission and steroid-free clinical remission at weeks 24 and 52. 100 Proportion of patients (%) 75 t ip cr 50 39% us 33% 32% 30% 25 32/84 an 25/84 18/54 17/54 M 0 Week 24 Week 52 e d pt Clinical remission Steroid-free clinical remission ce Ac 22