Inflammatory Bowel Diseases, 2022, 28, 1725–1736 https://doi.org/10.1093/ibd/izab357 Advance access publication 15 February 2022 Original Research Articles - Clinical Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study María Chaparro, MD, PhD,∗, Iria Baston-Rey, MD,† Estela Fernández-Salgado, MD,‡ Javier González García, MD,§ Laura Ramos, MD,¶ María Teresa Diz-Lois Palomares, MD, PhD,‖ Federico Argüelles-Arias, MD, PhD,∗∗, Eva Iglesias Flores, MD,†† Mercedes Cabello, MD, PhD,‡‡ Saioa Rubio Iturria, MD,§§ Andrea Núñez Ortiz, MD,¶¶ Mara Charro, MD,‖‖ Daniel Ginard, MD,∗∗∗ Carmen Dueñas Sadornil, MD,††† Olga Merino Ochoa, MD,‡‡‡ David Busquets, MD,§§§, Eduardo Iyo, MD,¶¶¶ Ana Gutiérrez Casbas, MD, PhD,‖‖‖, Patricia Ramírez de la Piscina, MD,∗∗∗∗ Marta Maia Boscá-Watts, MD, PhD,†††† Maite Arroyo, MD, PhD,‡‡‡‡ María José García, MD,§§§§ Esther Hinojosa, MD,¶¶¶¶ Jordi Gordillo, MD, PhD,‖‖‖‖ Pilar Martínez Montiel, MD, PhD,∗∗∗∗∗ Benito Velayos Jiménez, MD,††††† Cristina Quílez Ivorra, MD,‡‡‡‡‡ Juan María Vázquez Morón, MD, PhD,§§§§§ José María Huguet, MD,¶¶¶¶¶ Yago González-Lama, MD, PhD,‖‖‖‖‖ Ana Isabel Muñagorri Santos, MD,∗∗∗∗∗∗ Víctor Manuel Amo, MD,†††††† María Dolores Martín-Arranz, MD,‡‡‡‡‡‡ Fernando Bermejo, MD, PhD,§§§§§§, Jesús Martínez Cadilla, MD,¶¶¶¶¶¶ Cristina Rubín de Célix, MD,∗ Paola Fradejas Salazar, MD,‖‖‖‖‖‖ Antonio López San Román, MD,∗∗∗∗∗∗∗ Nuria Jiménez, MD,††††††† Santiago García López, MD,‡‡‡‡‡‡‡ Anna Figuerola, MD,§§§§§§§ Itxaso Jiménez, MD,¶¶¶¶¶¶¶ Francisco José Martínez Cerezo, MD,‖‖‖‖‖‖‖ Carlos Taxonera, MD,∗∗∗∗∗∗∗∗, Pilar Varela, MD,†††††††† Ruth de Francisco, MD,‡‡‡‡‡‡‡‡ David Monfort, MD,§§§§§§§§ Gema Molina Arriero, MD,¶¶¶¶¶¶¶¶ Alejandro Hernández Camba, PhD,‖‖‖‖‖‖‖‖ Francisco Javier García-Alonso, MD, PhD,∗∗∗∗∗∗∗∗∗, Manuel Van Domselaar, MD,††††††††† Ramón Pajares Villarroya, MD,‡‡‡‡‡‡‡‡‡ Alejandro Núñez, PhD,§§§§§§§§§ Francisco Rodríguez Moranta, MD, PhD,¶¶¶¶¶¶¶¶¶ Ignacio Marín-Jiménez, MD, PhD,‖‖‖‖‖‖‖‖‖ Virginia Robles Alonso, MD, PhD,∗∗∗∗∗∗∗∗∗∗ María del Mar Martín Rodríguez, MD,†††††††††† Patricia Camo-Monterde, MD,‡‡‡‡‡‡‡‡‡‡ Iván García Tercero, MD,§§§§§§§§§§ Mercedes Navarro Llavat, MD,¶¶¶¶¶¶¶¶¶¶ Lara Arias García, MD,‖‖‖‖‖‖‖‖‖‖ Daniel Hervías Cruz, MD,∗∗∗∗∗∗∗∗∗∗∗ Sara Sulleiro, MSc,††††††††††† Cynthia Novella, MD,††††††††††† Eugenia Vispo, MD,††††††††††† Manuel Barreiro-de Acosta, MD, PhD,†,# and Javier P. Gisbert, MD, PhD∗,#, From the ∗Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain † Gastroenterology Department, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain ‡ Gastroenterology Department, Complejo Hospitalario de Pontevedra, Pontevedra, Spain § Gastroenterology Department, Hospital Público Comarcal la Inmaculada, Almería, Spain ¶ Gastroenterology Department, Hospital Universitario de Canarias, Tenerife, Spain ‖ Gastroenterology Department, Hospital Universitario A Coruña, A Coruña, Spain ∗∗ Gastroenterology Department, Hospital Universitario Virgen Macarena, Facultad de Medicina, Universidad de Sevilla, Seville, Spain †† Gastroenterology Department, Hospital Universitario Reina Sofía, Universidad de Córdoba, Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain ‡‡ Gastroenterology Department, Hospital Universitario Virgen de Valme, Seville, Spain §§ Gastroenterology Department, Complejo Hospitalario de Navarra, Pamplona, Spain ¶¶ Gastroenterology Department, Hospital Universitario Virgen del Rocío, Seville, Spain Received for publication: September 10, 2021. Editorial Decision: December 20, 2021 © 2022 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 1726 Chaparro et al ‖‖ Gastroenterology Department, Hospital de Barbastro, Barbastro, Spain ∗∗∗ Gastroenterology Department, Hospital Universitario Son Espases, Palma, Spain ††† Gastroenterology Department, Hospital San Pedro de Alcántara, Cáceres, Spain ‡‡‡ Gastroenterology Department, Hospital Universitario Cruces, Barakaldo, Spain §§§ Gastroenterology Department, Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain ¶¶¶ Gastroenterology Department, Hospital Comarcal de Inca, Inca, Spain ‖‖‖ Gastroenterology Department, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante, Alicante, Spain and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain ∗∗∗∗ Gastroenterology Department, Hospital Universitario de Araba-Txagorritxu, Araba-Txagorritxu, Spain †††† Gastroenterology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain ‡‡‡‡ Gastroenterology Department, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain §§§§ Gastroenterology Department, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitario Valdecilla (IDIVAL), Santander, Spain ¶¶¶¶ Gastroenterology Department, Hospital de Manises, Manises, Spain ‖‖‖‖ Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ∗∗∗∗∗ Gastroenterology Department, Hospital Universitario 12 de Octubre, Madrid, Spain ††††† Gastroenterology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain ‡‡‡‡‡ Gastroenterology Department, Hospital Marina Baixa, Villajoyosa, Spain §§§§§ Gastroenterology Department, Hospital Universitario Juan Ramón Jiménez, Huelva, Spain ¶¶¶¶¶ Gastroenterology Department, Hospital General Universitario de Valencia, Valencia, Spain ‖‖‖‖‖ Gastroenterology Department, Hospital Universitario Puerta de Hierro, Majadahonda, Spain ∗∗∗∗∗∗ Gastroenterology Department, Hospital Universitario de Donostia, Donostia-San Sebastián, Spain †††††† Gastroenterology Department, Hospital Regional de Málaga, Málaga, Spain ‡‡‡‡‡‡ Gastroenterology Department, Hospital Universitario de La Paz, Institute for Health Research La Paz, Universidad Autónoma de Madrid, Madrid, Spain §§§§§§ Gastroenterology Department, Instituto de Investigación Sanitaria del Hospital La Paz, Hospital Universitario de Fuenlabrada, Madrid, Spain ¶¶¶¶¶¶ Gastroenterology Department, Hospital Alvaro Cunqueiro, Vigo, Spain ‖‖‖‖‖‖ Gastroenterology Department, Hospital Virgen de la Concha, Zamora, Spain ∗∗∗∗∗∗∗ Gastroenterology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain ††††††† Gastroenterology Department, Hospital General Universitario de Elche, Elche, Spain ‡‡‡‡‡‡‡ Gastroenterology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain §§§§§§§ Gastroenterology Department, Hospital General Universitario de Castellón, Castellón de la Plana, Spain ¶¶¶¶¶¶¶ Gastroenterology Department, Hospital Universitario de Galdakao-Usansolo, Galdakao, Spain ‖‖‖‖‖‖‖ Gastroenterology Department, Hospital Universitario Sant Joan de Reus, Reus, Spain ∗∗∗∗∗∗∗∗ Gastroenterology Department, Instituto de Investigación del Hospital Clínico San Carlos, Hospital Clínico Universitario San Carlos, Madrid, Spain †††††††† Gastroenterology Department, Hospital Universitario de Cabueñes, Gijón, Spain ‡‡‡‡‡‡‡‡ Gastroenterology Department, Instituto de Investigación Biosanitaria del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Spain §§§§§§§§ Gastroenterology Department, Consorci Sanitari de Terrassa, Terrassa, Spain ¶¶¶¶¶¶¶¶ Gastroenterology Department, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain ‖‖‖‖‖‖‖‖ Gastroenterology Department, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain ∗∗∗∗∗∗∗∗∗ Gastroenterology Department, Hospital Universitario Rio Hortega, Valladolid, Spain ††††††††† Gastroenterology Department, Hospital Universitario de Torrejón, Torrejón de Ardoz, Madrid, Spain ‡‡‡‡‡‡‡‡‡ Gastroenterology Department, Hospital Universitario Infanta Sofía, Madrid, Spain §§§§§§§§§ Gastroenterology Department, Hospital Clínico Universitario de Salamanca, Salamanca, Spain ¶¶¶¶¶¶¶¶¶ Gastroenterology Department, Hospital Universitario Bellvitge, Barcelona, Spain ‖‖‖‖‖‖‖‖‖ Servicio de Aparato Digestivo, IiSGM, Hospital General Universitario Gregorio Marañón, Madrid, Spain and Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain ∗∗∗∗∗∗∗∗∗∗ Gastroenterology Department, Hospital Universitario Vall d´Hebrón, Barcelona, Spain †††††††††† Gastroenterology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain ‡‡‡‡‡‡‡‡‡‡ Gastroenterology Department, Hospital Universitario San Jorge, Huesca, Spain §§§§§§§§§§ Gastroenterology Department, Hospital General Universitario Santa Lucía, Cartagena, Spain ¶¶¶¶¶¶¶¶¶¶ Gastroenterology Department, Hospital de Sant Joan Despí Moisès Broggi, Sant Joan Despí, Spain ‖‖‖‖‖‖‖‖‖‖ Gastroenterology Department, Hospital Universitario de Burgos, Burgos, Spain ∗∗∗∗∗∗∗∗∗∗∗ Gastroenterology Department, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain ††††††††††† Janssen Medical Department, Madrid, Spain # Both authors had equal contribution as senior authors. Address correspondence to: María Chaparro, MD, PhD, Inflammatory Bowel Disease Unit, Department of Gastroenterology, Hospital Universitario de La Princesa, Diego de León, 62 - 28006 Madrid, Spain (mariachs2005@gmail.com). Background: Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn’s disease (CD) patients in real-world clinical practice. Methods: A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study 1727 Results: A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were as- sociated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). Conclusions: Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice. Lay Summary This large retrospective study demonstrated the short- and long-term effectiveness and safety of ustekinumab in patients with Crohn’s disease in real-world clinical practice, including those with refractory disease. Key Words: Crohn’s disease, effectiveness, real-world evidence, safety, ustekinumab Introduction benefit and the safety of ustekinumab during follow-up in clin- Crohn’s disease (CD) is a chronic immune-mediated inflam- ical practice. matory disease affecting the gastrointestinal tract.1-3 It is a relapsing disease characterized by recurrent, destructive pathological inflammation1,3,4 that causes significant mor- Methods bidity and impact on quality of life.5-7 While it is currently Study Design and Patient Population an incurable disease,8 there are a number of treatments that A retrospective, multicenter, noninterventional study was target clinical symptoms, including biologic therapies, such carried out in 61 Spanish hospitals. Patients included were as tumor necrosis factor (TNF) inhibitors, integrin inhibitors, ≥18 years of age, had active CD (Harvey-Bradshaw Index and interleukin (IL)-12/23 inhibitors.9 However, approxi- [HBI] >4), had received ≥1 initial dose of intravenous (IV) mately 30% of patients receiving biologics do not respond ustekinumab ≥6 months prior to the start of the study, and to induction, 30% to 50% eventually have a loss of response were followed up by gastroenterologists in the hospital set- (LoR), and some develop adverse events (AEs).9-12 ting. Patients who had received ustekinumab for a different Ustekinumab is a fully human IgG1κ monoclonal indication, who received subcutaneous (SC) ustekinumab as antibody that binds with specificity to the shared p40 induction therapy, who had been or were involved in clin- protein subunit of human cytokines IL-12 and IL-23.13 ical trials of ustekinumab, who had a stoma (as in these Ustekinumab is used to treat adult patients with moder- patients, the number of daily stools is unknown, and there- ately to severely active CD who have had an inadequate fore disease activity and HBI cannot be calculated), or response, lost response, or are intolerant either to conven- those with CD in remission (HBI ≤4) were excluded. The tional therapy or to a TNF-α inhibitor, or who have med- study was conducted according to the ethical principles of ical contraindications to such therapies.13 The efficacy and the Declaration of Helsinki. The study protocol was ap- safety of induction therapy with ustekinumab in patients proved by the Drug Research Ethics Committee (Comité de with moderately to severely active CD was demonstrated Ética de la Investigación con Medicamentos) at the Hospital in the IM-UNITI trials, in which ustekinumab was shown Universitario de La Princesa in Madrid, Spain, and patients to be effective and safe in the long-term (up to 5 years in gave written or verbal informed consent to participate in the preliminary data).14-16 study. Real-world data are needed to provide supporting evidence for the efficacy and safety observed in randomized clinical Ustekinumab Treatment trials. Some studies have been published evaluating the effi- Eligible patients received SC ustekinumab 90 mg at week 8, cacy of ustekinumab in clinical practice.17-33 The sample size and were then scheduled to receive SC ustekinumab 90 mg at in these studies was small and many of the studies did not in- regular intervals every 8 to 12 weeks (maintenance therapy), vestigate the durability of response (ie, the time from reaching as per the approved dosage in the Summary of Product remission to LoR). LoR to biologic therapies is common in Characteristics (SPC).13 Patients underwent dose optimiza- patients with CD,34-37 and is a significant challenge for phys- tion during maintenance therapy (escalation/intensification icians managing these patients in clinical practice. Hence, it or de-escalation/de-intensification) at the judgment of the is important to gather long-term postmarketing data on the treating physician. durability of response of agents used to treat patients with CD and to confirm the long-term benefit and safety of this Study Outcomes drug in the clinical practice setting. The primary outcome of interest was the ustekinumab re- We therefore designed a nationwide cohort study in patients tention rate from the start of ustekinumab treatment (first with CD treated with ustekinumab in order to systematically ustekinumab dose received by the patient) to the last re- assess its real-world effectiveness and safety. The aim of our corded dose. Secondary outcomes were the retention rate of study was to evaluate the durability of ustekinumab treatment ustekinumab with and without immunosuppressive treatment and reasons for ustekinumab discontinuation in a real-world and according to previous lines of treatment; evaluation of setting. We also aimed to assess the short-term effectiveness the short-term effectiveness at 8 and 16 weeks, and to identify and to identify predictive factors for the short- and long-term predictive factors of remission; evaluation of ustekinumab 1728 Chaparro et al long-term effectiveness; evaluation of prognostic factors [IQR]) were calculated, depending on whether or not they related to the cumulative retention rate of ustekinumab; were normally distributed. proportion of patients who underwent dose escalation or With respect to the retention on ustekinumab treatment, the intensification during the follow-up period and response to Kaplan-Meier method was used, in which patients were cen- dose adjustments; and proportion of patients who under- sored at the time of treatment discontinuation for any reason. went de-escalation or de-intensification of the dose during the Any differences between survival curves were evaluated using follow-up period. To evaluate the tolerability of ustekinumab, the log-rank test. Stepwise multivariate analysis using the Cox safety endpoints, including AEs, serious AEs, and the relation- regression model was used to investigate factors potentially ship of the AEs to ustekinumab were assessed. associated with ustekinumab discontinuation. In the log-rank test and in the multivariate analysis, P values of <.05 were Data Collection considered to be statistically significant. The same method During the study period, there was 1 study visit sched- was used to estimate the incidence of LoR and to identify pre- uled for each patient in which the available clinical prac- dictive factors of LoR. Only patients in remission at week 16 tice data were collected in an electronic case report form. were included in the LoR analysis. Data collected included patient demographics and disease For the short-term effectiveness endpoint, the dependent characteristics, treatment history for CD and reasons for variables were clinical remission and response at week 16; discontinuation, concomitant use of immunomodulators or the nonresponse imputation method was used for missing steroids, and biologic treatments for diseases other than CD. values. In the univariate analysis, categorical variables were Ustekinumab treatment data collected included treatment compared using the chi-square test, and quantitative vari- start date, response to ustekinumab, maintenance dosing ables were compared using the appropriate test. A logistic regimen, treatment after LoR to ustekinumab, ustekinumab regression model was used to evaluate variables associated dose intensification or de-intensification, response after dose with the likelihood of achieving remission after ustekinumab de-intensification, and AEs. Endoscopic evaluation and bio- induction. logic markers (C-reactive protein [CRP] or fecal calprotectin) The primary analysis was conducted using data from all were recorded when available. Patients were followed up patients included in the study. In addition, a subanalysis of until last administration of ustekinumab or last visit, which- patients who received only the approved ustekinumab dosage ever came first. Data were remotely monitored to assess data (SPC subgroup) was performed. quality. Definitions Results Dosing-related definitions Patient Population Dose escalation was defined as a shortening of the adminis- A total of 526 patients were screened for inclusion, and 463 tration interval from every 12 weeks to every 8 weeks; dose patients met the inclusion criteria and were included in the intensification was defined as a shortening of the ustekinumab study population; 293 (63.3%) received the treatment as administration interval to <8 weeks (every 4 or 6 weeks) or per the approved dosage and were considered as the SPC receipt of a reinduction IV dose of ustekinumab. subgroup (Supplementary Tables 1-4 and Supplementary Dose de-escalation was defined as an increase in the Figure 1). Patients were followed up for a median of 15.5 interval between administration of SC ustekinumab 90 mg (IQR, 12.6-18.5) months. from every 8 weeks to every 12 weeks; dose de-intensification Patient demographics and baseline characteristics are sum- was defined as an increase in the ustekinumab administration marized in Table 1. Mean age was 47 years, mean age at diag- interval to less often than every 12 weeks. nosis was 33 years, and approximately 50% of patients were As the present study was retrospective and observational, female. Mean disease duration was 14.1 years, and mean time there was no specific protocol for dose adjustments; therefore, until ustekinumab initiation was 12.6 years. Most patients the indications for dosage adjustments were based on the clin- had ileocolonic or ileal CD, and inflammatory disease was icians’ criteria. the most common disease type at ustekinumab initiation, fol- lowed by stricturing disease. Active perianal disease at base- Response-related definitions line was seen in 14% of patients. Retention rate was defined as the proportion of patients Prior use of biologics was reported by >96% of patients, maintained under ustekinumab treatment at a certain time most commonly adalimumab and infliximab (Table 1). point. Remission was defined as an HBI value of ≤4 and clin- Approximately one-third of patients were receiving concomi- ical response as a decrease in HBI of ≥3 points from baseline. tant immunosuppressants at baseline (Table 1), and approxi- LoR was defined as the reappearance of symptoms along with mately 40% of patients were receiving steroids. At least 1 endoscopic, radiographic, or biochemical evidence (eg, CRP previous abdominal surgery for CD was reported in 47.1% levels ≥5 mg/L, fecal calprotectin levels >150 µg/g), which led of patients. to treatment intensification, dose escalation, addition of other At the time of the first ustekinumab dose, endoscopic drugs, switching to other treatment, or surgery. assessment was available in 174 (37.6%) patients, of whom 128 showed disease activity: 56.3% had moderate Statistical Analysis and 35.2% had severe disease activity. With regard to For categorical variables, percent values and their 95% con- other indicators of disease activity, mean HBI was 8.4, fidence intervals (CIs) were calculated. For continuous vari- mean CRP was 18.3 mg/L, and mean fecal calprotectin ables, the mean ± SD or the median (interquartile range was 892.5 mg/kg. Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study 1729 Table 1. Patient baseline demographics and disease characteristics Table 2. Summary of primary and secondary outcomes (N = 463) Result Demographics Primary outcome  Age, y 47.1 ± 13.4 Ustekinumab retention rate 76.9% (95% CI, 72.8%-  Age at diagnosis, y 33.4 ± 14.5 80.7%)  Female 232 (50.1) Median follow-up: 15.5 mo  Smokers 118 (25.5) Discontinuation incidence 18.4% per patient-year of  Comorbidities 230 (49.7) follow-up Disease characteristics at baseline Predictive factors of discontinuation Previous intestinal sur-  Disease duration, y 14.1 ± 9 gery, concomitant steroid  Time from diagnosis to UST initiation, y 12.6 ± 9 ­treatment  Age at UST initiation, y 45.6 ± 13.4 Secondary outcomes  Extraintestinal manifestations 181 (39.1) Short-term effectiveness  CD location • Clinical remission at 8 wk 44.0%    Ileocolonic 218 (47.1) • Clinical remission at 16 wk 56.1%    Ileal 190 (41) • Predictive factor of lower Older age, higher HBI at ­probability of remission at 16 wk baseline, previous abdom-    Colonic 55 (11.9) inal surgery   Upper gastrointestinal tract 37 (8) • Clinical response at 8 wk 57.6%  CD behavior • Clinical response at 16 wk 70.2%    Inflammatory 245 (52.9) • Predictive factors of lower Previous surgery    Stricturing 132 (28.5) ­probability of response at 16 wk    Penetrating 86 (18.6) Long-term effectiveness  Active perianal disease 65 (14.0) • Loss of response incidence 29.7% per patient-year of  Harvey-Bradshaw Index score 8.4 ± 3.5 follow-up  Prior use of biologics for CD treatment 447 (96.5) • Predictive factors of higher risk of Number of previous    Previous anti-TNF loss of response biologics, higher HBI at baseline, severe vs mild     Adalimumaba 374 (83.7) • Probability of sustaining remission     Infliximaba 348 (77.9) ◦ 6 mo 84%    Previous vedolizumaba 109 (24.4) ◦ 12 mo 74%  Previous surgery for CDb 281 (60.7) ◦ 18 mo 66%   Abdominal 218 (47.1) • Clinical remission at 6 mo 57.9%    Perianal 106 (22.9) • Clinical remission at 18 mo 57.2%  ≥1 concomitant immunosuppressant 163 (35.2) Dose optimization   Azathioprine 106 (65) • Dose escalation 4.5%    Methotrexate 47 (28.8) • Dose intensification 21.6%    Mercaptopurine 13 (8) • Dose de-escalation 5.8%  Number of biologics for CD treatment    1 138 (30.9) Abbreviations: CI, confidence interval; HBI, Harvey-Bradshaw Index.    2 168 (37.6)    ≥3 141 (31.5) (Figure 2). The reasons for discontinuation were primary Values are mean ± SD or n (%). failure (27.1%), LoR (26.2%), partial response (25.2%), AE Abbreviations: CD, Crohn’s disease; TNF, tumor necrosis factor; UST, (5.6%), patient’s decision (4.7%), and other reasons (11.2%). ustekinumab. a Percentages are based on the number of patients who received previous Regarding maintenance treatment, 396 (85.5%) patients biologics for CD treatment. started SC ustekinumab with a schedule of once every 8 b Total number of surgeries (patients could have had more than 1). weeks, 48 (10.4%) every 12 weeks, and 2 (0.4%) every 4 weeks. Five patients received only 1 ustekinumab dose and Ustekinumab Retention Rate 12 patients received only 2 doses, and therefore did not start Primary and secondary outcomes are summarized in Table 2. the maintenance phase. After a median follow-up of 15.5 months, 356 patients (76.9%; In the multivariate analysis (Table 3), previous intestinal 95% CI, 72.8%-80.7%) were still receiving ustekinumab and surgery and concomitant treatment with steroids were associ- 107 (23.1%) had discontinued the treatment. The incidence ated with a higher risk of ustekinumab discontinuation, while of ustekinumab discontinuation was 18.4% per patient-year a maintenance schedule of once every 12 weeks was asso- of follow-up (Figure 1). The incidence was similar between ciated with a lower risk. Other factors, such as the severity patients receiving ustekinumab monotherapy or combination of the disease at the start of treatment, combination therapy therapy with immunosuppressants (17.5% vs 18.9%, P = .71) with immunomodulators, or previous exposure to biologics 1730 Chaparro et al Figure 1. A and B, Survival curve of patients who maintained ustekinumab treatment over time and maintained clinical remission over time. (irrespective of the line of treatment) had no impact on treat- The multivariate analysis showed that older age (odds ment retention. ratio [OR], 0.6; 95% CI, 0.4-0.9), previous abdominal sur- gery (OR, 0.6; 95% CI, 0.4-0.9), and higher HBI at base- Short-term effectiveness line (OR, 0.8; 95% CI, 0.8-0.9) were associated with a lower Overall, 44.0% of patients reached clinical remission at week probability of achieving remission at week 16. With regard 8 and 56.1% at week 16 (Figure 3). With respect to clinical to response to ustekinumab, the only factor associated with response (including both patients with response and with re- a lower probability of having a response at week 16 was pre- mission), 57.6% of patients achieved this endpoint at week 8 vious surgery (OR, 0.7; 95% CI, 0.4-1.0). and 70.2% at week 16 (Figure 3). Patients who were in remission at week 16, compared with Long-term effectiveness those who were not, were younger (mean age 44.5 ± 13.9 Long-term effectiveness was analyzed in patients achieving years vs 47.3 ± 12.5 years; P = .01) at baseline, had a lower clinical remission at week 16. The probability of maintaining weight at baseline (67.0 ± 14.6 kg vs 71.4 ± 15.6 kg; P < .01), clinical remission over time is shown in Figure 2. In the pa- had a lower HBI score at first dose (7.6 ± 3.0 vs 9.6 ± 3.8; P tients who achieved clinical remission at week 16 (n = 256), < .01), and had a higher CRP at first dose (19.1 ± 30.6 mg/L the median time of follow-up was 15.7 (IQR, 12.9-19.0) vs 17.2 ± 38.1 mg/L; P = .02). months and the median time to LoR was 11.1 (IQR, 7.1-14.7) Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study 1731 months. The incidence of LoR was 29.7% per patient-year sustaining remission between patients receiving a mainten- of follow-up. The probability of sustaining remission was ance schedule of ustekinumab once every 12 weeks compared 84%, 74%, and 66% at 6, 12, and 18 months, respectively. with once every 8 weeks (P = .36). In addition, no difference was observed in the probability of The number of previous biologics (hazard ratio [HR], 1.2; 95% CI, 1.0-1.5) and higher HBI score at baseline (moderate vs mild [HR, 1.5; 95% CI, 1.0-2.3] and severe vs mild [HR, 4.0; 95% CI, 1.0-17.0]) were associated with a higher risk of LoR. Neither concomitant treatment with immunomodulators nor the number of previous biologics was associated with the likelihood of maintaining remission during follow-up. More than half of patients achieved clinical remission at 6 months, the majority of whom had steroid-free remis- sion. Specifically, at 6 months, 57.9% (n = 268 of 463) of patients had clinical remission and 53.3% (n = 247 of 463) had steroid-free remission. At 12 months, 57.2% (n = 250 of 437) and 50.8% (n = 222 of 437) of patients had clin- ical remission and steroid-free remission, respectively. At 18 months, the percentages of patients who had clinical remis- sion and steroid-free remission were 41.5% (n = 113 of 272) and 35.7% (n = 97 of 272), respectively. Dose Optimization Of the 463 patients analyzed, the dose was escalated in 21 (4.5%) due to LoR (n = 14 [66.7%]) or primary failure (n = 5 [23.8%]). Other reasons for dose escalation were persistently high fecal calprotectin levels and capsule endoscopy showing involvement of the proximal jejunum (n = 1 [4.8%]) and par- Figure 2. Ustekinumab retention based on the concomitant use of tial response (n = 1 [4.8%]). immunosuppressive therapy. Patient characteristics based on ustekinumab dose opti- mization are summarized in Table 4. The proportion of pa- Table 3. Multivariate analysis of factors associated with ustekinumab tients with previous exposure to vedolizumab and median discontinuation CRP levels at baseline were significantly higher among pa- tients who received escalated or intensified treatment than in Factor HR 95% CI those who did not. The distribution of other variables did not significantly differ between the subgroups (Table 4). Previous abdominal surgery (yes vs no) 2.14 1.47-3.18 One hundred (21.6%) patients intensified treatment: Concomitant steroid treatment (yes vs no) 1.82 1.24-2.67 61 (13.2%) increased dose frequency from every 8 weeks Maintenance schedule (every 8 wk vs every 12 wk) 0.26 0.08-0.81 to every 4 weeks, 33 (7.1%) increased dose frequency from every 8 weeks to every 6 weeks, and 6 patients Abbreviations: CI, confidence interval; HR, hazard ratio. received reinduction with IV ustekinumab. The main Figure 3. Short-term effectiveness of ustekinumab at weeks 8 and 16. 1732 Chaparro et al Table 4. Baseline demographics and disease characteristics by treatment modification Treatment Not Escalated Treatment Escalated P or Intensified (n = 342) or Intensified (n = 121) Value Demographics  Age, y 47.1 ± 12.8 47.0 ± 15.1 .97  Age at diagnosis, y 33.1 ± 14.4 34.3 ± 14.8 .45  Female 179 (52.3) 53 (43.8) .11  Smokers 87 (25.4) 31 (25.6) .30  Comorbidities at entry 171 (50.0) 59 (48.8) .83 Disease characteristics at baseline  Disease duration, years 14.4 ± 8.9 13.1 ± 9.4 .07  Time from diagnosis to UST initiation, y 13.0 ± 8.9 11.6 ± 9.3 .05  Age at UST initiation, y 45.7 ± 12.8 45.4 ± 15.1 .98  Extraintestinal manifestations 130 (38.0) 51 (42.1) .45  CD location    Ileocolonic 166 (48.5) 52 (43.0) .51    Ileal 135 (39.5) 55 (45.5)    Colonic 41 (12.0) 14 (11.6)   Upper gastrointestinal tract 27 (7.9) 10 (8.3) .85  CD behavior    Inflammatory 181 (52.9) 64 (52.9) .74    Stricturing 100 (29.2) 32 (26.4)    Penetrating 61 (17.8) 25 (20.7)  Active perianal disease 48 (14.0) 17 (14.0) .91  Harvey-Bradshaw Index score 7.5 (6.0-10.0) 8.0 (6.0-10.0) .64  CRP, mg/L 5.3 (1.4-15.0) 10 (3.2-22.2) <.01  FC, µg/g 459.0 (127.5-1256.0) 639.0 (305.0-1430.0) .29  Prior use of biologics for CD treatment 331 (96.8) 116 (95.9) .576    Previous anti-TNF     Adalimumaba 276 (83.4) 98 (84.5) .884     Infliximaba 254 (76.7) 94 (81.0) .366    Previous vedolizumaba 71 (21.5) 38 (32.8) .017  Previous surgery for CDb 217 (63.5) 64 (52.9) .051   Abdominal 169 (49.4) 49 (40.5) .112    Perianal 77 (22.5) 29 (24.0) .801  ≥1 concomitant immunosuppressant 125 (36.5) 38 (31.4) .321   Azathioprine 82 (65.6) 24 (63.2) .847    Methotrexate 34 (27.2) 13 (34.2) .419    Mercaptopurine 11 (8.8) 2 (5.3) .734  Number of biologics for CD treatment    1 105 (31.7) 33 (28.4) .15    2 130 (39.3) 38 (32.8)    ≥3 96 (29.0) 45 (38.8) Values are mean ± SD, n (%), or median (interquartile range). Abbreviations: CD, Crohn’s disease; CRP, C-reactive protein; FC, fecal calprotectin; TNF, tumor necrosis factor; UST, ustekinumab. a Percentages are based on the number of patients who received previous biologics for CD treatment. b Total number of surgeries (patients could have had more than 1). reasons for treatment intensification were LoR in 71 of 80 patients regained remission following treatment (71.0%) patients and primary failure in 17 (17.0%) pa- intensification. tients (Supplementary Table 5). Treatment intensification Ustekinumab administration was de-escalated from every resulted in remission in 42 (77.8%) of 54 patients who 8 weeks to every 12 weeks in 27 (5.8%) patients: 24 (88.9%) increased administration from every 8 weeks to every 4 due to sustained remission, 1 (3.7%) due to sustained re- weeks, 16 (80.0%) of 20 patients who increased from sponse, 1 (3.7%) due to herpes simplex infection, and 1 every 12 weeks to every 8 weeks, and 5 (83.3%) of 6 pa- (3.7%) for clinician choice. Among patients who de-escalated tients who underwent reinduction. Overall, 63 (78.8%) treatment due to sustained remission, 15 (62.5%) maintained Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study 1733 Table 5. Most frequent adverse events reported during ustekinumab patients with refractory CD reported that treatment persist- treatment ence on ustekinumab was 83% at the end of follow-up (~1 year),23 and only 6.7% of patients discontinued ustekinumab Adverse Event Patients (N = 463) within the first year.27 Infusion reaction 29 (6.3) In our study, ustekinumab was associated with an overall clinical response rate of 57.6% at week 8 and 70.2% at week Allergic reaction 9 (1.9) 16, and clinical remission rates of 44.0% and 56.1% at weeks Arthralgias 5 (1.1) 8 and 16, respectively. These findings are consistent with those Dyspnea 5 (1.1) of other real-world studies of ustekinumab, which reported Headache 7 (1.5) early response (≤16 weeks) and remission rates of 46.0% to Psoriasis 5 (1.1) 73.9% and 16.0% to 55.6%, respectively.17,18,22,24-27,29-32 Long- Severe and opportunistic infections 5 (1.1) term remission rates (≥1 year) in other real-world studies Pruritus 4 (0.9) ranged from 14.0% to 49.0%,20,24,28,32 showing some vari- Asthenia 3 (0.6) ation between studies. In addition, older age, previous surgery, and higher HBI at Herpes zoster 3 (0.6) baseline were associated with a lower probability of achieving Lupus 2 (0.4) remission at week 16. Other studies have identified the same Blurred vision 1 (0.2) negative prognostic factors.21 Although we demonstrated Dizziness 1 (0.2) that previous exposure to biologics had no impact on the ef- Fever 1 (0.2) fectiveness of ustekinumab, in previous studies, prior use of Granuloma annulare 1 (0.2) anti-TNF agents was associated with the absence of clinical Neoplasm 1 (0.2) remission or response.26,29,32 Moreover, we have demonstrated that concomitant immunomodulator use does not affect the Values are n (%). effectiveness of ustekinumab, while in the study conducted by Engel et al,24 prior administration or concomitant use of immunomodulators were associated with better outcomes. remission over time and 9 (37.5%) subsequently needed to Other predictive factors identified in previous studies in- reescalate treatment. cluded body mass index, which was associated with lower Thirty-one of the 121 patients who increased the dose as rates of steroid-free remission21; age and smoking, which were the first treatment change required a second change: 19 in- associated with poor response22; and stricturing phenotype, tensified, 1 escalated, 4 received reinduction, 5 returned to which was associated with poor outcomes.24 the initial dose, and 2 received IV ustekinumab (260-520 mg, The rate of LoR was 29.7% per patient-year of depending on the patient’s weight) maintenance therapy on follow-up. This rate was similar among patients receiving regular basis. None of these patients had de-escalation of SC ustekinumab 90 mg every 12 weeks and those who were treatment. treated every 8 weeks. In our study, the characteristics of patients who started receiving ustekinumab every 12 weeks Safety were similar to those who started receiving it every 8 weeks, Fifty AEs (30.3%) were reported in 39 (8.4%) patients, of except that the prevalence of perianal disease was higher which only 4 were severe (2 infections, 1 malignancy, and 1 in the group receiving ustekinumab every 12 weeks. In pa- fever). The association with ustekinumab was considered pos- tients with CD, LoR to all biologic drugs is expected.17,21,32 sible in 36 (72%) patients, probable in 13 (26%) patients, However, LoR to ustekinumab is probably not due to an im- and very likely in 1 (2%) patient (Table 5). These AEs led to munogenic mechanism, because as the results of our study temporary interruption of treatment in 19.6% of patients and show, immunomodulators that decrease antibody formation suspension of treatment in 17.9%. do not affect drug response or treatment duration or reten- tion, likely due to the activation of an alternative inflamma- tory pathway. Dose escalation or intensification may be an Discussion option to counteract LoR. In our study, 4.5% of patients re- To our knowledge, our study has the largest cohort and quired dose escalation and 21.6% required treatment intensi- one of the longest follow-up periods among the pub- fication (ie, increased dose frequency or reinduction with IV lished real-world studies of refractory CD patients treated ustekinumab); approximately 79% of these patients regained with ustekinumab, including a total of 463 patients and a response following these changes; however, 24.8% of patients follow-up of up to 24 months. Our results provide new data who needed a dose increase required a second change and regarding the effectiveness and safety of ustekinumab in clin- did not reduce the dosage again during follow-up. In patients ical practice. who had increased administration frequency from every 8 Although the patients in our study had refractory CD, after weeks to every 4 weeks, remission was regained in 77.8%. a median follow-up of 15.5 months, 76.9% were still re- The intensification rates observed in the current study are ceiving ustekinumab, and only 23.1% had discontinued treat- substantially lower in comparison with those of a previous ment, with an ustekinumab discontinuation rate of 18.4% retrospective cohort study that included 238 patients with per patient-year. In addition, our results showed that previous CD, which found that over half of the patients required dose exposure to biologics (irrespective of the line of treatment) intensification after almost 1 year of treatment.38 It is pos- and concomitant use of immunomodulators had no effect on sible that this difference was due to the disease state at the ustekinumab discontinuation. Previous studies conducted in time of intensification, as in Dalal et al,38 some of the patients 1734 Chaparro et al who underwent intensification had a longer CD duration and could not evaluate mucosal healing. This reflects real-world greater proportions of patients used ≥2 prior TNF antagon- clinical practice, in which endoscopy studies are generally not ists, and had penetrating disease. In the study presented here, carried out if patients show good response after induction. almost all patients (96.5%) had received a prior biologic treat- Concomitant use of steroids can be difficult to evaluate in ment, with approximately one-third receiving 1 biologic treat- real-world studies, in which follow-up is often not defined in ment, including TNF antagonists, and two-thirds receiving the study protocol (follow-up time was different for each pa- ≥2 biologic treatments. Similar to Dalal et al, more patients tient). Finally, as almost 100% of our patients had previously receiving ≥2 biologic treatments, including TNF antagonists, failed treatment with biologic agents, we could not properly prior to study initiation required treatment intensification or assess the effect of exposure to these drugs on the effective- dose escalation (25.1%) in comparison with patients who re- ness of ustekinumab. ceived only 1 biologic treatment (10.0%). Thus, it is possible Nevertheless, our study has several strengths. First, this is that the low number of patients who required a second dose the largest and longest real-world study to evaluate the ef- increase was due to the disease state and prior treatment of fectiveness of ustekinumab in CD published to date. Second, our population sample. clinical activity was categorized based on HBI, and several The effectiveness of increasing ustekinumab dose frequency other objective parameters were also reported, including to once every 4 weeks is becoming increasingly relevant. A CRP and fecal calprotectin levels. We also investigated the recent study reported similar results to our study, with two- effect of the concomitant immunomodulator use, LoR, thirds of patients regaining response following intensification and the evolution of the disease after ustekinumab dose of ustekinumab to 90 mg every 4 weeks.25 Similarly, another adjustment. study reported a response rate of 65.8% at week 16 after treatment intensification to every 4 weeks.30 In our study, reinduction with IV ustekinumab was also effective, resulting Conclusions in 83% of patients regaining response. Although there are Ustekinumab was effective in patients with CD in real-world limited data for this outcome, a recent study has shown endo- clinical practice, including those with refractory disease. scopic improvement and remission in patients who under- Concomitant immunomodulator use did not appear to pro- went ustekinumab reinduction.19 vide an additional benefit either in the short term or in the Regarding treatment de-escalation, currently there are long term. Approximately 20% of patients discontinued no criteria for deciding whether patients should receive ustekinumab per patient-year of follow-up, mainly owing to ustekinumab every 8 weeks or every 12 weeks. In our study, primary failure and LoR. A relevant proportion of patients the only significant difference in clinical characteristics be- who had achieved remission later relapsed, but treatment in- tween patients who started treatment on a regimen of once tensification was able to regain remission in approximately every 8 weeks or once every 12 weeks was a history of peri- 79% of patients. Finally, safety was consistent with the anal surgery. Therefore, we cannot conclude that there was a known profile of ustekinumab. pattern for the selection of a treatment schedule. However, the ustekinumab schedule was de-escalated from every 8 weeks to every 12 weeks in 27 patients due to sustained remission or Supplementary Data sustained response, and among these patients, 65.2% main- Supplementary data is available at Inflammatory Bowel tained remission over time. Thus, dose de-escalation may be Diseases online. an option in patients with adequate response to maintenance treatment administered once every 8 weeks. In this context, it is worth noting that different maintenance dosing is re- Acknowledgments commended by the U.S. Food and Drug Administration and We thank Eliana Mesa, MD, Sheridan Henness, PhD, and the European Medicines Agency; the European Medicines Fernando Sánchez Barbero, PhD, who provided assist- Agency recommends maintenance therapy every 12 or 8 ance with manuscript development on behalf of Springer weeks,13 whereas the Food and Drug Administration recom- Healthcare Communications. This medical writing assistance mends an SC dose of 90 mg every 8 weeks.39 was funded by Janssen-Cilag Spain. The safety of ustekinumab has been recently evaluated in 2 systematic reviews and meta-analyses comparing the rates of AEs in patients treated with ustekinumab vs placebo in clin- Author Contributions ical trials, showing no differences between these groups.40,41 M.Ch., M.B.-d.A. and J.P.G. contributed to the study de- This was also true when comparing high vs low doses of sign, data collection, data analysis, data interpretation, and ustekinumab.40,41 In our cohort, AEs were infrequent (8.4% writing of the manuscript. The remaining authors were re- of patients), with a similar rate to that reported in some sponsible for identifying patients for inclusion in the study real-world studies30 and lower than in others.17,18,24,26 The AE and extracting data from their medical records. All authors rate reported in our study is also lower than that reported approved the final version of the manuscript, including the in clinical trials of ustekinumab,14,42 maybe because AEs are authorship list. underreported in real-life studies.43 The limitations of the present study are mainly those as- sociated with its retrospective design, including the potential Funding for missing data in clinical records. To overcome the poten- This work was supported by Janssen-Cilag Spain. This spon- tial heterogeneity in clinical assessment, clinicians were asked sor had a partial role in study design, analysis, and interpret- to provide HBI score values at every visit. In addition, we ation of data. Medical writing and editorial assistance for Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn’s Disease Patients: The SUSTAIN Study 1735 the preparation of this article was funded by Janssen-Cilag or received research funding from MSD, AbbVie, Takeda, Spain. This assistance was provided by the following indi- Janssen, Pfizer, Biogen, Amgen, Ferring, Faes Farma, Tillotts viduals, who are either employees of Springer Healthcare Pharma, Dr. Falk Pharma, Chiesi, and Gebro Pharma. N.J. Communications (S.H.C.), or were contracted by S.H.C. to has received fees from Janssen, Takeda, AbbVie and Tillots. undertake editorial work in connection with the preparation C.T. has served as a speaker, consultant, and advisory board of the article: Eliana Mesa, MD, Sheridan Henness, PhD, member for MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Fernando Sánchez Barbero, PhD. Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, and Tillots. A.H.C. has served as speaker for or received research or education funding from AbbVie, Takeda, Kern Pharma, Conflicts of Interest Pfizer, Janssen, Adacyte Therapeutics, and Ferring. F.R.M. has M.Ch. has served as a speaker, or has received research or served as advisory member or received financial support for education funding from MSD, AbbVie, Hospira, Pfizer, traveling and educational activities from Pfizer, Jansen, MSD, Takeda, Janssen, Ferring, Shire Pharmaceuticals, Dr. Falk AbbVie, and Takeda. M.M.M.R. has served as speaker or re- Pharma, and Tillotts Pharma. I.B.-R. has served as a speaker ceived financial support for educational activities from MSD, for MSD, Janssen, Pfizer, and Takeda. E.F.-S. has served as Takeda, Janssen, AbbVie, Tillotts Pharma and Ferring. I.G.T. a speaker for Janssen, AbbVie, Tillotts Pharma, Ferring, has served as a speaker from MSD, AbbVie, Pfizer, Takeda, MSD, Shire, Takeda, Falk, and Faes Farma. L.R. has served Kern, Shire Pharmaceuticals, and Janssen. M.N.L. has served as a speaker or has received education funding from MSD, as a speaker or received financial support for traveling or re- AbbVie, Takeda, Janssen, and Ferring. F.A.-A. has served as ceived research funding from AbbVie, Janssen, Takeda, MSD, a speaker, consultant, and advisory member for or has re- Pfizer, Ferring, Dr. Falk Pharma, Tillots Pharma, and Biogen. ceived research funding from Janssen, MSD, AbbVie, Pfizer, M.B.-d.A. has served as a speaker, consultant, and advisory Kern Pharma, Biogen, Sandoz, Takeda, Ferring, Faes Farma, member for or received research funding from MSD, AbbVie, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Hospira, Takeda, Janssen, Kern, Ferring, Faes Farma, Shire Gebro Pharma, Amgen, and Vifor Pharma. E.I.F. has served Pharmaceuticals, Dr. Falk Pharma, Chiesi, Gebro Pharma, as a consultant or advisory member or received research Otsuka Pharmaceuticals, and Tillotts Pharma. J.P.G. has and education funding from AbbVie, MSD, Pfizer, Takeda, served as a speaker, consultant, and advisory member for Janssen, Ferring, and Dr. Falk Pharma. S.R.I. has served as or received research funding from MSD, AbbVie, Hospira, a speaker or received research or education funding from Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, MSD, AbbVie, Pfizer, Takeda, Janssen, Ferring, Faes Farma, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Shire Pharmaceuticals, Chiesi, Gebro Pharma, Otsuka Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceuticals, and Tillotts Pharma. D.B. has served as Pharmaceutical, and Vifor Pharma. S.S., C.N. and E.V. are a speaker for AbbVie, Pfizer, Takeda, Janssen, Ferring, and employees of Janssen. All other authors have nothing to de- Tillots Pharma. A.G.C. has served as a speaker, consultant, clare. and advisory member for or received research funding from MSD, AbbVie, Pfizer, Kern Pharma, Takeda, Janssen, Ferring, Faes Farma, Shire Pharmaceuticals, Tillotts Pharma, Chiesi, References and Otsuka Pharmaceutical. M.M.B.-W. has served as speaker 1. Baumgart DC, Sandborn WJ. 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