874202 research-article20192019 TAG0010.1177/1756284819874202Therapeutic Advances in GastroenterologyM Chaparro, MG Donday Therapeutic Advances in Gastroenterology Study Protocol Anti-tumour necrosis factor discontinuation Ther Adv Gastroenterol 2019, Vol. 12: 1–10 in inflammatory bowel disease patients in DOI: 10.1177/ https://doi.org/10.1177/1756284819874202 https://doi.org/10.1177/1756284819874202 1756284819874202 remission: study protocol of a prospective, © The Author(s), 2019. Article reuse guidelines: sagepub.com/journals- multicentre, randomized clinical trial permissions María Chaparro , María G. Donday, Manuel Barreiro-de Acosta, Eugeni Domènech, María Correspondence to: Esteve, Valle García-Sánchez, Pilar Nos, Julián Panés, Concepción Martínez and Javier P. Javier P. Gisbert Gisbert on behalf of the EXIT study group of GETECCU Gastroenterology Department, Hospital Universitario de La Princesa, Instituto de Abstract Investigación Sanitaria Princesa (IIS-IP), Background: Patients with inflammatory bowel disease who achieve remission with anti- Universidad Autónoma tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety de Madrid, Centro de Investigación Biomédica concerns and cost considerations, but there is a lack of prospective, controlled data en Red de Enfermedades investigating this strategy. The primary study aim is to compare the rates of clinical remission Hepáticas y Digestivas (CIBEREHD), Diego de at 1 year in patients who discontinue anti-TNF treatment versus those who continue treatment. Leon 62, Madrid, 28006, Spain Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo- javier.p.gisbert@gmail. controlled study in patients with Crohn’s disease or ulcerative colitis who have achieved com María Chaparro clinical remission for ⩾6 months with an anti-TNF treatment and an immunosuppressant. María G. Donday Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Gastroenterology Department, Hospital Randomization stratifies patients by the type of inflammatory bowel disease and drug Universitario de La (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is Princesa, IIS-IP, Universidad Autónoma sustained clinical remission at 1 year. Other endpoints include endoscopic and radiological de Madrid, CIBEREHD, Madrid, Spain activity, patient-reported outcomes (quality of life, work productivity), safety and predictive Manuel Barreiro-de factors for relapse. The required sample size is 194 patients. In addition to the main analysis Acosta Gastroenterology (discontinuation versus continuation), subanalyses will include stratification by type of Department, Hospital inflammatory bowel disease, phenotype and previous treatment. Biological samples will be Clínico Universitario de Santiago de Compostela, obtained to identify factors predictive of relapse after treatment withdrawal. Spain Results: Enrolment began in 2016, and the study is expected to end in 2020. Eugeni Domènech Gastroenterology Conclusions: This study will contribute prospective, controlled data on outcomes and Department, Hospital predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF Germans Trias i Pujol, CIBEREHD, Badalona, agents following achievement of clinical remission. Spain Clinical trial reference number: EudraCT 2015-001410-10 María Esteve Gastroenterology Department, Hospital Universitari Mútua Keywords: anti-tumour necrosis factor, inflammatory bowel disease, withdrawal Terrasa, CIBEREHD, Barcelona, Spain Received: 17 May 2019; revised manuscript accepted: 14 August 2019. Valle García-Sánchez Gastroenterology Department, Hospital Universitario Reina Sofía, Córdoba, Spain Introduction steroid-refractory or steroid-dependent.1,2 In Pilar Nos Gastroenterology Anti-tumour necrosis factor (anti-TNF) agents addition to being effective for the induction of Department, Hospital such as infliximab and adalimumab are recom- remission, anti-TNF agents are also used for Universitario y Politécnico La Fe, CIBEREHD, mended therapies for the medical management maintenance therapy in patients with IBD.1,2 Valencia, Spain of moderate to severe inflammatory bowel dis- Although these agents have been shown to be Julián Panés ease (IBD), that is, Crohn’s disease and ulcera- effective at maintaining remission, promoting Gastroenterology Department, IBD Unit, tive colitis, particularly in patients who are mucosal healing and improving disease course Hospital Clínic, IDIBAPS, journals.sagepub.com/home/tag 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Gastroenterology 12 CIBEREHD, Barcelona, Spain and long-term outcomes,1–4 long-term therapy Methods Concepción Martínez might be associated with safety concerns, such as Gastroenterology possible increased risks of opportunistic infection Study design Department, Servicio de Farmacia, Hospital and malignancy, and a substantial cost.4 Thus, it This study was designed to prospectively investi- Universitario de La has been suggested that, after a period of stable gate the effect of anti-TNF discontinuation on the Princesa, Madrid. Spain remission, anti-TNF maintenance therapy could risk of relapse in patients with IBD. A quadruple- be discontinued in some patients. blind, randomized study design was chosen, in which the patient, physician, data manager and Withdrawal of anti-TNF therapy may be associ- statistician were all blinded to the patient’s treat- ated with a risk of relapse. A meta-analysis of 27 ment allocation. The study is being conducted at studies found that the risk of relapse 1 year follow- 47 IBD hospital units across Spain, with enrol- ing discontinuation of anti-TNF treatment was ment starting in 2016 and continuing until 2019. 40% for patients with Crohn’s disease and 28% The study is expected to end in 2020, when the for those with ulcerative colitis.5 In a retrospective last enrolled patient will complete the final follow- study of 1055 patients who had anti-TNF ther- up visit. There are two strategies that are being apy withdrawn after achieving clinical remission, compared: discontinuation of anti-TNF treat- the rate of relapse was 19% per patient-year in ment versus continuation of anti-TNF after achiev- patients with Crohn’s disease, and 17% per ing remission, as shown in Figure 1. Patients are patient-year in patients with ulcerative colitis.6 being randomized to one of two groups (anti-TNF Although some factors, such as mucosal healing,7 continuation or placebo) using a decision-tree appear to be associated with lower risk of relapse, type format and an interactive web response sys- investigations into the rate of relapse after anti- tem. Randomization is stratified by the type of TNF discontinuation and the associated predic- IBD (Crohn’s disease or ulcerative colitis), and tive factors is confounded by differences in study the anti-TNF agent (infliximab or adalimumab) design, the retrospective design of most of the at the time of study inclusion (Figure 1). studies and insufficient data to allow assessment of all potential contributing factors.5–7 In addi- The primary objective of this study is to compare tion, many of the studies investigating outcomes the rates of clinical remission at 1 year in patients following anti-TNF withdrawal enroll only a who discontinue treatment with an anti-TNF small number of patients.8–12 Thus, prospective agent versus those who continue. Secondary end- controlled data from a large, appropriately pow- points being compared between the two groups ered population are clearly needed. include: the duration of relapse-free time; mucosal healing; quality of life (QoL) and work productiv- It is noteworthy that there are no randomized ity; safety; and the identification of predictive fac- clinical trials comparing anti-TNF discontinua- tors for relapse. tion with continuation in patients with IBD. Patients who continue treatment can also experi- As described above, the quadruple-blind study ence relapse, due to loss of efficacy of long-term design renders the patient, physician, data man- anti-TNF treatment, thus it is crucial that any ager and statistician blind to the study treatment. study of anti-TNF withdrawal includes a control Only the pharmacy staff and the nurse responsi- group, in order to compare the rate of relapse in ble for study drug administration know the treat- those continuing and discontinuing therapy.13 ment assigned to any given patient. The aim of the present study is, therefore, to evalu- Ethics approval for this study has been granted by ate the risk of relapse in patients with IBD who dis- a Central Clinical Research Ethics Committee at continue anti-TNF therapy after achieving the Hospital Universitario de La Princesa. The remission in comparison with those who continue trial is being conducted according to the ethical receiving treatment, in a randomized controlled principles set out in the Declaration of Helsinki trial. In addition, we aim at identifying predictors of and relevant Spanish law regarding clinical trials. relapse, in order to select patients who can safely It is registered in both European and United discontinue biologic therapy with low risk of States clinical trial registers (EudraCT number relapse. We anticipate that the results provided by 2015-001410-10, and ClinicalTrials.gov identi- this trial will have a significant impact on how fier NCT02994836). Written, informed consent patients with IBD are managed in clinical practice. is being obtained from all participating patients. 2 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. Figure 1. Randomization scheme. Treatment arms Patients Patients in group 1 continue their current anti- Patients are eligible for enrolment in this study if TNF treatment (infliximab or adalimumab) while they are aged over 18 years with IBD (either patients in group 2 are given a placebo matched Crohn’s disease or ulcerative colitis) diagnosed to the drug they were previously receiving. That according to the European Crohn’s and Colitis is, patients who were on infliximab receive an Organisation (ECCO) criteria and receiving intravenous placebo, while patients who were treatment with an anti-TNF biologic (infliximab receiving adalimumab receive a placebo adminis- or adalimumab) and an immunosuppressant. tered subcutaneously. The placebo for infliximab Patients with Crohn’s disease are eligible only if is provided in the same pharmaceutical form and their anti-TNF treatment was prescribed for route of administration as the active drug, while luminal involvement (not perianal). At the time the syringes for adalimumab and its placebo are of inclusion, patients must be in steroid-free clini- masked so they cannot be seen by the patient cal remission (see definition in the section enti- when the nurse is administering them. Infliximab tled ‘Endpoints’) for at least 6 months at a (5 mg/kg) or infliximab placebo is administered nonintensified dose of anti-TNF and also be every 8 weeks, while adalimumab (40 mg) or its receiving concomitant immunosuppressants (thi- placebo is administered every 2 weeks. Patients in opurine or methotrexate) at stable doses for at both groups will continue to receive their usual least 3 months prior to inclusion in the study. immunosuppressant therapy (thiopurine or Intensified doses of anti-TNF therapy are defined methotrexate). as ⩾10 mg/kg/8 weeks or 5 mg/kg/⩽4 weeks for journals.sagepub.com/home/tag 3 Therapeutic Advances in Gastroenterology 12 infliximab and 40 mg/week for adalimumab. Clinical activity assessment. Clinical activity was Patients must have had a colonoscopy, or mag- assessed at study visits (Figure 2) using the CDAI netic resonance enterography (MRE) for patients in patients with Crohn’s disease and the PMS in with ileal or ileocolic Crohn’s disease, within patients with ulcerative colitis. 3 months of study inclusion, and this baseline assessment must not show significant lesions (see Radiological assessment. In patients with ileal or definition in the section entitled ‘Assessments’). ileocolic Crohn’s disease participating in the study, disease activity is assessed by MRE at base- Exclusion criteria include: age <18 years; receiv- line and at the end of the study period. If the ing anti-TNF therapy for a non-IBD indication; patient has had a previous MRE within 3 months Crohn’s disease treated with anti-TNF agents for of the baseline visit that contains all the informa- perianal involvement (or both perianal and lumi- tion required for the study, that MRE can be used nal); no concomitant treatment with immuno- for study inclusion. Absence of activity in the suppressants (thiopurine or methotrexate) at the small intestine or colon is defined as the absence time of enrolment and within the prior 3 months; of contrast enhancement, oedema, or ulcers. A history of bowel resection surgery; presence of thickening of the wall without enhancement is significant endoscopic or radiological lesions; considered as remission. Significant radiological advanced chronic disease or any other condition lesions by MRE are defined as the presence of that results in an inability to attend the clinic for oedema in T2 or ulcers in two or more intestinal monitoring or follow up; women who are preg- segments (rectum, descending colon, transverse nant or breastfeeding, or who intend to become colon, ascending colon, ileum). pregnant during the study period; and refusal to consent to study participation. Endoscopic assessment. All patients participating in the study have to undergo a baseline colonos- copy, but if the patient had a colonoscopy within Endpoints 3 months of the baseline visit and this contains all The primary endpoint of the study is ‘sustained of the information required for the study, it will be clinical remission at 1 year’ after randomization. acceptable for patient inclusion. A second colo- Any need for intensification of anti-TNF, modifi- noscopy will be performed in all patients at the cation of concomitant treatment, or therapy addi- end of the assessment period. tion to maintain clinical remission is considered as failure to maintain remission. Clinical remis- At each endoscopic assessment in patients with sion for patients with Crohn’s disease is defined Crohn’s disease, disease activity is being assessed as a Crohn’s Disease Activity Index (CDAI) score using the Simplified Endoscopic Activity Score of <150 points,14 while for patients with ulcera- for Crohn’s Disease (SES-CD),15 with significant tive colitis remission is defined as a Partial Mayo endoscopic lesions defined as the presence of any Score (PMS) of ⩽2, with all scores from the par- of the following: an SES-CD score of ⩾5, any tial score being ⩽1, and a rectal bleeding subscore deep ulcer, or superficial ulcers covering >10% of of 0.14 Clinical relapse is defined as a CDAI > 150 the surface of at least one intestinal segment. For points or a PMS > 2 (as applicable) in two con- patients with ulcerative colitis, endoscopic activ- secutive visits, separated by at least 1 week. If a ity is being assessed using the Mayo Endoscopic patient has a clinical relapse after randomization, Subscore;16 a Mayo Endoscopic Subscore of 3 is the responsible physician will take any measure considered to indicate the presence of significant deemed necessary to manage the relapse. endoscopic lesions in these patients. The assess- ment of endoscopic activity before study entry Other endpoints include endoscopic activity, and at the end of follow up is being performed by radiological activity, patient-reported outcomes, the investigator, as well as centrally by an investi- QoL, work productivity and safety. gator who assesses anonymised endoscopic images of the ileum (in patients with Crohn’s dis- ease) and of each colonic segment scanned. Assessments The timeline for study visits conducted at each Patient-reported outcomes. Assessment of QoL is blinded study visit is presented in Figure 2. being undertaken using the shortened CCVEII-9 4 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. Figure 2. Schedule of study visits throughout the study. CCVEII-9, ‘Cuestionario de Calidad de Vida Específico para la Enfermedad Inflamatoria Intestinal-9’ (Questionnaire on Quality of Life for Inflammatory Bowel Disease-9). CDAI, Crohn’s Disease Activity Index; d, day; IV, intravenous; mo, month; MRE, magnetic resonance enterography; SC, subcutaneous; TNF, tumour necrosis factor; V, visit; WPAI, Work Productivity and Activity Index. aPatients with ileal or ileocolic Crohn’s disease. bPatients with Crohn’s disease. cPatients with ulcerative colitis. dA shortened version of the CCVEII-9 questionnaire is being used. QoL questionnaire17 and assessment of work pro- drug (certain, probable, possible, conditional or ductivity and activity is being assessed using a unlikely, or unrelated). All AEs are being followed Spanish version of the Work Productivity and until their resolution or for at least 30 days after Activity Impairment (WPAI) questionnaire.18,19 study drug discontinuation, until toxicity is ⩽1 or it is deemed irreversible. Similarly, any pregnan- Laboratory assessments. Blood samples are cies occurring during the study will be followed being taken for haematology and biochemistry and their outcomes recorded, in order to rule out profiles, as well as cytokine profiling, drug any abnormalities or congenital malformations. (trough) levels and antidrug antibodies. In addi- tion, faecal and urinary samples are being obtained at baseline and at every visit during fol- Data collection low up; biomarkers associated with IBD recur- Study data are being collected and managed using rence will be investigated in those samples. an electronic data capture tool [Research Electronic Data Capture (REDCap)],20 which is hosted at Asociación Española de Gastroenterología Safety endpoints (AEG; www.aegastro.es), a nonprofit medical Information on toxicity/adverse events (AEs) is society. AEG provides this service free of charge, being collected at all study visits via spontaneous with the aim of promoting investigator-driven patient reporting and patient interviews at each research. REDCap is a secure, web-based applica- visit. AEs, adverse drug reactions (ADRs) and tion designed to support data capture for research reports of pregnancy are being collected from the studies that provides the following: an intuitive time the patient provides their informed consent interface for validated data entry; audit trails for until up to 30 days after the last dose of study drug tracking data manipulation and export proce- or the last visit. All AEs and ADRs are assigned an dures; automated export procedures for seamless intensity (mild, moderate or severe), and AEs are data downloads to common statistical packages; being classified by the principal investigator and procedures for importing data from external according to their causal relationship to the study sources.20 journals.sagepub.com/home/tag 5 Therapeutic Advances in Gastroenterology 12 Statistical analysis smoking, type of IBD, infliximab trough levels Sample size calculation. We estimated that 194 and indication for anti-TNF treatment. patients (97 patients in each group) would be required to compare the effect of anti-TNF with- drawal versus continuation. This is based on the Discussion assumption that 10% of patients continuing anti- The worldwide burden of IBD is significant, and TNF treatment for longer than 1 year will experi- is particularly high in Europe and North ence a loss of efficacy at 1 year,21 while the America.22 According to a review of published incidence of relapse after anti-TNF discontinua- epidemiological studies, the prevalence of Crohn’s tion is expected to be 25% at 1 year.6 Therefore, disease in Europe ranges from 1.51 cases per 194 patients would be required to demonstrate 100,000 people in Romania to 322.0 cases per statistically significant differences between the 100,000 in Germany.22 The prevalence of ulcera- two strategies with 80% power at a 5% signifi- tive colitis is slightly higher, ranging from 2.42 per cance level. 100,000 (again in Romania) to 505.0 per 100,000 in south-eastern Norway.22 Overall, an estimated Description of intention-to-treat and per-protocol 0.3% of the European population is affected by populations. Patients who meet the inclusion cri- IBD, equating to around 2.5–3 million people.23 teria and have been randomized are included in the intention-to-treat (ITT) analysis irrespective The onset of IBD is usually during adolescence or of whether they strictly adhere to the protocol. early adulthood, so there is considerable cumula- The per-protocol (PP) analysis will include only tive healthcare resource use associated with this those patients who have completed treatment and disease over the lifetime of a patient.24 Although follow up according to the protocol. Patients who for most patients, IBD follows a relapsing–remit- provide signed informed consent but do not ting course, between 20% and 25% of European receive the first dose of study medication for any patients will have continuous chronic symp- reason are being replaced to maintain the required toms.23 In addition, as many as 20–40% of sample size. Patients withdrawing due to preg- patients with Crohn’s disease and 15–20% with nancy will be considered as failure in the ITT ulcerative colitis have extraintestinal manifesta- analysis, and as not assessable in the PP analysis. tions, including arthropathies, ocular and skin conditions.23 According to estimates by the Data presentation and analyses. Qualitative vari- ECCO, IBD was associated with direct health- ables will be presented as percentages with 95% care costs of between €4.6 billion and €5.6 billion confidence intervals, while quantitative variables per year in 2013.23 In addition to the direct will be presented as means and standard devia- healthcare costs, IBD is associated with lost pro- tions (normal distribution) or medians and inter- ductivity when patients are unable to work or quartile ranges (non-normal distribution). pursue their education because of their symp- Categorical variables will be compared using the toms.23,24 As well as impacting the patient eco- Chi-square test and quantitative variables by the nomically, the inability to work has a significant appropriate test for their distribution (Student’s t negative effect on their QoL.25 test or Wilcoxon test). Mean and median time to relapse in the anti-TNF discontinuation versus The introduction of biologic therapy has not continuation groups will be compared. only changed treatment patterns for IBD, but also the type of costs incurred. Before the wide- The Kaplan–Meier method will be used to evalu- spread use of biologic therapy, hospitalization ate recurrence-free time, and the log-rank test will and surgery accounted for the greatest portion of be used to assess differences between the anti- treatment costs, but today medication makes up TNF discontinuation or continuation curves. the greatest proportion of the total cost.24 The variables associated with IBD recurrences According to 2016 estimates, the cost of biologic following treatment discontinuation will be ana- therapy varies widely across Europe (the lowest lysed using a Cox regression model, with treat- annual cost per patient is approximately €6000 ment strategy (anti-TNF discontinuation versus for an infliximab biosimilar).26 In many European continuation) as an independent variable, and countries, 100% of these costs are borne by the including other factors possibly related to an public healthcare system; in others, most of the increased recurrence risk, such as age, sex, cost is borne by the public healthcare system, 6 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. with patients contributing a small co-pay of 10– AEG-REDCap (from the Spanish Association of 25%.26 Therefore, it is important from a health Gastroenterology) as well as the Spanish Clinical economic perspective to determine whether these Research Network, from the Instituto de Salud agents can be safely discontinued in patients who Carlos III, for data monitoring. have achieved a stable remission. Furthermore, since long-term use of these agents can be associ- We would like to thank the Spanish Working ated with the risk of malignancy and opportunis- Group on Crohn’s Disease and Ulcerative Colitis tic infections,4 it is also important to determine (GETECCU) for the critical review of the proto- whether discontinuation of anti-TNF agents can col by the scientific evaluation committee, and for reduce such risks. the support of the scientific secretariat. The current study was designed to provide robust We would like to thank Eva Rodríguez, Project evidence about the effect of anti-TNF discontin- Manager of the study and scientific secretary of uation on the natural history of IBD. While stud- GETECCU. We would also like to thank ies and analyses exist demonstrating that a Sheridan Henness, who provided assistance with proportion of patients relapse after withdrawal of manuscript development on behalf of Springer anti-TNF treatment following clinical remis- Healthcare Communications. This editorial assis- sion,5,6,8–12 identification of predictors of response tance was funded by Fundación de Investigación and extrapolation of these data to the broader Biomédica, Hospital Universitario de La Princesa. IBD population is hampered by different study designs, small populations, and variable results. J.P. Gisbert and M. Chaparro designed the study In addition, to the best of our knowledge there is and are leading its development. All other authors currently no published randomized, controlled contributed to study design and critically revised trial comparing patients continuing anti-TNF the protocol, and were involved in patient enrol- treatment with those discontinuing treatment. ment and follow up. The data obtained in this study will contribute to resolving some of the uncertainties remaining in J.P. Gisbert and M. Chaparro are the guarantors this controversial aspect of IBD management. of the article. In conclusion, no randomized clinical trial has yet List of collaborators: F. Abad, M. Aguas Peris, E. been undertaken to compare the strategy of dis- Agüero Tejado, C. Alba, M. Albert, H. Alemán, continuing anti-TNF treatment with mainte- A. Algaba, I. Alonso Abreu, M.P. Amador, M. nance of these drugs in patients with IBD. Amat, T. Angueira, C. Arajol, L. Arias-González, Therefore, it has not been possible to adequately A. Arrondo Velasco, M. Baldán, B. Bardán compare the natural history of the condition in García, A. Bargalló García, M. Barreiro de Acosta, the absence versus presence of anti-TNF mainte- J. Barrio Andrés, G. Bastida Paz, I. Bastón Rey, L. nance therapy, particularly since the latter group Batista, M. Bellver Martínez, B. Beltrán Niclós, of patients may also experience disease relapses J.M. Benítez, Y. Ber Nieto, F. Bermejo, D. due to the loss of effectiveness of long-term anti- Bernardo, I. Blázquez Gómez, A. Bouhmidi TNF treatment. The current study was designed Assakali, D. .Busquets Casals, J.L. Cabriada to address the existing knowledge gap about the Nuño, X. Calvet Calvo, M.V. Calvo Hernández, clinical impact of withdrawing anti-TNF therapy M. Calvo, B. Camps, A.Y. Carbajo, G. Cardona in patients with IBD who have achieved a sus- Peitx, T. Caro-Patón, M. Carrillo Palau, S. tained remission. By incorporating robust Carrión Bolorino, M.J. Casanova, J.A. Casellas research techniques, including randomization, Valdé, A. Castaño García, B. Castro Senosiain, the use of a control group, and blinding, this D. Ceballos, E. Cerrillo, S. Chacón Martínez, F. study will provide important information on the Consuelo Cañete Pizarro, M.L. de Castro Parga, management of patients with IBD and how to M. de Miguel, R. de Francisco García, M.D. de la manage the growing burden of this illness within Cruz Ramírez, J. del Hoyo Francisco, P. Delgado the constraints of a public healthcare system. Guillena, T. Desongles Corrales, A. Echarri Piudo, E. Espino Paisan, M. Espona Quer, M. Acknowledgements Esteve, A. Fernández Pordomingo, J.L. Fernández The authors wish to thank A.G. McNicholl and Forcelledo, S. Fernández-Tomé, R. Ferreiro J. Calvo for programming the e-CRF in Iglesias, I. Ferrer Bradley, A. Ferrer, A. Figueroa, journals.sagepub.com/home/tag 7 Therapeutic Advances in Gastroenterology 12 M. Gallach Montero, P. García Iglesias, C. García supported by the Instituto de Salud Carlos III García-Lezcún, L. García Ramírez, M.J. García (PI15/00560). Project financed with FEDER García, O. García-Bosh, A. Garre, T. Giménez funds. Poderós, L. Gómez Irwin, B. Gómez Pastrana, E. Gómez Delgado, Y. González Lama, Á. Gracia Conflict of interest statement García, B. Gracia García, J. Guardiola, I. Guerra, J.P. Gisbert has served as a speaker, a consultant E. Guerra, V. Guillot, S. Gustmancher Saiz, A. and advisory member for or has received research Gutiérrez Casbas, V. Hernández Ramírez, M.M. funding from AbbVie, Advia, Allergan, Almirall, Hernando Verdugo, B. Hernández Muniesa, R. AstraZeneca, Biogen, Casen Fleet, Casen Hernanz Chaves, J.M. Herrera Justiniano, J Recordati, Celgene, Chiesi, Diasorin, Dr. Falk Hinojosa del Val, S Ibáñez Feijoo, M Iborra Pharma GmbH, Faes Farma, Ferring Colomino, E Iglesias Flores, E. Izquierdo García, Pharmaceuticals, Gebro Pharma, Janssen, M J Sampedro González, A J. Lucendo, N Jiménez Hospira, Kern Pharma, Mayoly, MSD, Nycomed, García, E. Leo Carnerero, I. Loizaga Díaz, A Otsuka Pharmaceutical, Pfizer, Roche, Sandoz, López de Torre Querejazu, P López Sánchez, J Shire Pharmaceuticals, Takeda, Tillotts Pharma Luis Parras, M Maia Boscá, M Mañosa, S Marín AG and Vifor Pharma. Pedrosa, A Marín, Á Marinero, I Marín-Jiménez, M. Chaparro has served as a speaker, or has L Márquez Mosquera, JL Márquez Galán, E received research or education funding from Martín Arranz, MD Martín Arranz, J Martínez AbbVie, Dr. Falk Pharma GmbH, Ferring Cadilla, JM Martínez Sesmero, B Martínez Pharmaceuticals, Janssen, Hospira, MSD, Pfizer, Sánchez, V Matallana, MI Mateos Hernández, Shire Pharmaceuticals, Takeda and Tillotts AG McNicholl, R Mejuto Fernández, L Melcarne, Pharma AG. L Menchén, J Méndez-Castrillón Rodríguez, O Merino Ochoa, M Mínguez, G Molas Ferrer, M M. Barreiro-de Acosta has served as a speaker, a Montoro Huguet, A Montserrat Torres, F Mora, consultant and advisory member for or has received I Moraleja Yudego, VJ Morales Alvarado, L research funding from AbbVie, AMGEN, Chiesi, Morales Martínez, A Morell, C Motos García, F Dr. Falk Pharma GmbH, Faes Farma, Ferring Muñoz Alonso, MC Muñoz Villafranca, JE Pharmaceuticals, Gebro Pharma, Janssen, Hospira, Muñoz, A Mur, Ó Nantes, P Navarro, M Navarro- Kern Pharma, MSD, Otsuka Pharmaceuticals, Llavat, P Nos Mateu, A Núñez Alonso, A Núñez Pfizer, Sandoz, Shire Pharmaceuticals, Takeda and Ortiz, D Olivares, V Ollero Pena, J Orobitg, L Tillotts Pharma AG. Ortega, J Ortiz de Zárate, H Pallarés Manrique, A E. Domènech has served as a speaker, or has Paradela Carreiro, L Peral Ballester, S Pereira received research or education funding or advisory Bueno, I Pérez Martínez, JR Pineda Mariño, C fees from AbbVie, Adacyte Therapeutics, Celgene, Piñero Pérez, A Planas Giner, MR Plaza Santos, Ferring Pharmaceuticals, Gebro Pharma GmbH, Á Ponferrada Díaz, J Poza Cardón, V Prieto Grifols, Janssen, Kern Pharma, MSD, Otsuka Vicente, L Puchades, L Ramos López, S Redondo, Pharmaceuticals, Pfizer, Shire Pharmaceuticals, S Riestra Menéndez, M Rivero Tirado, I Takeda, Thermofisher and Tillots Pharma AG. Rodríguez Lago, C Rodríguez Gutiérrez, E Rodríguez, S Romero Izquierdo, S Rubio Iturria, M. Esteve reports personal fees from Janssen, MB Ruiz Antorán, A Ruiz, LF Salazar, A Sánchez Menarini, Pfizer, Takeda and Tillots Pharma Ulayar, E Sánchez Gómez, C Sánchez, C AG, and grants from AbbVie and MSD, outside Sangrador, K Serra, K Spicakova, C Suárez the submitted work. Ferrer, A Talavera Fabuel, C Taxonera, M P. Nos has participated in educational activities, Tordera, E Torrella Cortés, J Tosca, C Trigo research projects and scientific meetings spon- Salado, F Uriarte Estefanía, M Van Domselaar, sored by AbbVie, Faes Farma, Ferring JM Vázquez Morón, P Ventura López, M Vera, Pharmaceuticals, Janssen, MSD, Otsuka, Takeda M Vicuña Arregui, A Villoria Ferrer, T Virgós and Tillots Pharma AG. Aller, D Yáñez Feria. J. Panés has received consulting fees from AbbVie, Funding Arena Pharmaceuticals, Boehringer Ingelheim, The authors disclosed receipt of the following Celgene, Celltrion, Ferring Pharmaceuticals, financial support for the research, authorship, Genentech, GlaxoSmithKline, Janssen, MSD, and/or publication of this article: this work was Nestle, Oppilan, Progenity, Pfizer, Robarts, Roche, 8 journals.sagepub.com/home/tag M Chaparro, MG Donday et al. Second Genome, Takeda, Theravance, TiGenix 10. Hlavaty T, Krajcovicova A, Letkovsky J, et al. and Topivert; speaker fees from AbbVie, Biogen, Relapse rates of inflammatory bowel disease Ferring Pharmaceuticals, Janssen, MSD, Shire patients in deep and clinical remission after Pharmaceuticals, Takeda and Tillotts Pharma discontinuing anti-tumor necrosis factor alpha therapy. Bratisl Lek Listy 2016; 117: 205–211. AG; and research funding from AbbVie and MSD. 11. Legue C, Brochard C, Bessi G, et al. Outcomes ORCID iD of perianal fistulising Crohn’s disease following María Chaparro https://orcid.org/0000-0002- anti-TNFalpha treatment discontinuation. 9275-4242 Inflamm Bowel Dis 2018; 24: 1107–1113. 12. Molander P, Farkkila M, Kemppainen H, et al. Long-term outcome of inflammatory bowel disease patients with deep remission after References discontinuation of TNFalpha-blocking agents. 1. Gomollón F, Dignass A, Annese V, et al. Third Scand J Gastroenterol 2017; 52: 284–290. European evidence-based consensus on the diagnosis and management of Crohn’s disease 13. Gisbert JP and Panes J. Loss of response and 2016: part 1: diagnosis and medical management. requirement of infliximab dose intensification J Crohns Colitis 2017; 11: 3–25. in Crohn’s disease: a review. Am J Gastroenterol 2009; 104: 760–767. 2. Harbord M, Eliakim R, Bettenworth D, et al. Third European evidence-based consensus on 14. D’haens G, Feagan B, Colombel JF, et al. diagnosis and management of ulcerative colitis. Challenges to the design, execution, and analysis Part 2: current management. J Crohns Colitis of randomized controlled trials for inflammatory 2017; 11: 769–784. bowel disease. Gastroenterology 2012; 143: 1461–1469. 3. Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, 15. Daperno M, D’haens G, Van Assche G, et al. surgeries, and procedures in fistulizing Crohn’s Development and validation of a new, simplified disease. Gastroenterology 2005; 128: 862–869. endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004; 60: 4. Pariente B and Laharie D. Review article: 505–512. why, when and how to de-escalate therapy in inflammatory bowel diseases. Aliment Pharmacol 16. Schroeder KW, Tremaine WJ and Ilstrup DM. Ther 2014; 40: 338–353. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. 5. Gisbert JP, Marin AC and Chaparro M. The A randomized study. N Engl J Med 1987; 317: risk of relapse after anti-TNF discontinuation in 1625–1629. inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol 2016; 111: 17. Alcala MJ, Casellas F, Fontanet G, et al. 632–647. Shortened questionnaire on quality of life for inflammatory bowel disease. Inflamm Bowel Dis 6. Casanova MJ, Chaparro M, Garcia-Sanchez V, 2004; 10: 383–391. et al. Evolution after anti-TNF discontinuation in patients with inflammatory bowel disease: a 18. Vergara M, Montserrat A, Casellas F, et al. multicenter long-term follow-up study. Am J Validation of the Spanish Work Productivity Gastroenterol 2017; 112: 120–131. and activity impairment questionnaire: Crohn’s disease version. Eur J Gastroenterol Hepatol 2009; 7. Gisbert JP, Marin AC and Chaparro M. 21: 809–815. Systematic review: factors associated with relapse of inflammatory bowel disease after 19. Vergara M, Montserrat A, Casellas F, et al. A discontinuation of anti-TNF therapy. Aliment new validation of the Spanish work productivity Pharmacol Ther 2015; 42: 391–405. and activity impairment questionnaire-Crohn’s disease version. Value Health 2011; 14: 859–861. 8. Farkas K, Lakatos PL, Nagy F, et al. Predictors of relapse in patients with ulcerative 20. Harris PA, Taylor R, Thielke R, et al. Research colitis in remission after one-year of infliximab electronic data capture (REDCap)–a metadata- therapy. Scand J Gastroenterol 2013; 48: driven methodology and workflow process for 1394–1398. providing translational research informatics support. J Biomed Inform 2009; 42: 377–381. 9. Helwig U, Lutter F, Koppka N, et al. Proposal for an anti-TNF-exit strategy based on trough 21. Chaparro M, Panes J, Garcia V, et al. Long-term serum level. Biologicals 2017; 47: 81–85. durability of infliximab treatment in Crohn’s journals.sagepub.com/home/tag 9 Therapeutic Advances in Gastroenterology 12 disease and efficacy of dose “escalation” in 24. Cohen RD. The pharmacoeconomics of biologic patients losing response. J Clin Gastroenterol therapy for IBD. Nat Rev Gastroenterol Hepatol 2011; 45: 113–118. 2010; 7: 103–109. 25. Hoivik ML, Bernklev T, Solberg IC, et al. Patients 22. Ng SC, Shi HY, Hamidi N, et al. Worldwide with Crohn’s disease experience reduced general incidence and prevalence of inflammatory bowel health and vitality in the chronic stage: ten-year disease in the 21st century: a systematic review results from the IBSEN study. J Crohns Colitis of population-based studies. Lancet 2018; 390: 2012; 6: 441–453. 2769–2778. Visit SAGE journals online 26. Pentek M, Lakatos PL, Oorsprong T, et al. journals.sagepub.com/ 23. Burisch J, Jess T, Martinato M, et al. The Access to biologicals in Crohn’s disease in ten home/tag burden of inflammatory bowel disease in Europe. European countries. World J Gastroenterol 2017; SAGE journals J Crohns Colitis 2013; 7: 322–337. 23: 6294–6305. 10 journals.sagepub.com/home/tag