Deep Remission at 1 Year Prevents Progression of Early Crohn's Disease

Abstract

Background & aims: We investigated the effects of inducing deep remission in patients with early Crohn's disease (CD).

Methods: We collected follow-up data from 122 patients (mean age, 31.2 ± 11.3 y) with early, moderate to severe CD (median duration, 0.2 years; interquartile range, 0.1-0.5) who participated in the Effect of Tight Control Management on CD (CALM) study, at 31 sites, representing 50% of the original CALM patient population. Fifty percent of patients (n = 61) were randomly assigned to a tight control strategy (increased therapy based on fecal level of calprotectin, serum level of C-reactive protein, and symptoms), and 50% were assigned to conventional management. We categorized patients as those who were vs were not in deep remission (CD endoscopic index of severity scores below 4, with no deep ulcerations or steroid treatment, for 8 or more weeks) at the end of the follow-up period (median, 3.02 years; range, 0.05-6.26 years). The primary outcome was a composite of major adverse outcomes that indicate CD progression during the follow-up period: new internal fistulas or abscesses, strictures, perianal fistulas or abscesses, or hospitalization or surgery for CD. Kaplan-Meier and penalized Cox regression with bootstrapping were used to compare composite rates between patients who achieved or did not achieve remission at the end of the follow-up period.

Results: Major adverse outcomes were reported for 34 patients (27.9%) during the follow-up period. Significantly fewer patients in deep remission at the end of the CALM study had major adverse outcomes during the follow-up period (P = .01). When we adjusted for potential confounders, deep remission (adjusted hazard ratio, 0.19; 95% confidence interval, 0.07-0.31) was significantly associated with a lower risk of major adverse outcome.

Conclusions: In an analysis of follow-up data from the CALM study, we associated induction of deep remission in early, moderate to severe CD with decreased risk of disease progression over a median time of 3 years, regardless of tight control or conventional management strategy.

Trial registration: ClinicalTrials.gov NCT01235689.

Keywords: Adalimumab; CDEIS; IBD; Inflammatory Bowel Diseases.

Conflict of interest statement

Conflicts of interest

These authors disclose the following: Ryan C. Ungaro has served as an advisory board member or consultant for Eli Lilly, Janssen, Pfizer, and Takeda and has received research grants from AbbVie, Boehringer Ingelheim, and Pfizer. Peter Bossuyt has received financial support for research from AbbVie, Mundipharma, Pfizer, Janssen, and Mylan; lecture fees from AbbVie, Takeda, Pfizer, and Janssen; and advisory board fees from AbbVie, Takeda, Hospira, Janssen, MSD, Mundipharma, Roche, Pfizer, Sandoz, and Pentax. Filip J. Baert has received research grants from AbbVie, Chiesi, Ipsen, MSD, Roche and speakers and consultancy fees from AbbVie, Falk, Ferring, Janssen, Mundipharma, MSD, Pfizer, Takeda, and Vifor. Thomas Vinasek has served as advisory member for Hospira, Pfizer, and Takeda and has received lecture fees from Takeda. Remo Panaccione has received consultant fees from AbbVie, ActoGeniX, AGI Therapeutics, Alba Therapeutics Albireo, Alfa Wasserman, Amgen, AMPharma BV, Anaphore, Aptalis, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celek, Cellerix, Cerimon, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine PharmaSciences, Eagle, Eisai Medical Research, Elan, enGene, Eli Lilly, EnteroMedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genentech, Genzyme, Gilead, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, KaloBios, Lexicon, Lycera, Meda, Merck & Co, Merck Research Laboratories, Merck Serono, Millennium, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProTAB, Purgenesis Technologies, Receptos, Relypsa, Salient, Salix, Santarus, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris (a GlaxoSmithKline company), SLA Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, UCB Pharma, Vascular Biogenics, and Viamet. Walter Reinisch has been a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; has been a consultant for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Roland Berger GmbH, Bioclinica, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, Elan, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, Mallinckrodt, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, Parexel, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, SetPoint Medical, Sigmoid, Takeda, Therakos, TiGenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; has been an advisory board member for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Biogen IDEC, Boehringer Ingelheim, Bristol Myers Squibb, Cellerix, ChemoCentryx, Celgene, Centocor, Celltrion, Danone Austria, Elan, Ferring, Galapagos, Genentech, Grünenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestlé, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, SetPoint Medical, Takeda, Therakos, TiGenix, UCB, Zealand, Zyngenia, and 4SC; and has received research funding from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and MSD. Alessandro Armuzzi has received consultant fees from AbbVie, Allergan, Amgen, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring, Hospira, Janssen, MSD, Mundipharma, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz, Sofar, Takeda; has received lecture fees from AbbVie, Amgen, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, Medtronic, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Otsuka, Pfizer, Samsung Bioepis, Takeda, TiGenix, Zambon and has received research grants from MSD, Takeda, Pfizer. Simon P. Travis has received grants/research support from AbbVie, Buhlmann, Celgene, International Organization for the study of Inflammatory Bowel Diseases, Janssen, Lilly, Takeda, UCB, Vifor, and Norman Collisson Foundation; has received consulting fees from Abacus, AbbVie, Actial, ai4gi, Alcimed, Allergan, Amgen, Arena, Asahi, Astellas, Atlantic, AstraZeneca, Barco, Biocare, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Buhlmann, Calcico, Celgene, Celsius, Cellerix, Cerimon, ChemoCentryx, Cisbio, Coronado, Cosmo, Ducentis, Dynavax, Elan, Enterome, Falk, Ferring, FPRT Bio, Giuliani SpA, Genentech, Genzyme, Glenmark, Grunenthal, GlaxoSmithKline, GW Pharmaceuticals, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Medarex, Merck, MSD, Netbiotix, Neovacs, Novartis, Novo Nordisk, NPS Pharmaceuticals, Ocera, Ptima, Otsuka, Palau, Pentax, Pfizer, Philips, Procter & Gamble, Pronota, Proximagen, Resolute, Receptos, Robarts, Roche, Sandoz, Santarus, Sensyne, Shire, Sigmoid Pharma, SynDermix, Synthon, Takeda, Theravance, TiGenix, Tillotts, Topivert, TxCell, UCB, Vertex, VHsquared, Vifor, Warner Chilcott, and Zeria; and has received speaker fees from AbbVie, Amgen, Biogen, Falk, Ferring, GlaxoSmithKline, Janssen, Shire, Takeda, and Zeria. Xavier Hébuterne has served an advisory board member or consultant for AbbVie, Arkopharma, Astellas, Janssen, Nutricia, Pfizer, and Takeda; has received speaker’s fees from AbbVie, ARARD, Arkopharma, Baxter, Bristol Myers Squibb, Ferring, Janssen, MSD, Nutricia, Pfizer, Tillotts, Sanofi-Aventis, and Takeda; has undertaken clinical research activities with AbbVie, Abivax, Alfasigma, Arena, Celgene, Gilead, Eli Lilly, Enterome, Janssen, InDex Pharmaceuticals, Pfizer, Roche, Salix, Takeda, and Theravance. Gerhard Rogler has consulted to AbbVie, Augurix, Bristol Myers Squibb, Boehringer, Calypso, Celgene, Dr Falk Pharma, Ferring, Fisher, Genentech, Gilead, Janssen, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillotts, Vifor, Vital Solutions, and Zeller; has received educational grants and research grants from AbbVie, Ardeypharm, Augurix, Calypso, Dr Falk Pharma, Flamentera, MSD, Novartis, Pfizer, Roche, Takeda, Tillotts, UCB, and Zeller; has served as an advisory board member or consultant for AbbVie, Boehringer Ingelheim, Sandoz, Ferring Pharmaceuticals, Janssen, Pfizer, and Biocodex Polska; and has been a speaker for AbbVie, Ferring, Astellas, Takeda, Gilead, Genentech, Alvogen, Biocodex Polska, and Walmark. Marc Ferrante has received speaker fees and/or consultant fees from AbbVie, MSD, Ferring, Takeda, Janssen, Pfizer, Boehringer Ingelheim, Biogen, Tillotts, Celgene, and Gilead. Mathurin Fumery has received research grants from Janssen, Pfizer, Takeda; has received consultancy fees from AbbVie, Boehringer Ingelheim, Ferring, Janssen, Mitsubishi Tanabe, MSD, and Pfizer; and has received speakers fees from AbbVie, Boehringer Ingelheim, Chiesi, Dr Falk Pharma, Ferring, Janssen, Lamepro, Mitsubishi Tanabe, MSD, Pfizer, Tramedico, Tillotts, and Zeria. Silvio Danese reports personal fees from AbbVie, Actelion Pharmaceuticals, Alfa Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Grunenthal, Johnson & Johnson, Millennium Pharmaceuticals, Merck & Co, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor. Grazyna Rydzewska has received speaker’s honoraria from AstraZeneca, AbbVie, Dr Falk Pharma, Janssen, MSD, Pfizer, Phadia, Takeda, Tillotts, UCB, Vifor, and Zeller. Benjamin Pariente has served as an advisory board member or consultant for AbbVie, Lilly, Ferring, Janssen, Pfizer, and Takeda; has served as a speaker for AbbVie, Ferring, Takeda, Theradiag, MSD, and Janssen; and has received research grants from AbbVie and Janssen. Erik Hertervig has served on advisory boards for AbbVie, Pfizer, Takeda, and Janssen and has received lecture fees from Takeda. Laurent Peyrin-Biroulet has served as a consultant, advisory board member, or speaker for Tillotts, Celltrion, Allergan, Biogen, MSD, Genentech, Index Pharmaceuticals, Ferring, Roche, Arena, Sterna, Gilead, Nestlé, Boehringer Ingelheim, Sandoz, Celgene, Enterome, Pfizer, Samsung, AbbVie, Takeda, Pharmacosmos, Janssen, Hikma, Alma, Amgen. David Laharie has received board and lecture fees from AbbVie, Biogaran, Biogen, Ferring, HAC Pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag, Tillotts. Jonas Halfvarson has served as an advisory board member or consultant for AbbVie, Celgene, Celltrion, Ferring, Hospira, Janssen, Meda, Medivir, MSD, Pfizer, Prometheus Laboratories, Sandoz, Shire, Takeda, Tillotts Pharma, and Vifor Pharma and has received grant support from Janssen, MSD, and Takeda. James W. Butler and Joel Petersson are employees of AbbVie, Inc. Jean-Frederic Colombel has served as an advisory board member or consultant for AbbVie, Amgen, Boehringer Ingelheim, Arena Pharmaceuticals, Celgene Corporation, Celltrion, Enterome, Eli Lilly, Ferring Pharmaceuticals, Genentech, Janssen and Janssen, Medimmune, Merck & Co., Nextbiotix, Novartis Pharmaceuticals Corporation, Otsuka Pharmaceutical Development & Commercialization, Inc, Pfizer, Protagonist, Second Genome, Gilead, Seres Therapeutics, Shire, Takeda, Theradiag; has served as a speaker for AbbVie, Ferring, Takeda, and Celgene Corporation; holds stock options for Intestinal Biotech Development and Genefit; and research grants from AbbVie, Takeda, Janssen. The remaining authors disclose no conflicts.

Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Flow chart of the study cohort creation. There were 32 patients in deep remission and 56 patients not in deep remission at the end of the CALM study who did not have any events during follow up (right-censored). The median follow-up was similar between these 2 groups (deep remission: 1274 days; IQR, 748–1688 vs no deep remission: 1219 days; IQR, 885–1665; P = .97).

Figure 2.

Kaplan-Meier estimates of CD disease progression based on clinical remission at the end of the CALM study with 95% CIs. Disease progression was defined as any major adverse outcome: composite of new internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalization, or CD surgery since end of the CALM study.

Figure 3.

Kaplan-Meier estimates of CD disease progression based on endoscopic remission at the end of the CALM study with 95% CIs. Disease progression was defined as any major adverse outcome: composite of new internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalization, or CD surgery since end of the CALM study.

Figure 4.

Kaplan-Meier estimates of CD disease progression based on deep remission at the end of the CALM study with 95% CIs. Disease progression was defined as any major adverse outcome: composite of new internal fistula/abscess, stricture, perianal fistula/abscess, CD hospitalization, or CD surgery since end of the CALM study.