Prediction of Relapse After Anti–Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies
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Background & Aims: Tools for stratification of relapse risk of Crohn's disease (CD) after anti–tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. Methods: Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. Results: This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2–4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11–1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18–172), smoking (HR, 1.4; 95% CI, 1.15–1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01–1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96–1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99–1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1–1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00–1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98–1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). Conclusions: This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Clinical Gastroenterology and Hepatology |
| Vol/bind | 20 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1671-1686.e16 |
| ISSN | 1542-3565 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
The authors thank Wichor M. Bramer (Biomedical information Specialist, Medical Library, Erasmus Erasmus University Medical Centre, Rotterdam, The Netherlands), Jasmijn A.M. Sleutjes (Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands), Alenka J. Brooks (Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, National Health Service Foundation Trust, Sheffield, United Kingdom), Peter J. Hamlin (Department of Gastroenterology, Leeds Teaching Hospitals, National Health Service Trust, St James's University Hospital, West Yorkshire, United Kingdom), Shaji Sebastian (Digestive Diseases, Hospital Universitario Virgen del Roc?o, Seville, Spain), Alan J. Lobo (Gastroenterology and Liver Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals National Health Service Foundation Trust, Sheffield, UK), J.M. Garc?a-Ortiz (Digestive Diseases, Hospital Universitario Virgen del Roc?o, Seville, Spain), Casper Steenholdt (Department of Gastroenterology, Herlev Hospital, Herlev, Denmark), Levinus (Leo) A. Dieleman (Division of Gastroenterology, Zeidler Ledcor Center, University of Alberta, Edmonton, Alberta, Canada), and Shomron Ben-Horin (Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Israel; and Sackler School of Medicine, Tel-Aviv University, Tel Aviv-Yafo, Israel), and the BiOcYcle (BIOlogical therapy CYCLEs towards tailored, needs-driven, safer and cost-effective management of Crohn's Disease) project. Poster presentation at the 14th congress of ECCO?Inflammatory Bowel Diseases 2018 (March 6?9, 2018; Copenhagen, Denmark): P138 Prediction model to safely cease anti-TNF therapy in Crohn's disease: individual participant data meta-analysis (IPD-MA). Oral presentation at the Dutch Digestive Days (Veldhoven, the Netherlands) 2019 (March 20?21, 2019): 53 Prediction model to safely cease anti-TNF therapy in Crohn's disease: individual participant data meta-analysis (IPD-MA). The CEASE (Safe anti-TNF cessation in Crohn's disease) study group comprises the following members: Annemarie C. de Vries, Renske W. M. Pauwels, C. Janneke van der Woude, Daan Nieboer, Ewout W. Steyerberg, Jasmijn A.M. Sleutjes, Marjolijn Duijvestein, Geert R. D'Haens, Mar?a J. Casanova, Javier P. Gisbert, Nick A. Kennedy, Charlie W. Lees, Edouard Louis, Tam?s Moln?r, Kata Sz?nt?, Eduardo Leo, J.M. Garc?a-Ort?z, Robert Downey, Alenka J. Brooks, Peter J. Hamlin, Shaji Sebastian, Alan J. Lobo, Milan Lukas, Wei C. Lin, Aurelien Amiot, Cathy Lu, Levinus (Leo) A. Dieleman, Xavier Roblin, Shomron Ben-Horin, Klaudia Farkas, Jakob B. Seidelin, Casper Steenholdt, and Steven Bots. Conflicts of interest These authors disclose the following: C. Janneke van der Woude has received grant support from Falk Benelux and Pfizer, speaker fees from AbbVie, Takeda, Ferring, Dr. Falk Pharma, Hospira, and Pfizer, and served as a consultant for AbbVie, MSD, Takeda, Celgene, Mundipharma, and Janssen; Mar?a Jos? Casanova has received education funding from Pfizer, Takeda, Janssen, MSD, Ferring, and AbbVie; Javier P. Gisbert has served as a speaker, a consultant, and advisory member for or has received research funding from MSD, AbbVie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma; Nick A. Kennedy has served as a speaker and/or advisory board member for Allergan, Falk, Janssen, Mylan, Pharmacosmos, Takeda, and Tillotts, and he has received support to attend meetings from AbbVie, Falk, Janssen, Norgine, and Tillotts; Tam?s Moln?r has received speaker's honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, and Teva; Aurelien Amiot has received consulting fees from AbbVie, Hospira, Takeda, Gilead, and Biocodex, lecture fees and travel accommodations from AbbVie, Janssen, Biocodex, Hospira, Ferring, Takeda, and MSD, advisory board fees from Gilead, Takeda, and AbbVie; Xavier Roblin has received grants/fees from AbbVie, MSD, Pfizer, Janssen, Takeda, Amgen Biogen, Takeda, Gilead, and Roche; Klaudia Farkas has received speaker's honoraria from AbbVie, Janssen, Ferring, and Takeda; Jakob B. Seidelin has served as national coordinator on studies from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, and Roche/Genentech, and received an unrestricted research grant from Takeda; Marjolijn Duijvestein has received advisory fees from Echo Pharma and Robarts Clinical Trials, Inc, speaker fees from Janssen, Merck & Co, Inc, Pfizer, Takeda, and Tillotts Pharma, and nonfinancial support from Dr Falk Pharma; Geert R. D'Haens has served as an advisor for AbbVie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, Dr Falk Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor, received speaker fees from AbbVie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor; and Annemarie C. de Vries has participated in advisory boards and/or received financial compensation from Janssen, Takeda, AbbVie, and Tramedico. The remaining authors disclose no conflicts.
Funding Information:
Conflicts of interest These authors disclose the following: C. Janneke van der Woude has received grant support from Falk Benelux and Pfizer, speaker fees from AbbVie, Takeda, Ferring, Dr. Falk Pharma, Hospira, and Pfizer, and served as a consultant for AbbVie, MSD, Takeda, Celgene, Mundipharma, and Janssen; María José Casanova has received education funding from Pfizer, Takeda, Janssen, MSD, Ferring, and AbbVie; Javier P. Gisbert has served as a speaker, a consultant, and advisory member for or has received research funding from MSD, AbbVie, Hospira, Pfizer, Kern Pharma, Biogen, Takeda, Janssen, Roche, Sandoz, Celgene, Ferring, Faes Farma, Shire Pharmaceuticals, Dr. Falk Pharma, Tillotts Pharma, Chiesi, Casen Fleet, Gebro Pharma, Otsuka Pharmaceutical, and Vifor Pharma; Nick A. Kennedy has served as a speaker and/or advisory board member for Allergan, Falk, Janssen, Mylan, Pharmacosmos, Takeda, and Tillotts, and he has received support to attend meetings from AbbVie, Falk, Janssen, Norgine, and Tillotts; Tamás Molnár has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, and Teva; Aurelien Amiot has received consulting fees from AbbVie, Hospira, Takeda, Gilead, and Biocodex, lecture fees and travel accommodations from AbbVie, Janssen, Biocodex, Hospira, Ferring, Takeda, and MSD, advisory board fees from Gilead, Takeda, and AbbVie; Xavier Roblin has received grants/fees from AbbVie, MSD, Pfizer, Janssen, Takeda, Amgen Biogen, Takeda, Gilead, and Roche; Klaudia Farkas has received speaker’s honoraria from AbbVie, Janssen, Ferring, and Takeda; Jakob B. Seidelin has served as national coordinator on studies from AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, and Roche/Genentech, and received an unrestricted research grant from Takeda; Marjolijn Duijvestein has received advisory fees from Echo Pharma and Robarts Clinical Trials, Inc, speaker fees from Janssen, Merck & Co, Inc, Pfizer, Takeda, and Tillotts Pharma, and nonfinancial support from Dr Falk Pharma; Geert R. D’Haens has served as an advisor for AbbVie, Ablynx, Allergan, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, Bristol Meiers Squibb, Boerhinger Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, Dr Falk Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo Smith Kline, Hospira/Pfizer, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Photopill, Prometheus laboratories/Nestle, Progenity, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor, received speaker fees from AbbVie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor; and Annemarie C. de Vries has participated in advisory boards and/or received financial compensation from Janssen, Takeda, AbbVie, and Tramedico. The remaining authors disclose no conflicts.
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