{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T15:28:42Z","timestamp":1784042922594,"version":"3.55.0"},"reference-count":51,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Current evidence remains ambiguous regarding whether biologics should be added to conventional treatment of rheumatoid arthritis for specific patients, which may cause potential overuse or treatment delay.<\/jats:p><\/jats:sec>Objectives<\/jats:title>To estimate the benefit of adding biologics to conventional antirheumatic drugs for the treatment of rheumatoid arthritis given baseline characteristics.<\/jats:p><\/jats:sec>Data Sources<\/jats:title>Cochrane CENTRAL, Scopus, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform were searched for articles published from database inception to March 2, 2022.<\/jats:p><\/jats:sec>Study Selection<\/jats:title>Randomized clinical trials comparing certolizumab plus conventional antirheumatic drugs with placebo plus conventional drugs were selected.<\/jats:p><\/jats:sec>Data Extraction and Synthesis<\/jats:title>Individual participant data of the prespecified outcomes and covariates were acquired from the Vivli database. A 2-stage model was fitted to estimate patient-specific relative outcomes of adding certolizumab vs conventional drugs only. Stage 1 was a penalized logistic regression model to estimate the baseline expected probability of the outcome regardless of treatment using baseline characteristics. Stage 2 was a bayesian individual participant data meta-regression model to estimate the relative outcomes for a particular baseline expected probability. Patient-specific results were displayed interactively on an application based on a 2-stage model.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The primary outcome was low disease activity or remission at 3 months, defined by 3 disease activity indexes (ie, Disease Activity Score based on the evaluation of 28 joints, Clinical Disease Activity Index, or Simplified Disease Activity Index).<\/jats:p><\/jats:sec>Results<\/jats:title>Individual participant data were obtained from 3790 patients (2996 female [79.1%] and 794 male [20.9%]; mean [SD] age, 52.7 [12.3] years) from 5 large randomized clinical trials for moderate to high activity rheumatoid arthritis with usable data for 22 prespecified baseline covariates. Overall, adding certolizumab was associated with a higher probability of reaching low disease activity. The odds ratio for patients with an average baseline expected probability of the outcome was 6.31 (95% credible interval, 2.22-15.25). However, the benefits differed in patients with different baseline characteristics. For example, the estimated risk difference was smaller than 10% for patients with either low or high baseline expected probability.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this individual participant data meta-analysis, adding certolizumab was associated with more effectiveness for rheumatoid arthritis in general. However, the benefit was uncertain for patients with low or high baseline expected probability, for whom other evaluations were necessary. The interactive application displaying individual estimates may help with treatment selection.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2023.21398","type":"journal-article","created":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T15:31:50Z","timestamp":1688139110000},"page":"e2321398","source":"Crossref","is-referenced-by-count":4,"title":["Estimating Patient-Specific Relative Benefit of Adding Biologics to Conventional Rheumatoid Arthritis Treatment"],"prefix":"10.1001","volume":"6","author":[{"given":"Yan","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"Population Health and Policy Research Unit, Medical Education Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Chalkou","sequence":"additional","affiliation":[{"name":"Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland"},{"name":"Graduate School for Health Sciences, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Funada","sequence":"additional","affiliation":[{"name":"Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, Keio University, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Salanti","sequence":"additional","affiliation":[{"name":"Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshi A.","family":"Furukawa","sequence":"additional","affiliation":[{"name":"Department of Health Promotion and Human Behavior, School of Public Health, Graduate School of Medicine, Kyoto University, Kyoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2023,6,30]]},"reference":[{"issue":"6","key":"zoi230631r1","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1136\/annrheumdis-2019-216655","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.","volume":"79","author":"Smolen","year":"2020","journal-title":"Ann Rheum Dis"},{"issue":"7","key":"zoi230631r2","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.1002\/art.v73.7","article-title":"2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.","volume":"73","author":"Fraenkel","year":"2021","journal-title":"Arthritis Rheumatol"},{"issue":"66","key":"zoi230631r3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3310\/hta22660","article-title":"Assessing prognosis and prediction of treatment response in early rheumatoid arthritis: systematic reviews.","volume":"22","author":"Archer","year":"2018","journal-title":"Health Technol Assess"},{"issue":"7","key":"zoi230631r4","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1016\/j.mayocp.2017.05.009","article-title":"Prediction of response to targeted treatment in rheumatoid arthritis.","volume":"92","author":"Wijbrandts","year":"2017","journal-title":"Mayo Clin Proc"},{"issue":"12","key":"zoi230631r5","doi-asserted-by":"publisher","first-page":"2063","DOI":"10.1136\/ard.2010.148015","article-title":"Optimising treatment in rheumatoid arthritis: a review of potential biological markers of response.","volume":"70","author":"Emery","year":"2011","journal-title":"Ann Rheum Dis"},{"issue":"4","key":"zoi230631r6","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1007\/s00281-017-0630-4","article-title":"Genetics of rheumatoid arthritis susceptibility, severity, and treatment response.","volume":"39","author":"Viatte","year":"2017","journal-title":"Semin Immunopathol"},{"issue":"2","key":"zoi230631r7","first-page":"216","article-title":"Adverse events and infections in patients with rheumatoid arthritis treated with conventional drugs or biologic agents: a real world study.","volume":"33","author":"Lampropoulos","year":"2015","journal-title":"Clin Exp Rheumatol"},{"key":"zoi230631r8","doi-asserted-by":"publisher","first-page":"965","DOI":"10.3389\/fphar.2019.00965","article-title":"Adverse events in patients with rheumatoid arthritis and psoriatic arthritis receiving long-term biological agents in a real-life setting.","volume":"10","author":"de Camargo","year":"2019","journal-title":"Front Pharmacol"},{"key":"zoi230631r9","doi-asserted-by":"publisher","first-page":"144","DOI":"10.3389\/fmed.2019.00144","article-title":"Major challenges in rheumatology: will we ever treat smarter, instead of just harder?","volume":"6","author":"Rom\u00e3o","year":"2019","journal-title":"Front Med (Lausanne)"},{"key":"zoi230631r10","doi-asserted-by":"publisher","first-page":"c221","DOI":"10.1136\/bmj.c221","article-title":"Meta-analysis of individual participant data: rationale, conduct, and reporting.","volume":"340","author":"Riley","year":"2010","journal-title":"BMJ"},{"issue":"4","key":"zoi230631r11","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1002\/jrsm.v6.4","article-title":"Get real in individual participant data (IPD) meta-analysis: a review of the methodology.","volume":"6","author":"Debray","year":"2015","journal-title":"Res Synth Methods"},{"issue":"10","key":"zoi230631r12","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001886","article-title":"Individual participant data (IPD) meta-analyses of diagnostic and prognostic modeling studies: guidance on their use.","volume":"12","author":"Debray","year":"2015","journal-title":"PLoS Med"},{"issue":"20","key":"zoi230631r13","doi-asserted-by":"publisher","first-page":"4362","DOI":"10.1002\/sim.v40.20","article-title":"A two-stage prediction model for heterogeneous effects of treatments.","volume":"40","author":"Chalkou","year":"2021","journal-title":"Stat Med"},{"issue":"1","key":"zoi230631r14","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/s13643-020-01401-x","article-title":"Predicting the treatment response of certolizumab for individual adult patients with rheumatoid arthritis: protocol for an individual participant data meta-analysis.","volume":"9","author":"Luo","year":"2020","journal-title":"Syst Rev"},{"issue":"16","key":"zoi230631r15","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1001\/jama.2015.3656","article-title":"Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement.","volume":"313","author":"Stewart","year":"2015","journal-title":"JAMA"},{"issue":"9","key":"zoi230631r16","doi-asserted-by":"publisher","first-page":"2569","DOI":"10.1002\/art.27584","article-title":"2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology\/European League Against Rheumatism collaborative initiative.","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheum"},{"issue":"3","key":"zoi230631r17","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1002\/(ISSN)1529-0131","article-title":"The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.","volume":"31","author":"Arnett","year":"1988","journal-title":"Arthritis Rheum"},{"issue":"1","key":"zoi230631r19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.rdc.2005.09.005","article-title":"The definition and measurement of disease modification in inflammatory rheumatic diseases.","volume":"32","author":"Aletaha","year":"2006","journal-title":"Rheum Dis Clin North Am"},{"issue":"5","key":"zoi230631r20","first-page":"S93","article-title":"The Disease Activity Score and the EULAR response criteria.","volume":"23","author":"Fransen","year":"2005","journal-title":"Clin Exp Rheumatol"},{"issue":"4","key":"zoi230631r21","doi-asserted-by":"publisher","first-page":"R796","DOI":"10.1186\/ar1740","article-title":"Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score.","volume":"7","author":"Aletaha","year":"2005","journal-title":"Arthritis Res Ther"},{"issue":"9","key":"zoi230631r22","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1002\/(ISSN)1529-0131","article-title":"Remission and active disease in rheumatoid arthritis: defining criteria for disease activity states.","volume":"52","author":"Aletaha","year":"2005","journal-title":"Arthritis Rheum"},{"issue":"6","key":"zoi230631r23","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1002\/(ISSN)1529-0131","article-title":"Preliminary definition of improvement in rheumatoid arthritis.","volume":"38","author":"Felson","year":"1995","journal-title":"Arthritis Rheum"},{"key":"zoi230631r24","doi-asserted-by":"publisher","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: a revised tool for assessing risk of bias in randomised trials.","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"issue":"5","key":"zoi230631r25","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1002\/sim.7141","article-title":"Meta-analysis using individual participant data: one-stage and two-stage approaches, and why they may differ.","volume":"36","author":"Burke","year":"2017","journal-title":"Stat Med"},{"issue":"7","key":"zoi230631r26","doi-asserted-by":"publisher","first-page":"1276","DOI":"10.1002\/sim.v38.7","article-title":"Minimum sample size for developing a multivariable prediction model, part II: binary and time-to-event outcomes.","volume":"38","author":"Riley","year":"2019","journal-title":"Stat Med"},{"issue":"1","key":"zoi230631r27","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1161\/CIRCOUTCOMES.113.000497","article-title":"Using internally developed risk models to assess heterogeneity in treatment effects in clinical trials.","volume":"7","author":"Burke","year":"2014","journal-title":"Circ Cardiovasc Qual Outcomes"},{"issue":"1","key":"zoi230631r28","doi-asserted-by":"publisher","first-page":"35","DOI":"10.7326\/M18-3667","article-title":"The Predictive Approaches to Treatment effect Heterogeneity (PATH) Statement.","volume":"172","author":"Kent","year":"2020","journal-title":"Ann Intern Med"},{"issue":"4","key":"zoi230631r30","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1002\/sim.v30.4","article-title":"Multiple imputation using chained equations: issues and guidance for practice.","volume":"30","author":"White","year":"2011","journal-title":"Stat Med"},{"issue":"7","key":"zoi230631r32","doi-asserted-by":"publisher","first-page":"3492","DOI":"10.3390\/ijerph18073492","article-title":"Bayesian methods for meta-analyses of binary outcomes: implementations, examples, and impact of priors.","volume":"18","author":"Al Am","year":"2021","journal-title":"Int J Environ Res Public Health"},{"issue":"1","key":"zoi230631r35","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1136\/annrheumdis-2015-207511","article-title":"The first double-blind, randomised, parallel-group certolizumab pegol study in methotrexate-naive early rheumatoid arthritis patients with poor prognostic factors, C-OPERA, shows inhibition of radiographic progression.","volume":"75","author":"Atsumi","year":"2016","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"zoi230631r36","doi-asserted-by":"publisher","first-page":"2174","DOI":"10.1136\/annrheumdis-2014-205325","article-title":"Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase.","volume":"73","author":"Schiff","year":"2014","journal-title":"Ann Rheum Dis"},{"issue":"6","key":"zoi230631r37","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.3904\/kjim.2016.213","article-title":"Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate in patients with active rheumatoid arthritis.","volume":"33","author":"Kang","year":"2018","journal-title":"Korean J Intern Med"},{"key":"zoi230631r38","doi-asserted-by":"publisher","DOI":"10.1016\/j.conctc.2021.100770","article-title":"Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain\u2014study protocol for a randomized double-blind controlled study.","volume":"22","author":"Schenker","year":"2021","journal-title":"Contemp Clin Trials Commun"},{"issue":"2","key":"zoi230631r39","first-page":"227","article-title":"Efficacy and safety of certolizumab pegol in combination with methotrexate in methotrexate-inadequate responder Chinese patients with active rheumatoid arthritis: 24-week results from a randomised, double-blind, placebo-controlled phase 3 study.","volume":"37","author":"Bi","year":"2019","journal-title":"Clin Exp Rheumatol"},{"issue":"5","key":"zoi230631r40","doi-asserted-by":"publisher","first-page":"715","DOI":"10.3109\/14397595.2013.864224","article-title":"Efficacy and safety of certolizumab pegol plus methotrexate in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: the J-RAPID randomized, placebo-controlled trial.","volume":"24","author":"Yamamoto","year":"2014","journal-title":"Mod Rheumatol"},{"issue":"11","key":"zoi230631r41","doi-asserted-by":"publisher","first-page":"3319","DOI":"10.1002\/art.v58:11","article-title":"Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.","volume":"58","author":"Keystone","year":"2008","journal-title":"Arthritis Rheum"},{"issue":"6","key":"zoi230631r42","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1136\/ard.2008.101659","article-title":"Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study: a randomised controlled trial.","volume":"68","author":"Smolen","year":"2009","journal-title":"Ann Rheum Dis"},{"issue":"12","key":"zoi230631r43","doi-asserted-by":"publisher","first-page":"2204","DOI":"10.1093\/rheumatology\/kes150","article-title":"Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study.","volume":"51","author":"Weinblatt","year":"2012","journal-title":"Rheumatology (Oxford)"},{"issue":"7","key":"zoi230631r44","doi-asserted-by":"publisher","first-page":"1226","DOI":"10.1093\/rheumatology\/ker519","article-title":"Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX.","volume":"51","author":"Choy","year":"2012","journal-title":"Rheumatology (Oxford)"},{"issue":"1","key":"zoi230631r45","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1136\/annrheumdis-2015-209057","article-title":"Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-na\u00efve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study.","volume":"76","author":"Emery","year":"2017","journal-title":"Ann Rheum Dis"},{"issue":"3","key":"zoi230631r46","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.2312","article-title":"Predicting probability of response to tumor necrosis factor inhibitors for individual patients with ankylosing spondylitis.","volume":"5","author":"Wang","year":"2022","journal-title":"JAMA Netw Open"},{"issue":"3","key":"zoi230631r47","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2019.0606","article-title":"Assessment of a deep learning model based on electronic health record data to forecast clinical outcomes in patients with rheumatoid arthritis.","volume":"2","author":"Norgeot","year":"2019","journal-title":"JAMA Netw Open"},{"issue":"6","key":"zoi230631r48","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1002\/art.v61:6","article-title":"Association of concomitant fibromyalgia with worse disease activity score in 28 joints, health assessment questionnaire, and short form 36 scores in patients with rheumatoid arthritis.","volume":"61","author":"Ranzolin","year":"2009","journal-title":"Arthritis Rheum"},{"issue":"8","key":"zoi230631r49","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1002\/art.v66.8","article-title":"Subgrouping of patients with rheumatoid arthritis based on pain, fatigue, inflammation, and psychosocial factors.","volume":"66","author":"Lee","year":"2014","journal-title":"Arthritis Rheumatol"},{"issue":"7","key":"zoi230631r50","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1136\/annrheumdis-2017-212862","article-title":"Defining refractory rheumatoid arthritis.","volume":"77","author":"Buch","year":"2018","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"zoi230631r51","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s12874-020-01145-1","article-title":"Predictive approaches to heterogeneous treatment effects: a scoping review.","volume":"20","author":"Rekkas","year":"2020","journal-title":"BMC Med Res Methodol"},{"key":"zoi230631r29","first-page":"199","volume-title":"Missing Data in Randomised Controlled Trials: A Practical Guide","author":"Carpenter","year":"2007"},{"key":"zoi230631r33","year":"2021"},{"key":"zoi230631r18","unstructured":"European Medicines Agency. Clinical investigation of medicinal products for the treatment of rheumatoid arthritis: scientific guideline. 2018. Accessed May 27, 2023. https:\/\/www.ema.europa.eu\/en\/clinical-investigation-medicinal-products-treatment-rheumatoid-arthritis-scientific-guideline"},{"key":"zoi230631r31","unstructured":"R: A Language and Environment for Statistical Computing [computer program]. R Foundation for Statistical Computing; 2013. Accessed May 27, 2023. http:\/\/www.R-project.org\/"},{"key":"zoi230631r34","unstructured":"Gibhub. y-luo06 \/ IPDMA_CTZ. Accessed May 27, 2023. https:\/\/github.com\/y-luo06\/IPDMA_CTZ"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2806709\/luo_2023_oi_230631_1687536361.37972.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,30]],"date-time":"2023-06-30T15:32:00Z","timestamp":1688139120000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2806709"}},"subtitle":["An Individual Participant Data Meta-Analysis"],"short-title":[],"issued":{"date-parts":[[2023,6,30]]},"references-count":51,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2023.21398","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,30]]}}}