Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis
Synthesis of evidence on the long-term use of first-line biologic therapy in patients with early rheumatoid arthritis (RA) is required. We compared the efficacy of up to 5 years’ treatment with first-line tumor necrosis factor inhibitors (TNFis) versus other treatment strategies in this population.
Previous systematic reviews, PubMed and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials (RCTs) involving treatment of methotrexate-naïve RA patients with first-line TNFis. Literature was synthesized qualitatively, and a meta-analysis conducted to evaluate American College of Rheumatology (ACR) responses, clinical remission defined by any standard measure, and Health Assessment Questionnaire Disability Index (HAQ) at Years 2 and/or 5.
Ten RCTs involving 4306 patients [first-line TNFi, n = 2234; other treatment strategies (control), n = 2072] were included in the meta-analysis. Three studies were double-blind for the first 2 years, while seven were partly/completely open label during this period. Five studies reported data at Year 5; all were open label at this time point. At Year 2, ACR50 response, ACR70 response and remission rates were significantly improved with first-line TNFi versus control in double-blind RCTs [log-odds ratio (OR) 0.32 [95% confidence interval (CI) 0.02, 0.62; p = 0.035], log-OR 0.48 (95% CI 0.20, 0.77; p = 0.001), and log-OR 0.44 (95% CI 0.13, 0.74; p = 0.005), respectively], but not in open-label studies. No significant between-group differences were observed in mean HAQ at Year 2 in double-blind or open-label RCTs or in ACR response or remission outcomes at Year 5.
In double-blind studies, 2-year efficacy outcomes were significantly improved with first-line TNFi versus other treatment strategies in patients with MTX-naïve RA. No significant differences in these outcomes were observed when data from open-label RCTs were considered on their own. Further data on the efficacy of TNFi therapy over ≥ 2 years in patients with methotrexate-naïve RA are required.
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KeywordsBiologic Disease-modifying antirheumatic drug Early Efficacy First line Meta-analysis Methotrexate-naïve Systematic review Tumor necrosis factor inhibitor
The authors received no funding for the analyses reported here. The article processing charges were funded by Celltrion Healthcare Co., Ltd (Incheon, Republic of Korea).
At the time of publication of the current article, the authors are performing additional work related to the analyses reported here; funding for this work will be provided by Celltrion Healthcare Co., Ltd.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the article to be published.
Medical Writing, Editorial, and Other Assistance
Medical writing support for this article (including copyediting and fact checking) was provided to the authors by Rick Flemming, PhD CMPP and Emma Evans, PhD CMPP at Aspire Scientific Limited (Bollington, UK) and was funded by Celltrion Healthcare Co., Ltd.
László Gulácsi has received consultancy and lecturing fees from Astellas, BMS, Celltrion, Egis Pharmaceuticals, GSK, Hikma, Hospira, Lilly Hungaria Ltd, MSD Hungary, Pfizer, Roche, Sandoz and UCB. Zsombor Zrubka used to be a full-time employee of Egis Pharmaceuticals, Janssen Cilag, Sandoz and Pfizer. Valentin Brodszky has received grants and personal fees from Celltrion, Egis Pharmaceuticals, Pfizer and Sager Pharma. Fanni Rencz has received consultancy fees from Celltrion and Hospira. Rieke Alten has received honoraria from Celltrion. Zoltán Szekanecz has received consultancy and lecturing fees from AbbVie, Amgen, BMS, Lilly, MSD, Novartis, Pfizer, Roche and UCB. Márta Péntek has received grants and personal fees from Celltrion, Egis Pharmaceuticals, Merck, Pfizer and Sager Pharma.
Compliance with Ethics Guidelines
This article does not contain any new studies with human or animal subjects performed by any of the authors.
All data used in this systematic review and meta-analysis are available in the published sources.
- 1.Silman A, Hochberg M. Epidemiology of the rheumatic diseases. 2nd ed. New York: Oxford University Press; 2001.Google Scholar
- 9.Donahue KE, Gartlehner G, Schulman ER, et al. Drug therapy for early rheumatoid arthritis: a systematic review update. Agency for Healthcare Research and Quality (US). Report No: 18-EHC015-EF. 2018.Google Scholar
- 11.National Institute for Health and Care Excellence. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed. 2015. https://www.nice.org.uk/guidance/ta375/documents/rheumatoid-arthritis-adalimumab-etanercept-infliximab-certolizumab-pegol-golimumab-abatacept-and-tocilizumab-review-id537-appraisal-consultation-document2. Accessed Oct 11, 2018.
- 17.The Center for Biosimilars. Biosimilar competition has led to consistent price reduction in Europe. 2017. https://www.centerforbiosimilars.com/news/biosimilar-competition-has-led-to-consistent-price-reduction-in-europe. Accessed Oct 11, 2018.
- 20.DAS28.nl. Alternative validated formulae. 2018. http://www.das-score.nl/das28/en/difference-between-the-das-and-das28/how-to-measure-the-das28/how-to-calculate-the-das28/alternative-validated-formulae.html. Accessed Aug 28, 2018.
- 21.Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. 2011. The Cochrane Collaboration. http://handbook.cochrane.org.
- 33.Emery P, Bingham CO 3rd, Burmester GR, et al. Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive 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. Ann Rheum Dis. 2017;76:96–104.PubMedCrossRefGoogle Scholar
- 35.Atsumi T, Yamamoto K, Takeuchi T, et al. 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. Ann Rheum Dis. 2016;75:75–83.PubMedCrossRefGoogle Scholar
- 36.Atsumi T, Tanaka Y, Yamamoto K, et al. Clinical benefit of 1-year certolizumab pegol (CZP) add-on therapy to methotrexate treatment in patients with early rheumatoid arthritis was observed following CZP discontinuation: 2-year results of the C-OPERA study, a phase III randomised trial. Ann Rheum Dis. 2017;76:1348–56.PubMedPubMedCentralCrossRefGoogle Scholar
- 37.Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet. 2008;372:375–82.PubMedCrossRefGoogle Scholar
- 39.Durez P, Malghem J, Nzeusseu Toukap A, et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum. 2007;56:3919–27.PubMedCrossRefGoogle Scholar
- 43.Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60:2272–83.PubMedCrossRefPubMedCentralGoogle Scholar
- 44.Emery P, Fleischmann RM, Doyle MK, et al. Golimumab, a human anti-tumor necrosis factor monoclonal antibody, injected subcutaneously every 4 weeks in patients with active rheumatoid arthritis who had never taken methotrexate: 1-year and 2-year clinical, radiologic, and physical function findings of a phase III, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Care Res (Hoboken). 2013;65:1732–42.PubMedCrossRefPubMedCentralGoogle Scholar
- 49.Detert J, Bastian H, Listing J, et al. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis. 2013;72:844–50.PubMedCrossRefPubMedCentralGoogle Scholar
- 50.Yamanaka H, Ishiguro N, Takeuchi T, et al. Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial. Rheumatology (Oxford). 2014;53:904–13.CrossRefGoogle Scholar
- 53.Nam JL, Villeneuve E, Hensor EM, et al. Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study). Ann Rheum Dis. 2014;73:75–85.PubMedCrossRefPubMedCentralGoogle Scholar
- 56.Leirisalo-Repo M, Kautiainen H, Laasonen L, et al. Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis. 2013;72:851–7.PubMedCrossRefPubMedCentralGoogle Scholar
- 57.Rantalaiho V, Kautiainen H, Korpela M, et al. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis. 2014;73:1954–61.PubMedCrossRefPubMedCentralGoogle Scholar
- 63.Horslev-Petersen K, Hetland ML, Junker P, et al. Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial. Ann Rheum Dis. 2014;73:654–61.PubMedCrossRefGoogle Scholar
- 65.Axelsen MB, Eshed I, Horslev-Petersen K, et al. A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial. Ann Rheum Dis. 2015;74:867–75.PubMedCrossRefPubMedCentralGoogle Scholar
- 67.Horslev-Petersen K, Hetland ML, Ornbjerg LM, et al. Clinical and radiographic outcome of a treat-to-target strategy using methotrexate and intra-articular glucocorticoids with or without adalimumab induction: a 2-year investigator-initiated, double-blinded, randomised, controlled trial (OPERA). Ann Rheum Dis. 2016;75:1645–53.PubMedCrossRefPubMedCentralGoogle Scholar
- 72.Ornbjerg LM, Ostergaard M, Jensen T, et al. Hand bone loss in early rheumatoid arthritis during a methotrexate-based treat-to-target strategy with or without adalimumab-a substudy of the optimized treatment algorithm in early RA (OPERA) trial. Clin Rheumatol. 2017;36:781–9.PubMedCrossRefPubMedCentralGoogle Scholar
- 73.Brahe CH, Ostergaard M, Johansen JS, et al. Predictive value of a multi-biomarker disease activity score for clinical remission and radiographic progression in patients with early rheumatoid arthritis: a post hoc study of the OPERA trial. Scand J Rheumatol. 2018. https://doi.org/10.1080/03009742.2018.1464206.CrossRefPubMedPubMedCentralGoogle Scholar
- 76.Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2013;72:64–71.PubMedCrossRefGoogle Scholar
- 78.Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26–37.PubMedCrossRefGoogle Scholar
- 84.Quinn MA, Conaghan PG, O’Connor PJ, et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52:27–35.PubMedCrossRefPubMedCentralGoogle Scholar
- 85.clinicaltrials.gov. NCT03492658. 2018. https://clinicaltrials.gov/ct2/show/NCT03492658. Accessed July 25, 2018.
- 86.clinicaltrials.gov. NCT02504268. 2017. https://clinicaltrials.gov/ct2/show/NCT02504268. Accessed July 15, 2018.
- 87.clinicaltrials.gov. NCT00901550. 2012. https://clinicaltrials.gov/ct2/show/NCT00901550. Accessed July 15, 2018.
- 88.clinicaltrials.gov. NCT00480272. 2017. https://clinicaltrials.gov/ct2/show/NCT00480272. Accessed July 15, 2018.
- 89.clinicaltrials.gov. NCT03160001. 2018. https://clinicaltrials.gov/ct2/show/NCT03160001. Accessed July 15, 2018.
- 90.clinicaltrials.gov. NCT01491815. 2018. https://clinicaltrials.gov/ct2/show/NCT01491815. Accessed July 15, 2018.
- 91.clinicaltrials.gov. NCT02935387. 2018. https://clinicaltrials.gov/ct2/show/NCT02935387. Accessed July 15, 2018.
- 92.clinicaltrials.gov. NCT00523692. 2007. https://clinicaltrials.gov/ct2/show/NCT00523692. Accessed July 15, 2018.
- 93.clinicaltrials.gov. NCT01245452. 2013. https://clinicaltrials.gov/ct2/show/NCT01245452. Accessed July 15, 2018.
- 94.clinicaltrials.gov. NCT02837146. 2016. https://clinicaltrials.gov/ct2/show/NCT02837146. Accessed July 15, 2018.
- 95.clinicaltrialregister.eu. EUCTR2011-004017-17-GB. 2013. https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-004017-17/GB. Accessed July 15, 2018.
- 96.clinicaltrialregister.eu. EUCTR2010-023910-30-GB. 2011. https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-023910-30/GB. Accessed July 15, 2018.
- 97.cris.nih.go.kr. KCT0000089. https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=1201. Accessed July 15, 2018.
- 98.isrctn.com. ISRCTN49682259. 2015. http://www.isrctn.com/ISRCTN49682259?q=&filters=conditionCategory:Musculoskeletal%20Diseases. Accessed July 15, 2018.
- 106.Stevenson M, Archer R, Tosh J, et al. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health Technol Assess. 2016;20:1–610.PubMedPubMedCentralGoogle Scholar