Skip to main content
SpringerLink
Log in

Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusion

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.

Plain Language Summary

Plain language summary available for this article.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Silman A, Hochberg M. Epidemiology of the rheumatic diseases. 2nd ed. New York: Oxford University Press; 2001.

    Google Scholar 

  2. Curtis JR, Singh JA. Use of biologics in rheumatoid arthritis: current and emerging paradigms of care. Clin Ther. 2011;33:679–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Monaco C, Nanchahal J, Taylor P, Feldmann M. Anti-TNF therapy: past, present and future. Int Immunol. 2015;27:55–62.

    Article  CAS  PubMed  Google Scholar 

  4. Watson K, Symmons D, Griffiths I, Silman A. The British Society for Rheumatology biologics register. Ann Rheum Dis. 2005;64(Suppl 4):iv42–3.

    PubMed  PubMed Central  Google Scholar 

  5. van Nies JA, Krabben A, Schoones JW, Huizinga TW, Kloppenburg M, van der Helm-van Mil AH. What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review. Ann Rheum Dis. 2014;73:861–70.

    Article  PubMed  Google Scholar 

  6. Dennison EM, Packham J, Hyrich K. The BSRBR-RA at 15 years. Rheumatology (Oxford). 2016;55:2093–5.

    Article  Google Scholar 

  7. Singh JA, Hossain A, Mudano AS, et al. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2017;5:CD012657.

    PubMed  Google Scholar 

  8. Cai W, Gu Y, Cui H, et al. The efficacy and safety of mainstream medications for patients with DMARD-naive rheumatoid arthritis: a network meta-analysis. Front Pharmacol. 2018;9:138.

    Article  CAS  PubMed  PubMed Central  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.

  10. van der Velde G, Pham B, Machado M, et al. Cost-effectiveness of biologic response modifiers compared to disease-modifying antirheumatic drugs for rheumatoid arthritis: a systematic review. Arthritis Care Res (Hoboken). 2011;63:65–78.

    Article  PubMed  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.

  12. Smolen JS, Landewe R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76:960–77.

    Article  PubMed  Google Scholar 

  13. Putrik P, Ramiro S, Kvien TK, et al. Variations in criteria regulating treatment with reimbursed biologic DMARDs across European countries. Are differences related to country’s wealth? Ann Rheum Dis. 2014;73:2010–21.

    Article  PubMed  Google Scholar 

  14. Pentek M, Poor G, Wiland P, et al. Biological therapy in inflammatory rheumatic diseases: issues in Central and Eastern European countries. Eur J Health Econ. 2014;15(Suppl 1):S35–43.

    Article  PubMed  Google Scholar 

  15. Baji P, Pentek M, Czirjak L, et al. Efficacy and safety of infliximab-biosimilar compared to other biological drugs in rheumatoid arthritis: a mixed treatment comparison. Eur J Health Econ. 2014;15(Suppl 1):S53–64.

    Article  PubMed  Google Scholar 

  16. Brodszky V, Baji P, Balogh O, Pentek M. Budget impact analysis of biosimilar infliximab (CT-P13) for the treatment of rheumatoid arthritis in six Central and Eastern European countries. Eur J Health Econ. 2014;15(Suppl 1):S65–71.

    Article  PubMed  Google Scholar 

  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.

  18. Haddaway NR, Collins AM, Coughlin D, Kirk S. The role of Google Scholar in evidence reviews and its applicability to grey literature searching. PLoS ONE. 2015;10:e0138237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hobbs KF, Cohen MD. Rheumatoid arthritis disease measurement: a new old idea. Rheumatology (Oxford). 2012;51(Suppl 6):vi21–7.

    Article  PubMed  Google Scholar 

  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.

  22. St Clair EW, van der Heijde DM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50:3432–43.

    Article  CAS  PubMed  Google Scholar 

  23. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  24. Bejarano V, Quinn M, Conaghan PG, et al. Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis. Arthritis Rheum. 2008;59:1467–74.

    Article  PubMed  Google Scholar 

  25. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005;52:3381–90.

    Article  CAS  PubMed  Google Scholar 

  26. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406–15.

    Article  PubMed  Google Scholar 

  27. van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis. 2009;68:914–21.

    Article  PubMed  Google Scholar 

  28. Klarenbeek NB, Guler-Yuksel M, van der Kooij SM, et al. The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study. Ann Rheum Dis. 2011;70:1039–46.

    Article  PubMed  Google Scholar 

  29. Markusse IM, Dirven L, Han KH, et al. Continued participation in a ten-year tight control treat-to-target study in rheumatoid arthritis: why keep patients doing their best? Arthritis Care Res (Hoboken). 2015;67:739–45.

    Article  PubMed  Google Scholar 

  30. Akdemir G, Markusse IM, Dirven L, et al. Effectiveness of four dynamic treatment strategies in patients with anticitrullinated protein antibody-negative rheumatoid arthritis: a randomised trial. RMD Open. 2016;2:e000143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Markusse IM, Akdemir G, Dirven L, et al. Long-term outcomes of patients with recent-onset rheumatoid arthritis after 10 years of tight controlled treatment: a randomized trial. Ann Intern Med. 2016;164:523–31.

    Article  PubMed  Google Scholar 

  32. Bergstra SA, Landewe RBM, Huizinga TWJ, Allaart CF. Rheumatoid arthritis patients with continued low disease activity have similar outcomes over 10 years, regardless of initial therapy. Rheumatology (Oxford). 2017;56:1721–8.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  34. Weinblatt ME, Bingham CO 3rd, Burmester GR, et al. A Phase III study evaluating continuation, tapering, and withdrawal of certolizumab pegol after one year of therapy in patients with early rheumatoid arthritis. Arthritis Rheumatol. 2017;69:1937–48.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  38. Emery P, Breedveld F, van der Heijde D, et al. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Arthritis Rheum. 2010;62:674–82.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  40. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586–93.

    Article  CAS  PubMed  Google Scholar 

  41. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes. Arthritis Rheum. 2002;46:1443–50.

    Article  CAS  PubMed  Google Scholar 

  42. Genovese MC, Bathon JM, Fleischmann RM, et al. Long term safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumatol. 2005;32:1232–42.

    CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  45. Baker JF, Conaghan PG, Emery P, Baker DG, Ostergaard M. Validity of early MRI structural damage end points and potential impact on clinical trial design in rheumatoid arthritis. Ann Rheum Dis. 2016;75:1114–9.

    Article  CAS  PubMed  Google Scholar 

  46. Emery P, Fleischmann RM, Strusberg I, et al. Efficacy and safety of subcutaneous golimumab in methotrexate-naive patients with rheumatoid arthritis: five-year results of a randomized clinical trial. Arthritis Care Res (Hoboken). 2016;68:744–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Baker JF, Conaghan PG, Emery P, Baker DG, Ostergaard M. Relationship of patient-reported outcomes with MRI measures in rheumatoid arthritis. Ann Rheum Dis. 2017;76:486–90.

    Article  PubMed  Google Scholar 

  48. Soubrier M, Puechal X, Sibilia J, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford). 2009;48:1429–34.

    Article  CAS  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  Google Scholar 

  51. Takeuchi T, Yamanaka H, Ishiguro N, et al. Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study. Ann Rheum Dis. 2014;73:536–43.

    Article  CAS  PubMed  Google Scholar 

  52. Tanaka Y, Yamanaka H, Ishiguro N, et al. Low disease activity for up to 3 years after adalimumab discontinuation in patients with early rheumatoid arthritis: 2-year results of the HOPEFUL-3 Study. Arthritis Res Ther. 2017;19:56.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google Scholar 

  54. Bissell LA, Hensor EM, Kozera L, et al. Improvement in insulin resistance is greater when infliximab is added to methotrexate during intensive treatment of early rheumatoid arthritis-results from the IDEA study. Rheumatology (Oxford). 2016;55:2181–90.

    Article  CAS  Google Scholar 

  55. Marcora SM, Chester KR, Mittal G, Lemmey AB, Maddison PJ. Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients with early rheumatoid arthritis. Am J Clin Nutr. 2006;84:1463–72.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  58. Kuusalo L, Puolakka K, Kautiainen H, et al. Impact of physicians’ adherence to treat-to-target strategy on outcomes in early rheumatoid arthritis in the NEO-RACo trial. Scand J Rheumatol. 2015;44:449–55.

    Article  CAS  PubMed  Google Scholar 

  59. Kuusalo LA, Puolakka KT, Kautiainen H, et al. Intra-articular glucocorticoid injections should not be neglected in the remission targeted treatment of early rheumatoid arthritis: a post hoc analysis from the NEO-RACo trial. Clin Exp Rheumatol. 2016;34:1038–44.

    PubMed  Google Scholar 

  60. Kuusalo L, Puolakka K, Kautiainen H, et al. Patient-reported outcomes as predictors of remission in early rheumatoid arthritis patients treated with tight control treat-to-target approach. Rheumatol Int. 2017;37:825–30.

    Article  PubMed  Google Scholar 

  61. Vaananen T, Vuolteenaho K, Kautiainen H, et al. Glycoprotein YKL-40: a potential biomarker of disease activity in rheumatoid arthritis during intensive treatment with csDMARDs and infliximab.Evidence from the randomised controlled NEO-RACo trial. PLoS ONE. 2017;12:0183294.

    Article  CAS  Google Scholar 

  62. Kuusalo L, Puolakka K, Kautiainen H, et al. High burden of adverse events is associated with reduced remission rates in early rheumatoid arthritis. Clin Rheumatol. 2018;37:1689–94.

    Article  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  64. Andersen T, Hvid M, Johansen C, et al. Interleukin-23 in early disease development in rheumatoid arthritis. Scand J Rheumatol. 2015;44:438–42.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  66. Greisen SR, Moller HJ, Stengaard-Pedersen K, et al. Macrophage activity assessed by soluble CD163 in early rheumatoid arthritis: association with disease activity but different response patterns to synthetic and biologic DMARDs. Clin Exp Rheumatol. 2015;33:498–502.

    PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  68. Kragstrup TW, Greisen SR, Nielsen MA, et al. The interleukin-20 receptor axis in early rheumatoid arthritis: novel links between disease-associated autoantibodies and radiographic progression. Arthritis Res Ther. 2016;18:61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Krintel SB, Dehlendorff C, Hetland ML, et al. Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J. 2016;16:141–6.

    Article  CAS  PubMed  Google Scholar 

  70. Heftdal LD, Stengaard-Pedersen K, Ornbjerg LM, et al. Soluble CD206 plasma levels in rheumatoid arthritis reflect decrease in disease activity. Scand J Clin Lab Invest. 2017;77:385–9.

    Article  CAS  PubMed  Google Scholar 

  71. Kristensen AM, Stengaard-Pedersen K, Hetland ML, et al. Expression of soluble CD83 in plasma from early-stage rheumatoid arthritis patients is not modified by anti-TNF-alpha therapy. Cytokine. 2017;96:1–7.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  PubMed  Google Scholar 

  74. Sode J, Krintel SB, Carlsen AL, et al. Plasma microRNA profiles in patients with early rheumatoid arthritis responding to adalimumab plus methotrexate vs methotrexate alone: a placebo-controlled clinical trial. J Rheumatol. 2018;45:53–61.

    Article  CAS  PubMed  Google Scholar 

  75. Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet. 2014;383:321–32.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  77. Emery P, Smolen JS, Ganguli A, et al. Effect of adalimumab on the work-related outcomes scores in patients with early rheumatoid arthritis receiving methotrexate. Rheumatology (Oxford). 2016;55:1458–65.

    Article  CAS  Google 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.

    Article  CAS  PubMed  Google Scholar 

  79. van der Heijde D, Breedveld FC, Kavanaugh A, et al. Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate: 5-year results of PREMIER. J Rheumatol. 2010;37:2237–46.

    Article  PubMed  Google Scholar 

  80. Strand V, Rentz AM, Cifaldi MA, Chen N, Roy S, Revicki D. Health-related quality of life outcomes of adalimumab for patients with early rheumatoid arthritis: results from a randomized multicenter study. J Rheumatol. 2012;39:63–72.

    Article  CAS  PubMed  Google Scholar 

  81. Landewe R, Smolen JS, Florentinus S, Chen S, Guerette B, van der Heijde D. Existing joint erosions increase the risk of joint space narrowing independently of clinical synovitis in patients with early rheumatoid arthritis. Arthritis Res Ther. 2015;17:133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Stephens S, Botteman MF, Cifaldi MA, van Hout BA. Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease. BMJ Open. 2015;5:e006560.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Moller B, Everts-Graber J, Florentinus S, Li Y, Kupper H, Finckh A. Low hemoglobin and radiographic damage progression in early rheumatoid arthritis: secondary analysis from a phase III trial. Arthritis Care Res (Hoboken). 2018;70:861–8.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google 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.

  99. Albert DA. Are all biologics the same? Optimal treatment strategies for patients with early rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. J Clin Rheumatol. 2015;21:398–404.

    Article  PubMed  Google Scholar 

  100. Hifinger M, Hiligsmann M, Ramiro S, et al. Economic considerations and patients’ preferences affect treatment selection for patients with rheumatoid arthritis: a discrete choice experiment among European rheumatologists. Ann Rheum Dis. 2017;76:126–32.

    Article  CAS  PubMed  Google Scholar 

  101. Taylor PC, Alten R, Reino JJG, et al. Factors influencing the use of biologic therapy and adoption of treat-to-target recommendations in current European rheumatology practice. Patient Prefer Adherence. 2018;12:2007–14.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther. 2015;17:181.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Nam JL, Villeneuve E, Hensor EM, et al. A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial. Ann Rheum Dis. 2014;73:1027–36.

    Article  CAS  PubMed  Google Scholar 

  104. Stamm TA, Machold KP, Aletaha D, et al. Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial. Arthritis Res Ther. 2018;20:174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Combe B, Landewe R, Daien CI, et al. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. 2017;76:948–59.

    Article  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  107. Dorner T, Strand V, Cornes P, et al. The changing landscape of biosimilars in rheumatology. Ann Rheum Dis. 2016;75:974–82.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Funding

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.

Authorship

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.

Disclosures

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.

Data Availability

All data used in this systematic review and meta-analysis are available in the published sources.

Author information

Author notes

  1. László Gulácsi and Zsombor Zrubka contributed equally to this work.

Authors and Affiliations

  1. Department of Health Economics, Corvinus University of Budapest, Budapest, Hungary

    László Gulácsi, Zsombor Zrubka, Valentin Brodszky, Fanni Rencz & Márta Péntek

  2. Doctoral School of Business and Management, Corvinus University of Budapest, Budapest, Hungary

    Zsombor Zrubka

  3. Rheumatology Research Center, Schlosspark-Klinik Charite, University Medicine Berlin, Berlin, Germany

    Rieke Alten

  4. Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Zoltán Szekanecz

  5. Department of Rheumatology, Flór Ferenc County Hospital, Kistarcsa, Hungary

    Márta Péntek

Authors
  1. László Gulácsi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zsombor Zrubka
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentin Brodszky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fanni Rencz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rieke Alten
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zoltán Szekanecz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Márta Péntek
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to László Gulácsi.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.7498988.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 3153 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gulácsi, L., Zrubka, Z., Brodszky, V. et al. Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naïve Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis. Adv Ther 36, 721–745 (2019). https://doi.org/10.1007/s12325-018-0869-8

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-018-0869-8

Keywords

Search

Navigation