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The Challenge of Treating Early-Stage Rheumatoid Arthritis: The Contribution of Mixed Treatment Comparison to Choosing Appropriate Biologic Agents

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Abstract

Background

Use of biologic drugs is approved for treatment in rheumatoid arthritis (RA), both in established disease and at the early stage of RA (ERA). Identification of ERA and an early therapeutic strategy would lead to greater clinical improvement. Only a few indirect comparisons of the efficacy of different biologic agents in established RA have been performed and, to date, no studies reporting direct comparisons have been performed in ERA.

Objective

The aim of this study was to compare, by use of a mixed treatment comparison (MTC), the efficacy profiles of biologic agents in ERA.

Methods

An extensive literature search was performed to identify results of randomized, controlled trials (RCTs) evaluating biologic agents at licensed doses to treat patients affected by ERA. The primary end points for the analysis were the American College of Rheumatology 20 % improvement (ACR20), ACR50, and ACR70 responses from baseline to various times of follow-up. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses. The MTC results are reported as the relative risk of a response for every single treatment coadministered with methotrexate, versus methotrexate plus placebo, which was used as a comparator in all RCTs.

Results

Ten scientific papers met the study inclusion criteria and were included in the analysis. Data on the use of infliximab, adalimumab, etanercept, abatacept, golimumab, and rituximab were included. No studies reported on the use of certolizumab pegol or tocilizumab in ERA. All biologic agents coadministered with methotrexate proved to be more efficacious than methotrexate plus placebo in inducing ACR20, ACR50, and ACR70 responses. The biologic agent characterized by the highest probability of inducing an ACR70 response was adalimumab (33.28 %). Etanercept was the biologic agent with the highest probability of inducing ACR20 and ACR50 responses, in comparison with all other biologic agents, with probability rates of 62.95 and 37.1 %, respectively.

Conclusion

In our analysis, adalimumab proved to be the biologic agent with the highest probability of inducing an ACR70 response in patients affected by ERA, while etanercept was the biologic agent with the highest probability of inducing ACR50 and ACR20 responses.

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References

  1. Smolena JS, Aletaha D, Redlich K. The pathogenesis of rheumatoid arthritis: new insights from old clinical data? Nat Rev Rheumatol. 2012;8(4):235–43.

    Article  Google Scholar 

  2. Navarro-Millán I, Curtis JR. Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis. Curr Opin Rheumatol. 2013;25(3):384–90.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Demoruelle MK, Deane KD. Treatment strategies in early rheumatoid arthritis and prevention of rheumatoid arthritis. Curr Rheumatol Rep. 2012;14(5):472–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. McQueen FM. Imaging in early rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2013;27(4):499–522. doi:10.1016/j.berh.2013.09.005.

    Article  PubMed  Google Scholar 

  5. van der Helm-van Mil AH, le Cessie S, van Dongen H, Breedveld FC, Toes RE, Huizinga TW. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 2007;56:433–40.

  6. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569–81.

    Article  PubMed  Google Scholar 

  7. Zeidler H. The need to better classify and diagnose early and very early rheumatoid arthritis. J Rheumatol. 2012;39:212–7.

    Article  PubMed  Google Scholar 

  8. Cader MZ, Filer A, Hazlehurst J, de Pablo P, Buckley CD, Raza K. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis. 2011;70:949–55.

    Article  PubMed  Google Scholar 

  9. van der Linden MP, Knevel R, Huizinga TW, van der Helmvan Mil AH. Classification of rheumatoid arthritis: comparison of the 1987 American College of Rheumatology criteria and the 2010 American College of Rheumatology/European League Against Rheumatism criteria. Arthritis Rheum. 2011;63:37–42.

    Article  CAS  PubMed  Google Scholar 

  10. Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. Comparative efficacy of novel DMARDs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with inadequate response to conventional DMARDs: a network meta-analysis. J Manag Care Spec Pharm. 2015;21(5):409–23.

    Article  PubMed  Google Scholar 

  11. Hochberg MC, Berry S, Broglio K, Rosenblatt L, Nadkarni A, Trivedi D, Hebden T. Mixed treatment comparison of efficacy and tolerability of biologic agents in patients with rheumatoid arthritis. Curr Med Res Opin. 2013;29(10):1213–22.

    Article  CAS  PubMed  Google Scholar 

  12. Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A. Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70. Biologics. 2012;6:429–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Devine EB, Alfonso-Cristancho R, Sullivan SD. Effectiveness of biologic therapies for rheumatoid arthritis: an indirect comparisons approach. Pharmacotherapy. 2011;31(1):39–51.

    Article  CAS  PubMed  Google Scholar 

  14. Bergman GJ, Hochberg MC, Boers M, Wintfeld N, Kielhorn A, Jansen JP. Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs. Semin Arthritis Rheum. 2010;39(6):425–41.

    Article  CAS  PubMed  Google Scholar 

  15. 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(8):398–404.

    Article  PubMed  Google Scholar 

  16. Jansen JP, Crawford B, Bergman G, Stam W. Bayesian meta-analysis of multiple treatment comparisons: an introduction to mixed treatment comparisons. Value Health. 2008;11(5):956–64.

  17. Moher D, Liberati A, Tetzlaff J, Altman DG; The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9, W64.

  18. Detert J, Bastian H, Listing J, Weiß A, Wassenberg S, Liebhaber A, Rockwitz K, Alten R, Krüger K, Rau R, Simon C, Gremmelsbacher E, Braun T, Marsmann B, Höhne-Zimmer V, Egerer K, Buttgereit F, Burmester GR. 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(6):844–50.

    Article  CAS  PubMed  Google Scholar 

  19. Emery P, Kvien TK, Combe B, Freundlich B, Robertson D, Ferdousi T, Bananis E, Pedersen R, Koenig AS. Combination etanercept and methotrexate provides better disease control in very early (≤4 months) versus early rheumatoid arthritis (>4 months and <2 years): post hoc analyses from the COMET study. Ann Rheum Dis. 2012;71(6):989–92.

    Article  CAS  PubMed  Google Scholar 

  20. Karlsson JA, Neovius M, Nilsson JÅ, Petersson IF, Bratt J, van Vollenhoven RF, Ernestam S, Geborek P. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled. SWEFOT trial. Ann Rheum Dis. 2013;72(12):1927–33.

    Article  CAS  PubMed  Google Scholar 

  21. St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50(11):3432–43.

  22. Quinn MA, Conaghan PG, O’Connor PJ, Karim Z, Greenstein A, Brown A, Brown C, Fraser A, Jarret S, Emery P. 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(1):27–35.

    Article  CAS  PubMed  Google Scholar 

  23. Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT. 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(1):26–37.

    Article  CAS  PubMed  Google Scholar 

  24. Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, Luyten FP, Corluy L, Houssiau FA, Verschueren P. 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(12):3919–27.

    Article  CAS  PubMed  Google Scholar 

  25. Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B. 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(9636):375–82.

    Article  CAS  PubMed  Google Scholar 

  26. Bejarano V, Quinn M, Conaghan PG, Reece R, Keenan AM, Walker D, Gough A, Green M, McGonagle D, Adebajo A, Jarrett S, Doherty S, Hordon L, Melsom R, Unnebrink K, Kupper H, Emery P, Yorkshire Early Arthritis Register Consortium. 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(10):1467–74.

    Article  PubMed  Google Scholar 

  27. Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, Becker JC, Covucci A, Helfrick R, Bathon J. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis. 2009;68(12):1870–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, Nash P, Amante EJ, Churchill M, Park W, Pons-Estel BA, Doyle MK, Visvanathan S, Xu W, Rahman MU. 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(8):2272–83.

    Article  CAS  PubMed  Google Scholar 

  29. Tak PP, Rigby W, Rubbert-Roth A, Peterfy C, van Vollenhoven RF, Stohl W, Healy E, Hessey E, Reynard M, Shaw T. Sustained inhibition of progressive joint damage with rituximab plus methotrexate in early active rheumatoid arthritis: 2-year results from the randomised controlled trial IMAGE. Ann Rheum Dis. 2012;71(3):351–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kavanaugh A, Fleischmann RM, Emery P, Kupper H, Redden L, Guerette B, Santra S, Smolen JS. 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(1):64–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Uhlig T, Moe RH, Kvien TK. The burden of disease in rheumatoid arthritis. Pharmacoeconomics. 2014;32(9):841–51.

    Article  PubMed  Google Scholar 

  32. Chevreul K, Haour G, Lucier S, Harvard S, Laroche ML, Mariette X, Saraux A, Durand-Zaleski I, Guillemin F, Fautrel B. Evolution of direct costs in the first years of rheumatoid arthritis: impact of early versus late biologic initiation—an economic analysis based on the ESPOIR cohort. PLoS One. 2014;9(5):e97077.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Hallert E, Husberg M, Kalkan A, Skogh T, Bernfort L. Early rheumatoid arthritis 6 years after diagnosis is still associated with high direct costs and increasing loss of productivity: the Swedish TIRA project. Scand J Rheumatol. 2014;43(3):177–83.

    Article  CAS  PubMed  Google Scholar 

  34. Smolen JS, Aletaha D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol. 2015;11(5):276–89.

    Article  PubMed  Google Scholar 

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Author contributions

Alberto Migliore contributed to the conception of the study and to the selection of studies for inclusion in the MTC analysis. Emanuele Bizzi and Vincenzo Bruzzese contributed to the selection of studies for inclusion in the MTC analysis and to the drafting of the manuscript. Lea Petrella contributed to the statistical analysis and to the interpretation of the data. Maurizio Cassol and Davide Integlia contributed to the conception of the study and to the drafting of the manuscript.

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Authors and Affiliations

  1. Rheumatology Department, San Pietro Fatebenefratelli Hospital, via Cassia 600, 00189, Rome, Italy

    Alberto Migliore & Emanuele Bizzi

  2. International Society For Pharmacoeconomics and Outcomes Research (ISPOR), Rome, Italy

    Alberto Migliore

  3. Methods and Models for Economics, Territory and Finance (MEMOTEF) Department, Sapienza University of Rome, Rome, Italy

    Lea Petrella

  4. Internal Medicine and Gastroenterology Department, Nuovo Regina Margherita Hospital, Rome, Italy

    Vincenzo Bruzzese

  5. Internal Medicine Department, San Pietro Fatebenefratelli Hospital, Rome, Italy

    Maurizio Cassol

  6. Integrated Solutions Health Economics and Organization (ISHEO), Rome, Italy

    Davide Integlia

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  1. Alberto Migliore
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  4. Vincenzo Bruzzese
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Corresponding author

Correspondence to Emanuele Bizzi.

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Conflicts of interest

Alberto Migliore has received grants as a consultant for Pfizer, Abbvie and Bristol-Myers Squibb. Vincenzo Bruzzese has received grants as a consultant for Pfizer and Abbvie. Emanuele Bizzi, Lea Petrella, Maurizio Cassol, and Davide Integlia have no conflicts of interest that are directly relevant to the content of this article.

Funding

This study was performed with unrestricted funding from ANTIAGE Onlus (Non-lucrative National Association for Ultrasound-Guided Intra-articular Injection of the Hip), of which Alberto Migliore is the President.

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Migliore, A., Bizzi, E., Petrella, L. et al. The Challenge of Treating Early-Stage Rheumatoid Arthritis: The Contribution of Mixed Treatment Comparison to Choosing Appropriate Biologic Agents. BioDrugs 30, 105–115 (2016). https://doi.org/10.1007/s40259-016-0164-7

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  • DOI: https://doi.org/10.1007/s40259-016-0164-7

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