Skip to main content
SpringerLink
Log in

Efficacy and safety of methotrexate plus certolizumab pegol or placebo in active rheumatoid arthritis

Meta-analysis of randomized controlled trials

Wirksamkeit und Sicherheit von Methotrexat plus Certolizumab Pegol vs. MTX plus Placebo bei aktiver rheumatoider Arthritis

Metaanalyse randomisierter kontrollierter Studien

  • Originalien
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Abstract

Objectives

This study aimed to assess the relative efficacy and safety of certolizumab pegol (CZP) 200 and 400 mg + methotrexate (MTX) compared to placebo + MTX in patients with active rheumatoid arthritis (RA).

Methods

We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of CZP 200 and 400 mg + MTX and placebo + MTX (MTX group) in patients with active RA despite receiving MTX or a disease-modifying antirheumatic drug (DMARD).

Results

Six RCTs (30349 patients) met the inclusion criteria. The ACR20 response rate was significantly higher in the CZP 200 and 400 mg + MTX group than in the MTX group (OR 7.30, 95 % credible interval [CrI] 3.31–16.92 and OR 5.48, 95 % CrI 2.98–10.30, respectively). CZP 400 mg + MTX tended to be more efficacious than CZP 200 mg + MTX (OR 1.33, 95 % CrI 0.61–2.97). A surface under the cumulative ranking curve (SUCRA)-based ranking probability indicated that CZP 400 mg + MTX had the highest probability of achieving the ACR20 response rate, followed by CZP 200 mg + MTX and MTX (SUCRA = 0.9007, 0.7156, and 0.0002, respectively). The ACR20, 50, and 70 response rate distributions were comparable. However, the safety based on the number of adverse event (AE)-related withdrawals did not differ significantly among the three interventions.

Conclusions

CZP, at dosages of 200 and 400 mg, in combination with MTX, was the efficacious intervention for active RA without causing a significant risk of AE-related withdrawals.

Zusammenfassung

Zielsetzung

Ziel der Studie war die Evaluierung der relativen Wirksamkeit und der Sicherheit von Certolizumab Pegol (CZP) 200 und 400 mg in Kombination mit Methotrexat (MTX) im Vergleich zu Placebo plus MTX bei aktiver rheumatoider Arthritis (RA).

Methode

Durchgeführt wurde eine Netzwerk-Metaanalyse nach Bayes, um direkte wie indirekte Evidenz aus randomisierten kontrollierten Studien (RCTs) zur Effektivität und Sicherheit von CZP 200 und 400 mg + MTX und Placebo + MTX (MTX-Gruppe) bei Patienten mit aktiver RA trotz Anwendung von MTX oder einem Basistherapeutikum („disease-modifying anti-rheumatic drug“, DMARD) zusammenzustellen.

Ergebnisse

Sechs RCTs (3349 Patienten) erfüllten die Einschlusskriterien. In der Gruppe, die CZP 200 und 400 mg + MTX erhielt, war die ACR20-Ansprechrate höher als in der MTX-Gruppe (Odds Ratio [OR] 7,30, 95 %-CrI [„credible interval“] 3,31–16,92 bzw. OR 5,48, 95 %-CrI 2,98–10,30). CZP 400 mg + MTX war tendenziell wirksamer als CZP 200 mg + MTX (OR 1,33, 95 %-CrI 0,61–2,97). Anhand der SUCRA(„surface under the cumulative ranking“)-Kurve zeigte sich, dass die Wahrscheinlichkeit für ein ACR20-Ansprechen bei der Kombination CZP 400 mg + MTX am höchsten war, gefolgt von CZP 200 mg + MTX und MTX (SUCRA: 0,9007, 0,7156 bzw. 0,0002). Die Verteilungen der ACR20-, -50- und -70-Ansprechraten waren vergleichbar. Hinsichtlich der Sicherheit, basierend auf der Anzahl von Therapieabbrüchen bei unerwünschten Arzneimittelwirkungen, bestanden bei den 3 Interventionen keine signifikanten Unterschiede.

Schlussfolgerung

In Kombination mit MTX war CZP in Dosierungen von 200 und 400 mg eine effektive Intervention bei RA ohne signifikantes Risiko für Therapieabbrüche durch unerwünschte Arzneimittelwirkungen.

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. Harris ED Jr. (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322(18):1277–1289

    Article  PubMed  Google Scholar 

  2. Choi SJ, Rho YH, Ji JD, Song GG, Lee YH (2006) Genome scan meta-analysis of rheumatoid arthritis. Rheumatology (Oxford) 45(2):166–170

    Article  CAS  Google Scholar 

  3. Brennan FM, Maini RN, Feldmann M (1992) TNF alpha-a pivotal role in rheumatoid arthritis? Br J Rheumatol 31(5):293–298

    Article  CAS  PubMed  Google Scholar 

  4. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Furst D, Weisman MH et al (2004) Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum 50(4):1051–1065

    Article  CAS  PubMed  Google Scholar 

  5. Mohler KM, Murray KM, Mann DL, Francis G (2000) Use of targeted anticytokine treatments in heart failure. Circulation 102(9):E65

    Article  CAS  PubMed  Google Scholar 

  6. Goel N, Stephens S (2010) Certolizumab pegol. MAbs 2(2):137–147

    Article  PubMed  PubMed Central  Google Scholar 

  7. Nesbitt A, Fossati G, Bergin M, Stephens P, Stephens S, Foulkes R et al (2007) Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor alpha agents. Inflamm Bowel Dis 13(11):1323–1332

    Article  PubMed  Google Scholar 

  8. McDonnell T, Ioannou Y, Rahman A (2014) PEGylated drugs in rheumatology-why develop them and do they work? Rheumatology 53(3):391–396

    Article  CAS  PubMed  Google Scholar 

  9. Smolen JS, Vollenhoven R van, Kavanaugh A, Strand V, Vencovsky J, Schiff M et al (2015) Certolizumab pegol plus methotrexate 5‑year results from the rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and long-term extension in rheumatoid arthritis patients. Arthritis Res Ther 17:245

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K et al (2014) 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. Mod Rheumatol 24(5):715–724

    Article  CAS  PubMed  Google Scholar 

  11. Weinblatt ME, Fleischmann R, Huizinga TW, Emery P, Pope J, Massarotti EM et al (2012) Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study. Rheumatology (Oxford) 51(12):2204–2214

    Article  CAS  Google Scholar 

  12. Choy E, McKenna F, Vencovsky J, Valente R, Goel N, Vanlunen B et al (2012) Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX. Rheumatology (Oxford) 51(7):1226–1234

    Article  CAS  Google Scholar 

  13. Smolen J, Landewe RB, Mease P, Brzezicki J, Mason D, Luijtens K et al (2009) Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 68(6):797–804

    Article  CAS  PubMed  Google Scholar 

  14. Keystone E, Heijde D, Mason D Jr., Landewe R, Vollenhoven RV, Combe B et al (2008) 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. Arthritis Rheum 58(11):3319–3329

    Article  CAS  PubMed  Google Scholar 

  15. Zhou Q, Zhou Y, Chen H, Wang Z, Tang Z, Liu J (2014) The efficacy and safety of certolizumab pegol (CZP) in the treatment of active rheumatoid arthritis (RA): a meta-analysis from nine randomized controlled trials. Int J Clin Exp Med 7(11):3870–3880

    PubMed  PubMed Central  Google Scholar 

  16. Caldwell DM, Ades A, Higgins J (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331(7521):897

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12

    Article  CAS  PubMed  Google Scholar 

  18. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269

    Article  PubMed  Google Scholar 

  19. Brown S, Hutton B, Clifford T, Coyle D, Grima D, Wells G et al (2014) A Microsoft-Excel-based tool for running and critically appraising network meta-analyses-an overview and application of NetMetaXL. Syst Rev 3(1):110

    Article  PubMed  PubMed Central  Google Scholar 

  20. Salanti G, Ades A, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64(2):163–171

    Article  PubMed  Google Scholar 

  21. Dias S, Welton NJ, Sutton AJ, Caldwell DM, Lu G, Ades A (2013) Evidence synthesis for decision making 4 inconsistency in networks of evidence based on randomized controlled trials. Med Decis Making 33(5):641–656

    Article  PubMed  PubMed Central  Google Scholar 

  22. Higgins J, Jackson D, Barrett J, Lu G, Ades A, White I (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Valkenhoef G, Lu G, Brock B, Hillege H, Ades A, Welton NJ (2012) Automating network meta-analysis. Res Synth Methods 3(4):285–299

    Article  PubMed  Google Scholar 

  24. Strand V, Mease P, Burmester GR, Nikai E, Coteur G, Vollenhoven R van et al (2009) Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial. Arthritis Res Ther 11(6):R170

    Article  PubMed  PubMed Central  Google Scholar 

  25. Strand V, Smolen JS, Vollenhoven RF van, Mease P, Burmester GR, Hiepe F et al (2011) Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial. Ann Rheum Dis 70(6):996–1002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fleischmann R, Vencovsky J, Vollenhoven RF van, Borenstein D, Box J, Coteur G et al (2009) Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 68(6):805–811

    Article  CAS  PubMed  Google Scholar 

  27. Herman S, Zurgil N, Deutsch M (2005) Low dose methotrexate induces apoptosis with reactive oxygen species involvement in T lymphocytic cell lines to a greater extent than in monocytic lines. Inflamm Res 54(7):273–280

    Article  CAS  PubMed  Google Scholar 

  28. Mavridis D, Giannatsi M, Cipriani A, Salanti G (2015) A primer on network meta-analysis with emphasis on mental health. Evid Based Ment Health 18(2):40–46

    Article  PubMed  Google Scholar 

  29. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C et al (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162(11):777–784

    Article  PubMed  Google Scholar 

  30. Schmitz S, Adams R, Walsh CD, Barry M, FitzGerald O (2011) A mixed treatment comparison of the efficacy of anti-TNF agents in rheumatoid arthritis for methotrexate non-responders demonstrates differences between treatments: a Bayesian approach. Ann Rheum Dis : doi:10.1136/annrheumdis-2011-200228

    PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported in part by a grant of the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (HI15C2958).

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Korea University Anam Hospital, 73 Inchon-ro, 02841, Seoul, Korea

    Y. H. Lee M.D., Ph.D.

  2. Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea

    S.-C. Bae

Authors
  1. Y. H. Lee M.D., Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S.-C. Bae
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y. H. Lee M.D., Ph.D..

Ethics declarations

Conflict of interest

Y. H. Lee and S.-C. Bae state that there are no conflicts of interest.

The accompanying manuscript does not include studies on humans or animals performed by any of the authors.

Additional information

Redaktion

U. Müller-Ladner, Bad Nauheim

U. Lange, Bad Nauheim

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, Y.H., Bae, SC. Efficacy and safety of methotrexate plus certolizumab pegol or placebo in active rheumatoid arthritis. Z Rheumatol 76, 528–534 (2017). https://doi.org/10.1007/s00393-016-0133-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-016-0133-z

Keywords

Schlüsselwörter

Search

Navigation