Clinical Rheumatology

, Volume 37, Issue 5, pp 1199–1205 | Cite as

Comparative efficacy and safety of biosimilar adalimumab and originator adalimumab in combination with methotrexate in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials

  • Sang-Cheol Bae
  • Young Ho LeeEmail author
Original Article


We aimed to assess the relative efficacy and safety of biosimilar adalimumab and originator adalimumab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA) who showed an inadequate response to MTX. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of biosimilar + MTX and adalimumab + MTX versus placebo + MTX (MTX group) in patients with active RA despite treatment with MTX. A total of eight RCTs involving 2543 patients met the inclusion criteria. The ACR20 response rate was significantly higher in the biosimilar + MTX (odds ratio [OR] 2.91, 95% credible interval [CrI] 1.57–5.74) and adalimumab + MTX (OR 2.80, 95% CrI 1.81–4.46) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar + MTX and adalimumab + MTX groups. Biosimilar + MTX had the highest probability of being the best treatment in terms of the ACR20 response rate (surface under the cumulative ranking curve [SUCRA] = 0.7896), followed by adalimumab + MTX (SUCRA = 0.7082) and MTX (SUCRA = 0.0022). The ACR50 and ACR70 response rates showed a distribution pattern similar to that of the ACR20 response rate. Safety based on the number of serious adverse events did not differ significantly among the three interventions in the follow-up period of 12 to 24 weeks. Biosimilar and originator adalimumab, in combination with MTX, represent an effective intervention for active RA despite treatment with MTX. No significant difference was found between biosimilar and originator adalimumab in terms of efficacy and safety. However, follow-up in RCTs is short and not all safety outcomes can be assessed in RCTs. Thus, additional long-term evaluations are needed.


Adalimumab Biosimilar Network meta-analysis Rheumatoid arthritis 


Funding information

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).

Compliance with ethical standards



Supplementary material

10067_2018_4002_MOESM1_ESM.docx (70 kb)
ESM 1 (DOCX 70 kb)


  1. 1.
    Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. The LancetGoogle Scholar
  2. 2.
    Salfeld J, Kaymakcalan Z, Tracey D, Roberts A, Kamen R (1998) Generation of fully human anti-TNF antibody D2E7. Arthritis Rheum 41:S57Google Scholar
  3. 3.
    Weinblatt ME, Baranauskaite A, Niebrzydowski J, Dokoupilova E, Zielinska A, Jaworski J, Racewicz A, Pileckyte M, Jedrychowicz-Rosiak K, Cheong SY (2017) Phase 3 randomized study of SB5, an adalimumab biosimilar, versus reference adalimumab in patients with moderate to severe rheumatoid arthritis Arthritis RheumatolGoogle Scholar
  4. 4.
    Jamshidi A, Gharibdoost F, Vojdanian M, Soroosh SG, Soroush M, Ahmadzadeh A, Nazarinia MA, Mousavi M, Karimzadeh H, Shakibi MR (2017) A phase III, randomized, two-armed, double-blind, parallel, active controlled, and non-inferiority clinical trial to compare efficacy and safety of biosimilar adalimumab (CinnoRA®) to the reference product (Humira®) in patients with active rheumatoid arthritis. Arthritis Res Ther 19:168CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cohen S, Genovese MC, Choy E, Perez-Ruiz F, Matsumoto A, Pavelka K, Pablos JL, Rizzo W, Hrycaj P, Zhang N (2017) Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study Annals of the Rheumatic Diseases: annrheumdis-2016-210459Google Scholar
  6. 6.
    Jani RH, Gupta R, Bhatia G, Rathi G, Ashok Kumar P, Sharma R, Kumar U, Gauri LA, Jadhav P, Bartakke G (2016) A prospective, randomized, double-blind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis. Int J Rheum Dis 19(11):1157–1168. CrossRefPubMedGoogle Scholar
  7. 7.
    Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, Fischkoff SA, Chartash EK (2003) Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 30(12):2563–2571PubMedGoogle Scholar
  8. 8.
    Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, Chartash EK (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheumatol 50:1400–1411CrossRefGoogle Scholar
  9. 9.
    Chen D-Y, Chou S-J, Hsieh T-Y, Chen Y-H, Chen H-H, Hsieh C-W, Lan J-L (2009) Randomized, double-blind, placebo-controlled, comparative study of human anti-TNF antibody adalimumab in combination with methotrexate and methotrexate alone in Taiwanese patients with active rheumatoid arthritis. J Formos Med Assoc 108(4):310–319. CrossRefPubMedGoogle Scholar
  10. 10.
    KIM HY, LEE SK, Song YW, YOO DH, KOH EM, Yoo B, Luo A (2007) A randomized, double-blind, placebo-controlled, phase III study of the human anti-tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate. Int J Rheum Dis 10:9–16Google Scholar
  11. 11.
    Dörner T, Strand V, Castañeda-Hernández G, Ferraccioli G, Isaacs JD, Kvien TK, Martin-Mola E, Mittendorf T, Smolen JS, Burmester GR (2012) The role of biosimilars in the treatment of rheumatic diseases Annals of the Rheumatic Diseases: annrheumdis-2012-202715Google Scholar
  12. 12.
    Caldwell DM, Ades A, Higgins J (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ: Br Med J 331:897CrossRefGoogle Scholar
  13. 13.
    Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F (1992) The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 35(5):498–502. CrossRefPubMedGoogle Scholar
  14. 14.
    Aletaha D, Landewe R, Karonitsch T, Bathon J, Boers M, Bombardier C, Bombardieri S, Choi H, Combe B, Dougados M (2008) Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Arthritis Care Res 59(10):1371–1377. CrossRefGoogle Scholar
  15. 15.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12. CrossRefPubMedGoogle Scholar
  16. 16.
    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. CrossRefPubMedGoogle Scholar
  17. 17.
    Brown S, Hutton B, Clifford T, Coyle D, Grima D, Wells G, Cameron C (2014) A Microsoft-Excel-based tool for running and critically appraising network meta-analyses—an overview and application of NetMetaXL. Syst Rev 3:110Google Scholar
  18. 18.
    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 64:163–171Google Scholar
  19. 19.
    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 Mak 33(5):641–656. CrossRefGoogle Scholar
  20. 20.
    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. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Valkenhoef G, Lu G, Brock B, Hillege H, Ades A, Welton NJ (2012) Automating network meta-analysis. Res Synth Methods 3(4):285–299. CrossRefPubMedGoogle Scholar
  22. 22.
    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 54:273–280CrossRefPubMedGoogle Scholar
  23. 23.
    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 Annals of the Rheumatic Diseases: annrheumdis-2011-200228Google Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Department of RheumatologyHanyang University Hospital for Rheumatic DiseasesSeoulSouth Korea
  2. 2.Department of Rheumatology, Korea University Anam HospitalKorea University College of MedicineSeoulSouth Korea

Personalised recommendations