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  • Review Article
  • Published:

Biosimilars in rheumatology: current perspectives and lessons learnt

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Key Points

  • Biosimilars are biopharmaceuticals that have been assessed by regulatory agencies to have efficacy and safety similar to their reference products and are expected to be marketed at substantially lower prices

  • CT-P13 (an infliximab biosimilar) was the first monoclonal antibody biosimilar to be approved, but not all national regulatory agencies granted extrapolation to all infliximab indications

  • A substantial proportion of patients treated with biopharmaceuticals develop antidrug antibodies, regardless of whether they received a biosimilar or the reference product

  • Establishing a nomenclature system that facilitates traceability for the purpose of pharmacovigilance is a key issue in the adoption of biosimilars in clinical practice

  • Extrapolation of indications for biosimilars is possible, but concerns have been raised regarding the potential efficacy and safety of a biosimilar in diseases for which it has not been studied


Biosimilars, based on biopharmaceuticals approved by regulatory agencies that are no longer under patent protection, have efficacy and safety comparable to their reference products, and are a new therapeutic option to treat inflammatory diseases. Biosimilars must be distinguished from 'biomimics' or 'biocopies', which are marketed in some countries but have not been evaluated according to the stringent regulatory pathway used for biosimilars. CT-P13, based on infliximab, was the first biosimilar approved for the treatment of inflammatory diseases; however, some countries did not allow extrapolation of indications to all eight diseases for which the reference drug infliximab is approved. Antidrug antibodies can reduce drug levels and affect clinical efficacy, but although available data suggest that biosimilars and their reference products have comparable immunogenicity, this important property might differ between individual biopharmaceuticals. This Review discusses biosimilars already approved within the past 3 years to treat rheumatic diseases, as well as others that are currently under development. The main challenges posed by biosimilars are also addressed, such as the extrapolation of indications to diseases only studied for the reference drug, and the definition of strategies for adequate pharmacovigilance to monitor biosimilars after marketing approval.

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Figure 1: Mechanisms of protein diversity and consequences for the immune system.
Figure 2: EMA guidance on biosimilar mAbs: a stepwise approach.
Figure 3: ADA induction after treatment with infliximab or CT-P13.
Figure 4: Study design to compare the efficacy of reference drugs and biosimilars.

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Change history

  • 25 August 2015

    In the version of this article initially published online, the line colours in Figure 4 were incorrect. The error has been corrected for the print, HTML and PDF versions of the article.


  1. Dörner, T. et al. The role of biosimilars in the treatment of rheumatic diseases. Ann. Rheum. Dis. 72, 322–328 (2013).

    Article  Google Scholar 

  2. Scheinberg, M. A. & Kay, J. The advent of biosimilar therapies in rheumatology—“O Brave New World”. Nat. Rev. Rheum. 8, 430–436 (2012).

    Article  CAS  Google Scholar 

  3. Schneider, C. K. Biosimilars in rheumatology: the wind of change. Ann. Rheum. Dis. 72, 315–318 (2013).

    Article  CAS  Google Scholar 

  4. Aringer, M. & Dörner, T. Biosimilars. Current state of the build up to series production [German]. Z. Rheumatol. 72, 873–877 (2013).

    Article  CAS  Google Scholar 

  5. Castañeda-Hernandez, G. et al. Biopharmaceuticals for rheumatic diseases in Latin America, Europe, Russia, and India: innovators, biosimilars, and intended copies. Joint Bone Spine 81, 471–477 (2014).

    Article  Google Scholar 

  6. European Medicines Agency. Guideline on similar biological medicinal products [online], (2014).

  7. Barile-Fabris, L. A., Irazoque-Palazuelos, F., Vasquez, R. H., Vazquez, S. C. & Guzman, R. Incidence of adverse events in patients treated with intended copies of biologic therapeutic agents in Colombia and Mexico [abstract 1506]. Arthritis Rheumatol. 66, S662 (2014).

    Article  Google Scholar 

  8. Enbrel (etanercept) product monograph (Immunex Corporation & Amgen Canada Inc., 2013) [online], (2013).

  9. Castañeda-Hernández, G., Gonzalez-Ramirez, R., Kay, J. & Scheinberg, M. Biosimilars in rheumatology: what clinicians should know. RMD Open 2015, e000010 (2015).

    Article  Google Scholar 

  10. Yi, S. et al. Comparative pharmacokinetics of HD203, a biosimilar of etanercept, with marketed etanercept (Enbrel): a double-blind, single-dose, crossover study in healthy volunteers. BioDrugs 26, 177–184 (2012).

    Article  CAS  Google Scholar 

  11. Bae, S. C. et al. A randomized, double-blind, phase 3 equivalence trial comparing the etanercept biosimilar, HD203, with etanercept (Enbrel), in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) [abstract]. Arthritis Rheumatol. 66, S1234 (2014).

    Google Scholar 

  12. HD203 biosimilar is clinically equivalent to etanercept [online], (2014).

  13. European Medicines Agency. Applications for new human medicines under evaluation by the Committee for Medicinal Products for Human Use (EMA/9499/2015). European Medicines Agency [online], (2015).

  14. Park, W. et al. A randomised, double-blind, multicentre, parallel-group, prospective study comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator infliximab in patients with ankylosing spondylitis: the PLANETAS study. Ann. Rheum. Dis. 72, 1605–1612 (2013).

    Article  CAS  Google Scholar 

  15. Yoo, D. H. et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann. Rheum. Dis. 72, 1613–1620 (2013).

    Article  CAS  Google Scholar 

  16. Celltrion. Celltrion's Remsima (infliximab) receives positive opinion from EMA's CHMP. Celltrion [online], (2013).

  17. Egis Pharmaceuticals PLC. Egis is first to launch biosimilar monoclonal antibody within the European Union. Budapest Stock Exchange Ltd [online], (2013).

  18. Serebrov, M. Celltrion hopes to blaze path for first U. S. biosimilar MAb. BioWorld [online], (2014).

    Google Scholar 

  19. Song-hoon, L. Celltrion gets license to sell Remsima in Venezuela. BusinessKorea [online], (2015).

    Google Scholar 

  20. [No authors listed]. Biosimilar infliximab receives approval in Japan and Turkey. Generics and Biosimilars Initiative [online], (2014).

  21. Health Canada. Inflectra. Drugs and Health Products [online], (2015).

  22. Hazlewood, G. S. et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology 148, 344–354 (2015).

    Article  CAS  Google Scholar 

  23. Kawalec, P., Mikrut, A., Wisniewska, N. & Pilc, A. Tumor necrosis factor-α antibodies (infliximab, adalimumab and certolizumab) in Crohn's disease: systematic review and meta-analysis. Arch. Med. Sci. 9, 765–779 (2013).

    Article  CAS  Google Scholar 

  24. [No authors listed]. Biosimilar infliximab approved in Japan, but not with full extrapolation. The Biosimilarz Blog! [online], (2014).

  25. Lambert, J. et al. Pharmacokinetic results from a phase 1, single-centre, double-blind, randomised, single-dose, parallel group study comparing 5 mg/kg IV infusion of BOW015 and reference infliximab in healthy male volunteers [abstract]. Ann. Rheum. Dis. 74 (Suppl. 2), 462 (2015).

    Google Scholar 

  26. Kay, J. et al. BOW015, a biosimilar infliximab, in patients with active rheumatoid arthritis on stable methotrexate doses: 54-week results of a randomized, double-blind, active comparator study [abstract L20]. Arthritis Rheumatol. 66, 3538 (2014).

    Google Scholar 

  27. [No authors listed]. Infliximab 'similar biologic' receives Indian approval. Generics and Biosimilars Initiative [online], (2014).

  28. Zydus Cadila. Zydus launches world's first biosimilar of Adalimumab. Zydus Cadila [online], (2014).

  29. Bandyopadhyay, S. et al. Physicochemical and functional characterization of a biosimilar adalimumab ZRC-3197. Biosimilars 5, 1–18 (2015).

    CAS  Google Scholar 

  30. Exemptia. Clinical Data [online], (2015).

  31. Exemptia. Adalimumab. Exemptia [online], (2014).

  32. Braun, J., Baraliakos, X., Kudrin, A., Kim, H. & Lee, S. J. Striking discrepancy in the development of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in response to infliximab (INF) and its biosimilar CT-P13 [abstract L21]. Arthritis Rheumatol. 66, 3538–3539 (2014).

    Google Scholar 

  33. Udata, C. et al. Immunogenicity assessment of PF-06438179, a potential biosimilar to infliximab, in healthy volunteers [abstract SAT0142]. Ann. Rheum. Dis. 74 (Suppl. 2), 702 (2015).

    Google Scholar 

  34. Kay, J., Lassen, C., Trokan, L. & Wyand, M. Safety profile of BOW015, a biosimilar infliximab, in healthy subjects and patients with active rheumatoid arthritis [abstract]. Ann. Rheum. Dis. 74 (Suppl. 2), 706 (2015).

    Google Scholar 

  35. Mok, C. C., van der Kleij, D. & Wolbink, G. J. Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNF α biologics in rheumatic diseases. Clin. Rheumatol. 32, 1429–1435 (2013).

    Article  CAS  Google Scholar 

  36. van Schouwenburg, P. A., Rispens, T. & Wolbink, G. J. Immunogenicity of anti-TNF biologic therapies for rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 164–172 (2013).

    Article  CAS  Google Scholar 

  37. Mazilu, D. et al. Monitoring drug and antidrug levels: a rational approach in rheumatoid arthritis patients treated with biologic agents who experience inadequate response while being on a stable biologic treatment. Biomed. Res. Int. 2014, 702701. (2014).

    PubMed  PubMed Central  Google Scholar 

  38. D'Haens, G. R., Sartor, R. B., Silverberg, M. S., Petersson, J. & Rutgeerts, P. Future directions in inflammatory bowel disease management. J. Crohns Colitis 8, 726–734 (2014).

    Article  Google Scholar 

  39. US Department of Health & Human Services. The Affordable Care Act. [online], (2015).

  40. ACR Committee on Rheumatologic Care. ACR Position Statements—Biosimilars. American College of Rheumatology [online], (2015).

  41. EULAR. Biosimilars: what do patients need to consider? The European League Against Rheumatism [online], (2015).

  42. US National Library of Medicine. [online], (2015).

  43. Curtis, J. R. et al. A comparison of patient characteristics and outcomes in selected European and US rheumatoid arthritis registries. Semin. Arthritis Rheum. 40, 2–14 (2010).

    Article  Google Scholar 

  44. [No authors listed] The INN crowd. Nat. Biotechnol. 31, 1055 (2013).

  45. World Health Organization. 55th Consultation on International Nonproprietary Names for Pharmaceutical Substances, Geneva, 16–18 October 2012 [online], (2013).

  46. European Commission. Commission implementing directive 2012/52/EU of 20 December 2012 laying down measures to facilitate the recognition of medical prescriptions issued in another Member State [online], (2012).

  47. Pineda, C. et al. Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a point of view. Clin. Rheumatol. 34, 635–640 (2015).

    Article  Google Scholar 

  48. Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: nonclinical and clinical issues. European Medicines Agency [online], (2006).

  49. US Department of Health & Human Services. Biosimilars: questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. US Food and Drug Administration [online], (2012).

  50. Arguelles-Arias, F., Barreiro-de Acosta, M., Carballo, F., Hinojosa, J. & Tejerina, T. Joint position statement by “Sociedad Espanola de Patologia Digestiva” (Spanish Society of Gastroenterology) and “Sociedad Espanola de Farmacologia” (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease. Rev. Esp. Enferm. Dig. 105, 37–43 (2013).

    Article  Google Scholar 

  51. Danese, S. & Gomollon, F. ECCO position statement: The use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD). J. Crohns Colitis 7, 586–589 (2013).

    Article  Google Scholar 

  52. Danese, S., Florino, G. & Michetti, P. Viewpoint: Knowledge and viewpoints on biosimilar monoclonal antibodies among members of the European Crohn's and Colitis Organization. J. Crohns Colitis 8, 1548–1550 (2014).

    Article  Google Scholar 

  53. Fiorino, G. & Danese, S. The biosimilar road in inflammatory bowel disease: the right way? Best Pract. Res. Clin. Gastroenterol. 28, 465–471 (2014).

    Article  Google Scholar 

  54. Fiorino, G. et al. The use of biosimilars in immune-mediated disease: a joint Italian Society of Rheumatology (SIR), Italian Society of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG–IBD) position paper. Autoimmun. Rev. 13, 751–755 (2014).

    Article  Google Scholar 

  55. Gecse, K. B. et al. Biosimilars in IBD: hope or expectation? Gut 62, 803–807 (2013).

    Article  CAS  Google Scholar 

  56. Hlavaty, T. & Letkovsky, J. Biosimilars in the therapy of inflammatory bowel diseases. Eur. J. Gastroenterol. Hepatol. 26, 581–587 (2014).

    Article  CAS  Google Scholar 

  57. Schreiber, S. et al. Evolution of biologicals in inflammation medicine—biosimilars in gastroenterology, rheumatology and dermatology [German]. Dtsch Med. Wochenschr. 139, 2399–2404 (2014).

    Article  CAS  Google Scholar 

  58. US National Library of Medicine. [online], (2015).

  59. European Medicines Agency. EU Clinical Trials Register [online], (2015).

  60. [No authors listed]. Biosimilars of adalimumab. Generics and Biosimilars Initiative [online], (2014).

  61. [No authors listed]. Biosimilars of etanercept. Generics and Biosimilars Initiative [online], (2014).

  62. Protalix Biotherapeutics. PRX-106 (Oral antiTNF). Protalix Biotherapeutics [online], (2015).

  63. Emery, P. et al. A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy. Ann. Rheum. Dis.

  64. [No authors listed]. Biosimilars of infliximab. Generics and Biosimilars Initiative [online], (2015).

  65. Amgen Biosimilars. Our pipeline. Amgen Biosimilars [online], (2015).

  66. Epirus Biopharmaceuticals. BOW070 (tocilizumab). Epirus Biopharmaceuticals [online], (2015).

  67. [No authors listed]. Biosimilars of rituximab. Generics and Biosimilars Initiative [online], (2015).

  68. LatinLink. Latin America pharma. LatinLink [online], (2015).

  69. Azevedo, V. F., Galli, N., Kleinfelder, A., D'Ippolito, J. & Urbano, P. C. Etanercept biosimilars. Rheumatol. Int. 35, 197–209 (2015).

    Article  CAS  Google Scholar 

  70. Vital, E. M, Kay, J. & Emery, P. Rituximab biosimilars. Expert Opin. Biol. Ther. 13, 1049–1062 (2013).

    Article  CAS  Google Scholar 

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Both authors contributed equally to all aspects of the manuscript, including researching data for the article, discussions of its content, writing, review and editing of the manuscript before submission.

Corresponding author

Correspondence to Thomas Dörner.

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Competing interests

T.D. declares that he has received honoraria for study support and consultations from Hospira, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Roche/Chugai, Samsung, Sanofi and UCB. J.K. declares that he has received research support (paid to the University of Massachusetts Medical School) from AbbVie, Genentech, Pfizer and Roche Laboratories, and honoraria for consultations from Amgen, AbbVie, Boehringer Ingelheim, Bristol–Myers Squibb, Epirus Biopharmaceuticals, Genentech, Hospira, Janssen Biotech, Merck Sharp & Dohme, Nippon Kayaku, Novartis Pharmaceuticals, Pfizer, Samsung Bioepis, Roche Laboratories and UCB.

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Dörner, T., Kay, J. Biosimilars in rheumatology: current perspectives and lessons learnt. Nat Rev Rheumatol 11, 713–724 (2015).

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