Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The Japanese experience with biologic therapies for rheumatoid arthritis

Nature Reviews Rheumatology volume 6, pages 644–652 (2010)Cite this article

Subjects

Abstract

The unique genetic, environmental and medical backgrounds of people in Japan might influence the effectiveness and safety of biologic agents in patients with rheumatoid arthritis (RA). Indeed, clinical trials revealed higher response rates to some biologic agents (including infliximab, etanercept and tocilizumab) in patients with RA in Japan than patients treated with the same agents in Western countries, although response rates to adalimumab were comparable in both populations. The reasons why response rates to some biologic agents differ in Japanese individuals is currently under investigation. Post-marketing surveillance data have been collected for all patients with RA who were treated with biologic agents in Japan to monitor drug safety. These data clearly demonstrated that only ∼5% of these patients experienced adverse drug reactions to biologic agents, which were well tolerated. Pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis are considered important severe adverse reactions and risk factors for these adverse effects have been identified. Adverse drug reactions could exaggerate the risks associated with biologic therapy in Japanese patients with RA. Attempts have, therefore, been made to predict clinical response and adverse effects to enable personalized therapy with biologic agents and to optimize the outcomes of these patients.

Key Points

  • The effectiveness and safety of biologic agents in Japanese patients with rheumatoid arthritis (RA) could be influenced by the unique genetic, environmental and medical backgrounds of these individuals

  • Japanese patients with RA with highly active disease and rapid progression of structural joint damage have favorable clinical responses (including retardation of joint destruction) when treated with biologic agents

  • Post-marketing surveillance data for all patients with RA treated with biologic agents in Japan demonstrated a low incidence of adverse reactions (∼5%)

  • In Japanese patients, important adverse reactions to biologic agents include pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis

  • Identification of predictive markers could facilitate personalized therapy with biologic agents and optimize the outcomes of patients with RA

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Japanese clinical trials of biologic therapies for RA.
Figure 2: Effectiveness of biologic agents in Japanese patients with RA.
Figure 3: Collection of post-marketing surveillance data on biologic therapies for RA in Japan.

Similar content being viewed by others

References

  1. Khan, M. A. HLA-B27 and its subtypes in world populations. Curr. Opin. Rheumatol. 7, 263–269 (1995).

    Article  CAS  Google Scholar 

  2. Takeuchi, T. et al. Postmarketing surveillance of the safety profile of infliximab in 5,000 Japanese patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 189–194 (2008).

    Article  CAS  Google Scholar 

  3. Health white paper [Japanese]. Japanese Ministry of Health [online], (2010).

  4. Abe, T. et al. A multicenter, double-blind, randomized, placebo controlled trial of infliximab combined with low dose methotrexate in Japanese patients with rheumatoid arthritis. J. Rheumatol. 33, 37–44 (2006).

    CAS  PubMed  Google Scholar 

  5. Koike, T. et al. Postmarketing surveillance of the safety and effectiveness of etanercept in Japan. J. Rheumatol. 36, 898–906 (2009).

    Article  CAS  Google Scholar 

  6. Miyasaka, N. ; CHANGE Study Investigators. Clinical investigation in highly disease-affected rheumatoid arthritis patients in Japan with adalimumab applying standard and general evaluation: the CHANGE study. Mod. Rheumatol. 18, 252–262 (2008).

    Article  CAS  Google Scholar 

  7. Sokka, T., Envalds, M. & Pincus, T. Treatment of rheumatoid arthritis: a global perspective on the use of antirheumatic drugs. Mod. Rheumatol. 18, 228–239 (2008).

    Article  CAS  Google Scholar 

  8. Kameda, H. et al. Factors predicting response to a low-dose methotrexate therapy in patients with rheumatoid arthritis: A better response in male patients. Mod. Rheumtol 14, 442–446 (2004).

    Article  CAS  Google Scholar 

  9. Smolen, J. S. et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann. Rheum. Dis. 69, 631–637 (2010).

    Article  Google Scholar 

  10. Visser, K. & van der Heijde, D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann. Rheum. Dis. 68, 1094–1099 (2009).

    Article  CAS  Google Scholar 

  11. Sekiguchi, N., Kameda, H., Amano, K. & Takeuchi, T. Efficacy and safety of bucillamine, a D-penicillamine analogue, in patients with active rheumatoid arthritis. Mod. Rheumatol. 16, 85–91 (2006).

    Article  CAS  Google Scholar 

  12. Ichikawa, Y. et al. Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study. Mod. Rheumatol. 15, 323–328 (2005).

    Article  CAS  Google Scholar 

  13. Osiri, M, et al. Leflunomide for the treatment of rheumatoid arthritis: a systematic review and meta-analysis. J. Rheumatol. 30, 1182–1190 (2003).

    CAS  PubMed  Google Scholar 

  14. Sawada, T. et al. Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 48, 1069–1072 (2009).

    Article  CAS  Google Scholar 

  15. Sato, T. et al. Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis. Rheumatology (Oxford) 48, 1265–1268 (2009).

    Article  Google Scholar 

  16. Safety information of leflunomide in Japan [Japanese]. Sanofi-Aventis [online], (2010).

  17. Suzuki, K. et al. Single center prospective study of tacrolimus efficacy and safety in treatment of rheumatoid arthritis. Rheumatol. Int. 29, 431–436 (2009).

    Article  CAS  Google Scholar 

  18. Takeuchi, T., Kawai, S., Yamamoto, K. & Miyasaka, N. Post-marketing surveillance of the safety and effectiveness of tacrolimus in 3,267 Japanese patients with rheumatoid arthritis. Ann. Rheum. Dis. 69 (Suppl. 3), 219 (2010).

    Google Scholar 

  19. Nishimoto, N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50, 1761–1769 (2004).

    Article  CAS  Google Scholar 

  20. Phase II dose-finding clinical trials for abatacept [Japanese]. Enbrel [online], (2010).

  21. Takeuchi, T., Abe, T., Yamamoto, A. & Miyasaka, N. New biologics for rheumatoid arthritis in Japan; A multi-center randomized double-blind, controlled, dose-response study of abatacept (BMS-188667) in Japanese active rheumatoid arthritis (RA) patients with an inadequate response to methotrexate. Mod. Rheumatol. 19, S32 (2009).

    Article  Google Scholar 

  22. Takeuchi, T., Miyasaka, N., Inoue, K., Abe, T. & Koike, T. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod. Rheumatol. 19, 478–487 (2009).

    Article  CAS  Google Scholar 

  23. Kameda, H. et al. Etanercept (ETN) with methotrexate (MTX) is better than ETN monotherapy in patients with active rheumatoid arthritis despite MTX therapy: A randomized trial. Mod. Rheum. doi: 10.1007/s10165-010-0324-4.

  24. Yamanaka, H. et al. Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan (RECONFIRM). Mod. Rheumatol. 17, 28–32 (2007).

    Article  CAS  Google Scholar 

  25. Tanaka, Y. et al. Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: One-year clinical and radiographic outcomes (RECONFIRM-II). Mod. Rheumatol. 18, 146–152 (2008).

    Article  CAS  Google Scholar 

  26. Takeuchi, T. et al. Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan: one-year outcome of joint destruction (RECONFIRM-2J). Mod. Rheumatol. 18, 447–454 (2008).

    Article  CAS  Google Scholar 

  27. Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N. Engl. J. Med. 343, 1594–1602 (2000).

    Article  CAS  Google Scholar 

  28. Kameda, H. et al. Etanercept (ETN) plus methotrexate (MTX) combination therapy resulted in a better outcome in joint damage and physical function than ETN monotherapy even in patients with active rheumatoid arthritis despite MTX treatment: 52-week results from the JESMR study. Ann. Rheum. Dis. 68 (Suppl. 3), 121 (2009).

    Google Scholar 

  29. Kawai, S. et al. Comparability of etanercept pharmacokinetics in healthy Japanese and American subjects. J. Clin. Pharmacol. 46, 418–423 (2006).

    Article  CAS  Google Scholar 

  30. van de Putte, L. B. et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed. Ann. Rheum. Dis. 63, 508–516 (2004).

    Article  CAS  Google Scholar 

  31. Nishimoto, N. et al. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod. Rheumatol. 19, 12–19 (2009).

    Article  CAS  Google Scholar 

  32. Nishimoto, N. et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann. Rheum. Dis. 66, 1162–1167 (2007).

    Article  CAS  Google Scholar 

  33. Nishimoto, N. et al. Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the STREAM study): evidence of safety and efficacy in a 5-year extension study. Ann. Rheum. Dis. 68, 1580–1584 (2009).

    Article  CAS  Google Scholar 

  34. Yamanaka, H. et al. Efficacy of tocilizumab in rheumatoid arthritis patients with daily clinical practice in Japan: Results from a retorspective study (REACTION). Ann. Rheum. Dis. 69 (Suppl. 3), 547 (2010).

    Google Scholar 

  35. Miyasaka, N., Takeuchi, T. & Eguchi, K. Proposed [corrected] Japanese guidelines for the use of infliximab for rheumatoid arthritis. Mod. Rheumatol. 15, 4–8 (2005).

    Article  CAS  Google Scholar 

  36. Miyasaka, N., Takeuchi, T. & Eguchi, K. Guidelines for the proper use of etanercept in Japan. Mod. Rheumatol. 16, 63–67 (2006).

    Article  CAS  Google Scholar 

  37. Koike, R., Takeuchi, T., Eguchi, K. & Miyasaka, N. Update on the Japanese guidelines for the use of infliximab and etanercept in rheumatoid arthritis. Mod. Rheumatol. 17, 451–458 (2007).

    Article  CAS  Google Scholar 

  38. Koike, R. et al. Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod. Rheumatol. 19, 351–357 (2009).

    Article  CAS  Google Scholar 

  39. Guidelines for adalimumab [Japanese]. Japan College of Rheumatology [online], (2008).

  40. Keane, J. et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N. Engl. J. Med. 345, 1098–1104 (2001).

    Article  CAS  Google Scholar 

  41. Arthritis advisory committee. Safety Update on TNF-α antagonists: infliximab and etanercept. FDA [online], (2001).

  42. Komano, Y. et al. Pneumocystis jiroveci pneumonia in patients with rheumatoid arthritis treated with infliximab: a retrospective review and case-control study of 21 patients. Arthritis Rheum. 61, 305–312 (2009).

    Article  CAS  Google Scholar 

  43. Tokuda, H. et al. Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: a multicenter study. Intern. Med. 47, 915–923 (2008).

    Article  Google Scholar 

  44. Saijo, S. et al. Dectin-1 is required for host defense against Pneumocystis carinii but not against Candida albicans. Nat. Immunol. 8, 39–46 (2007).

    Article  CAS  Google Scholar 

  45. Steele, C. et al. Alveolar macrophage-mediated killing of Pneumocystis carinii f. sp. muris involves molecular recognition by the Dectin-1 β-glucan receptor. J. Exp. Med. 198, 1677–1688 (2003).

    Article  CAS  Google Scholar 

  46. Hahn, P. Y. et al. Pneumocystis carinii cell wall β-glucan induces release of macrophage inflammatory protein-2 from alveolar epithelial cells via a lactosylceramide-mediated mechanism. J. Biol. Chem. 278, 2043–2050 (2003).

    Article  CAS  Google Scholar 

  47. Tasaka, S. et al. Serum indicators for the diagnosis of pneumocystis pneumonia. Chest 131, 1173–1180 (2007).

    Article  CAS  Google Scholar 

  48. Ohosone, Y. et al. Clinical characteristics of patients with rheumatoid arthritis and methotrexate induced pneumonitis. J. Rheumatol. 24, 2299–2303 (1997).

    CAS  PubMed  Google Scholar 

  49. Shidara, K. et al. Incidence of and risk factors for interstitial pneumonia in patients with rheumatoid arthritis in a large Japanese observational cohort, IORRA. Mod. Rheumatol. 20, 280–286 (2010).

    Article  Google Scholar 

  50. Kameda, H. & Takeuchi, T. Recent advances in the treatment of interstitial lung disease in patients with polymyositis/dermatomyositis. Endocr. Metab. Immune Disord. Drug Targets 6, 409–415 (2006).

    Article  CAS  Google Scholar 

  51. Azuma, A., Hagiwara, K. & Kudoh, S. Basis of acute exacerbation of idiopathic pulmonary fibrosis in Japanese patients. Am. J. Respir. Crit. Care Med. 177, 1397–1398 (2008).

    Article  Google Scholar 

  52. Kudoh, S. et al. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am. J. Respir. Crit. Care Med. 177, 1348–1357 (2008).

    Article  Google Scholar 

  53. Abe, T. & Takeuchi, T. The other side of TNF-targeted therapy of patients with rheumatoid arthritis. Curr. Rheumatol. Rep. 3, 1–2 (2001).

    Article  CAS  Google Scholar 

  54. Quinn, M. A. 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. 52, 27–35 (2005).

    Article  CAS  Google Scholar 

  55. van der Kooij, S. M. 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. 68, 914–921 (2009).

    Article  CAS  Google Scholar 

  56. Tanaka, Y. et al. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann. Rheum. Dis. 69, 1286–1291 (2010).

    Article  CAS  Google Scholar 

  57. Radovits, B. J. et al. Influence of age on the outcome of antitumour necrosis factor alpha therapy in rheumatoid arthritis. Ann. Rheum. Dis. 68, 1470–1473 (2009).

    Article  CAS  Google Scholar 

  58. Tutuncu, Z. et al. Fcgamma receptor type IIIA polymorphisms influence treatment outcomes in patients with inflammatory arthritis treated with tumor necrosis factor alpha-blocking agents. Arthritis Rheum. 52, 2693–2696 (2005).

    Article  CAS  Google Scholar 

  59. Canete, J. D. et al. Influence of variants of Fcγ receptors IIA and IIIA on the American College of Rheumatology and European League Against Rheumatism responses to anti-tumour necrosis factor α therapy in rheumatoid arthritis. Ann. Rheum. Dis. 68, 1547–1552 (2009).

    Article  CAS  Google Scholar 

  60. Sekiguchi, N. et al. Messenger ribonucleic acid expression profile in peripheral blood cells from RA patients following treatment with an anti-TNF-α monoclonal antibody, infliximab. Rheumatology (Oxford) 47, 780–788 (2008).

    Article  CAS  Google Scholar 

  61. Tanino, M. et al. Prediction of efficacy of anti-TNF biologic agent, infliximab, for rheumatoid arthritis patients using a comprehensive transcriptome analysis of white blood cells. Biochem. Biophys. Res. Commun. 387, 261–265 (2009).

    Article  CAS  Google Scholar 

  62. Sugihara, M. et al. Effects of infliximab therapy on gene expression levels of tumor necrosis factor α, tristetraprolin, T cell intracellular antigen 1, and Hu antigen R. in patients with rheumatoid arthritis. Arthritis Rheum. 56, 2160–2169 (2007).

    Article  CAS  Google Scholar 

  63. Tsuzaka, K., Itami, Y., Takeuchi, T., Shinozaki, N. & Morishita, T. ADAMTS5 is a biomarker for prediction of the response to infliximab in patients with rheumatoid arthritis. J. Rheumatol. 37, 1454–1460 (2010).

    Article  CAS  Google Scholar 

  64. Kastbom, A. et al. Fcγ receptor type IIIA genotype and response to tumor necrosis factor α-blocking agents in patients with rheumatoid arthritis. Arthritis Rheum. 56, 448–452 (2007).

    Article  CAS  Google Scholar 

  65. Pavy, S. et al. Tumour necrosis factorα −308G->A polymorphism is not associated with response to TNFα blockers in Caucasian patients with rheumatoid arthritis: systematic review and meta-analysis. Ann. Rheum. Dis. 69, 1022–1028 (2010).

    Article  CAS  Google Scholar 

  66. Hughes, L. B. et al. Genetic risk factors for infection in patients with early rheumatoid arthritis. Genes Immun. 5, 641–647 (2004).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku, 160-8582, Tokyo, Japan

    Tsutomu Takeuchi & Hideto Kameda

Authors
  1. Tsutomu Takeuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideto Kameda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Tsutomu Takeuchi.

Ethics declarations

Competing interests

T. Takeuchi has received honoraria from Abbott, Bristol-Myers-Squibb, Chugai Pharmaceutical, Eisai Pharmaceuticals, Janssen Pharmaceutica, Mitsubishi Tanabe Pharma, Novartis, Takeda Pharmaceuticals and Wyeth Japan and research grants from Chugai Pharmaceutical, Eisai Pharmaceuticals, Mitsubishi Tanabe Pharma, Takeda Pharmaceuticals and Wyeth Japan. H. Kameda has received honoraria from Abbott, Centocor Ortho Biotech, Chugai Pharmaceutical, Eisai Pharmaceuticals, Mitsubishi Tanabe Pharma, Takeda Pharmaceuticals and Wyeth Japan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takeuchi, T., Kameda, H. The Japanese experience with biologic therapies for rheumatoid arthritis. Nat Rev Rheumatol 6, 644–652 (2010). https://doi.org/10.1038/nrrheum.2010.154

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2010.154

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing