Skip to main content
Log in

IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by polyarthritis. Numerous agents with varying mechanisms are used in the treatment of RA, including non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs, and some biological agents. Studies to uncover the cause of RA have recently ended up scrutinizing the importance of pro-inflammatory cytokine such as tumor necrosis factor α (TNF-α) and interleukin (IL)-6 in the pathogenesis of RA. TNF-α inhibitors are increasingly used to treat RA patients who are non-responsive to conventional anti-arthritis drugs. Despite its effectiveness in a large patient population, up to two thirds of RA patients are found to be partially responsive to anti-TNF therapy. Therefore, agents targeting IL-6 such as tocilizumab (TCZ) attracted significant attention as a promising agent in RA treatment. In this article, we review the mechanism of anti-IL-6 in the treatment of RA, provide the key efficacy and safety data from clinical trials of approved anti-IL-6, TCZ, as well as six candidate IL-6 blockers including sarilumab, ALX-0061, sirukumab, MEDI5117, clazakizumab, and olokizumab, and their future perspectives in the treatment of RA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Al-Shakarchi, I., N.J. Gullick, and D.L. Scott. 2013. Current perspectives on tocilizumab for the treatment of rheumatoid arthritis: A review. Patient Preference and Adherence 7: 653–666.

    Article  PubMed Central  PubMed  Google Scholar 

  • Boers, M. 2009. Cost-effectiveness of biologics as first-line treatment of rheumatoid arthritis: case closed? Annals of Internal Medicine 151: 668–669.

    Article  PubMed  Google Scholar 

  • Dasgupta, B., M. Corkill, B. Kirkham, T. Gibson, and G. Panayi. 1992. Serial estimation of interleukin-6 as a measure of systemic disease in rheumatoid arthritis. The Journal of Rheumatology 19: 22–25.

    CAS  PubMed  Google Scholar 

  • Dayer, J.M., and E. Choy. 2010. Therapeutic targets in rheumatoid arthritis: The interleukin-6 receptor. Rheumatology 49: 15–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dougados, M., K. Kissel, T. Sheeran, P.P. Tak, P.G. Conaghan, E.M. Mola, G. Schett, H. Amital, F. Navarro-Sarabia, A. Hou, C. Bernasconi, and T.W. Huizinga. 2013. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Annals of the Rheumatic Diseases 72: 43–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Finch, D.K., M.A. Sleeman, J. Moisan, F. Ferraro, S. Botterell, J. Campbell, D. Cochrane, S. Cruwys, E. England, S. Lane, E. Rendall, M. Sinha, C. Walker, G. Rees, M.A. Bowen, A. Schneider, M. Liang, R. Faggioni, M. Fung, P.R. Mallinder, T. Wilkinson, R. Kolbeck, T. Vaughan, and D.C. Lowe. 2011. Whole-molecule antibody engineering: Generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics. Journal of Molecular Biology 411: 791–807.

    Article  CAS  PubMed  Google Scholar 

  • Gabay, C., P. Emery, R. van Vollenhoven, A. Dikranian, R. Alten, K. Pavelka, M. Klearman, D. Musselman, S. Agarwal, J. Green, and A. Kavanaugh. 2013. TCZ monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet 381: 1541–1550.

    Article  CAS  PubMed  Google Scholar 

  • Gaffo, A., K.G. Saag, and J.R. Curtis. 2006. Treatment of rheumatoid arthritis. American Journal of Health-System Pharmacy 63: 2451–2465.

    Article  CAS  PubMed  Google Scholar 

  • Genovese, M.C., R. Fleischmann, D. Furst, N. Janssen, J. Carter, B. Dasgupta, J. Bryson, B. Duncan, W. Zhu, C. Pitzalis, P. Durez, and K. Kretsos. 2014. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: Outcomes of a randomised Phase IIb study. Annals of the Rheumatic Diseases 73: 1607–1615.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gibofsky, A. 2012. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. The American Journal of Managed Care 18: S292–S302.

    Google Scholar 

  • Hashimoto, J., P. Garnero, D. van der Heijde, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, H. Yoshikawa, and N. Nishimoto. 2011. Humanized anti-interleukin-6-receptor antibody (tocilizumab) monotherapy is more effective in slowing radiographic progression in patients with rheumatoid arthritis at high baseline risk for structural damage evaluated with levels of biomarkers, radiography, and BMI: Data from the SAMURAI study. Modern Rheumatology/the Japan Rheumatism Association 21: 10–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hetland, M.L., I.J. Christensen, U. Tarp, L. Dreyer, A. Hansen, I.T. Hansen, G. Kollerup, L. Linde, H.M. Lindegaard, U.E. Poulsen, A. Schlemmer, D.V. Jensen, S. Jensen, G. Hostenkamp, M. Østergaard, and All Departments of Rheumatology in Denmark. 2010. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide DANIBO registry. Arthritis and Rheumatism 62: 22–32.

    Article  CAS  PubMed  Google Scholar 

  • Hibi, M., M. Murakami, M. Saito, T. Hirano, T. Taga, and T. Kishimoto. 1990. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63: 1149–1157.

    Article  CAS  PubMed  Google Scholar 

  • Holz, J.B., L. Sargentini-Maier, S. De Bruyn, B. Gachályi, I. Udvaros, B. Rojkovich, S. Bruk, P. Sramek, M. Korkosz, K. Krause, P. Schoen, J. D’Artois, K. Verschueren, W. Willems, K. De Swert, and G. Arold. 2013. Twenty-four weeks of treatment with a novel anti-IL6 receptor nanobody (ALX-0061) resulted in 84 % ACR20 improvement and 58 % DAS28 remission in a phase I/II study in RA. Annals of the Rheumatic Diseases 72: A64.

    Article  Google Scholar 

  • Huizinga, T.W., R.M. Fleischmann, M. Jasson, A.R. Radin, J. van Adelsberg, S. Fiore, X. Huang, G.D. Yancopoulos, N. Stahl, and M.C. Genovese. 2014. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Annals of the Rheumatic Diseases 73: 1626–1634.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hushaw, L.L., R. Sawaqed, G. Sweis, J. Reigle, A. Gopal, D. Brandt, N. Sweis, J. Curran, T.B. Niewold, and N.J. Sweiss. 2010. Critical appraisal of tocilizumab in the treatment of moderate to severe rheumatoid arthritis. Therapeutics and Clinical Risk Management 6: 143–152.

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jones, G., A. Sebba, J. Gu, M.B. Lowenstein, A. Calvo, J.J. Gomez-Reino, D.A. Siri, M. Tomsic, E. Alecock, T. Woodworth, and M.C. Genovese. 2010. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Annals of the Rheumatic Diseases 69: 88–96.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kremer, J.M., R. Blanco, M. Brzosko, R. Burgos-Vargas, A.M. Halland, E. Vernon, P. Ambs, and R. Fleischmann. 2011. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate—results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis and Rheumatism 63: 609–621.

    Article  CAS  PubMed  Google Scholar 

  • Kishimoto, T. 2005. Interleukin-6: from basic science to medicine–40 years in immunology. Annual Review of Immunology 23: 1–21.

    Article  CAS  PubMed  Google Scholar 

  • Kotake, S., K. Sato, K.J. Kim, N. Takahash, N. Udagawa, I. Nakamura, A. Yamaguchi, T. Kishimoto, T. Suda, and S. Kashiwazaki. 1996. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluid from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. Journal of Bone and Mineral Research 11: 88–95.

    Article  CAS  PubMed  Google Scholar 

  • Lee, W.Y., H.Y. Chen, K.C. Chen, and C.Y. Chen. 2014. Treatment of rheumatoid arthritis with traditional chinese medicine. BioMed Research International 2014: 528018.

    PubMed Central  PubMed  Google Scholar 

  • Li, R., L. Cai, D.Y. Ren, X.F. Xie, C.M. Hu, and J. Li. 2012. Therapeutic effect of 7, 3′-dimethoxy hesperetin on adjuvant arthritis in rats through inhibiting JAK2-STAT3 signal pathway. International Immunopharmacology 14: 157–163.

    Article  CAS  PubMed  Google Scholar 

  • Mease, P., V. Strand, L. Shalamberidze, A. Dimic, T. Raskina, L.A. Xu, Y. Liu, and J. Smith. 2012. A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate. Annals of the Rheumatic Diseases 71: 1183–1189.

    Article  CAS  PubMed  Google Scholar 

  • Mihara, M., K. Kasutani, M. Okazaki, A. Nakamura, S. Kawai, M. Sugimoto, Y. Matsumoto, Y. Ohsugi. 2005. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. International immunopharmacology 5: 1731–1740.

  • Miyagawa, I., S. Nakayamada, K. Saito, K. Hanami, M. Nawata, N. Sawamukai, K. Nakano, K. Yamaoka, and Y. Tanaka. 2014. Study on the safety and efficacy of tocilizumab, an anti-IL-6 receptor antibody, in patients with rheumatoid arthritis complicated with AA amyloidosis. Modern Rheumatology/the Japan Rheumatism Association 24: 405–409.

    Article  CAS  PubMed  Google Scholar 

  • Nakahara, H., J. Song, M. Sugimoto, K. Haqihara, T. Kishimoto, K. Yoshizaki, and N. Nishimoto. 2003. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis and Rheumatism 48: 1521–1529.

    Article  CAS  PubMed  Google Scholar 

  • Navarro-Millán, I., J.A. Singh, and J.R. Curtis. 2012. Systematic review of Tocilizumab for rheumatoid arthritis: A new biologic agent targeting the interleukin-6 receptor. Clinical Therapeutics 34: 788–802.

    Article  PubMed Central  PubMed  Google Scholar 

  • Nishida, S., K. Hagihara, Y. Shima, M. Kawai, Y. Kuwahara, J. Arimitsu, T. Hirano, M. Narazaki, A. Oqata, K. Yoshizaki, I. Kawase, T. Kishimoto, and T. Tanaka. 2009. Rapid improvement of AA amyloidosis with humanized anti-interleukin 6 receptor antibody treatment. Annals of the Rheumatic Diseases 68: 1235–1236.

    Article  CAS  PubMed  Google Scholar 

  • Nishimoto, N., J. Hashimoto, N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, N. Murata, D. Heijde, and T. Kishimoto. 2007. 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. Annals of the Rheumatic Diseases 66: 1162–1167.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nishimoto, N., N. Miyasaka, K. Yamamoto, S. Kawai, T. Takeuchi, J. Azuma, and T. Kishimoto. 2009. 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. Modern Rheumatology/the Japan Rheumatism Association 19: 12–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nishimoto, N., and T. Kishimoto. 2008. Humanized antihuman IL-6 receptor antibody, tocilizumab. Handbook of Experimental Pharmacology 181: 151–160.

    Article  CAS  PubMed  Google Scholar 

  • Okuda, Y. 2008. Review of tocilizumab in the treatment of rheumatoid arthritis. Biologics: Targets and Therapy 2: 75–82.

    CAS  Google Scholar 

  • Oldfield, V., S. Dhillon, and G.L. Plosker. 2009. Tocilizumab: A review of its use in the management of rheumatoid arthritis. Drugs 69: 609–632.

    Article  CAS  PubMed  Google Scholar 

  • Rafique, A., J. Martin, M. Blome, T. Huang, A. Ouyang, and N. Papadopoulos. 2013. Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human IL-6 receptor (IL-6R) alpha. Annals of the Rheumatic Diseases 72(Suppl3): 797.

    Article  Google Scholar 

  • Shakib, S., B. Francis, and J. Smith. 2010. Safety, pharmacokinetics and pharmacodynamics of ALD518 (BMS-945429), a high-affinity monoclonal antibody directed against interleukin-6 (IL-6) administered by subcutaneous injection: a phase I trial. Arthritis and Rheumatism 62(Suppl 10): 1124.

    Google Scholar 

  • Shaw, S., T. Bourne, C. Meier, B. Carrington, R. Gelinas, A. Henry, A. Popplewell, R. Adams, T. Baker, S. Rapecki, D. Marshall, A. Moore, H. Neale, and A. Lawson. 2014. Discovery and characterization of olokizumab: A humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. mAbs 6: 774–782.

    Article  PubMed  Google Scholar 

  • Silman, A.J., and J.E. Pearson. 2002. Epidemiology and genetics of rheumatoid arthritis. Arthritis Research 4(Suppl 3): S265–S272.

    Article  PubMed Central  PubMed  Google Scholar 

  • Smolen, J.S., R. Landewé, F.C. Breedveld, M. Buch, G. Burmester, M. Dougados, P. Emery, C. Gaujoux-Viala, L. Gossec, J. Nam, S. Ramiro, K. Winthrop, M. de Wit, D. Aletaha, N. Betteridge, J.W. Bijlsma, M. Boers, F. Buttgereit, B. Combe, M. Cutolo, N. Damjanov, J.M. Hazes, M. Kouloumas, T.K. Kvien, X. Mariette, K. Pavelka, P.L. van Riel, A. Rubbert-Roth, M. Scholte-Voshaar, D.L. Scott, T. Sokka-Isler, J.B. Wong, and D. van der Heijde. 2014a. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Annals of the Rheumatic Diseases 73: 492–509.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Smolen, J.S., M.E. Weinblatt, S. Sheng, Y. Zhuang, and B. Hsu. 2014b. Sirukumab, a human anti-interleukin-6 monoclonal antibody: A randomized, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Annals of the Rheumatic Diseases 73: 1616–1625.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Van Roy, M., H. Ulrichts, S. Rossenu, S. Jacobs, S. Poelmans, G. Verheyden, M. Vierboom, B. Hart, J. Baumeister, and J. Holz. 2012. Preclinical development of ALX-0061, an anti-IL-6R nanobody for therapeutic use in rheumatoid arthritis with a high in vitro affinity and potency and a competitive in vivo pharmacological profile. Arthritis & Rheumatism 64: S146.

    Google Scholar 

  • Yokota, S., T. Imagawa, M. Mori, T. Miyamae, S. Takei, N. Iwata, H. Umebayashi, T. Murata, M. Miyoshi, M. Tomiita, N. Nishimoto, and T. Kishimoto. 2013. Long-term treatment of systemic juvenile idiopathic arthritis with tocilizumab: Results of an open-label extension study in Japan. Annals of the Rheumatic Disease 72: 627–628.

    Article  CAS  Google Scholar 

  • Yokota, S., T. Imagawa, M. Mori, T. Miyamae, Y. Aihara, S. Takei, N. Iwata, H. Umebayashi, T. Murata, M. Miyoshi, M. Tomiita, N. Nishimoto, and T. Kishimoto. 2008. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: A randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371: 998–1006.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Technology Development Program of the Ministry for Food, Agriculture, Forest, and Fisheries of Republic of Korea (project number 114010031HD030).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sung Hyun Chung.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, G.W., Lee, N.R., Pi, R.H. et al. IL-6 inhibitors for treatment of rheumatoid arthritis: past, present, and future. Arch. Pharm. Res. 38, 575–584 (2015). https://doi.org/10.1007/s12272-015-0569-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12272-015-0569-8

Keywords

Navigation