Advertisement

Rheumatology International

, Volume 36, Issue 8, pp 1065–1075 | Cite as

Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials

  • Sumit KunwarEmail author
  • Khagendra Dahal
  • Sharan Sharma
Meta-Analyses

Abstract

IL-17 has a role in inflammation in RA, and its levels in joints correlate with disease severity. Multiple RCTs have been performed to study effects of anti-IL-17 agents. The objective of this study was to perform a systematic review and meta-analysis to analyze the efficacy and safety of anti-IL-17 agents in the management of RA. This work is based on a systematic review of studies retrieved by a sensitive search strategy in PubMed, EMBASE and Cochrane CENTRAL from inception through 9/7/15. Study selection criteria were the following: adult patients (age ≥ 18 years) with RAs, random selection of patients for anti-IL-17 therapy and treatment response compared to placebo. We performed systematic literature review per PRISMA guideline and two investigators independently selected seven randomized clinical trials (RCTs) for meta-analysis. We used random effect model calculating odds ratio (OR) and 95 % confidence interval (CI) to measure the efficacy with ACR20/50/70 responses and the safety with adverse events. Seven studies with total of 1226 patients including 905 in anti-IL-17 group and 321 in placebo were included in the meta-analysis. Anti-IL-17 was effective in achieving ACR20 and ACR50 compared to placebo (OR 2.47, 95 % CI 1.29–4.72, P = 0.006, I 2 77 % and OR 2.94, 95 % CI 1.37–6.28, P = 0.005, I 2 64 %, respectively). Data analysis for ACR70 showed a favorable trend toward anti-IL-17 (OR 2.62, 95 % CI 1–6.89, P = 0.05, I 2 15 %). Subgroup analysis of ACR20 for individual anti-IL-17 agents showed that ixekizumab was more effective than placebo, while secukinumab showed a trend toward achieving the ACR20 response. However, brodalumab was not effective compared to placebo. Safety analysis did not show increased risk of any or serious adverse effects by anti-IL-17 compared to placebo (OR 1.23, 95 % CI 0.94–1.61, P = 0.13, I 2 = 0 % and OR 1.28, 95 % CI 0.57–2.88, P = 0.55, I 2 = 0 %, respectively). This meta-analysis concludes that anti-IL-17 is effective in the treatment of RA without increased risk of any or serious adverse effects; however, the results are limited by significant heterogeneity and small duration of studies.

Keywords

Anti-IL-17 Rheumatoid arthritis Secukinumab Ixekizumab Brodalumab 

Notes

Author contributions

Dr. Kunwar is guarantor of the study, had full access to all of the data and takes responsibility for the integrity of the data and the accuracy of data analysis. Kunwar, Dahal and Sharma were involved in study concept and design. Kunwar, Dahal and Sharma were involved in data acquisition and analyzed and interpreted the data. Kunwar and Dahal drafted the manuscript. Dahal was involved in statistical analysis. Kunwar and Sharma supervised the study.

Compliance with ethical standards

Conflict of interest

Authors SK, KD and SS declare no conflict of interest.

Ethical approval

This article does not contain any studies with animals or human participants performed directly by any of its authors. Authors of the included studies have declared in their published articles that their protocols were approved by institutional review boards or ethics committee at each participating site.

Informed consent

The authors of this article did not directly involve any human subjects; however, the individual studies have declared obtaining informed consent from the patients.

References

  1. 1.
    Martin DA, Churchill M, Flores-Suarez L et al (2013) A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther 15:R164. doi: 10.1186/ar4347 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27:485–517. doi: 10.1146/annurev.immunol.021908.132710 CrossRefPubMedGoogle Scholar
  3. 3.
    Ely LK, Fischer S, Garcia KC (2009) Structural basis of receptor sharing by interleukin 17 cytokines. Nat Immunol 10:1245–1251. doi: 10.1038/ni.1813 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Miossec P, Korn T, Kuchroo VK (2009) Interleukin-17 and type 17 helper T cells. N Engl J Med 361:888–898. doi: 10.1056/NEJMra0707449 CrossRefPubMedGoogle Scholar
  5. 5.
    Furst DE, Emery P (2014) Rheumatoid arthritis pathophysiology: update on emerging cytokine and cytokine-associated cell targets. Rheumatol Oxf Engl 53:1560–1569. doi: 10.1093/rheumatology/ket414 CrossRefGoogle Scholar
  6. 6.
    Moseley TA, Haudenschild DR, Rose L, Reddi AH (2003) Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev 14:155–174CrossRefPubMedGoogle Scholar
  7. 7.
    Miossec P (2000) Are T cells in rheumatoid synovium aggressors or bystanders? Curr Opin Rheumatol 12:181–185CrossRefPubMedGoogle Scholar
  8. 8.
    Cai L, Yin JP, Starovasnik MA et al (2001) Pathways by which interleukin 17 induces articular cartilage breakdown in vitro and in vivo. Cytokine 16:10–21. doi: 10.1006/cyto.2001.0939 CrossRefPubMedGoogle Scholar
  9. 9.
    Nakae S, Nambu A, Sudo K, Iwakura Y (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol Baltim Md 1950 171:6173–6177Google Scholar
  10. 10.
    Lubberts E (2008) IL-17/Th17 targeting: on the road to prevent chronic destructive arthritis? Cytokine 41:84–91. doi: 10.1016/j.cyto.2007.09.014 CrossRefPubMedGoogle Scholar
  11. 11.
    Alzabin S, Abraham SM, Taher TE et al (2012) Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway. Ann Rheum Dis 71:1741–1748. doi: 10.1136/annrheumdis-2011-201024 CrossRefPubMedGoogle Scholar
  12. 12.
    Chabaud M, Durand JM, Buchs N et al (1999) Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum 42:963–970. doi: 10.1002/1529-0131(199905)42:5<963:AID-ANR15>3.0.CO;2-E CrossRefPubMedGoogle Scholar
  13. 13.
    Ziolkowska M, Koc A, Luszczykiewicz G et al (2000) High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J Immunol Baltim Md 1950 164:2832–2838Google Scholar
  14. 14.
    Tang C, Chen S, Qian H, Huang W (2012) Interleukin-23: as a drug target for autoimmune inflammatory diseases. Immunology 135:112–124. doi: 10.1111/j.1365-2567.2011.03522.x CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    van den Berg WB, Miossec P (2009) IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol 5:549–553. doi: 10.1038/nrrheum.2009.179 CrossRefPubMedGoogle Scholar
  16. 16.
    Leipe J, Grunke M, Dechant C et al (2010) Role of Th17 cells in human autoimmune arthritis. Arthritis Rheum 62:2876–2885. doi: 10.1002/art.27622 CrossRefPubMedGoogle Scholar
  17. 17.
    Singh JA, Furst DE, Bharat A et al (2012) 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 64:625–639. doi: 10.1002/acr.21641 CrossRefGoogle Scholar
  18. 18.
    Storage SS, Agrawal H, Furst DE (2010) Description of the efficacy and safety of three new biologics in the treatment of rheumatoid arthritis. Korean J Intern Med 25:1–17. doi: 10.3904/kjim.2010.25.1.1 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mewar D, Wilson AG (2011) Treatment of rheumatoid arthritis with tumour necrosis factor inhibitors. Br J Pharmacol 162:785–791. doi: 10.1111/j.1476-5381.2010.01099.x CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gordon KB, Leonardi CL, Lebwohl M et al (2014) A 52-week, open-label study of the efficacy and safety of ixekizumab, an anti-interleukin-17A monoclonal antibody, in patients with chronic plaque psoriasis. J Am Acad Dermatol 71:1176–1182. doi: 10.1016/j.jaad.2014.07.048 CrossRefPubMedGoogle Scholar
  21. 21.
    Xiong H-Z, Gu J-Y, He Z-G et al (2015) Efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. Int J Clin Exp Med 8:3156–3172PubMedPubMedCentralGoogle Scholar
  22. 22.
    Genovese MC, Durez P, Richards HB et al (2014) One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study. J Rheumatol 41:414–421. doi: 10.3899/jrheum.130637 CrossRefPubMedGoogle Scholar
  23. 23.
    Strand V, Kosinski M, Gnanasakthy A et al (2014) Secukinumab treatment in rheumatoid arthritis is associated with incremental benefit in the clinical outcomes and HRQoL improvements that exceed minimally important thresholds. Health Qual Life Outcomes 12:31. doi: 10.1186/1477-7525-12-31 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Genovese MC, Greenwald M, Cho C-S et al (2014) A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol Hoboken NJ 66:1693–1704. doi: 10.1002/art.38617 CrossRefGoogle Scholar
  25. 25.
    Burmester GR, Durez P, Shestakova G et al (2015) Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis. Rheumatol Oxf Engl. doi: 10.1093/rheumatology/kev258 Google Scholar
  26. 26.
    Pavelka K, Chon Y, Newmark R et al (2015) A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J Rheumatol 42:912–919. doi: 10.3899/jrheum.141271 CrossRefPubMedGoogle Scholar
  27. 27.
    Hueber W, Patel DD, Dryja T et al (2010) Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci Transl Med 2:52ra72. doi: 10.1126/scitranslmed.3001107 CrossRefPubMedGoogle Scholar
  28. 28.
    Genovese MC, Durez P, Richards HB et al (2013) Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 72:863–869. doi: 10.1136/annrheumdis-2012-201601 CrossRefPubMedGoogle Scholar
  29. 29.
    Genovese MC, Van den Bosch F, Roberson SA et al (2010) LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: a phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 62:929–939. doi: 10.1002/art.27334 CrossRefPubMedGoogle Scholar
  30. 30.
    Maringwa J, Kågedal M, Hamrén UW et al (2014) Pharmacokinetic-pharmacodynamic modeling of fostamatinib efficacy on ACR20 to support dose selection in patients with rheumatoid arthritis (RA). J Clin Pharmacol. doi: 10.1002/jcph.406 PubMedGoogle Scholar
  31. 31.
    Lee YH, Bae S-C, Song GG (2015) Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Rheumatol Int. doi: 10.1007/s00296-015-3291-4 Google Scholar
  32. 32.
    Mease PJ, Genovese MC, Greenwald MW et al (2014) Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 370:2295–2306. doi: 10.1056/NEJMoa1315231 CrossRefPubMedGoogle Scholar
  33. 33.
    Baeten D, Baraliakos X, Braun J et al (2013) Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial. Lancet Lond Engl 382:1705–1713. doi: 10.1016/S0140-6736(13)61134-4 CrossRefGoogle Scholar
  34. 34.
    Koenders MI, Marijnissen RJ, Joosten LAB et al (2012) T cell lessons from the rheumatoid arthritis synovium SCID mouse model: CD3-rich synovium lacks response to CTLA-4Ig but is successfully treated by interleukin-17 neutralization. Arthritis Rheum 64:1762–1770. doi: 10.1002/art.34352 CrossRefPubMedGoogle Scholar
  35. 35.
    van Baarsen LGM, Lebre MC, van der Coelen D et al (2014) Heterogeneous expression pattern of interleukin 17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for nonresponse to anti-IL-17 therapy? Arthritis Res Ther 16:426. doi: 10.1186/s13075-014-0426-z CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Medicine, LRGHealthcareUniversity of New EnglandLaconiaUSA

Personalised recommendations