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IDEOM – Original Paper

Free Access

Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

Naik G.S.a, b · Ming W.K.a,c,d · Magodoro I.M.a, e · Akinwunmi B.a, f · Dar S.a,g,h · Poulsen H.E.i-k · Kristensen L.E.j, l · Ellervik C.a,j,m,n

Author affiliations

aHarvard Medical School, bCenter for Immuno-Oncology, Department of Medical Oncology, Dana Faber Cancer Institute, and cDivision of Pharmacoepidemiology and Pharmacoeconomics, Brigham and Women's Hospital, Boston, MA, USA; dThe First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China; eCentre for Global Health, Massachusetts General Hospital, and Departments of fObstetrics and Gynecology, gPsychiatry and hRadiology, Brigham and Women's Hospital, Boston, MA, USA; iLaboratory of Clinical Pharmacology, Rigshospitalet, jFaculty of Health and Medical Sciences, University of Copenhagen, kDepartment of Clinical Pharmacology, Bispebjerg Hospital, and lThe Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; mDepartment of Laboratory Medicine, Boston Children's Hospital, Boston, MA, USA; nDepartment of Production, Research and Innovation - Region Zealand, Sorø, Denmark

Corresponding Author

Christina Ellervik, MD, PhD, DMSci, Associate Director

Department of Laboratory Medicine

Boston Children's Hospital

Boston, MA 02115 (USA)

E-Mail christina.ellervik@childrens.harvard.edu

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Dermatology 2017;233:366–377

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Abstract

Background: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α antagonists as first-line biologic agents. We determined the overall treatment effect of Th17 pathway inhibitors compared to placebo or active control on American College of Rheumatology (ACR) 20 response at week 12 (primary objective), risk of infections, discontinuation of treatment due to adverse events, and serious adverse events during the placebo-controlled period (12-24 weeks) in adults with active PsA in published randomized controlled trials. Methods: The SCOPUS database was searched. The Cochrane risk of bias tool was used for assessing quality. The pooled relative risk (RR) was derived from random effects models. Results: Seven randomized controlled trials were included which randomized 1,718 patients to Th17 inhibitors and 840 to placebo. Patients treated with Th17 inhibitors had an RR of 2.04 (95% CI: 1.79-2.33; p < 0.001) for achieving an ACR20 response at week 12 (I2 = 0%; p = 0.89) compared to placebo-treated patients. There was no evidence of publication bias. The result was consistent for study phase and outcome (ACR50/70), mechanism of action and TNF-α naivety. RR of infections was 1.06 (0.91-1.23), that of candida infections was 3.35 (0.75-14.95), that of serious adverse events was 0.82 (0.42-1.59) and that of discontinuation of treatment was 0.54 (0.31-0.93) among treated versus placebo subjects. No incident cases of tuberculosis were reported. Conclusion: In patients with active PsA, biologics targeting the Th17 axis produce a clinically significant improvement in joint disease activity with acceptable safety and tolerability for short-term treatment compared to placebo.

© 2017 S. Karger AG, Basel


References

  1. Gladman D, Antoni C, Mease P, Clegg D, Nash P: Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64:ii14-ii17.
  2. Radtke MA, Reich K, Blome C, Rustenbach S, Augustin M: Prevalence and clinical features of psoriatic arthritis and joint complaints in 2,009 patients with psoriasis: results of a German national survey. J Eur Acad Dermatol Venereol 2009;23:683-691.
  3. Mease PJ: Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol 2015;27:127-133.
  4. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A: Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010;130:1373-1383.
  5. Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al: Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 2011;187:490-500.
  6. Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Caňete JD, et al: Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99-109.
  7. Menon B, Gullick NJ, Walter GJ, Rajasekhar M, Garrood T, Evans HG, et al: Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol 2014;66:1272-1281.
  8. Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS: Clinical use of anti-TNF therapy and increased risk of infections. Drug Healthc Patient Saf 2013;5:79-99.
  9. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al: American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-735.
  10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.
  11. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al: Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665-2673.
  12. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al: The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
  13. STATACorp: Stata statistical software: release 13. College Station, StataCorp LP, 2013.
  14. Review Manager (RevMan) (computer program). Version 5.3. Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  15. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich RS, Shuler CL, et al: Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis 2017;76:79-87.
  16. Mease PJ, McInnes IB, Kirkham B, Kavanaugh A, Rahman P, van der Heijde D, et al: Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med 2015;373:1329-1339.
  17. McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, et al: Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Lond Engl 2015;386:1137-1146.
  18. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, Deodhar A, et al: Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 2014;370:2295-2306.
  19. Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et al: Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014;73:990-999.
  20. McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, et al: Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet Lond Engl 2013;382:780-789.
  21. Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C, et al: Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet Lond Engl 2009;373:633-640.
  22. Miossec P, Korn T, Kuchroo VK: Interleukin-17 and type 17 helper T cells. N Engl J Med 2009;361:888-898.
  23. Van den Berg WB, McInnes IB: Th17 cells and IL-17A - focus on immunopathogenesis and immunotherapeutics. Semin Arthritis Rheum 2013;43:158-170.
  24. Frleta M, Siebert S, McInnes IB: The interleukin-17 pathway in psoriasis and psoriatic arthritis: disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep 2014;16:414.
  25. Lories RJ, McInnes IB: Primed for inflammation: enthesis-resident T cells. Nat Med 2012;18:1018-1019.
  26. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al: European League against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016;75:499-510.
  27. Robinson KM, Manni ML, Biswas PS, Alcorn JF: Clinical consequences of targeting IL-17 and TH17 in autoimmune and allergic disorders. Curr Allergy Asthma Rep 2013;13.
  28. Ungprasert P, Thongprayoon C, Davis JM: Indirect comparisons of the efficacy of biological agents in patients with psoriatic arthritis with an inadequate response to traditional disease-modifying anti-rheumatic drugs or to non-steroidal anti-inflammatory drugs: a meta-analysis. Semin Arthritis Rheum 2016;45:428-438.

Article / Publication Details

First-Page Preview
Abstract of IDEOM – Original Paper

Received: May 08, 2017
Accepted: October 19, 2017
Published online: December 20, 2017
Issue release date: February 2018

Number of Print Pages: 12
Number of Figures: 6
Number of Tables: 1

ISSN: 1018-8665 (Print)
eISSN: 1421-9832 (Online)

For additional information: https://www.karger.com/DRM

References

  1. Gladman D, Antoni C, Mease P, Clegg D, Nash P: Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis 2005;64:ii14-ii17.
  2. Radtke MA, Reich K, Blome C, Rustenbach S, Augustin M: Prevalence and clinical features of psoriatic arthritis and joint complaints in 2,009 patients with psoriasis: results of a German national survey. J Eur Acad Dermatol Venereol 2009;23:683-691.
  3. Mease PJ: Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis. Curr Opin Rheumatol 2015;27:127-133.
  4. Kagami S, Rizzo HL, Lee JJ, Koguchi Y, Blauvelt A: Circulating Th17, Th22, and Th1 cells are increased in psoriasis. J Invest Dermatol 2010;130:1373-1383.
  5. Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, et al: Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 2011;187:490-500.
  6. Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Caňete JD, et al: Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99-109.
  7. Menon B, Gullick NJ, Walter GJ, Rajasekhar M, Garrood T, Evans HG, et al: Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. Arthritis Rheumatol 2014;66:1272-1281.
  8. Ali T, Kaitha S, Mahmood S, Ftesi A, Stone J, Bronze MS: Clinical use of anti-TNF therapy and increased risk of infections. Drug Healthc Patient Saf 2013;5:79-99.
  9. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al: American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727-735.
  10. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.
  11. Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, et al: Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum 2006;54:2665-2673.
  12. Higgins JPT, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al: The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
  13. STATACorp: Stata statistical software: release 13. College Station, StataCorp LP, 2013.
  14. Review Manager (RevMan) (computer program). Version 5.3. Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
  15. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich RS, Shuler CL, et al: Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis 2017;76:79-87.
  16. Mease PJ, McInnes IB, Kirkham B, Kavanaugh A, Rahman P, van der Heijde D, et al: Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis. N Engl J Med 2015;373:1329-1339.
  17. McInnes IB, Mease PJ, Kirkham B, Kavanaugh A, Ritchlin CT, Rahman P, et al: Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Lond Engl 2015;386:1137-1146.
  18. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, Deodhar A, et al: Brodalumab, an anti-IL17RA monoclonal antibody, in psoriatic arthritis. N Engl J Med 2014;370:2295-2306.
  19. Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et al: Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014;73:990-999.
  20. McInnes IB, Kavanaugh A, Gottlieb AB, Puig L, Rahman P, Ritchlin C, et al: Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet Lond Engl 2013;382:780-789.
  21. Gottlieb A, Menter A, Mendelsohn A, Shen Y-K, Li S, Guzzo C, et al: Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet Lond Engl 2009;373:633-640.
  22. Miossec P, Korn T, Kuchroo VK: Interleukin-17 and type 17 helper T cells. N Engl J Med 2009;361:888-898.
  23. Van den Berg WB, McInnes IB: Th17 cells and IL-17A - focus on immunopathogenesis and immunotherapeutics. Semin Arthritis Rheum 2013;43:158-170.
  24. Frleta M, Siebert S, McInnes IB: The interleukin-17 pathway in psoriasis and psoriatic arthritis: disease pathogenesis and possibilities of treatment. Curr Rheumatol Rep 2014;16:414.
  25. Lories RJ, McInnes IB: Primed for inflammation: enthesis-resident T cells. Nat Med 2012;18:1018-1019.
  26. Gossec L, Smolen JS, Ramiro S, de Wit M, Cutolo M, Dougados M, et al: European League against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis 2016;75:499-510.
  27. Robinson KM, Manni ML, Biswas PS, Alcorn JF: Clinical consequences of targeting IL-17 and TH17 in autoimmune and allergic disorders. Curr Allergy Asthma Rep 2013;13.
  28. Ungprasert P, Thongprayoon C, Davis JM: Indirect comparisons of the efficacy of biological agents in patients with psoriatic arthritis with an inadequate response to traditional disease-modifying anti-rheumatic drugs or to non-steroidal anti-inflammatory drugs: a meta-analysis. Semin Arthritis Rheum 2016;45:428-438.
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