Systematic Review

Comparison of Janus kinase inhibitors in the treatment of rheumatoid arthritis: a systemic literature review

University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Medicine, London, ON, Canada

Search for more papers by this author

Matthew Turk

University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Medicine, London, ON, Canada

Search for more papers by this author

Janet E Pope

*Author for correspondence: Tel.: +1 519 646 6332; Fax: +1 519 646 6334;

E-mail Address: janet.pope@sjhc.london.on.ca

University of Western Ontario, Schulich School of Medicine & Dentistry, Department of Medicine, London, ON, Canada

Professor of Medicine, Division of Rheumatology, St. Joseph’s Health Care & University of Western Ontario, London, Ontario, Canada

Search for more papers by this author

Published Online:8 Apr 2019https://doi.org/10.2217/imt-2018-0178

View article

Abstract

Several Janus kinase (JAK) inhibitors, oral targeted disease-modifying drugs, will be approved for the treatment of rheumatoid arthritis (RA) and other diseases. This review compares and contrasts the efficacy of JAK inhibitors (tofacitinib, baricitinib, upadacitinib, filgotinib, peficitinib and decernotinib) in RA including: early RA methotrexate-naive patients, post methotrexate failure and post biologics. Trials in monotherapy, combination with disease modifying drugs such as methotrexate, and comparing with adalimumab in biologic-naive patients were studied. The efficacy is superior to methotrexate in naive patients and equal or superior to adalimumab depending on the drug and dose. There is a class effect of adverse events. Serious infections occur at a rate similar to other advanced therapies in RA, although more reactivation of herpes zoster occurs.

Keywords:

References

1. Higgins JPT, Altman DG, Gøtzsche PC et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomized trials. BMJ 343, d5928 (2011).
MedlineGoogle Scholar
2. Fleischmann R, Cutolo M, Genovese MC et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 64(3), 617–629 (2012).
Medline CASGoogle Scholar
3. Kremer JM, Cohen S, Wilkinson BE et al. A Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 64(4), 970–981 (2012).
Medline CASGoogle Scholar
4. Kremer JM, Bloom BJ, Breedveld FC et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled Phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 60(7), 1895–1905 (2009).
Medline CASGoogle Scholar
5. Tanaka Y, Takeuchi T, Yamanaka H, Nakamura H, Toyoizumi S, Zwillich S. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, Phase II study. Modern Rheum. 25(4), 514–521 (2015).
Medline CASGoogle Scholar
6. van der Heijde D, Tanaka Y, Fleischmann R et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving MTX twelve-month data from a twenty-four–month Phase III randomized radiographic study. Arthritis Rheum. 65(3), 559–570 (2013).
MedlineGoogle Scholar
7. van Vollenhoven R, Fleischmann R, Cohen S et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl. J. Med. 367, 508–519 (2012).
Medline CASGoogle Scholar
8. Kremer J, Li ZG, Hall S et al. Tofacitinib in combination with non- biologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 159(4), 253–261 (2013).
MedlineGoogle Scholar
9. Burmester GR, Blanco R, Charles-Schoeman CH et al. Tofacitinib (CP-690,550) in combination with MTX in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomized Phase III trial. Lancet 381(9865), 451–460 (2013).
Medline CASGoogle Scholar
10. Lee EB, Fleischmann R, Hall S et al. Tofacitinib versus MTX in rheumatoid arthritis. N Engl. J. Med. 370, 2377–2386 (2014).
MedlineGoogle Scholar
11. Fleischmann R, Kremer J, Cush J et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl. J. Med. 367(6), 495–507 (2012).
Medline CASGoogle Scholar
12. Fleischmann R, Mysler E, Hall S et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with MTX, and adalimumab with MTX in patients with rheumatoid arthritis (ORAL Strategy): a Phase IIIb/IV, double-blind, head-to-head, randomized controlled trial. Lancet 390(10093), 457–468 (2017).
Medline CASGoogle Scholar
13. Fleischmann R, Mease PJ, Schwartzman S et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group. Clin. Rheum. 36(1), 15–24 (2017).
Medline CASGoogle Scholar
14. Bae SC, Lee YH. Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Z Rheumatol. (2018). doi: 10.1007/s00393-018-0531-5. [Epub ahead of print]
Google Scholar
15. Keystone EC, Taylor PC, Drescher E et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann. Rheum. Dis. 74(2), 333–340 (2015).
Medline CASGoogle Scholar
16. Tanaka Y, Emoto K, Cai Z et al. Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J. Rheum. 43(3), 504–511 (2016).
MedlineGoogle Scholar
17. Dougados M, van der Heijde D, Chen Y et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann. Rheum. Dis. 76(1), 88–95 (2017).
Medline CASGoogle Scholar
18. Genovese MC, Kremer J, Zamani O et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374(13), 1243–1252 (2016).
Medline CASGoogle Scholar
19. Fleischmann R, Schiff M, van der Heijde D et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 69(3), 506–517 (2017).
Medline CASGoogle Scholar
20. Taylor PC, Keystone EC, van der Heijde D et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N. Engl. J. Med. 376(7), 652–662 (2017).
Medline CASGoogle Scholar
21. van der Heijde D, Durez P, Schett G et al. Structural damage progression in patients with early rheumatoid arthritis treated with methotrexate, baricitinib, or baricitinib plus methotrexate based on clinical response in the Phase III RA-BEGIN study. Clin. Rheumatol. 37(9), 2381–2390 (2018).
MedlineGoogle Scholar
22. Smolen JS, Genovese MC, Takeuchi T et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment. J. Rheumatol. 46(1), 7–18 (2019).
Medline CASGoogle Scholar
23. Kremer JM, Emery P, Camp HS et al. A Phase IIb study of ABT-494, a selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to antitumor necrosis factor therapy. Arthritis Rheum. 68(12), 2867–2877 (2016).
Medline CASGoogle Scholar
24. Genovese MC, Smolen JS, Weinblatt ME et al. Efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in a Phase IIb study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheum. 68(12), 2857–2866 (2016).
Medline CASGoogle Scholar
25. Burmester GR, Kremer JM, Van den Bosch F et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomized, double-blind, placebo-controlled Phase III trial. Lancet 391(10139), 2503–2512 (2018).
Medline CASGoogle Scholar
26. Genovese MC, Fleischmann R, Combe B et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomized controlled Phase III trial. Lancet 391(10139), 2513–2524 (2018).
Medline CASGoogle Scholar
27. Vanhoutte F, Mazur M, Voloshyn O et al. Efficacy, safety, pharmacokinetics, and pharmacodynamics of filgotinib, a selective jak-1 inhibitor, after short-term treatment of rheumatoid arthritis: results of two randomized Phase IIa trials. Arthritis Rheum. 69(10), 1949–1959 (2017).
CASGoogle Scholar
28. Westhovens R, Taylor PC, Alten R et al. Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomized, dose-finding study (DARWIN 1). Ann. Rheum. Dis. 76(6), 998–1008 (2017).
Medline CASGoogle Scholar
29. Kavanaugh A, Kremer J, Ponce L et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomized, dose-finding study (DARWIN 2). Ann. Rheum. Dis. 76(6), 1009–1019 (2017).
Medline CASGoogle Scholar
30. Genovese MC, Greenwald M, Codding C et al. Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic disease-modifying antirheumatic drugs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis Rheum. 69(5), 932–942 (2017).
Medline CASGoogle Scholar
31. Kivitz AJ, Gutierrez-Ureña SR, Poiley J et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheum. 69(4), 709–719 (2017).
Medline CASGoogle Scholar
32. Takeuchi T, Tanaka Y, Iwasaki M, Ishikura H, Saeki S, Kaneko Y. Efficacy and safety of the oral Janus kinase inhibitor peficitinib (ASP015K) monotherapy in patients with moderate to severe rheumatoid arthritis in Japan: a 12-week, randomized, double-blind, placebo-controlled Phase IIb study. Ann. Rheum. Dis. 75(6), 1057–1064 (2016).
Medline CASGoogle Scholar
33. Fleischmann RM, Damjanov NS, Kivitz AJ, Legedza A, Hoock T, Kinnman N. A randomized, double-blind, placebo-controlled, twelve-week, dose-ranging study of decernotinib, an oral selective JAK-3 inhibitor, as monotherapy in patients with active rheumatoid arthritis. Arthritis Rheum. 67(2), 334–343 (2015).
Medline CASGoogle Scholar
34. Genovese MC, Van Vollenhoven RF, Pacheco-Tena C, Zhang Y, Kinnman N. VX-509 (Decernotinib), an oral selective JAK-3 inhibitor, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 68(1), 46–55 (2016).
CASGoogle Scholar
35. Genovese MC, Yang F, Østergaard M, Kinnman N. Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Ann. Rheum. Dis. 75(11), 1979–1983 (2016).
Medline CASGoogle Scholar
36. Hodge JA, Kawabata TT, Krishnaswami S et al. The mechanism of action of tofacitinib – an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. Clin. Exp. Rheum. 34(2), 318–328 (2016).
MedlineGoogle Scholar
37. Meyer DM, Jesson MI, Li X et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J. inflamm. 7, 1–12 (2010).
Google Scholar
38. Cao YJ, Sawamoto T, Valluri U et al. Pharmacokinetics, pharmacodynamics, and safety of ASP015K (Peficitinib), a new janus kinase inhibitor, in healthy subjects. Clin. Pharmacol. Drug Dev. 5(6), 435–449 (2016).
Medline CASGoogle Scholar
39. Markham A. Baricitinib: first global approval. Drugs 77(6), 697–704 (2017).
Medline CASGoogle Scholar
40. Baker KF, Isaacs JD. Novel therapies for immune-mediated inflammatory diseases: what can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn’s disease and ulcerative colitis? Ann. Rheum. Dis. 77(2), 175–187 (2018).
Medline CASGoogle Scholar
41. AbbVie Upadacitinib meets all primary and ranked secondary endpoints including superiority versus adalimumab in Phase III study in rheumatoid arthritis( 2018). https://news.abbvie.com/news/upadacitinib-meets-all-primary-and-ranked-secondary-endpoints-including-superiority-versus-adalimumab-in-phase-3-study-in-rheumatoid-arthritis.htm
Google Scholar
42. Genovese MC, Kalunian KC, Walker D et al. Safety and efficacy of filgotinib in a Phase III trial of patients with active rheumatoid arthritis and inadequate response or intolerance to biologic dmards [abstract]. Arthritis Rheum. 70(suppl. 10), (2018). https://acrabstracts.org/abstract/safety-and-efficacy-of-filgotinib-in-a-phase-3-trial-of-patients-with-active-rheumatoid-arthritis-and-inadequate-response-or-intolerance-to-biologic-dmards/
Google Scholar
43. Harnett J, Curtis JR, Gerber R, Gruben D, Koenig A. Initial experience with tofacitinib in clinical practice: treatment patterns and costs of tofacitinib administered as monotherapy or in combination with conventional synthetic DMARDs in 2 US health care claims databases. Clin. Ther. 38(6), 1451–1463 (2016).
Medline CASGoogle Scholar
44. Claxton L, Jenks M, Taylor M et al. An economic evaluation of tofacitinib treatment in rheumatoid arthritis: modeling the cost of treatment strategies in the United States. J. Manag. Care Spec. Pharm. 22(9), 1088–1102 (2016).
MedlineGoogle Scholar
45. Pope J, Keystone E, Jamal S et al. Persistence of tofacitinib in the treatment of rheumatoid arthritis in open-label, long-term extension studies up to 8years. Arthritis Rheum. 68(suppl 10), (2016). https://acrabstracts.org/abstract/persistence-of-tofacitinib-in-the-treatment-of-rheumatoid-arthritis-in-open-label-long-term-extension-studies-up-to-8-years/
Google Scholar
46. Cohen SB, Tanaka Y, Mariette X et al. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann. Rheum. Dis. 76(7), 1253–1262 (2017).
Medline CASGoogle Scholar
47. Pawar A, Desai RJ, Solomon DH et al. Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann. Rheum. Dis. doi: 10.1136/annrheumdis-2018-214367 (Epub ahead of print).
Google Scholar
48. Desai RJ, Pawar A, Weinblatt ME, Kim SC. Comparative risk of venous thromboembolism with tofacitinib versus tumor necrosis factor inhibitors: a cohort study of rheumatoid arthritis patients [abstract]. Arthritis Rheum. 70(suppl. 10), (2018).
Google Scholar
49. Genovese MC, Smolen JS, Takeuchi T et al. Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 6 Years: An Updated Integrated Safety Analysis [abstract]. Arthritis Rheum. 70(suppl. 10), (2018). https://acrabstracts.org/abstract/safety-profile-of-baricitinib-for-the-treatment-of-rheumatoid-arthritis-up-to-6-years-an-updated-integrated-safety-analysis/
Google Scholar

Vol. 11, No. 8

Metrics

Downloaded 1,444 times

History

Received 12 November 2018

Accepted 18 March 2019

Published online 8 April 2019

Published in print June 2019

Information

Keywords

Financial & competing interests disclosure

J Jegatheeswaran has nothing to disclose. M Turk has nothing to disclose. JE Pope has consulted for AbbVie, Amgen, BMS, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

PDF download