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Inhibitors of Janus kinases in the treatment of rheumatoid arthritis.


Authors: M. Filková
Authors‘ workplace: Revmatologický ústav, Praha
Published in: Čes. Revmatol., 26, 2018, No. 3, p. 132-140.
Category: Review Article

Overview

Inhibitors of Janus kinases (JAK) are synthetic small molecules for oral use targeting intracellular signalling pathways of many mediators with the essential role in the pathogenesis of rheumatoid arthritis (RA). Tofacitinib inhibits JAK3, JAK1 and to a lesser extent JAK2, whilst baricitinib preferentially interferes with JAK1 and JAK2. Their clinical efficacy was proven in several phase III clinical trials in RA patients either treatment naive or with inadequate response to conventional and biological disease modifying antirheumatic drugs. The clinical response was shown shortly after treatment initiation and low disease activity remained throughout the study. Both tofacitinib and baricitinib reduced radiographic progression. Some results showed either superiority or non-inferiority to methotreaxte or adalimumab. Both clinical efficacy and favourable safety profile enabled approval of tofacitinib and baricitinib for use in adult patients with RA with inadequate response to methotrexate. Tofacitinib has also been approved for treatment of patients with psoriatic arthritis and ulcerative colitis. Ongoing clinical trials with these and other JAK inhibitors will show their efficacy and safety in patients with RA or other inflammatory conditions.

Key words:

JAK, tofacitinib, baricitinib, rheumatoid arthritis, efficacy, safety


Sources

1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001.

2. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76(6): 960–77.

3. Schwartz DM, Bonelli M, Gadina M, O’Shea JJ. Type I/II cytokines, JAKs, and new strategies for treating autoimmune diseases. Nat Rev Rheumatol 2016; 12(1): 25–36.

4. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Reviews Drug Disc 2017; 16(12) :843–62.

5. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. Janus kinase inhibitors in autoimmune diseases. Ann Rheum Dis 2013; 72 (Suppl 2): ii111–5.

6. Smolen JS, van der Heijde D, Machold KP, Aletaha D, Landewe R. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis 2014; 73(1): 3–5.

7. Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 201; 370(25): 2377–86.

8. Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012 ; 367(6): 495–507.

9. van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, Garcia Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012; 367(6): 508–19.

10. Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2010; 159(4): 253–61.

11. van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum 2013; 65(3): 559–70.

12. Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 2013; 381(9865): 451–60.

13. Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 2017; 390(10093): 457–68.

14. Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatology 2017; 69(3): 506–17.

15. Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017; 376(7): 652–62.

16. Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017; 76(1): 88–95.

17. Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med 2016; 374(13): 1243–52.

18. 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, randomised, double-blind, placebo-controlled phase IIb study. Ann Rheum Dis. 2016; 75(6): 1057-64.

19. Kivitz AJ, Gutierrez-Urena SR, Poiley J, Genovese MC, Kristy R, Shay K, et al. Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in patients with an inadequate response to methotrexate. Arthritis Rheumatology 2017; 69(4): 709–19.

20. Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, 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 Rheumatology 2017; 69(5): 932–42.

21. Kavanaugh A, Kremer J, Ponce L, Cseuz R, Reshetko OV, Stanislavchuk M, et al. Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2). Ann Rheum Dis 2017; 76(6): 100 9–19.

22. Westhovens R, Taylor PC, Alten R, Pavlova D, Enriquez-Sosa F, Mazur M, 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 randomised, dose-finding study (DARWIN 1). Ann Rheum Dis 2017; 76(6): 998–1008.

23. Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, et al. A Phase IIb study of ABT-494, a Selective JAK-1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-tumor necrosis factor therapy. Arthritis Rheumatology 2016; 68(12): 2867–77.

24. Genovese MC, Smolen JS, Weinblatt ME, Burmester GR, Meerwein S, Camp HS, 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 Rheumatology 2016; 68(12): 2857–66.

25. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol 2017; 13(5): 320.

26. Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatology 2014; 66(10): 2675–84.

27. Maneiro JR, Souto A, Gomez-Reino JJ. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis. Semin Arthritis Rheum 2017; 47(2) : 149–56.

28. Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, Boy M, Zuckerman A, Soma K, et al. Cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib, an oral Janus kinase inhibitor. Semin Arthritis Rheum 201; 46(3): 261–71.

29. Charles-Schoeman C, Fleischmann R, Davignon J, Schwartz H, Turner SM, Beysen C, et al. Potential mechanisms leading to the abnormal lipid profile in patients with rheumatoid arthritis versus healthy volunteers and reversal by tofacitinib. Arthritis Rheumatology 2015; 67(3): 616–25.

30. Šenolt L, Mann H, Závada J, Pavelka K, Vencovský J. Doporučení Českér evmatologické společnosti pro farmakoterapii revmatoidní artritidy 2017. Čes Revmatol 2017; 25(1): 8–24.

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Dermatology & STDs Paediatric rheumatology Rheumatology
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