Tofacitinib: A Review in Rheumatoid Arthritis

Abstract

Tofacitinib (Xeljanz®) is a potent, selective JAK inhibitor that preferentially inhibits Janus kinase (JAK) 1 and JAK3. In the EU, oral tofacitinib 5 mg twice daily is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant of, one or more DMARDs. Several clinical studies of ≤ 24 months’ duration showed that tofacitinib monotherapy (as first- or second-line treatment) and combination therapy with a conventional synthetic DMARD (csDMARD; as second- or third-line treatment) was effective in reducing signs and symptoms of disease and improving health-related quality of life (HR-QOL), with benefits sustained during long-term therapy (≤ 96 months). Tofacitinib monotherapy inhibited progression of structural damage in methotrexate-naïve patients during ≤ 24 months’ treatment, with beneficial effects also seen in patients receiving tofacitinib plus methotrexate as second-line therapy for 12 months. Tofacitinib was generally well tolerated during ≤ 114 months’ treatment, with most adverse events of mild or moderate severity. The tolerability profile of tofacitinib was generally similar to that of biological DMARDs (bDMARDs), with infections and infestations the most common adverse events (AEs) in tofacitinib recipients. However, the incidence of herpes zoster (HZ) was higher with tofacitinib than in the general RA population, although infections were clinically manageable. When added to background methotrexate, tofacitinib was noninferior to adalimumab in terms of efficacy, and both combination therapies had generally similar tolerability profiles. Although additional comparative studies are needed to more definitively position tofacitinib relative to bDMARDs and other targeted synthetic DMARDs, current evidence indicates that oral tofacitinib is a useful option for the treatment of patients with RA.

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References

  1. 1.

    O’Shea JJ, Laurence A, McInnes IB, et al. Back to the future: oral targeted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol. 2013;9(3):173–82.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Smolen JS, Landewe R, Bijlsma J, 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.

    Article  PubMed  Google Scholar 

  3. 3.

    Winthrop KL, Strand V, van der Heijde DM, et al. The unmet need in rheumatology: reports from the Targeted Therapies meeting 2016. Clin Exp Rheumatol. 2016;34(4 Suppl 98):69–76.

    PubMed  Google Scholar 

  4. 4.

    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 Rheumatol. 2016;34(2):318–28.

    PubMed  Google Scholar 

  5. 5.

    Pfizer Ltd. Xeljanz (tofacitinib): summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004214/WC500224911.pdf. Accessed 31 Oct 2017.

  6. 6.

    Scott LJ. Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73(8):857–74.

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    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. 2010;7:41.

    Article  CAS  Google Scholar 

  8. 8.

    Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32.

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Maeshima K, Yamaoka K, Kubo S, et al. The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-gamma and interleukin-17 production by human CD4 + T cells. Arthritis Rheum. 2012;64(6):1790–8.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015;74(6):1311–6.

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Conaghan PG, Ostergaard M, Bowes MA, et al. Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis. 2016;75(6):1024–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    LaBranche TP, Jesson MI, Radi ZA, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012;64(11):3531–42.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Kitano M, Kitano S, Sekiguchi M, et al. Early effect of tofacitinib on osteoclast regulator in rheumatoid arthritis [abstract no. AB0394]. Ann Rheum Dis. 2016;75(Suppl 2):1040.

    Article  Google Scholar 

  14. 14.

    van Vollenhoven R, Choy E, Lee EB, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: changes in lymphocytes and lymphocyte subset counts and reversibility after up to 8 years of tofacitinib treatment [abstract no. THU0199]. Ann Rheum Dis. 2016;75(Suppl 2).

  15. 15.

    McInnes IB, Kim HY, Lee SH, et al. Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann Rheum Dis. 2014;73(1):124–31.

    Article  PubMed  CAS  Google Scholar 

  16. 16.

    Isaacs JD, Zuckerman A, Krishnaswami S, et al. Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib: results from clinical trials. Arthritis Res Ther. 2014;16(4):R158.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Winthrop KL, Silverfield J, Racewicz A, et al. The effect of tofacitinib on pneumococcal and influenza vaccine responses in rheumatoid arthritis. Ann Rheum Dis. 2016;75(4):687–95.

    Article  PubMed  CAS  Google Scholar 

  18. 18.

    Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med. 2014;370(25):2377–86.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

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

    Article  PubMed  CAS  Google Scholar 

  20. 20.

    Fleischmann R, Mysler E, Hall S, 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.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    van der Heijde D, Tanaka Y, Fleischmann R, 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.

    Article  PubMed  CAS  Google Scholar 

  22. 22.

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

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013;159(4):253–61.

    Article  PubMed  Google Scholar 

  24. 24.

    Burmester GR, Blanco R, Charles-Schoeman C, 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.

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Fleischmann R, Mease PJ, Schwartzman S, et al. Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group. Clin Rheumatol. 2017;36(1):15–24.

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Landewe RB, Connell CA, Bradley JD, et al. Is radiographic progression in modern rheumatoid arthritis trials still a robust outcome? Experience from tofacitinib clinical trials. Arthritis Res Ther. 2016;18(1):212.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    Strand V, van Vollenhoven RF, Lee EB, et al. Tofacitinib or adalimumab versus placebo: patient-reported outcomes from a phase 3 study of active rheumatoid arthritis. Rheumatology (Oxford). 2016;55(6):1031–41.

    Article  CAS  Google Scholar 

  28. 28.

    Strand V, Kremer JM, Gruben D, et al. Tofacitinib in combination with conventional disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: patient-reported outcomes from a phase III randomized controlled trial. Arthritis Care Res (Hoboken). 2017;69(4):592–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 29.

    Strand V, Burmester GR, Zerbini CA, et al. Tofacitinib with methotrexate in third-line treatment of patients with active rheumatoid arthritis: patient-reported outcomes from a phase III trial. Arthritis Care Res (Hoboken). 2015;67(4):475–83.

    Article  PubMed  CAS  Google Scholar 

  30. 30.

    Strand V, Mysler E, Moots RJ, et al. Tofacitinib with and without methotrexate versus adalimumab with methotrexate for the treatment of rheumatoid arthritis: patient-reported outcomes from a phase 3b/4 randomized trial [abstract no. 1906]. Arthritis Rheumatol. 2017;69(Suppl 10).

  31. 31.

    Strand V, Kremer J, Wallenstein G, et al. Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs. Arthritis Res Ther. 2015;17:307.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Strand V, Lee EB, Fleischmann R, et al. Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL Start trial. RMD Open. 2016;2(2):e000308.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol. 2014;41(5):837–52.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Wollenhaupt J, Silverfield J, Lee EB. Tofacitinib, an oral janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and efficacy in open-label, long-term extension studies over 9 years [abstract no. 522]. Arthritis Rheumatol. 2017;69(Suppl 10).

  35. 35.

    van der Heijde D, Wollenhaupt J, Cohen SB, et al. Assessment of radiographic progression in patients with rheumatoid arthritis treated with tofacitinib: data from an open-label long-term extension study over 3 years [abstract no. 533]. 2017;69(Suppl 10).

  36. 36.

    Charles-Schoeman C, Burmester G, Nash P, et al. Efficacy and safety of tofacitinib following inadequate response to conventional synthetic or biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2016;75(7):1293–301.

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Hall S, Nash P, Rischmueller M, et al. Efficacy of tofacitinib in patients who are inadequate responders to disease-modifying antirheumatic drugs according to early versus late duration of rheumatoid arthritis: post-hoc analysis of data from phase 3 trials [abstract no. 1609]. Arthritis Rheumatol. 2016;68(Suppl 10).

  38. 38.

    Dikranian A, Gonzalez-Gay MA, Wellborne F, et al. The efficacy of tofacitinib in patients with rheumatoid arthritis stratified by baseline body mass index [abstract no. 2371]. Arthritis Rheumatol. 2017;69(Suppl 10).

  39. 39.

    Tesser J, Gül A, Olech E, et al. Efficacy and safety of tofacitinib in patients with rheumatoid arthritis and inadequate response or intolerance to prior therapies [abstract no. 2493]. Arthritis Rheumatol. 2017;69(Suppl 10).

  40. 40.

    Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther. 2016. https://doi.org/10.1186/s13075-016-0932-2.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    An Y, Li Z, Wu Q. Efficacy and safety of tofacitinib in chinese patients with active rheumatoid arthritis: subgroup analysis from a phase 3 study of tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs [abstract no. AB0514]. Ann Rheum Dis. 2015;74(Suppl 2).

  42. 42.

    Radominski SC, Cardiel MH, Citera G, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of Latin American patients with rheumatoid arthritis: pooled efficacy and safety analyses of phase 3 and long-term extension studies. Reumatol Clin. 2017;13(4):201–9.

    Article  PubMed  Google Scholar 

  43. 43.

    Cohen SB, Koenig A, Wang L, et al. Efficacy and safety of tofacitinib in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III. Clin Exp Rheumatol. 2016;34(1):32–6.

    PubMed  Google Scholar 

  44. 44.

    Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Clin Exp Rheumatol. 2017;35(3):390–400.

    PubMed  Google Scholar 

  45. 45.

    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. 2017;76(7):1253–62.

    Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    European Medicines Agency. Xeljanz (tofacitinib): assessment report. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/004214/WC500224913.pdf. Accessed 31 Oct 2017.

  47. 47.

    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 8 years [abstract no. 1602]. Arthritis Rheumatol. 2016;68(Suppl 10).

  48. 48.

    Winthrop K, Wouters A, Choy E, et al. Assessment of immunogenicity of live zoster vaccination in rheumatoid arthritis patients on background methotrexate before and after initiating tofacitinib or placebo [abstract no. FRI0110]. Ann Rheum Dis. 2016;75(Suppl 2):468.

    Article  Google Scholar 

  49. 49.

    Nurmohamed M, Choy E, Charles-Schoeman C, et al. Impact of tofacitinib treatment compared with placebo or methotrexate on cardiovascular risk scores in six phase 3 randomized controlled trials [abstract no. 2966]. Arthritis Rheumatol. 2017;69(Suppl 10).

  50. 50.

    Schulze-Koops H, Strand V, Nduaka C, et al. Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Rheumatology (Oxford). 2017;56(1):46–57.

    Article  Google Scholar 

  51. 51.

    Mariette X, Chen C, Biswas P, et al. Lymphoma in the tofacitinib rheumatoid arthritis clinical development program. Arthritis Care Res (Hoboken). 2017. https://doi.org/10.1002/acr.23421.

    PubMed  Article  Google Scholar 

  52. 52.

    Curtis JR, Lanas A, John A, et al. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1819–28.

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Burmester GR, Pope JE. Novel treatment strategies in rheumatoid arthritis. Lancet. 2017;389(10086):2338–48.

    Article  PubMed  Google Scholar 

  54. 54.

    Eli Lilly Nederland B.V. Olumiant® (baricitinib): summary of product characteristics. 2017. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004085/WC500223723.pdf. Accessed 31 Oct 2017.

  55. 55.

    National Institute of Health and Care Excellence. Tofacitinib for moderate to severe rheumatoid arthritis: technology appraisal guidance. 2017. https://www.nice.org.uk/guidance/ta480. Accessed 31 Oct 2017.

  56. 56.

    National Institute of Health and Care Excellence. Baricitinib for moderate to severe rheumatoid arthritis. 2017. https://www.nice.org.uk/guidance/ta466. Accessed 31 Oct 2017.

  57. 57.

    Mocsai A, Kovacs L, Gergely P. What is the future of targeted therapy in rheumatology: biologics or small molecules? BMC Med. 2014;12:43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. 58.

    Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13(4):234–43.

    Article  PubMed  CAS  Google Scholar 

  59. 59.

    Strand V, Ahadieh S, French J, et al. Systematic review and meta-analysis of serious infections with tofacitinib and biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis clinical trials. Arthritis Res Ther. 2015;17:362.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(10):2675–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. 61.

    Curtis JR, Xie F, Yun H, et al. Real-world comparative risks of herpes virus infections in tofacitinib and biologic-treated patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(10):1843–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 62.

    Vieira MC, Zwillich SH, Jansen JP, et al. Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors: results from a network meta-analysis. Clin Ther. 2016;38(12):2628–41.e5.

  63. 63.

    Bergrath E, Gerber RA, Gruben D, et al. Tofacitinib versus biologic treatments in moderate-to-severe rheumatoid arthritis patients who have had an inadequate response to nonbiologic DMARDs: systematic literature review and network meta-analysis. Int J Rheumatol. 2017;2017:8417249.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. 64.

    Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652–62.

    Article  PubMed  CAS  Google Scholar 

  65. 65.

    Weinblatt M, Taylor PC, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis [abstract no. 2352]. Arthritis. Rheumatol. 2017;69(Suppl 10):2352.

    Google Scholar 

  66. 66.

    Eli Lilly and Co Ltd. Olumiant (baricitinib): UK summary of product characteristics. 2017. https://www.medicines.org.uk/emc/medicine/32997#. Accessed 31 Oct 2017.

  67. 67.

    Souto A, Maneiro JR, Gomez-Reino JJ. Rate of discontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care databases. Rheumatology (Oxford). 2016;55(3):523–34.

    CAS  Google Scholar 

  68. 68.

    Smith T, Harnett J, Gruben D, et al. Real-world experience with tofacitinib versus adalimumab and etanercept in biologic-naive patients with RA previously treated with methotrexate: data from a US administrative healthcare insurance claims database [abstract no. 2831]. Arthritis Rheumatol. 2017;69(Suppl 10).

  69. 69.

    Marengo MF, Suarez-Almazor ME. Improving treatment adherence in patients with rheumatoid arthritis: what are the options? Int J Clin Rheumtol. 2015;10(5):345–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. 70.

    Alten R, Kruger K, Rellecke J, et al. Examining patient preferences in the treatment of rheumatoid arthritis using a discrete-choice approach. Patient Prefer Adherence. 2016;10:2217–28.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

During the peer review process, the manufacturer of tofacitinib (Xeljanz®) was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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Correspondence to Sohita Dhillon.

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The preparation of this review was not supported by any external funding.

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Sohita Dhillon is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Additional information about this Adis Drug Review can be found at http://www.medengine.com/Redeem/ED1CF06073837128.

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The manuscript was reviewed by: R. M. Fleischmann, Metroplex Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; E. B. Lee, Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; D. L Scott, Department of Clinical Rheumatology, Kings College London, Weston Education Centre, London, UK.

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Dhillon, S. Tofacitinib: A Review in Rheumatoid Arthritis. Drugs 77, 1987–2001 (2017). https://doi.org/10.1007/s40265-017-0835-9

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