Tofacitinib: A Review in Rheumatoid Arthritis
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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.
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.
Compliance with Ethical Standards
The preparation of this review was not supported by any external funding.
Conflict of interest
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.
- 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.
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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).Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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).Google Scholar
- 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).Google Scholar
- 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).Google Scholar
- 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).Google Scholar
- 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).Google Scholar
- 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).Google Scholar
- 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.PubMedPubMedCentralCrossRefGoogle Scholar
- 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).Google Scholar
- 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.CrossRefPubMedGoogle Scholar
- 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.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).Google Scholar
- 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).Google Scholar
- 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.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.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.
- 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.Google Scholar
- 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.CrossRefPubMedPubMedCentralGoogle Scholar
- 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.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.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.Google Scholar
- 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).Google Scholar