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Clinical Rheumatology

, Volume 38, Issue 2, pp 523–534 | Cite as

Adverse drug events associated with 5mg versus 10mg Tofacitinib (Janus kinase inhibitor) twice daily for the treatment of autoimmune diseases: A systematic review and meta-analysis of randomized controlled trials

  • Feng HuangEmail author
  • Zu-chun Luo
Original Article

Abstract

Several recently published clinical trials have shown tofacitinib to be effective in the treatment of autoimmune diseases. This drug is commonly prescribed either in a 5-mg or in a10-mg dosage twice daily. In this review, we aimed to systematically compare the adverse drug events which were observed with 5 mg versus 10 mg tofacitinib for the treatment of autoimmune diseases. MEDLINE, EMBASE, the Cochrane library, and www.ClinicalTrials.gov were searched (from March to April 2018) for suitable English publications (published before April 2018). The inclusion criteria were as follows: randomized controlled trials, autoimmune disorders (rheumatic arthritis, psoriatic arthritis, moderate to severe psoriasis, and ankylosing spondylitis), and comparison of adverse drug events associated with 5 mg versus 10 mg tofacitinib. This study had follow-up time periods of 3 months and ≥ 6 months. Statistical analysis was carried out by RevMan 5.3 whereby risk ratios (RRs) and 95% confidence intervals (CIs) were generated. A total number of 4287 participants were included (2144 versus 2143 participants who received 5 mg and 10 mg tofacitinib twice daily respectively). The results showed that at 3 months, similar risks of adverse drug events, serious adverse events, and adverse events leading to drug discontinuation were observed with 5 mg versus 10 mg tofacitinib (RR 1.04, 95% CI 0.98–1.10; P = 0.17, I2 = 0%; RR 1.06, 95% CI 0.77–1.48; P = 0.71, I2 = 0%; and RR 1.06, 95% CI 0.78–1.43; P = 0.73, I2 = 32%, respectively). The other outcomes including serious infection events, adjudicated herpes zoster infection, adjudicated opportunistic infection, mild and severe neutropenia, malignancies, and adjudicated major adverse cardiovascular events were also similarly manifested. However, a decreased level of hemoglobin significantly favored 5 mg tofacitinib (RR 1.75, 95% CI 1.19–2.58; P = 0.005, I2 = 49%). Even at a follow-up time period of ≥ 6 months, adverse drug events, serious adverse events, adverse drug events leading to drug discontinuation, and serious infection were still similarly observed. According to this current review, both dosages of tofacitinib were safe to use. Even if similar adverse drug events were observed with 5 mg versus 10 mg tofacitinib twice daily for the treatment of autoimmune disorders, anemia was more prominent with 10 mg tofacitinib at a 3 month follow-up. Nevertheless, future studies based on a larger population size with longer follow-up time periods should further be considered.

Keywords

Adverse drug events Anemia Autoimmune disorders Janus kinase inhibitor Tofacitinib 

Notes

Acknowledgements

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Authors’ information

Dr. Feng Huang (M.D) is the first author.

Authors’ contributions

FH and ZL were responsible for the conception and design, acquisition of data, analysis and interpretation of data, and drafting the initial manuscript and revising it critically for important intellectual content. FH wrote and approved the final manuscript.

Funding

No external funding was used in the preparation of this manuscript. This research was supported by the National Natural Science Foundation of China (No. 81560046, 81760057) and Guangxi Natural Science Foundation (No. 2016GXNSFAA380002).

Compliance with ethical standards

Disclosures

None.

References

  1. 1.
    O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A (2013) Janus kinase Inhibitors in autoimmune diseases. Ann Rheum Dis 72(0 2):ii111–ii115CrossRefGoogle Scholar
  2. 2.
    Steve C (2017) Janus kinase inhibitors for autoimmune disorders. Therapy reviewGoogle Scholar
  3. 3.
    Rivellese F, Lobasso A, Barbieri L, Liccardo B, De Paulis A, Rossi FW (2018) Novel therapeutic approaches in rheumatoid arthritis: role of Janus kinases inhibitors. Curr Med Chem 25.  https://doi.org/10.2174/0929867325666180209145243
  4. 4.
    Yamaoka K (2016) Janus kinase inhibitors for rheumatoid arthritis. Curr Opin Chem Biol 32:29–33CrossRefGoogle Scholar
  5. 5.
    Louder A, Singh A, Saverno K et al (2016) Patient preferences regarding rheumatoid arthritis therapies: a conjoint analysis. Am Health Drug Benefits 9:84–93Google Scholar
  6. 6.
    Sivaraman P, Cohen SB (2017) Malignancy and Janus kinase inhibition. Rheum Dis Clin N Am 43(1):79–93CrossRefGoogle Scholar
  7. 7.
    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700CrossRefGoogle Scholar
  8. 8.
    Fleischmann R, Kremer J, Cush J, Schulze-Koops H, Connell CA, Bradley JD, Gruben D, Wallenstein GV, Zwillich SH, Kanik KS, ORAL Solo Investigators (2012) Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 367(6):495–507CrossRefGoogle Scholar
  9. 9.
    Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba A, Kudlacz E, Wang C, Menon S, Hendrikx T, Kanik KS (2017) Tofacitinib for psoriatic arthritis in patients with an inadequate response to TNF inhibitors. N Engl J Med 377(16):1525–1536CrossRefGoogle Scholar
  10. 10.
    Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila-Zapata F, Cieślak D, Graham D, Wang C, Menon S, Hendrikx T, Kanik KS (2017) Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N Engl J Med 377(16):1537–1550CrossRefGoogle Scholar
  11. 11.
    Papp KA, Krueger JG, Feldman SR, Langley RG, Thaci D, Torii H, Tyring S, Wolk R, Gardner A, Mebus C, Tan H, Luo Y, Gupta P, Mallbris L, Tatulych S (2016) Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: long-term efficacy and safety results from 2 randomized phase-III studies and 1 open-label long-termextension study. J Am Acad Dermatol 74(5):841–850CrossRefGoogle Scholar
  12. 12.
    van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, Forejtova S, Zwillich SH, Gruben D, Koncz T, Wallenstein GV, Krishnaswami S, Bradley JD, Wilkinson B, Standard Investigators ORAL (2012) Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 367(6):508–519CrossRefGoogle Scholar
  13. 13.
    Burmester GR, Blanco R, Charles-Schoeman C, Wollenhaupt J, Zerbini C, Benda B, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Soma K, Bradley J, Mebus C, ORAL Step investigators (2013) To facitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoidarthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3trial. Lancet 381(9865):451–460CrossRefGoogle Scholar
  14. 14.
    Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin-Mola E, Isaacs JD, Gruben D, Wallenstein G, Krishnaswami S, Zwillich SH, Koncz T, Riese R, Bradley J (2013) Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patientswith active rheumatoid arthritis: a randomized trial. Ann Intern Med 159(4):253–261CrossRefGoogle Scholar
  15. 15.
    Higgins JP, et al. (2008) Assessing risk of bias in included studies, in Cochrane handbook for systematic reviews of interventions. Wiley 187–241Google Scholar
  16. 16.
    van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, Li D, Menon S, Kanik KS (2017) Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis 76(8):1340–1347CrossRefGoogle Scholar
  17. 17.
    Kawalec P, Mikrut A, Wiśniewska N, Pilc A (2013) The effectiveness of tofacitinib, a novel Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol 32(10):1415–1424CrossRefGoogle Scholar
  18. 18.
    Fleischmann R, Cutolo M, Genovese MC, Lee EB, Kanik KS, Sadis S, Connell CA, Gruben D, Krishnaswami S, Wallenstein G, Wilkinson BE, Zwillich SH (2012) Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumabmonotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying anti rheumatic drugs. Arthritis Rheum 64(3):617–629CrossRefGoogle Scholar
  19. 19.
    Ghoreschi K, Gadina M (2014) Jakpot! New small molecules in autoimmune and inflammatory diseases. Exp Dermatol 23(1):7–11CrossRefGoogle Scholar
  20. 20.
    Ports WC, Khan S, Lan S, Lamba M, Bolduc C, Bissonnette R, Papp K (2013) A randomized phase 2a efficacy and safety trial of the topical Janus kinase inhibitor tofacitinib in the treatment of chronic plaque psoriasis. Br J Dermatol 169(1):137–145CrossRefGoogle Scholar
  21. 21.
    Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley JD, Gruben D, Koncz T, Krishnaswami S, Wallenstein GV, Zang C, Zwillich SH, van Vollenhoven RF (2014) Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 370:2377–2386CrossRefGoogle Scholar
  22. 22.
    Fleischmann R, Huizinga T, Kavanaugh AF et al (2016) Efficacy of tofacitinib monotherapy in methotrexate-naive patients with early or established rheumatoid arthritis. RMD Open 2:e000262CrossRefGoogle Scholar
  23. 23.
    Dhillon S (2017) Tofacitinib: a review in rheumatoid arthritis. Drugs 77(18):1987–2001CrossRefGoogle Scholar
  24. 24.
    Wallenstein GV, Kanik KS, Wilkinson B, Cohen S, Cutolo M, Fleischmann RM, Genovese MC, Gomez Reino J, Gruben D, Kremer J, Krishnaswami S, Lee EB, Pascual-Ramos V, Strand V, Zwillich SH (2016) Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two phase 2 randomised controlled trials. Clin Exp Rheumatol 34(3):430–442Google Scholar
  25. 25.
    Lundquist LM, Cole SW, Sikes ML (2014) Efficacy and safety of tofacitinib for treatment of rheumatoid arthritis. World J Orthop 5(4):504–511CrossRefGoogle Scholar
  26. 26.
    Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J (2017) 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):1253–1262CrossRefGoogle Scholar
  27. 27.
    Machado MAÁ, Moura CS, Guerra SF, Curtis JR, Abrahamowicz M, Bernatsky S (2018) Effectiveness and safety of tofacitinib in rheumatoid arthritis: a cohort study. Arthritis Res Ther 20(1):60CrossRefGoogle Scholar
  28. 28.
    Schulze-Koops H, Strand V, Nduaka C, DeMasi R, Wallenstein G, Kwok K, Wang L (2017) Analysis of haematological changes in tofacitinib-treated patients with rheumatoid arthritis across phase 3 and long-term extension studies. Rheumatology (Oxford) 56(1):46–57CrossRefGoogle Scholar
  29. 29.
    Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, Burgos-Vargas R, Wilkinson B, Zerbini CA et al (2009) 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 60:1895–1905CrossRefGoogle Scholar
  30. 30.
    Tanaka Y, Suzuki M, Nakamura H, Toyoizumi S, Zwillich SH (2011) Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken) 63:1150–1158CrossRefGoogle Scholar
  31. 31.
    Ni H, Moe S, Myint KT, Htet A (2013) Oral Janus kinase inhibitor for the treatment of rheumatoid arthritis: tofacitinib. ISRN Rheumatol 2013:357904CrossRefGoogle Scholar
  32. 32.
    Gadina M (2013) Janus kinases: an ideal target for the treatment of autoimmune diseases. J Investig Dermatol Symp Proc 16(1):S70–S72CrossRefGoogle Scholar

Copyright information

© International League of Associations for Rheumatology (ILAR) 2018

Authors and Affiliations

  1. 1.Institute of Cardiovascular Diseases and Guangxi Key Laboratory Base of Precision Medicine in Cardio-cerebrovascular Disease Control and Prevention and Guangxi Clinical Research Center for Cardio-cerebrovascular DiseasesThe First Affiliated Hospital of Guangxi Medical UniversityNanningChina
  2. 2.Department of Internal Medicine EducationThe First Affiliated Hospital of Guangxi Medical UniversityNanningChina

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