Drug Safety

, Volume 41, Issue 7, pp 645–653 | Cite as

Thromboembolism with Janus Kinase (JAK) Inhibitors for Rheumatoid Arthritis: How Real is the Risk?

  • Ian C. Scott
  • Samantha L. Hider
  • David L. ScottEmail author
Current Opinion


Two different Janus kinase (JAK) inhibitors—baricitinib and tofacitinib—are effective and licensed in active rheumatoid arthritis (RA). There have been recent concerns about potential thromboembolic risks with these drugs. Concerns about baricitinib focus on clinical trial findings. Using all publically available data, we estimate thromboembolic risks are approximately five events per 1000 patient years with 4 mg baricitinib daily. Concerns about tofacitinib have been raised by analyses of the Federal Drug Administration Adverse Event Reporting System (FAERs). These show some evidence of increased risks of pulmonary thrombosis, though not pulmonary embolism or venous thrombosis. Observational studies suggest in the general population and non-RA controls there are one to four thromboembolic events per 1000 patient years. In RA, thromboembolic risks increase to three to seven per 1000 patient years. The impact of biologics and disease-modifying anti-rheumatic drugs (DMARDs) on disease risk appears minimal, and the number of thromboembolic events is between four and eight per 1000 patient years. In the short term, full details of thromboembolic events in trials of JAK inhibitors need to be published. As the numbers of thromboembolic events will be small and patients enrolled in trials are not representative of all RA patients who may receive JAK inhibitors, this information is unlikely to provide definitive answers. Consequently, in the longer term, large observational studies are needed to accurately quantify thromboembolic risks attributable to JAK inhibitors and other drugs used to treat RA, and differentiate these from risks attributable to RA itself and its comorbidities.



We have no acknowledgements to make.

Compliance with Ethical Standards

Conflict of interest

Dr. Ian Scott is the statistician on a retrospective study entitled “Factors Associated with Disability in Rheumatoid Arthritis (RA) Patients with Persistent Medium Disease Activity (MDAS)”. This study is being conducted by Guy’s and St Thomas’ NHS Trust and sponsored by Eli Lilly. Dr. Scott will be receiving funding for this work from Guy’s and St Thomas’ NHS Trust in the future. He has no other potential conflicts of interest directly relevant to this study. Dr. Samantha Hider has no conflicts of interest that are directly relevant to the content of this study. Professor David L. Scott has received fees for consulting and giving educational lectures from Eli Lilly and Co. of less than £5000 in the last 5 years, but none since 2015. He has no other potential conflicts of interest directly relevant to this study.


No sources of funding were used to assist in the preparation of this study.


  1. 1.
    Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017;77:521–46.CrossRefPubMedGoogle Scholar
  2. 2.
    McInnes IB, Schett G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet. 2017;389:2328–37.CrossRefPubMedGoogle Scholar
  3. 3.
    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 Rev Drug Discov. 2017;16:843–62.CrossRefPubMedGoogle Scholar
  4. 4.
    Lee YH, Bae SC. Comparative efficacy and safety of baricitinib 2 mg and 4 mg in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Z Rheumatol. 2017. Scholar
  5. 5.
    Richez C, Truchetet ME, Kostine M, Schaeverbeke T, Bannwarth B. Efficacy of baricitinib in the treatment of rheumatoid arthritis. Expert Opin Pharmacother. 2017;18:1399–407.CrossRefPubMedGoogle Scholar
  6. 6.
    Kuriya B, Cohen MD, Keystone E. Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential. Ther Adv Musculoskelet Dis. 2017;9:37–44.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Keystone EC, Genovese MC, Schlichting DE, de la Torre I, Beattie SD, Rooney TP, Taylor PC. Safety and efficacy of baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol. 2018;45:14–21.CrossRefPubMedGoogle Scholar
  8. 8.
    Smolen J, Genovese M, Takeuchi T, et al. Safety profile of baricitinib in patients with active RA: an integrated analysis. Ann Rheum Dis. 2016;75(Suppl. 2):243–4.Google Scholar
  9. 9.
    Genovese MC, Smolen JS, Takeuchi T, Hyslop D, Macias WL, Rooney TP, Chen L, Dickson CL, Camp JR, Cardillo T, Ishii T. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 5.5 years: an updated integrated safety analysis. Arthritis Rheumatol. 2017;69:511.Google Scholar
  10. 10.
    Lee YH, Bae SC, Song GG. Comparative efficacy and safety of tofacitinib, with or without methotrexate, in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Rheumatol Int. 2015;35:1965–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Chatzidionysiou K, Emamikia S, Nam J, Ramiro S, Smolen J, van der Heijde D, Dougados M, Bijlsma J, Burmester G, Scholte M, van Vollenhoven R, Landewé R. Efficacy of glucocorticoids, conventional and targeted synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2017;76:1102–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Scott DL, Stevenson MD. Treating active rheumatoid arthritis with Janus kinase inhibitors. Lancet. 2017;390:431–2.CrossRefPubMedGoogle Scholar
  13. 13.
    Fleischmann R. A review of tofacitinib efficacy in rheumatoid arthritis patients who have had an inadequate response or intolerance to methotrexate. Expert Opin Pharmacother. 2017;18:1525–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol. 2017;13:234–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CA, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo WL, Rooney T, Macias W, Takeuchi T. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69:506–17.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen Morales L, Reyes Gonzaga J, Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich C, Rooney T, Schlichting D, Macias WL, de Bono S, Tanaka Y. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376:652–62.CrossRefPubMedGoogle Scholar
  17. 17.
    Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76:88–95.CrossRefPubMedGoogle Scholar
  18. 18.
    Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T, Macias W. 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 Rheumatol. 2016;43:504–11.CrossRefPubMedGoogle Scholar
  19. 19.
    Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74:333–40.CrossRefPubMedGoogle Scholar
  20. 20.
    Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374:1243–52.CrossRefPubMedGoogle Scholar
  21. 21.
    Greenwald M, Fidelus-Gort R, Levy R, Liang J, Vaddi K, Williams WV, Newton R. A randomized dose-ranging, placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in subjects with active rheumatoid arthritis. Arthritis Rheum. 2010;62:2172.Google Scholar
  22. 22.
    European Medicines Agency Assessment report: baricitinib. Accessed 26 Nov 17.
  23. 23.
    Update on Baricitinib. Eli Lilly and Company. Accessed 26 Nov 17.
  24. 24.
    Weinblatt M, Taylor PC, Burmester GR, Witt S, Saifan C, Walls C, Rooney TP, Chen L, Takeuchi T. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis. Arthritis Rheumatol. 2017;69:2352.CrossRefGoogle Scholar
  25. 25.
    Tarp S, Eric Furst D, Boers M, Luta G, Bliddal H, Tarp U, Heller Asmussen K, Brock B, Dossing A, Schjødt Jørgensen T, Thirstrup S, Christensen R. Risk of serious adverse effects of biological and targeted drugs in patients with rheumatoid arthritis: a systematic review meta-analysis. Rheumatology. 2017;56:417–25.PubMedGoogle Scholar
  26. 26.
    Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB. Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf. 2017. Scholar
  27. 27.
    Silversides CK, Granton JT, Konen E, Hart MA, Webb GD, Therrien J. Pulmonary thrombosis in adults with Eisenmenger syndrome. J Am Coll Cardiol. 2003;42:1982–7.CrossRefPubMedGoogle Scholar
  28. 28.
    Seyahi E, Yazici H. Behçet’s syndrome: pulmonary vascular disease. Curr Opin Rheumatol. 2015;27:18–23.CrossRefPubMedGoogle Scholar
  29. 29.
    Ring A, Bakke JR. Chronic massive pulmonary artery thrombosis. Ann Intern Med. 1955;43:781–806.CrossRefPubMedGoogle Scholar
  30. 30.
    Yang Y, Lv J, Zhou F, Chen M, Wang R, Zhao M, Wang H. Risk factors of pulmonary thrombosis/embolism in nephrotic syndrome. Am J Med Sci. 2014;348:394–8.CrossRefPubMedGoogle Scholar
  31. 31.
    Kremer JM, Emery P, Camp HS, Friedman A, Wang L, Othman AA, Khan N, Pangan AL, Jungerwirth S, Keystone EC. 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 Rheumatol. 2016;68:2867–77.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Matta F, Singala R, Yaekoub AY, Najjar R, Stein PD. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009;101:134–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Liang KP, Liang KV, Matteson EL, McClelland RL, Christianson TJ, Turesson C. Incidence of noncardiac vascular disease in rheumatoid arthritis and relationship to extraarticular disease manifestations. Arthritis Rheum. 2006;54:642–8.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Holmqvist ME, Neovius M, Eriksson J, Mantel Ä, Wållberg-Jonsson S, Jacobsson LT, Askling J. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308:1350–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Choi HK, Rho YH, Zhu Y, Cea-Soriano L, Aviña-Zubieta JA, Zhang Y. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis. 2013;72:1182–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Kim SC, Schneeweiss S, Liu J, Solomon DH. Risk of venous thromboembolism in patients with rheumatoid arthritis. Arthritis Care Res. 2013;65:1600–7.Google Scholar
  37. 37.
    Bacani AK, Gabriel SE, Crowson CS, Heit JA, Matteson EL. Noncardiac vascular disease in rheumatoid arthritis: increase in venous thromboembolic events? Arthritis Rheum. 2012;64:53–61.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Yusuf HR, Hooper WC, Grosse SD, Parker CS, Boulet SL, Ortel TL. Risk of venous thromboembolism occurrence among adults with selected autoimmune diseases: a study among a U.S. cohort of commercial insurance enrollees. Thromb Res. 2015;135:50–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Ungprasert P, Srivali N, Spanuchart I, Thongprayoon C, Knight EL. Risk of venous thromboembolism in patients with rheumatoid arthritis: a systematic review and meta-analysis. Clin Rheumatol. 2014;33:297–304.CrossRefPubMedGoogle Scholar
  40. 40.
    Lee JJ, Pope JE. A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res Ther. 2014;16:435.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Ogdie A, Kay McGill N, Shin DB, Takeshita J, Jon Love T, Noe MH, Chiesa Fuxench ZC, Choi HK, Mehta NN, Gelfand JM. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J. 2017. Scholar
  42. 42.
    Kim SC, Solomon DH, Liu J, Franklin JM, Glynn RJ, Schneeweiss S. Risk of venous thromboembolism in patients with rheumatoid arthritis: initiating disease-modifying antirheumatic drugs. Am J Med. 2015;128:539.CrossRefPubMedGoogle Scholar
  43. 43.
    Meyer-Olesen CL, Nielsen SF, Nordestgaard BG. Increased rheumatoid factor and deep venous thrombosis: 2 cohort studies of 54628 individuals from the general population. Clin Chem. 2015;61:349–59.CrossRefPubMedGoogle Scholar
  44. 44.
    Petitpain N, Gambier N, Wahl D, Chary-Valckenaere I, Loeuille D, Gillet P, French Network of Pharmacovigilance Centers. Arterial and venous thromboembolic events during anti-TNF therapy: a study of 85 spontaneous reports in the period 2000-2006. Biomed Mater Eng. 2009;19:355–64.PubMedGoogle Scholar
  45. 45.
    Makol A, Grover M, Guggenheim C, Hassouna H. Etanercept and venous thromboembolism: a case series. J Med Case Rep. 2010;4:12.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Korswagen LA, Bartelds GM, Krieckaert CL, Turkstra F, Nurmohamed MT, van Schaardenburg D, Wijbrandts CA, Tak PP, Lems WF, Dijkmans BA, van Vugt RM, Wolbink GJ. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 2011;63:877–83.CrossRefPubMedGoogle Scholar
  47. 47.
    Masson PL. Thromboembolic events and anti-tumor necrosis factor therapies. Int Immunopharmacol. 2012;14:444–5.CrossRefPubMedGoogle Scholar
  48. 48.
    Davies R, Galloway JB, Watson KD, Lunt M, Symmons DP, Hyrich KL, BSRBR Control Centre Consortium, British Society for Rheumatology Biologics Register. Venous thrombotic events are not increased in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011;70:1831–4.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Huerta C, Johansson S, Wallander MA, García Rodríguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med. 2007;167:935–43.CrossRefPubMedGoogle Scholar
  50. 50.
    Ungprasert P, Srivali N, Wijarnpreecha K, Charoenpong P, Knight E. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology. 2015;54:736–42.CrossRefPubMedGoogle Scholar
  51. 51.
    Johannesdottir SA, Horváth-Puhó E, Dekkers OM, Cannegieter SC, Jørgensen JO, Ehrenstein V, Vandenbroucke JP, Pedersen L, Sørensen HT. Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study. JAMA Intern Med. 2013;173:743–52.CrossRefPubMedGoogle Scholar
  52. 52.
    Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, Ayanian JZ, Nallamothu BK. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:j1415.CrossRefPubMedGoogle Scholar
  53. 53.
    White R. The epidemiology of venous thromboembolism. Circulation. 2003;107:I4–8.CrossRefPubMedGoogle Scholar
  54. 54.
    Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12:464–74.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG. Paracetamol: not as safe as we thought? A systematic literature review of observational studies. Ann Rheum Dis. 2016;75:552–9.CrossRefPubMedGoogle Scholar
  56. 56.
    Myllykangas-Luosujärvi R, Aho K, Isomäki H. Death attributed to antirheumatic medication in a nationwide series of 1666 patients with rheumatoid arthritis who have died. J Rheumatol. 1995;22:2214–7.PubMedGoogle Scholar
  57. 57.
    Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancytopenia: serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology. 2005;44:1051–5.CrossRefPubMedGoogle Scholar
  58. 58.
    Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology. 2005;44:61–6.CrossRefPubMedGoogle Scholar
  59. 59.
    Sinicina I, Mayr B, Mall G, Keil W. Deaths following methotrexate overdoses by medical staff. J Rheumatol. 2005;32:2009–11.PubMedGoogle Scholar
  60. 60.
    Choi HK, Hernán MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173–7.CrossRefPubMedGoogle Scholar
  61. 61.
    de La Forest Divonne M, Gottenberg JE, Salliot C. Safety of biologic DMARDs in RA patients in real life: a systematic literature review and meta-analyses of biologic registers. Jt Bone Spine. 2017;84:133–40.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Ian C. Scott
    • 1
    • 2
  • Samantha L. Hider
    • 1
    • 2
  • David L. Scott
    • 3
    Email author
  1. 1.Research Institute for Primary Care & Health Sciences, Primary Care SciencesKeele UniversityKeeleUK
  2. 2.Haywood Academic Rheumatology Centre, Haywood HospitalBurslemUK
  3. 3.Academic RheumatologyKing’s College HospitalLondonUK

Personalised recommendations