Research ArticleArticle
Open Access

Safety and Efficacy of Tofacitinib, an Oral Janus Kinase Inhibitor, for the Treatment of Rheumatoid Arthritis in Open-label, Longterm Extension Studies

Jürgen Wollenhaupt, Joel Silverfield, Eun Bong Lee, Jeffrey R. Curtis, Susan P. Wood, Koshika Soma, Chudy I. Nduaka, Birgitta Benda, David Gruben, Hiroyuki Nakamura, Yoshihiro Komuro, Samuel H. Zwillich, Lisy Wang and Richard J. Riese
The Journal of Rheumatology May 2014, 41 (5) 837-852; DOI: https://doi.org/10.3899/jrheum.130683

REFERENCES

  1. 1.↵
    1. Strand V,
    2. Khanna D
    . The impact of rheumatoid arthritis and treatment on patients’ lives. Clin Exp Rheumatol 2010;28:S32–S40.
    OpenUrlPubMed
  2. 2.↵
    1. McInnes I,
    2. Schett G
    . The pathogenesis of rheumatoid arthritis. N Engl J Med 2011;365:2205–19.
    OpenUrlCrossRefPubMed
  3. 3.↵
    1. Meyer DM,
    2. Jesson MI,
    3. Li X,
    4. Elrick MM,
    5. Funckes-Shippy CL,
    6. Warner JD,
    7. 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.
    OpenUrlCrossRef
  4. 4.↵
    1. Kremer JM,
    2. Cohen S,
    3. Wilkinson BE,
    4. Connell CA,
    5. French JL,
    6. Gomez-Reino J,
    7. et al.
    A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum 2012;64:970–81.
    OpenUrlCrossRefPubMed
  5. 5.↵
    1. Fleischmann R,
    2. Cutolo M,
    3. Genovese MC,
    4. Lee EB,
    5. Kanik KS,
    6. Sadis S,
    7. et al.
    Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012;64:617–29.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Kremer JM,
    2. Bloom BJ,
    3. Breedveld FC,
    4. Coombs JH,
    5. Fletcher MP,
    6. Gruben D,
    7. et al.
    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 dose levels of CP-690,550 versus placebo. Arthritis Rheum 2009;60:1895–905.
    OpenUrlCrossRefPubMed
  7. 7.↵
    1. Tanaka Y,
    2. Suzuki M,
    3. Nakamura H,
    4. Toyoizumi S,
    5. Zwillich SH
    . 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 2011;63:1150–8.
    OpenUrlCrossRef
  8. 8.↵
    1. Tanaka Y,
    2. Takeuchi T,
    3. Yamanaka H,
    4. Suzuki M,
    5. Nakamura H,
    6. Toyoizumi S,
    7. et al.
    Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week Phase 2b study [abstract]. Arthritis Rheum 2011;63 Suppl:S854.
    OpenUrl
  9. 9.↵
    1. Kremer JM,
    2. Li ZG,
    3. Hall S,
    4. Fleischmann R,
    5. Genovese M,
    6. Martin-Mola E,
    7. et al.
    Tofacitinib (CP-690,550), an oral JAK inhibitor, in combination with traditional DMARDS: Phase 3 study in patients with active rheumatoid arthritis with inadequate response to DMARDs [abstract]. Ann Rheum Dis 2011;70 Suppl 3:170.
    OpenUrl
  10. 10.↵
    1. van Vollenhoven RF,
    2. Fleischmann R,
    3. Cohen S,
    4. Lee EB,
    5. García Meijide JA,
    6. Wagner S,
    7. et al.
    Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508–19.
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Lee EB,
    2. Fleischmann R,
    3. Hall S,
    4. van Vollenhoven RF,
    5. Bradley JD,
    6. Gruben D,
    7. et al.
    Radiographic, clinical and functional comparison of tofacitinib monotherapy versus methotrexate in methotrexate-naive patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2012;64 Suppl:S1049.
    OpenUrl
  12. 12.↵
    1. Fleischmann R,
    2. Kremer J,
    3. Cush J,
    4. Schulze-Koops H,
    5. Connell CA,
    6. Bradley JD,
    7. et al.
    Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495–507.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Burmester GR,
    2. Blanco R,
    3. Charles-Schoeman C,
    4. Wollenhaupt J,
    5. Zerbini C,
    6. Benda B,
    7. 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;381:451–60.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. van der Heijde D,
    2. Tanaka Y,
    3. Fleischmann R,
    4. Keystone E,
    5. Kremer J,
    6. Zerbini C,
    7. 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;65:559–70.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. McInnes IB,
    2. Kim HY,
    3. Lee SH,
    4. Mandel D,
    5. Song YW,
    6. Connell CA,
    7. et al.
    Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann Rheum Dis 2014;73:124–31.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Winthrop KL,
    2. Neal J,
    3. Hrycaj P,
    4. Soma K,
    5. Wilkinson B,
    6. Hodge J,
    7. et al.
    Evaluation of influenza and pneumococcal vaccine responses in rheumatoid arthritis patients using tofacitinib [abstract]. Ann Rheum Dis 2013;72 Suppl 3:107.
    OpenUrl
  17. 17.↵
    1. Boyle DL,
    2. Wei N,
    3. Singhal A,
    4. Rosengren S,
    5. Kaplan I,
    6. Soma K,
    7. et al.
    The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT1 signaling in rheumatoid arthritis [abstract]. Ann Rheum Dis 2013;72 Suppl 3:138.
    OpenUrl
  18. 18.↵
    1. Turner SM,
    2. Beysen C,
    3. Charles-Schoeman C,
    4. Fleischmann R,
    5. Davignon J,
    6. Schwartz H,
    7. et al.
    Increased selective clearance of cholesteryl-ester in patients with rheumatoid arthritis is reversed by treatment with tofacitinib [abstract]. Arterioscler Thromb Vasc Biol 2013;33:A124.
    OpenUrlCrossRef
  19. 19.↵
    1. Ahadieh S,
    2. Checchio T,
    3. Tensfeldt T,
    4. French J,
    5. Krishnaswami S,
    6. Riese R,
    7. et al.
    Meta-analysis of malignancies, serious infections, and serious adverse events with tofacitinib and biologic treatment in rheumatoid arthritis clinical trials [abstract]. Arthritis Rheum 2012;64 Suppl:S726.
    OpenUrl
  20. 20.↵
    1. Gottlieb AB,
    2. Gordon K,
    3. Giannini EH,
    4. Mease P,
    5. Li J,
    6. Chon Y,
    7. et al.
    Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications. J Drugs Dermatol 2011;10:289–300.
    OpenUrlPubMed
  21. 21.↵
    1. Gonzalez A,
    2. Maradit KH,
    3. Crowson CS,
    4. Nicola PJ,
    5. Davis JM III.,
    6. Therneau TM,
    7. et al.
    The widening mortality gap between rheumatoid arthritis patients and the general population. Arthritis Rheum 2007;56:3583–7.
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Bjornadal L,
    2. Baecklund E,
    3. Yin L,
    4. Granath F,
    5. Klareskog L,
    6. Ekbom A
    . Decreasing mortality in patients with rheumatoid arthritis: results from a large population based cohort in Sweden, 1964–95. J Rheumatol 2002;29:906–12.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Keane J,
    2. Gershon S,
    3. Wise RP,
    4. Mirabile-Levens E,
    5. Kasznica J,
    6. Schwieterman WD,
    7. et al.
    Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098–104.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Wolfe F,
    2. Michaud K,
    3. Anderson J,
    4. Urbansky K
    . Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum 2004;50:372–9.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Brassard P,
    2. Kezouh A,
    3. Suissa S
    . Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis 2006;43:717–22.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Burmester GR,
    2. Mariette X,
    3. Montecucco C,
    4. Monteagudo-Saez I,
    5. Malaise M,
    6. Tzioufas AG,
    7. et al.
    Adalimumab alone and in combination with disease-modifying antirheumatic drugs for the treatment of rheumatoid arthritis in clinical practice: the Research in Active Rheumatoid Arthritis (ReAct) trial. Ann Rheum Dis 2007;66:732–9.
    OpenUrlAbstract/FREE Full Text
  27. 27.↵
    1. Carmona L,
    2. Hernandez-Garcia C,
    3. Vadillo C,
    4. Pato E,
    5. Balsa A,
    6. Gonzalez-Alvaro I,
    7. et al.
    Increased risk of tuberculosis in patients with rheumatoid arthritis. J Rheumatol 2003;30:1436–9.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Carmona L,
    2. Gomez-Reino JJ,
    3. Rodriguez-Valverde V,
    4. Montero D,
    5. Pascual-Gomez E,
    6. Mola EM,
    7. et al.
    Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52:1766–72.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Seong SS,
    2. Choi CB,
    3. Woo JH,
    4. Bae KW,
    5. Joung CL,
    6. Uhm WS,
    7. et al.
    Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers. J Rheumatol 2007;34:706–11.
    OpenUrlAbstract/FREE Full Text
  30. 30.↵
    1. Yamada T,
    2. Nakajima A,
    3. Inoue E,
    4. Tanaka E,
    5. Hara M,
    6. Tomatsu T,
    7. et al.
    Increased risk of tuberculosis in patients with rheumatoid arthritis in Japan. Ann Rheum Dis 2006;65:1661–3.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Dixon WG,
    2. Hyrich KL,
    3. Watson KD,
    4. Lunt M,
    5. Galloway J,
    6. Ustianowski A,
    7. et al.
    Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522–8.
    OpenUrlAbstract/FREE Full Text
  32. 32.↵
    1. Baldin B,
    2. Dozol A,
    3. Spreux A,
    4. Chichmanian RM
    . La tuberculose et le traitement par infliximab. La surveillance nationale à partir du 1er Janvier 2000, le 30 Juin 2003 (French). Tuberculosis and infliximab treatment. National surveillance from January 1, 2000, through June 30, 2003. Presse Med 2005;34:353–7.
    OpenUrlCrossRefPubMed
  33. 33.↵
    1. Sichletidis L,
    2. Settas L,
    3. Spyratos D,
    4. Chloros D,
    5. Patakas D
    . Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis. Int J Tuberc Lung Dis 2006;10:1127–32.
    OpenUrlPubMed
  34. 34.↵
    1. Favalli EG,
    2. Desiati F,
    3. Atzeni F,
    4. Sarzi-Puttini P,
    5. Caporali R,
    6. Pallavicini FB,
    7. et al.
    Serious infections during anti-TNFalpha treatment in rheumatoid arthritis patients. Autoimmun Rev 2009;8:266–73.
    OpenUrlCrossRefPubMed
  35. 35.↵
    1. Galloway JB,
    2. Hyrich KL,
    3. Mercer LK,
    4. Dixon WG,
    5. Fu B,
    6. Ustianowski AP,
    7. et al.
    Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology 2011;50:124–31.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Kievit W,
    2. Fransen J,
    3. Adang EM,
    4. den Broeder AA,
    5. Bernelot Moens HJ,
    6. Visser H,
    7. et al.
    Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register. Rheumatology 2011;50:196–203.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Charles-Schoeman C,
    2. Wicker P,
    3. Sechtem U,
    4. Gonzalez-Gay MS,
    5. Wood S,
    6. Boy M,
    7. et al.
    Cardiovascular safety findings in rheumatoid arthritis patients treated with tofacitinib (CP-690,550), a novel, oral JAK inhibitor [abstract]. Ann Rheum Dis 2013;72 Suppl 3:245.
    OpenUrlAbstract/FREE Full Text
  38. 38.↵
    1. Mariette X,
    2. Curtis JR,
    3. Lee EB,
    4. Riese R,
    5. Kaplan I,
    6. Chew R,
    7. et al.
    Tofacitinib (CP-690,550), an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical programme [abstract]. Ann Rheum Dis 2012;71 Suppl 2:199.
    OpenUrl
  39. 39.↵
    1. Antonelli MA,
    2. Moreland LW,
    3. Brick JE
    . Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate. Am J Med 1991;90:295–8.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Wolfe F,
    2. Michaud K,
    3. Chakravarty EF
    . Rates and predictors of herpes zoster in patients with rheumatoid arthritis and non-inflammatory musculoskeletal disorders. Rheumatology 2006;45:1370–5.
    OpenUrlAbstract/FREE Full Text
  41. 41.↵
    1. Smitten AL,
    2. Choi HK,
    3. Hochberg MC,
    4. Suissa S,
    5. Simon TA,
    6. Testa MA,
    7. et al.
    The risk of herpes zoster in patients with rheumatoid arthritis in the United States and the United Kingdom. Arthritis Rheum 2007;57:1431–8.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Hoffmann-La Roche Inc. Tocilizumab Arthritis Advisory Committee
    . [updated 2008; Internet. Accessed March 3, 2014.] Available from www.fda.gov/ohrms/dockets/ac/08/slides/2008-4371s1-00-index.htm
  43. 43.↵
    1. Strangfeld A,
    2. Listing J,
    3. Herzer P,
    4. Liebhaber A,
    5. Rockwitz K,
    6. Richter C,
    7. et al.
    Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 2009;301:737–44.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. McDonald JR,
    2. Zeringue AL,
    3. Caplan L,
    4. Ranganathan P,
    5. Xian H,
    6. Burroughs TE,
    7. et al.
    Herpes zoster risk factors in a national cohort of veterans with rheumatoid arthritis. Clin Infect Dis 2009;48:1364–71.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. García-Doval I,
    2. Pérez-Zafrilla B,
    3. Descalzo MA,
    4. Roselló R,
    5. Hernández MV,
    6. Gómez-Reino JJ,
    7. et al.
    Incidence and risk of hospitalisation due to shingles and chickenpox in patients with rheumatic diseases treated with TNF antagonists. Ann Rheum Dis 2010;69:1751–5.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Galloway JB,
    2. Mercer LK,
    3. Moseley A,
    4. Dixon WG,
    5. Ustianowski AP,
    6. Helbert M,
    7. et al.
    Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2013;72:229–34.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. Wollenhaupt J,
    2. Silverfield J,
    3. Lee EB,
    4. Wood SP,
    5. Soma K,
    6. Wang L,
    7. et al.
    Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: open-label, long-term extension studies up to 36 months [abstract]. Arthritis Rheum 2011;63 Suppl:S152.
    OpenUrl
  48. 48.↵
    1. Cohen S,
    2. Radominski SC,
    3. Asavantanabodee P,
    4. Wood SP,
    5. Soma K,
    6. Nduaka CI,
    7. et al.
    Tofacitinib (CP-690,550), an oral Janus kinase inhibitor: analysis of infections and all-cause mortality across phase 3 and long-term extension studies in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2011;63 Suppl:S153.
    OpenUrl
  49. 49.↵
    1. Winthrop KL,
    2. Valdez H,
    3. Mortensen E,
    4. Chew R,
    5. Krishnaswami S,
    6. Kawabata T,
    7. et al.
    Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2012;64 Suppl:S1051.
    OpenUrl
  50. 50.↵
    1. Curtis JR,
    2. Xie F,
    3. Chen L,
    4. Spettell C,
    5. McMahan RM,
    6. Fernandes J,
    7. et al.
    The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum 2011;63:346–51.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Curtis JR,
    2. Lanas A,
    3. John A,
    4. Johnson DA,
    5. Schulman KL
    . Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res 2012;64:1819–28.
    OpenUrlCrossRef
  52. 52.↵
    1. Isaacs JD,
    2. Nduaka CI,
    3. Zuckerman A,
    4. Krishnaswami S,
    5. Riese R,
    6. Lan S,
    7. et al.
    Changes in serum creatinine in patients with active rheumatoid arthritis treated with tofacitinib (CP-690,550). Ann Rheum Dis 2012;71 Suppl:672.
    OpenUrl
  53. 53.↵
    1. Winthrop KL,
    2. Park S-H,
    3. Gul A,
    4. Cardiel M,
    5. Gomez-Reino JJ,
    6. Ponce de Leon D,
    7. et al.
    Tuberculosis and tofacitinib therapy in patients with rheumatoid arthritis [abstract]. Arthritis Rheum 2012;64 Suppl 3:S547.
    OpenUrl
  54. 54.↵
    1. Burmester G,
    2. Charles-Schoemann C,
    3. Isaacs J,
    4. Hendrikx T,
    5. Kowk K,
    6. Zwillich SH,
    7. et al.
    Tofacitinib, an oral Janus kinase inhibitor: safety comparison in patients with rheumatoid arthritis and an inadequate response to nonbiologic or biologic disease modifying anti-rheumatic drugs [abstract]. Ann Rheum Dis 2013;72 Suppl:245.
    OpenUrlAbstract/FREE Full Text
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

 Request Permissions

Bookmark this article

Jump to section

Keywords

TOFACITINIB
ANTIRHEUMATIC AGENTS
RHEUMATOID ARTHRITIS
CLINICAL TRIAL

Keywords