OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here. METHODS: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression. RESULTS: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported. CONCLUSION: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12-24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

Albany Medical College Albany New York

Biopharmaceutical Consultant Portola Valley California

Centro de Investigacion Clinica de Morelia Morelia Mexico

Centro Paulista de Investigação Clinica Sao Paulo Brazil

Institute of Rheumatology Prague Czech Republic

Leiden University Medical Center Leiden The Netherlands

Metroplex Clinical Research Center Dallas Texas

Mount Sinai Hospital Toronto Ontario Canada

Nambour General Hospital Nambour Queensland Australia and University of Queensland Brisbane Queensland Australia

Pfizer Inc Groton Connecticut

Seoul National University Hospital Seoul Republic of Korea

University of Occupational and Environmental Health Kitakyushu Japan

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Lee EB, Fleischmann R, Hall S, Wilkinson B, Bradley J, Gruben D, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014;370:2377–86. PubMed

Fleischmann R, Strand V, Wilkinson B, Kwok K, Bananis E. Relationship between clinical and patient‐reported outcomes in a phase 3 trial of tofacitinib or MTX in MTX‐naïve patients with rheumatoid arthritis. RMD Open 2016;2:e000232. PubMed PMC

Burmester GR, Blanco R, Charles‐Schoeman C, Wollenhaupt J, Zerbini C, Benda B, 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. PubMed

Kremer J, Li ZG, Hall S, Fleischmann R, Genovese M, Martin‐Mola E, et al. Tofacitinib in combination with nonbiologic disease‐modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med 2013;159:253–61. PubMed

Van der Heijde D, Tanaka Y, Fleischmann R, Keystone E, Kremer J, Zerbini C, 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. PubMed

Fleischmann R, Kremer J, Cush J, Schulze‐Koops H, Connell CA, Bradley JD, et al. Placebo‐controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med 2012;367:495–507. PubMed

Van Vollenhoven RF, Fleischmann R, Cohen S, Lee EB, García Meijide JA, Wagner S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med 2012;367:508–19. PubMed

Wollenhaupt J, Silverfield J, Lee EB, Curtis JR, Wood SP, Soma K, 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;41:837–52. PubMed

Yamanaka H, Tanaka Y, Takeuchi T, Sugiyama N, Yuasa H, Toyoizumi S, 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;18:34. PubMed PMC

Wollenhaupt J, Silverfield J, Lee EB, Terry K, Kwok K, Strengholt S, et al. 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]. Arthritis Rheumatol 2017;69 Suppl 10 URL: https://acrabstracts.org/abstract/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/.

Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35. PubMed

Prevoo ML, van ‘t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty‐eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995;38:44–8. PubMed

Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum 2011;63:573–86. PubMed PMC

National Heart, Lung, and Blood Institute: National Institutes of Health . JNC 7 complete report: the science behind the new guidelines. 2014. URL: https://www.nhlbi.nih.gov/health-pro/guidelines/current/hypertension-jnc-7/complete-report.

Canhao H, Rodrigues AM, Gregorio MJ, Dias SS, Melo Gomes JA, Santos MJ, et al. Common evaluations of disease activity in rheumatoid arthritis reach discordant classifications across different populations. Front Med (Lausanne) 2018;5:40. PubMed PMC

Schiff M, Weinblatt ME, Valente R, van der Heijde D, Citera G, Elegbe A, et al. Head‐to‐head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two‐year efficacy and safety findings from AMPLE trial. Ann Rheum Dis 2014;73:86–94. PubMed PMC

Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, 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;76:1253–62. PubMed PMC

Winthrop KL, Yamanaka H, Valdez H, Mortensen E, Chew R, Krishnaswami S, et al. Herpes zoster and tofacitinib therapy in patients with rheumatoid arthritis. Arthritis Rheumatol 2014;66:2675–84. PubMed PMC

Winthrop KL, Park SH, Gul A, Cardiel MH, Gomez‐Reino JJ, Tanaka Y, et al. Tuberculosis and other opportunistic infections in tofacitinib‐treated patients with rheumatoid arthritis. Ann Rheum Dis 2016;75:1133–8. PubMed PMC

Xeljanz (tofacitinib) prescribing information. New York (NY): Pfizer; 2017. URL: http://labeling.pfizer.com/ShowLabeling.aspx?id=959.

Buch MH, Aletaha D, Emery P, Smolen JS. Reporting of long‐term extension studies: lack of consistency calls for consensus. Ann Rheum Dis 2011;70:886–90. PubMed

Landewé R, van der Heijde D. Follow up studies in rheumatoid arthritis. Ann Rheum Dis 2002;61:479–81. PubMed PMC

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