Long-Term Radiographic and Patient-Reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses

Rheumatol Ther https://doi.org/10.1007/s40744-018-0113-7 ORIGINAL RESEARCH Long-Term Radiographic and Patient-Reported Outcomes in Patients with Rheumatoid Arthritis Treated with Tofacitinib: ORAL Start and ORAL Scan Post-hoc Analyses Vibeke Strand . Arthur Kavanaugh . Alan J. Kivitz . Désirée van der Heijde . Kenneth Kwok . Ermeg Akylbekova . Arif Soonasra . Mark Snyder . Carol Connell . Eustratios Bananis . Josef S. Smolen Received: March 6, 2018 Ó The Author(s) 2018 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40744018-0113-7) contains supplementary material, which is available to authorized users. (IR) patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily as either monotherapy or with background MTX. The modified total Sharp score (mTSS) and Health Assessment Questionnaire-Disability Index (HAQ-DI) were analyzed at month 24 according to disease activity at month 6 defined by the Clinical Disease Activity Index (CDAI) or the Disease Activity Score in 28 joints, C-reactive protein (DAS28CRP). Results: Mean changes from baseline in mTSS at month 24 were less in patients with CDAI remission at month 6 than in those with CDAI moderate/high disease activity (MDA/HDA) at month 6. A DAS28CRP of \ 1.9 most closely approximated CDAI remission (B 2.8). Tofacitinib appeared to inhibit joint damage in the presence of persistent inflammation compared with MTX. More patients receiving tofacitinib or MTX with CDAI remission or low V. Strand Division of Immunology/Rheumatology, Stanford University, Palo Alto, CA, USA K. Kwok
E. Bananis (&) Pfizer Inc, New York, NY, USA e-mail: A. Kavanaugh San Diego School of Medicine, University of California, La Jolla, CA, USA E. Akylbekova Quintiles, Durham, NC, USA ABSTRACT Introduction: Here we examine the relationship between achieving different levels of disease activity with tofacitinib (an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis), long-term structural progression, and patient-reported physical function. Methods: This was a post hoc analysis of two 24-month, phase III randomized controlled trials in methotrexate (MTX)-naı̈ve (ORAL Start [NCT01039688]) or MTX-inadequate responder Enhanced digital features To view enhanced digital features for this article go to https://doi.org/10.6084/ m9.figshare.6171377. A. J. Kivitz Altoona Center for Clinical Research, Duncansville, PA, USA D. van der Heijde Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands A. Soonasra
M. Snyder Pfizer Inc, Collegeville, PA, USA C. Connell Pfizer Inc, Groton, CT, USA J. S. Smolen Medical University of Vienna, Vienna, Austria Rheumatol Ther disease activity (LDA) at month 6 reported normative HAQ-DI scores (\ 0.5) at month 24 than did those with CDAI MDA/HDA. Conclusion: Regardless of treatment, in both MTX-naı̈ve and MTX-IR patients, remission or LDA at month 6 was associated with successful long-term outcomes: inhibition of structural progression and normative HAQ-DI scores. Long-term outcomes were similar when patients achieved CDAI remission or a DAS28CRP of \ 1.9, confirming that this is an appropriate cut-off for remission with DAS28CRP. Tofacitinib potentially inhibits joint damage even with persistent inflammation. Funding: Pfizer Inc. Trial registration: Clinicaltrials.gov identifiers: NCT01039688 and NCT00847613. Keywords: Disease activity; HAQ-DI; Janus kinase inhibitor; Radiographic outcomes; Rheumatoid arthritis; Tofacitinib INTRODUCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation, pain, joint stiffness, and progressive joint destruction [1]. Patients with RA often experience impaired health-related quality of life as a result of symptoms of pain and fatigue, and loss of physical function [2, 3]. Early intervention with disease-modifying antirheumatic drugs (DMARDs) can reduce or reverse signs and symptoms of disease, inhibit progression of structural damage, and form a cornerstone of treatment [4, 5]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib administered at doses of 5 and 10 mg twice daily (BID) either as monotherapy or in combination with conventional synthetic DMARDs, mainly methotrexate (MTX), in patients with moderately to severely active RA, have been demonstrated in phase II [6–12] and phase III [13–22] randomized controlled trials (RCTs) of up to 24 months’ duration and in long-term extension studies with up to 105 months’ observation [23, 24]. ORAL Start (NCT01039688; trial registered December 23, 2009) [18] and ORAL Scan (NCT00847613; trial registered February 17, 2009) [16] are two phase III RCTs that included radiographic outcomes. ORAL Start was conducted in MTX-naı̈ve patients and ORAL Scan in patients who were MTX-inadequate responders (IR) [16, 18]. Patients received tofacitinib 5 or 10 mg BID as monotherapy versus MTX monotherapy (ORAL Start) or with background MTX versus placebo (ORAL Scan). In both 24-month trials, tofacitinib improved signs and symptoms of RA and patient-reported outcomes and inhibited progression of structural damage versus comparator treatment by month 6 [16, 18, 19]. However, mean changes in van der Heijde modified total Sharp scores (mTSS) were statistically significant only with tofacitinib 10 mg BID versus placebo (tofacitinib 5 mg BID vs. placebo P = 0.079) in ORAL Scan [16]. Here we present a post hoc analysis of data from ORAL Start and ORAL Scan which examined the efficacy of tofacitinib (vs. MTX) on long-term radiographic and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, with a particular focus on the relationship between disease activity levels at month 6 and longer-term outcomes. METHODS Study Design and Patients Details of ORAL Start and ORAL Scan have been previously published [16, 18]. Eligible patients were aged C 18 years, fulfilled the American College of Rheumatology 1987 revised criteria [25], and had active disease (C 6 tender or painful joints and C 6 swollen joints, plus C 3 distinct joint erosions, or were rheumatoid factor or anti-citrullinated antibody protein positive). In ORAL Start, MTX-naı̈ve patients were randomized 2:2:1 to tofacitinib 5 or 10 mg BID, or MTX starting at 10 mg per week and increasing to 20 mg per week by week 8. In ORAL Scan, MTX-IR patients were randomized 4:4:1:1 to tofacitinib 5 or 10 mg BID, placebo Rheumatol Ther advanced to tofacitinib 5 mg BID, or placebo advanced to tofacitinib 10 mg BID, all with stable background MTX. Patients receiving placebo were advanced in a blinded manner to tofacitinib if they had not achieved C 20% improvement in swollen and tender joint counts after 3 months (defined as non-responders); after 6 months, all remaining placebo patients were advanced to tofacitinib. Both studies were conducted in accordance with the Declaration of Helsinki and In (...truncated)