Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials

Clinical Rheumatology https://doi.org/10.1007/s10067-018-4077-3 ORIGINAL ARTICLE Evaluation of disease activity in patients with rheumatoid arthritis treated with tofacitinib by RAPID3: post hoc analyses from two phase 3 trials Vibeke Strand 1 & Eun Bong Lee 2 & Yusuf Yazici 3 & Ara Dikranian 4 & Bethanie Wilkinson 5 & Liza Takiya 6 & Chuanbo Zang 6 & Eustratios Bananis 6 & Martin J. Bergman 7 Received: 7 February 2018 / Revised: 14 March 2018 / Accepted: 21 March 2018 # The Author(s) 2018 Abstract Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. We evaluated the relationship between disease activity, according to Routine Assessment of Patient Index Data 3 (RAPID3) after 6-month treatment with tofacitinib, and longterm outcomes at 24 months. This was a post hoc analysis of two 24-month, phase 3, randomized controlled trials in methotrexate (MTX)-naïve (ORAL Start [NCT01039688]) or MTX-inadequate responder patients (ORAL Scan [NCT00847613]) receiving tofacitinib 5 or 10 mg twice daily (BID) as monotherapy or with background MTX. RAPID3 scores were calculated at baseline, month (M)6, and M24, and defined as remission (≤ 3), low (LDA; > 3–≤ 6), moderate (MDA; > 6–≤ 12), or high disease activity (HDA; > 12). Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) scores, and radiographic non-progression (modified Total Sharp Scores ≤ 0) at M24 were evaluated by M6 RAPID3 response. Among patients receiving tofacitinib 5 or 10 mg BID, respectively, 42.2 and 51.5% (ORAL Start) and 29.8 and 39.0% (ORAL Scan) achieved RAPID3 remission/LDA at M6. Most patients maintained/improved RAPID3 responses at M24. A higher proportion of patients in RAPID3 remission/LDA versus MDA/HDA at M6 achieved CDAI remission, reported normative HAQ-DI scores (< 0.5), and achieved both normative HAQ-DI scores and radiographic non-progression at M24. Patients achieving RAPID3 remission/LDA after 6-month treatment with tofacitinib 5 or 10 mg BID have improved long-term outcomes versus patients with MDA/HDA. These findings support the use of RAPID3 to monitor longer-term disease activity in conjunction with physician-assessed measures. Keywords Low disease activity . RAPID3 . Remission . Rheumatoid arthritis . Tofacitinib Introduction * Liza Takiya 1 Division of Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, USA 2 Seoul National University, Seoul, Republic of Korea 3 Hospital of Joint Diseases, New York University, New York, NY, USA 4 Cabrillo Center for Rheumatic Disease, San Diego, CA, USA 5 Pfizer Inc, Groton, CT, USA 6 Pfizer Inc, Collegeville, PA, USA 7 Drexel University College of Medicine, Philadelphia, PA, USA Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease that affects approximately 0.4–1.3% of the global population [1]. RA is characterized by systemic inflammation, persistent synovitis, pain, and joint destruction. A treat-to-target approach for RA has been recommended by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), with sustained remission, or at least low disease activity (LDA) if remission cannot be achieved, as the therapeutic target for treatment [2, 3]. There are six measures of RA disease activity currently endorsed by ACR: Routine Assessment of Patient Index Data 3 (RAPID3), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), Disease Activity Score 28, and Patient Activity Scale (PAS) or PASII [2]. Clin Rheumatol RAPID3 is a patient-reported evaluation of disease activity based on a pooled index of the three ACR RA core dataset patient-reported outcomes (PROs): Patient Global Assessment of disease activity (PtGA), Patient Assessment of Arthritis Pain (PAIN), and Health Assessment Questionnaire-Disability Index (HAQ-DI) [4]. RAPID3 is a quick and easy means to assess disease activity, and patients can complete the assessment prior to meeting with a physician. RAPID3 requires less than one eighth of the time required to complete a 28-Joint Count Assessment [5], and its ease and rapidity in completion make it valuable for use in the clinical setting. Based exclusively upon PROs, it is frequently used to complement physician-assessed measures, rather than as a substitute for joint counts, or face-to-face visits with physicians [6]. Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs, mainly methotrexate (MTX), in patients with moderately to severely active RA, have been demonstrated in phase 2 [7–11] and phase 3 [12–17] randomized controlled trials (RCTs) of up to 24-month duration and in long-term extension (LTE) studies with as long as 114 months of observation [18–21]. Improvements in PROs have been reported in phase 2 [22], phase 3 [23–27], and LTE [18, 28] tofacitinib studies. Recently, the longer-term benefits of tofacitinib treatment, according to disease activity defined by CDAI at 6 months, were examined in two phase 3 RCTs: ORAL Start and ORAL Scan [29]. In this analysis, CDAI remission or LDA at month 6 was associated with attainment of normative HAQDI scores (< 0.5) and higher rates of radiographic nonprogression by modified Total Sharp Scores (mTSS) (change from baseline ≤ 0) at month 24. The objective of this post hoc analysis was to evaluate disease activity at month 24 according to RAPID3 response at month 6, in patients with RA who received tofacitinib 5 or 10 mg BID as monotherapy or with background MTX in ORAL Start and ORAL Scan. We also examined disease activity (CDAI) and physical functioning (HAQ-DI), including the proportions of patients reporting normal physical functioning with no radiographic progression (mTSS) at month 24, based on RAPID3 responses at month 6. Patients and methods Study design Data were analyzed from two phase 3, multicenter RCTs: ORAL Start (NCT01039688) [15] and ORAL Scan (NCT00847613) [16]. ORAL Start was a 24-month trial of tofacitinib monotherapy in MTX-naïve patients. Patients were randomized 2:2:1 to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, or MTX (at a starting dose of 10 mg per week, with 5 mg increments per week every 4 weeks, to 20 mg per week by week 8). ORAL Scan was a 24-month trial of tofacitinib in combination with MTX, in patients with an inadequate response to MTX (MTX-IR) [16]. Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, or placebo advanced to tofacitinib 5 or 10 mg BID, in combination with MTX. Patients receiving placebo who did not respond at month 3 (< 20% improvement in swollen and tender joint counts from baseline) were advanced blindly to tofacitinib 5 or 10 mg BID; at month 6, all remaining placebo patients were advanced t (...truncated)