Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Clinical outcomes, quality of life, and diagnostic uncertainty in the first year of polymyalgia rheumatica.

OBJECTIVE: To evaluate the impact of polymyalgia rheumatica (PMR) on clinical outcomes and quality of life (QOL); the relationship between laboratory measures and clinical outcomes, and changes in QOL; and agreement between rheumatologists in confirming the initial diagnosis. METHODS: We conducted a prospective study of 129 participants in 8 hospitals in England who met a modified version of the Jones and Hazleman criteria and had not started steroid therapy. The main outcome measures were response to steroids after 3 weeks (minimum 50% improvement in proximal pain, morning stiffness <30 minutes, acute-phase response not elevated), relapses, QOL as measured by the Short Form 36 and Health Assessment Questionnaire, and diagnosis reassessment at 1 year. RESULTS: At 3 weeks, 55% of participants failed to meet our definition of a complete response to steroid therapy. Both physical and mental QOL at presentation were substantially lower than general population norms and improved by 12.6 (95% confidence interval [95% CI] 10.8, 14.4) and 11.2 (95% CI 8.5, 13.8) points, respectively, at 1 year. Proximal pain and longer morning stiffness were significantly associated with lower physical QOL during followup, whereas erythrocyte sedimentation rate was most strongly associated with lower mental QOL during followup. There was moderate agreement between clinicians in confirming the PMR diagnosis (kappa coefficients 0.49-0.65). CONCLUSION: PMR is a heterogeneous disease with a major impact on QOL. Ongoing monitoring should include disease activity based on symptoms, emergence of alternative diagnoses, and early referral of atypical and severe cases.