Active conventional treatment and three different biological treatments in early rheumatoid arthritis: phase IV investigator initiated, randomised, observer blinded clinical trial

Abstract

Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis. Trial registration EudraCT2011-004720-35, NCT01491815 .

Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis—a spin-off study of the NORD-STAR randomized clinical trial

“…The study population consisted of 347 Swedish patients included in the NORD-STAR trial, a multinational phase four, investigator-initiated, randomized observer-blinded clinical trial of 812 patients with early untreated RA [ 24 ]. All patients fulfilled the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) 2010 criteria.…”

“…Details of the study protocol and data regarding clinical outcome at week 24 in the full NORD-STAR cohort are published [ 24 , 25 ]. In brief, Swedish patients were randomized 1:1:1:1 stratified by ACPA and sex to MTX escalated to 25 mg/week with folic acid supplementation combined with one of the following: arm 1, active conventional treatment (oral prednisone tapered from 20 to 5 mg/day in 9 weeks); arm 2, TNFi (certolizumab-pegol, 200 mg subcutaneously every other week, loading dose 400 mg at weeks 0, 2, and 4); arm 3, cytotoxic T-lymphocyte-associated molecule-4 immunoglobulin (CTLA-4Ig, abatacept, 125 mg subcutaneously every week); or arm 4, IL-6Ri (tocilizumab, 8 mg/kg intravenously every 4 weeks or 162 mg subcutaneously every week).…”

“…If the therapeutic effect is insufficient, another conventional, biologic, or targeted synthetic DMARD may be added. In the NORD-STAR cohort, active conventional treatment and biologic treatment with certolizumab-pegol, abatacept, and tocilizumab were compared head-to-head [ 24 ]. All four treatments achieved high remission rates on a group level.…”

Dynamical trajectory of glucocorticoids tapering and discontinuation in patients with rheumatoid arthritis commencing glucocorticoids with csDMARDs: a real-world data from 2009 to 2020

“…documented in controlled studies. [1][2][3][4][5] GC can not only significantly reduce the inflammation, but also rapidly relieve the articular symptoms in contrast to csDMARDs. [4][5][6] In the recommendations by the European League Against Rheumatism (EULAR) for the management of RA, short-term GC should be considered as a therapy bridging csDMARDs to exhibit efficacy.…”

“…[1][2][3][4][5] GC can not only significantly reduce the inflammation, but also rapidly relieve the articular symptoms in contrast to csDMARDs. [4][5][6] In the recommendations by the European League Against Rheumatism (EULAR) for the management of RA, short-term GC should be considered as a therapy bridging csDMARDs to exhibit efficacy. 2 7 Similarly, short-term GC was recommended in 2015 American College of Rheumatology (ACR) guidelines for both patients with early and established RA with moderate or high disease activity despite of using csDMARDs or biological DMARDs (bDMARDs).…”