Sustained effectiveness of methotrexate with step-down glucocorticoid remission induction (cobra slim) for early rheumatoid arthritis in a treat-to-target setting: 2-year results of the carera trial

Background: The CareRA trial showed that remission induction with MTX and a moderate-dose of Glucocorticoids (GC) (COBRA Slim) in a treat-to-target setting is effective and safe in early Rheumatoid Arthritis (eRA) patients. This strategy showed equally high remission rates at 52 weeks (W), a favourable safety profile compared to DMARD combinations and GC and very few patients had to start biologicals. Objectives: To compare the outcome of different intensive combination treatment strategies in high-risk patients of the CareRA trial at W104, focussing on persistent disease control. Methods: CareRA is a two-year prospective investigator-initiated pragmatic multicentre RCT; csDMARD naïve eRA patients were stratified into a high- or low-risk group based on classical prognostic markers (presence of erosions, RF, anti-CCP and DAS28-CRP). High-risk patients (n=289) were randomized to 1/3 arms: 1) COBRA Classic (n=98): Methotrexate (MTX)+Sulphasalazine+60mg prednisone tapered weekly to 7.5mg daily from W7; 2) COBRA Slim (n=98): MTX+30mg prednisone tapered to 5 mg daily from W6; 3) COBRA Avant-Garde (n=93): MTX+Leflunomide+30mg prednisone tapered to 5 mg daily from W6. From W28, GCs were tapered in all patients and stopped at W34. A predefined treat-to-target approach was applied until W52 and afterwards treatment was at the discretion of the rheumatologist. From W40, DMARD monotherapy was aimed for. From W28 onwards patients were evaluated every 3 months till W104. Efficacy measures were proportions of DAS28-CRP remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 (ITT analysis). Adverse events related to therapy (AEs) were registered. Missing data were imputed by last observation carried forward. Results: Remission rates at W104 in high-risk patients were 65.3%, 73.5% and 73.1% in the Classic, Slim and Avant-Garde group respectively (p=0.369). Also, other efficacy outcomes did not differ between groups (see table). From the high-risk patients that were in remission at year 1, 54.7%, 67.8% and 70.2% in the Classic, Slim and Avant-Garde group respectively, stayed in remission at every three-monthly evaluation until w104. Also DAS28-CRP scores remained relatively stable during the second year in these groups. In high-risk patients, the total numbers of AEs reported as related to study therapy, were 209 in 72 Classic patients, 164 in 69 Slim patients and 208 in 74 Avant-Garde patients (p=0.029). Serious AEs were reported in 3 Classic, 4 Slim and 3 Avant-Garde patients. Biologicals were started in 44 high-risk patients (15.2%), of which 7 receiving 2 different biologicals and 2 receiving 3 different ones. Biologicals were administered in 18 Classic, 11 Slim and 15 Avant-Garde patients. Conclusions: All groups showed persistently high remission rates 2 years after remission induction with csDMARDs and GCs in a treat to target setting. COBRA Slim showed comparable efficacy with less adverse events compared to DMARD combinations with moderate or high GC induction dosages. In almost 70% of COBRA Slim patients achieving remission at year 1, this was maintained throughout the second year.