Background/Purpose:

Remission induction with methotrexate (MTX) and a moderate-dose, step-down scheme of Glucocorticoids (GC), (COBRA Slim strategy), showed equally high remission rates at year 1 and a more favourable safety profile compared to DMARD combinations, even at a higher step-down GC dosage, in patients with early Rheumatoid Arthritis (eRA). Objectives were to compare response rates, disease activity states and medication use, 2 years after induction with different intensive combination strategies, focusing on the high-risk population from CareRA.

Methods: CareRA is a two-year prospective investigator-initiated multicentre RCT. csDMARD naïve eRA patients were stratified into a high- or low-risk group based on classical prognostic markers. High-risk patients (n=289) were randomized to 1/3 arms: 1) COBRA Classic: MTX+Sulphasalazine+60mg prednisone tapered over 6 weeks to 7.5mg daily; 2) COBRA Slim: MTX+30mg prednisone tapered over 5 weeks to 5 mg daily; 3) COBRA Avant-Garde: MTX+Leflunomide+30mg prednisone tapered over 5 weeks to 5 mg daily. From week 28, GC were tapered and stopped at week 34. From week 40, DMARD monotherapy was aimed for. A treat-to-target approach was applied per protocol until year 1 and afterwards at the discretion of the rheumatologist. Co-primary endpoint was proportion with DAS28-CRP<2.6 (“remission”), other efficacy measures were HAQ=0, DAS28-CRP change, ACR20/50/70 and clinically meaningful HAQ response (ITT analysis). Adverse events related to therapy (AEs) were registered, as well as RA medication use. Missing data were imputed by last observation carried forward.

Results: The proportion of high-risk patients with DAS28-CRP<2.6  at year 2 remained high and did not differ between the Classic (65.3%), Slim (73.5%) and Avant-garde (73.1%) group (p=0.369). Of patients with a DAS28-CRP<2.6 at year 1, 54.7% in Classic, 67.8% in Slim and 70.2% in Avant-Garde retained a DAS28-CRP<2.6 at every trimonthly evaluation until year 2. Persistently high and comparable ACR50 response rates were achieved in all groups. The total numbers of AEs 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). During the CareRA study, biologicals were started in 44 high-risk patients (15.2%): 18 Classic, 11 Slim and 15 Avant-Garde patients. At year 2, most patients were on MTX monotherapy: 67% in Classic, 63% in Slim and 49% in Avant-Garde. Only 14% of the high-risk population was taking oral GCs at year 2 at an average dose of 6.4mg prednisone equivalent.

Conclusion: All groups showed persistently high response rates and favourable disease activity states, 2 years after remission induction with csDMARDs and GCs in a treat to target setting. COBRA Slim showed comparable efficacy and ability to achieve sustained disease control with less adverse events, compared to DMARD combinations with GC at moderate or high induction dosages.