Background/Purpose: Intensive combination therapy with glucocorticoids (GCs) is the most favorable treatment to benefit from the window of opportunity in early Rheumatoid Arthritis (eRA) but debate remains about the content of the combination and the dose of GCs. CareRA is a prospective two year investigator-initiated multicenter RCT rooted in daily practice and aiming to identify the optimal treatment strategy for eRA. We report here the primary efficacy and safety at week (W)16, focusing on high risk patients.

Methods: DMARD naïve eRA patients were recruited between January 2009 and May 2013 and stratified into high or low risk according to classical prognostic markers (erosions, rheumatoid factor, ACPA and disease activity). High risk patients were randomized to 1/3 treatment strategies:  COBRA Classic (MTX+ Sulphasalazine + initially 60mg GCs tapered to 7.5mg daily from W7), COBRA Slim (MTX + initially 30mg GCs tapered to 5 mg from W6) and COBRA Avant-Garde (MTX + leflunomide + initially 30mg GCs tapered to 5 mg from W6). Treatment adaptations to target low disease activity (DAS28(CRP) ≤3.2) were mandatory from 8 weeks onwards. The primary outcome was remission (DAS28(CRP) <2.6) at W16 (ITT analysis). Our null hypothesis was that COBRA Classic and Avant-Garde would be superior to Cobra Slim (>80% power to detect a 20% difference = 3×85 patients). Secondary endpoints were proportion of good EULAR responders, clinically meaningful HAQ responders and HAQ equal to zero. All adverse events (AEs) were registered.

Results: Of all patients included in CareRA, 290 high risk patients were analyzed: 98 Classic, 98 Slim and 94 Avant-Garde patients. 79.7% was RF positive, 78.3% ACPA positive and 33.3% erosive, with a mean ± SD DAS28(CRP) of 4.77 ± 1.28.  Randomization was successful resulting in almost equal baseline characteristics between groups. 7 Classic (2 consent withdrawals, 1 lost to follow up, 2 safety and 2 efficacy failures), 2 Slim (1 consent withdrawal and 1 death) and 3 Avant-Garde patients (2 consent withdrawals and 1 efficacy failure) did not make W16.

At W16 no significant differences between groups were shown for DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ and HAQ equal to zero (see table).

Until W16 therapy related AEs were reported in 61.2% of Classic, in 46.9% of Slim and in 69.1% of Avant-Garde patients (p=0.006). The total number of AEs related to Classic, Slim and Avant-Garde treatment was 148, 70 and 130 respectively, with a similar distribution for discomfort and toxicity.

Conclusion: For remission induction of eRA at 4 months, DMARD combination therapies with moderate or even high step down GC doses were not superior to MTX monotherapy with a moderate step down dose of GCs. The short-term safety profile of the monotherapy with GCs was more favorable. The consequences for future disease control and several patient reported outcomes are awaited within the CareRA trial.