Effectiveness of methotrexate and bridging glucocorticoids with or without early introduction of a 6-month course of etanercept in early RA: results of the 2-year, pragmatic, randomised CareRA2020 trial

Abstract

Objectives: To investigate if patients with early rheumatoid arthritis responding insufficiently to initial methotrexate (MTX) and bridging glucocorticoids (GCs) could benefit from early but temporary etanercept introduction as a second remission-induction attempt.

Methods: CareRA2020 (NCT03649061) was a 2-year, open-label, multicentre, pragmatic randomised controlled trial. Treatment-naïve patients started MTX and GC bridging (COBRA-Slim: CS). Within a time window from week (W) 8 until W32, early insufficient responders (28-joint Disease Activity Score - C-reactive Protein (DAS28-CRP) >3.2 between W8 and W32 or ≥2.6 at W32) were randomised to a Standard-CS strategy (adding leflunomide first) or Bio-induction-CS strategy (adding etanercept for 24 weeks). Additional treatment adaptations followed the treat-to-target principle. Longitudinal disease activity (DAS28-CRP) over 104 weeks (primary outcome), achievement of DAS28-CRP <2.6 28 weeks after randomisation, and biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD) use at W104 were compared between randomisation groups.

Results: Following CS treatment, 142 patients were early responders; 55 early insufficient responders received Standard-CS and 55 Bio-induction-CS. Superiority of Bio-induction-CS over Standard-CS could not be demonstrated (ß=-0.204, (95% CI -0.486 to 0.078), p=0.157) for the primary outcome. More patients on Bio-induction-CS achieved DAS28-CRP <2.6 at 28 weeks after randomisation (59% (95% CI 44% to 72%) vs 44% (95% CI 31% to 59%) in Standard-CS) and they were treated less frequently with b/tsDMARDs at W104 (19/55, 35%) compared with Standard-CS (29/55, 53%).

Conclusion: Half of the patients responded well to initial COBRA-Slim induction therapy. In early insufficient responders, adding etanercept for 6 months did not improve disease control over 104 weeks versus adding leflunomide first. However, temporary introduction of etanercept resulted in improved disease control early after randomisation and less patients on b/tsDMARDs at W104.

Trial registration number: NCT03649061.

Ctr pilot approval belgium: S59474, EudraCT number: 2017-004054-41.

Keywords: biological therapy; early rheumatoid arthritis; glucocorticoids; methotrexate.

Figure 1. Study design of the CareRA2020 trial. In case of an insufficient response to initial treatment, the first adaptation was increasing methotrexate to 20 mg/week. Patients for which this was still not sufficient (=early insufficient responders) were 1:1 randomised during a time window between W8 and W32 (=randomisation window) to a T2T strategy starting with either the addition of leflunomide 10 mg/day orally (=Standard-CS strategy), or a second remission-induction attempt with 24 weeks of etanercept 50 mg/week subcutaneously (=Bio-induction-CS strategy). All adaptations were triggered by a DAS28-CRP >3.2 except for W32, where a DAS28-CRP ≥2.6 was applied. During the trial, treatment was further adapted according to the T2T principle. b, biologic; BL, baseline; cs, conventional synthetic; d, daily; DAS28-CRP, 28-joint Disease Activity Score – C-reactive Protein; DMARD, disease-modifying antirheumatic drug; T2T, treat-to-target; W, week; w, weekly.

Figure 2. Patient disposition during the CareRA2020 trial. Patients were classified as ‘early insufficient responders’ when they did not achieve DAS28-CRP ≤3.2 from W8 onwards until W32, despite MTX dose increase to 20 mg/week, or DAS28-CRP <2.6 at W32 independently of MTX dose increase. Early insufficient responders were 1:1 randomised to either Standard COBRA-Slim or COBRA-Slim Bio-induction. DAS28-CRP, 28-joint Disease Activity Score – C-reactive protein; ITT, intention-to-treat; N, number.

Figure 3. Evolution of disease activity, based on mean DAS28-CRP, and functionality, based on mean HAQ score, from baseline until W104 during the CareRA2020 trial. Error bars indicate the 95% CI. The early responders are shown as a reference. DAS28-CRP, 28-joint Disease Activity Score – C-reactive Protein; HAQ, Health Assessment Questionnaire.

Figure 4. Evolution of disease activity according to DAS28-CRP and functionality according to HAQ, starting from the moment of randomisation until 28 weeks after randomisation. Error bars indicate the 95% CI. DAS28-CRP, 28-joint Disease Activity Score – C-reactive Protein; HAQ, Health Assessment Questionnaire; R, randomisation.

Figure 5. DMARD use during the CareRA2020 trial from baseline until week 104. ‘Etanercept (randomisation)’ indicates the randomised 24 weeks of etanercept. If etanercept was restarted later during the trial, this was classified as ‘bDMARD’. The early responders are shown as a reference. b, biologic; cs, conventional synthetic; DMARD, disease-modifying antirheumatic drug; ts, targeted synthetic.