The Combinatietherapie Bij Reumatoide Artritis (CoBRA) trial was a milestone in the development of the present treatment paradigm for Rheumatoid Arthritis (RA). This study introduced the principle of fast remission induction by means of a combination of standard Disease Modifying AntiRheumatic Drugs (DMARDs) and a step down bridge therapy with high dose glucocorticoids in early Rheumatoid Arthritis.
The purpose of the present study is to compare different combinations of traditional DMARDs and glucocorticoids, based on the original CoBRA protocol, for treatment of early Rheumatoid Arthritis.
Besides the efficacy and effectiveness of these strategies, patient centered outcomes and potential implementation problems of such treatment strategies are evaluated.
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 naive 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 = 3x85 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. (Table Presented).
Background Whereas early intensive treatment to target is recommended in severe early Rheumatoid Arthritis (eRA), few data are available in patients presenting without bad prognostic markers. Objectives To evaluate the efficacy and safety of methotrexate (MTX) monotherapy compared to MTX combined with a glucocorticoid (GC) bridging scheme during the first 16 weeks of treatment in “low risk” eRA patients. Methods CareRA is a prospective two year investigator-initiated multicenter RCT rooted in daily practice. 400 eRA patients were stratified into a high or a low risk group. Low risk was defined as: - No erosions and ACPA and RF negative - Erosions, ACPA and RF negative and low disease activity (DAS28(CRP)≤3.2 - No erosions, ACPA and/or RF positive and low disease activity (DAS28(CRP) ≤3.2 Patients were randomized to 15 mg MTX, either with a bridging scheme of initially 30mg GCs tapered to 5 mg from week (W) 6 (Cobra Slim) or without GCs (MTX Tight Step Up (MTX-TSU)). Treatment modifications to target low disease activity were mandatory from W8 onwards. The primary outcome was remission (DAS28(CRP) <2.6) at W16 (ITT analysis). Secondary endpoints were good EULAR response, clinically meaningful HAQ response and HAQ=0. The Area Under the Curve (AUC) of DAS28(CRP) was calculated from baseline to W16. Adverse events (AEs) were registered. Results We included 90 low risk patients: 24.4% were RF positive, 25.6% ACPA positive and 1.1% erosive, with a mean ± SD DAS28(CRP) of 4.53±1.62; 43 patients were randomized in the Cobra Slim and 47 in the MTX-TSU arm. At W16, 65.1% of the Cobra Slim and 46.8% of the MTX-TSU patients were in remission (p=0.081). A good EULAR response was achieved in 44.7% of MTX-TSU and 58.1% COBRA SLIM patients (p=0.202). A clinically meaningful HAQ response was reached in 53.2% of the MTX-TSU and 62.8% of the COBRA SLIM group (p=0.357). More patients had a HAQ=0 at W16 with the Cobra Slim (51.2%) compared to the MTX-TSU (23.4%) schedule (p=0.006). The mean± SD AUC of DAS28(CRP) was 11.18±4.25 and 13.84±4.58 for the Slim and MTX-TSU arm respectively (p=0.006). Treatment adjustments were performed in 27.9% of Slim and 40.4% of MTX-TSU patients (p=0.212). Until W16, therapy related AEs were reported in 39.5% of Slim and in 44.7% of MTX-TSU patients (p=0.622). Conclusions Although the primary outcome, remission, was only numerically different after 16 weeks of treatment, cumulative disease activity over time and proportion with normalized HAQ were in favor of the Cobra Slim group, while related AEs didn't differ.
Background In line with the window of opportunity theory, intensive DMARD combination therapy with glucocorticoids (GCs) is probably the most effective treatment approach for early Rheumatoid Arthritis (eRA), but the ideal content of the combination and the dose of GCs is not yet known. Objectives To compare the efficacy and safety of intensive treatment strategies associated with GCs at week (W)16, focusing on high risk patients. Methods CareRA is a prospective two-year investigator-initiated multicenter RCT rooted in daily practice. In this trial, 400 DMARD naïve eRA patients were stratified into high or low risk according to classical prognostic markers such as the presence of erosions, RF/ACPA and disease activity. High risk patients were randomized to 1/3 treatment strategies: COBRA Classic (MTX+ Sulphasalazine + 60mg GCs tapered to 7.5mg daily from W7), COBRA Slim (MTX + 30mg GCs tapered to 5 mg from W6) and COBRA Avant-Garde (MTX + Leflunomide + 30mg GCs tapered to 5 mg from W6). Treatment modifications to target low disease activity were mandatory from W8 onwards, if desirable and feasible according to the rheumatologist. The primary outcome was remission (DAS28(CRP) <2.6) at W16 (ITT analysis). Secondary endpoints were good EULAR response, clinically meaningful HAQ response and HAQ=0. Area under the curve (AUC) for DAS28(CRP) and proportion of treatment adaptations and GC injections were calculated. Adverse events (AEs) were registered. Missing data were imputed by the maximum likelihood method. Results 290 patients were stratified as high risk: 98 Classic, 98 Slim and 94 Avant-Garde patients. Remission was achieved in 70.4% COBRA CLASSIC patients, 73.5% COBRA SLIM patients, 68.1% COBRA AVANT-GARDE patients (p=0.713) at W16. No significant differences between groups were shown in the proportion with a good EULAR response, clinically meaningful HAQ response and HAQ=0 (all p>0.05). The AUC for DAS28(CRP) in the 3 treatment arms was equal (p=0.521). No difference in treatment adaptions or GCs injections was found at W16.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). Conclusions At W16, MTX associated with a moderate step-down dose of GCs was as effective as DMARD combination therapies with moderate or even high step down GC doses in high-risk eRA. The short-term safety profile of MTX with GCs alone was more favorable.
Background: To date, intensive DMARD combination therapy with glucocorticoids (GCs) is the most effective treatment approach for the management of early Rheumatoid Arthritis (eRA). The ideal content of the combination and the dose of GCs are however not yet known. Objectives: To compare different intensive combination treatment strategies associated with GCs in eRA patients with a poor prognosis at week (W)52 in the CareRA trial. Methods: CareRA is a two year prospective investigator-initiated multicenter RCT rooted in daily practice. DMARD naïve eRA patients were stratified into a high or low-risk group based on classical prognostic markers (presence of erosions, rheumatoid factor, anti-cyclic citrullinated protein and DAS28(CRP). High-risk patients (n=290) were randomized to 1 of 3 treatment strategies. 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=94):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. From W40, we aimed for DMARD monotherapy. Efficacy measures were proportions of DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 (ITT analysis). Radiographic progression was measured via the Sharp Van der Heijde score. Adverse events related to therapy (AEs) were registered. Missing data were imputed by last observation carried forward. Results: Remission rates were 64.3%, 60.2% and 62.8% in the Classic, Slim and Avant-Garde group respectively (p=0.837). Also no other efficacy outcomes did not differ between groups. 82% of X-ray images were available at baseline. Radiographic progression was minimal. SvH scores were 1.3±2.1, 1.3±2.5 and 1.0±1.4 at baseline and changed over 52 weeks 0.3±0.5, 0.4±1.1 and 0.3±0.6 in the Classic, Slim and Avant-Garde group respectively (p=0.581). The total numbers of AEs were 182 in 65 Classic patients, 125 in 64 Slim patients and 174 in 72 Avant-Garde patients (p=0.026). Serious AEs were reported in 3 Classic, 2 Slim and 3 Avant-Garde patients. Conclusions: High rates of remission were achieved at week 52 with csDMARDs and GCs in all remission induction schemes. Cobra Slim showed comparable efficacy with less adverse events compared to DMARD combinations with moderate or high GC dosages.
INTRODUCTION: Considering a lack of efficacy data in patients with early rheumatoid arthritis (eRA) presenting without classical markers of poor prognosis, we compared methotrexate (MTX) with or without step-down glucocorticoids in the CareRA trial.
METHODS: Disease-modifying antirheumatic drug-naïve patients with eRA were stratified into a low-risk group based on prognostic markers that included non-erosiveness, anti-citrullinated protein antibodies and rheumatoid factor negativity and low disease activity (Disease Activity Score in 28 joints based on C-reactive protein (DAS28(CRP)) ≤3.2). Patients were randomized to 15 mg of MTX weekly (MTX with tight step-up (MTX-TSU)) or 15 mg of MTX weekly with prednisone bridging, starting at 30 mg and tapered to 5 mg daily from week 6 (COmbinatie therapie bij Reumatoïde Artritis (COBRA Slim)). A TSU approach was applied. Outcomes assessed were DAS28(CRP)-determined remission, cumulative disease activity, Health Assessment Questionnaire (HAQ) scores and adverse events (AEs) after 16 treatment weeks.
RESULTS: We analyzed 43 COBRA Slim and 47 MTX-TSU patients and found that 65.1% in the COBRA Slim group and 46.8% in the MTX-TSU group reached remission (P = 0.081). Mean ± standard deviation area under the curve values of DAS28(CRP) were 13.84 ± 4.58 and 11.18 ± 4.25 for the MTX-TSU and COBRA Slim patients, respectively (P = 0.006). More COBRA Slim patients had an HAQ score of 0 (51.2% versus 23.4%, P = 0.006) at week 16. Therapy-related AEs between groups did not differ.
CONCLUSION: In patients with low-risk eRA, MTX with step-down glucocorticoid bridging seems more efficacious than MTX step-up monotherapy, with a comparable number of AEs observed over the first 16 treatment weeks.
TRIAL REGISTRATION: EU Clinical Trials Register Identifier: EudraCT number 2008-007225-39 . Registered 5 November 2008.
Background: Early intensive treatment to target is recommended in severe early Rheumatoid Arthritis (eRA). However, data are lacking in patients presenting without markers of poor prognosis. Objectives: To compare Methotrexate (MTX) with or without Glucocorticoid (GC) remission induction in a tight control setting over 52 weeks in low-risk patients with eRA. Methods: CareRA is a two year prospective investigator-initiated multicenter RCT rooted in daily practice. DMARD naïve eRA patients were stratified into a high or low-risk group according to classical prognostic markers (presence of erosions, rheumatoid factor, anti-cyclic citrullinated protein and disease activity). In the low-risk arm, 43 patients were randomized to 15mg MTX monotherapy following a Tight Step Up (MTX-TSU) approach and 47 patients to a Cobra Slim schedule (MTX+30mg prednisone tapered to 5mg daily from W6). GCs were tapered from W28 and stopped at W34. A predefined treat to target approach was applied. Efficacy measures were proportions of DAS28(CRP) remission, good EULAR response, clinically meaningful HAQ response, HAQ=0 and Area Under the Curve (AUC) for DAS28(CRP) (ITT analysis). Radiographic progression was measured via the Sharp Van der Heijde (SvH) method. Adverse events related to therapy (AEs) were registered. No power was calculated in this explorative study. Missing data were imputed via last observation carried forward. Results: Remission rates at week 52 were 57.4% and 67.4% in the MTX-TSU and Cobra Slim group respectively (p=0.329). MTX-TSU patients had a higher AUC for DAS28(CRP) than Cobra Slim patients over 52 weeks of treatment (p=0.017). No other efficacy scores differed between groups. 76% of X-ray images were available at baseline. Radiographic progression was minimal. SvH scores were 0.7±1.1 and 0.9±1.5 at baseline and changed over 52 weeks 0.2±0.3 and 0.3±0.4 in the MTX-TSU and Cobra Slim group respectively (p=0.184). The numbers of AEs were 48 in 27 MTX-TSU patients and 49 in 20 Cobra Slim patients (p=0.871). Two serious AEs (pulmonary infection and anemia) were registered in the Cobra Slim group. We observed numerically more treatment adaptations and IM/IA GC injections in MTX-TSU patients. (Figure presented) Conclusions: Both RA therapies achieved high remission rates in a tight control setting at week 52. However, remission induction with Cobra Slim resulted in a more rapid and sustained disease control. MTX with or without GC remission induction showed a comparable safety profile.
OBJECTIVES: To compare the efficacy and safety of intensive combination strategies with glucocorticoids (GCs) in the first 16 weeks (W) of early rheumatoid arthritis (eRA) treatment, focusing on high-risk patients, in the Care in early RA trial.
METHODS: 400 disease-modifying antirheumatic drugs (DMARD)-naive patients with eRA were recruited and stratified into high risk or low risk according to classical prognostic markers. High-risk patients (n=290) were randomised to 1/3 treatment strategies: combination therapy for early rheumatoid arthritis (COBRA) Classic (methotrexate (MTX)+ sulfasalazine+60 mg prednisone tapered to 7.5 mg daily from W7), COBRA Slim (MTX+30 mg prednisone tapered to 5 mg from W6) and COBRA Avant-Garde (MTX+leflunomide+30 mg prednisone tapered to 5 mg from W6). Treatment modifications to target low-disease activity were mandatory from W8, if desirable and feasible according to the rheumatologist. The primary outcome was remission (28 joint disease activity score calculated with C-reactive protein <2.6) at W16 (intention-to-treat analysis). Secondary endpoints were good European League Against Rheumatism response, clinically meaningful health assessment questionnaire (HAQ) response and HAQ equal to zero. Adverse events (AEs) were registered.
RESULTS: Data from 98 Classic, 98 Slim and 94 Avant-Garde patients were analysed. At W16, remission was reached in 70.4% Classic, 73.6% Slim and 68.1% Avant-Garde patients (p=0.713). Likewise, no significant differences were shown in other secondary endpoints. However, 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).
CONCLUSIONS: For high-risk eRA, MTX associated with a moderate step-down dose of GCs was as effective in inducing remission at W16 as DMARD combination therapies with moderate or high step-down GC doses and it showed a more favourable short-term safety profile.
EUDRACT NUMBER: 2008-007225-39.
Background: The (Care in Early RA) CareRA trial compared different treatment strategies in patients with early Rheumatoid Arthritis (ERA) with or without markers of poor prognosis. No significant differences were shown between the treatment arms in terms of remission rate and functionality at 16 and 52 weeks. The differential cost-effectiveness of these therapeutic strategies could aid in determining the optimal approach for ERA. Objectives: To compare the cost-effectiveness of different therapeutic strategies used in the CareRA trial during the first treatment year in patients with early Rheumatoid Arthritis. Methods: The CareRA trial is a 2-year investigator-initiated randomized pragmatic superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD naïve ERA patients were stratified into a high- or low-risk group based on prognostic markers. High-risk patients were randomized to a COBRA Classic (Methotrexate (MTX) + Sulphasalazine + prednisone step-down from 60mg), COBRA Slim (MTX + prednisone step-down from 30mg) or COBRA Avant-Garde (MTX + Leflunomide + prednisone step-down from 30mg) scheme. Low-risk patients were randomized to MTX tight step-up (MTX-TSU) or COBRASlim. The direct costs for each patient in the trial were calculated by summing the cost of a rheumatology consultation, per protocol CareRA study medication and RA-related medication such as biologicals and extra glucocorticoids not stipulated in the protocol. The incremental cost-effectiveness ratio (ICER) was calculated using these costs and the treatment efficacy as observed in CareRA. Efficacy parameters investigated were the proportion of patients in remission (DAS28(CRP) <2.6) and the proportion with a clinically meaningful improvement of Health Assessment Questionnaire (HAQ change >0.22) at week 52. Results: 349 out of 379 patients had sufficient cost information to be evaluated at week 52. Remission was achieved in 65,6% Classic, 61.7% Slim (high-risk) and 64.1% Avant-Garde patients; and in 56.8% MTX-TSU and 70.0% Slim (low-risk) patients. A clinically meaningful HAQ response was reached in 66.7% Classic, 70.2% Slim (high-risk) and 75.6% Avant-Garde patients; and in 58.3% MTX-TSU and 60.0% Slim (low-risk) patients. Mean ±SD total costs during year one were Δ1044.3 ± Δ871.0 Δ859.7 ±Δ431.3 and Δ1267.7 ±Δ632.7 for the Classic, Slim (high-risk) and Avant-Garde respectively; and Δ880.6 ±Δ917.4 and Δ867.5 ±Δ364.0 for MTX-TSU and Slim (low-risk) patients. In MTX-TSU patients, the high average cost ±SD of Δ268.6 ±Δ876.5 was remarkable. Cost-effectiveness analysis in the high-risk arm showed a higher ICER for Classic (Δ47.3/1% remission) and Avant-Garde (Δ170.0/1% remission) compared to Slim (highrisk); In the low-risk arm, the cost-effectiveness of MTX-TSU was shown to be comparable to Slim (low-risk), with an ICER of Δ-0.99/1% remission. Conclusions: Cobra Slim, a combination of MTX with a moderately dosed glucocorticoid remission induction showed favorable cost-effectiveness in both ERA patients with or without poor prognosis.
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.
<b>OBJECTIVES: </b>Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year.<b>METHODS: </b>The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639).<b>RESULTS: </b>98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals.<b>CONCLUSIONS: </b>MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed.<b>Trial Registration Numbers: </b>EudraCT-number 2008-007225-39 and NCT01172639; Results.
Revista»Arthritis and rheumatology Conference: american college of rheumatology/association of rheumatology health professionals annual scientific meeting, ACR/ARHP
Background: EULAR guidelines recommend to treat all patients with early Rheumatoid Arthritis (eRA) with a combination of methotrexate (MTX) and a short-term course of Glucocorticoids (GC). The COBRA Slim strategy with MTX and a moderately dosed tapering down scheme of GC was effective, also in patients without classical markers of poor prognosis during the first year. Objectives: To compare the outcomes of MTX with or without initial step-down GC in Low-Risk patients during the second year of the CareRA trial, in terms of disease control, safety and DMARD use. Methods: CareRA is a two-year prospective investigator-initiated pragmatic multicentre RCT. DMARD 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). Low-Risk patients (n=90) were randomised to either Tight-Step Up (TSU) with MTX 15 mg weekly without GC or to COBRA Slim, a combination of MTX 15 mg weekly and prednisone tapering down scheme starting at 30 mg, tapered to 5 mg daily from w6 and stopped at w34. A treat-to-target approach was applied until year 1 and afterwards treatment was at the discretion of the rheumatologist. Proportions of DAS28-CRP remission at year 2 was a coprimary CareRA endpoint. Secondary outcomes were efficacy according to other remission criteria, EULAR/ACR response rates and functionality measured by HAQ (ITT analysis, last observation carried forward). Adverse events (AEs) and concomitant medication were registered. Results: At year 2, 67.4% of Slim and 70.2% of TSU patients were in remission according to DAS28CRP (p=0.777). Out of patients in DAS28CRP remission at year 1, 80.0% (24/30) in the Slim group, versus 69.0% (20/29) in the TSU group remained in remission at every three-monthly evaluation until year 2. Remission rates defined by Boolean criteria were higher in patients of the Slim (39.5%) versus TSU group (19.1%) (p=0.033). Functionality measured by mean area under the HAQ curve over 2 years was better in Slim patients (38.3±47.2) than in TSU patients (56.4±48.7) (p=0.025). Other secondary efficacy outcomes did not differ between the treatment arms. The total numbers of AEs reported as related to study therapy, were 69 in 34 TSU patients and 63 in 28 Slim patients. Biologicals were started in 14 Low-Risk patients (15.6%), more specifically in 8 Slim and 6 TSU patients during the CareRA trial. At the year 2 visit 62.5% of Slim patients were on MTX monotherapy and 12.5% on a combination of csDMARDs. In the TSU group 58.5% was taking MTX as only DMARD, and 19.5% took a combination of csDMARDs. Out of all Low-Risk patients 11.0% (8/73) was taking oral GC at the year 2 visit, 5 patients in the TSU group and 3 patients in Slim group, all at a low dosages. Conclusions: In eRA patients lacking classical markers of poor prognosis COBRA Slim showed persistently high remission rates and good disease control 2 years after initiating therapy in a treat to target setting. COBRA slim seems to be slightly more effective than TSU according to the year 2 Boolean remission criteria and the 2 year functionality AUC but the CareRA study was not powered for this analysis. (Table Presented).
Background: Rheumatoid arthritis (RA) causes high individual, medical and societal costs. EULAR guidelines suggest treating early, intensively and to target using disease modifying anti-rheumatic drugs (DMARDs), preferably with initial glucocorticoid (GC) bridging. COBRA slim, a combination of methotrexate (MTX) with a moderate dose prednisone step down bridge scheme showed a positive efficacy/tolerability balance in the Care in early RA (CareRA) trial. COBRA Slim in comparison to DMARD combination therapy with GC bridging, has the necessary intensity to induce remission, but with a lower risk of severe discomfort or adverse events, decreasing the early need for biologic (b)DMARDs. Objectives: Perform an economic evaluation on the 2 year pragmatic randomised CareRA trial. Methods: Patients with early RA (≤1 year) naïve to DMARDs were randomised to monotherapy or synthetic (cs)DMARD combination with or without GC bridging, after risk stratification based on classical prognostic markers. Clinical and patientreported data were collected at each visit (≥10 times in 2 years). Direct costs of visits and RA medication (systemic GCs, cs and bDMARDs) over 2 years were calculated for each patient from each of the 5 treatment arms (table 1). For cost-effectiveness analysis, benefits were expressed as the proportion of patients with DAS28CRP<2.6 at year 2. Missing data was imputed per item with expectation maximisation. For cost-utility analysis, utilities were calculated using a validated mapping algorithm reconstructing EQ-5D scores based on age, sex, HAQ and pain scores at relevant study visits. Quality-adjusted life years (QALYs) encapsulating the impact of treatment on a patient's length of life and health-related quality of life, were calculated as the time-weighted average of all available EQ-5D scores (area under the curve). Incremental cost-effectiveness ratios (ICERs) from each strategy were calculated. ICERs compare the additional costs a strategy imposes over another with the additional benefits it delivers. Means and medians based methods were calculated with confidence intervals via bootstrapping. Results: From the initial CareRA cohort (n=379), cost/benefit data of 326 patients was used for a 2 year economic analysis. The mayor driver of direct costs was bDMARDs (57%>87% of total costs). Number of consultations were comparable (±11) across all treatment strategies. The cost-effectiveness analysis in the high risk population showed a higher ICER for COBRA Avant Garde (mean € 198.65/1%, median € 78.41/1%) and a dominated ICER for COBRA Classic (mean € -181.40/1%, median € -35.01/1%) compared to the Slim. In the low risk arm, ICERs for COBRA Slim compared to Tight Step Up (TSU) were € 46.75/1% (mean) and € 43.64/1% (median). Cost-utility analysis in the high risk arm showed an incremental cost of € 1 469.36 for an increased utility of 0.012555 QALYS for COBRA Classic compared to COBRA Slim, resulting in an ICER of € 117 033.85/QALY. The ICER of COBRA Avant Garde vs COBRA Slim was € 69 329.19/QALY. In the low risk arm, the comparison of COBRA Slim to TSU yields an ICER of € 1 342.78 per QALY. Conclusions: COBRA Slim which consists of an initial combination of MTX and a moderate dosed GC remission induction scheme has a favourable cost-effective and cost-utility profile for patients with early RA independent of their prognostic factors. (Table Presented).
OBJECTIVES: To investigate whether MTX should be combined with an additional DMARD and bridging glucocorticoids as initial treatment for patients with early RA to induce an effective long‐term response. METHODS: The Care in early RA study is a two‐year investigator‐initiated pragmatic multicentre randomized trial. Early RA patients, naïve to DMARDs and glucocorticoids, were stratified based on prognostic factors. High‐risk patients were randomized to COBRA‐Classic (n = 98): MTX, sulfasalazine, prednisone step‐down from 60 mg; COBRA‐Slim (n = 98): MTX, prednisone step‐down from 30 mg; or COBRA‐Avant‐Garde (n = 93): MTX, leflunomide, prednisone step‐down from 30 mg. Low‐risk patients were randomized to COBRA‐Slim (n = 43); or Tight Step Up (TSU) (n = 47): MTX without prednisone. Clinical/radiological outcomes at year 2, sustainability of response, safety and treatment adaptations were assessed. RESULTS: In the high‐risk group 71/98 (72%) patients achieved a DAS28‐CRP < 2.6 with COBRA‐Slim compared with 64/98 (65%) with COBRA‐Classic and 69/93 (74%) with COBRA‐Avant‐Garde (P = 1.00). Other clinical/radiological outcomes and sustainability of response were similar. COBRA‐Slim treatment resulted in less therapy‐related adverse events compared with COBRA‐Classic (P = 0.02) or COBRA‐Avant‐Garde (P = 0.005). In the low‐risk group, 29/43 (67%) patients on COBRA‐Slim and 34/47 (72%) on TSU achieved a DAS28‐CRP < 2.6 (P = 1.00). On COBRA‐Slim, low‐risk patients had lower longitudinal DAS28‐CRP scores over 2 years, a lower need for glucocorticoid injections and a comparable safety profile compared with TSU. CONCLUSION: All regimens combining DMARDs with glucocorticoids were effective for patients with early RA up to 2 years. The COBRA‐Slim regimen, MTX monotherapy with glucocorticoid bridging, provided the best balance between efficacy and safety, irrespective of patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov, http://www.clinicaltrials.gov, NCT01172639.
Background: Commonly used disease activity scores in rheumatoid arthritis (RA) include one patient reported outcome (PRO)-the patient's global health assessment (PGA). Exploratory factor analysis (EFA) was performed on data from the 2 year Care in early Rheumatoid Arthritis (CareRA) trial to explain the evolution of disease burden extracting 3 factors.1 Objectives: To assess the evolution and relative responsiveness over time of clinical, laboratory and patient assessments included in composite scores, together with other PROs like pain, fatigue and functionality in patients with early RA (≤1 year) treated to target (T2T) within the CareRA trial. Methods: DMARD naïve patients with early RA (n=379) were included, randomized to remission induction with COBRA-like treatment schemes (n=332) or MTX monotherapy (n=47) and T2T. Components of disease activity scores (swollen/tender joint count (S/TJC), C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and physician (PhGH) or patient (PGA) global health assessment), pain and fatigue (both on 0-100 scale) and HAQ were recorded at every visit. Missing data was handled with multiple imputation (n=15). Clustering was removed with multiple outputation (n=1000), then each of the 15 000 datasets was analyzed by EFA with principal component extraction and oblimin rotation. The analyses were combined after re-ordering the factors by maximizing factor congruence. The 3 extracted factors and their individual components (with their loadings) were: 1. Patient containing PGA (0.87), pain (0.86), fatigue (0.90) and HAQ (0.5) 2.Clinical with SJC (0.92), TJC (0.89) and PhGH (0.76) and 3.Laboratory with CRP(0.87) and ESR (0.78).1(Pazmino, ACR 2019 abstract, Table 3) Afterwards, variables were first normalized to a 0-1 scale, then multiplied-weighted-by the factor loadings previously obtained.1 For each Patient, Clinical and Laboratory severity score, the weighted variables belonging to each score were summed together and then re-scaled to 0-1 (higher values suggest more burden). The percentage (%) improvement from baseline to week 104 and the area under the curve (AUC) across time points were calculated per factor. Differences in % improvement and AUC were compared between patients not achieving and achieving early and sustained (week 16 to 104) disease activity score remission (DAS28CRP <2.6) with ANOVA. Bonferroni correction was used for multiple testing. Results: Severity scores of Patient, Clinical and Laboratory factors improved rapidly over time (Figure 1). In patients achieving sustained remission (n=122), Patient, Clinical and Laboratory scores improved 56%, 90% and 27% respectively. In patients not achieving sustained remission (n=257) the improvement was 32%, 78% and 9% respectively (p<0.001 only for clinical improvement). Patients in CareRA who achieved sustained remission had an AUC of 15.1, 3.4 and 4.7 in Patient, Clinical and Laboratory scores respectively, compared to 32.3, 10.0, and 7.2 in participants not achieving sustained remission (p<0.001 for all comparisons). Conclusion: Patient, Clinical and Laboratory severity scores improved rapidly over time in patients achieving rapid and sustained disease control. However, overall, Patient burden seemed not to improve to the same extent as Clinical burden. Patient's unmet needs in terms of pain, fatigue, functionality and overall well-being should thus be given more attention, even in patients in sustained remission.
Background: The treat-to-target Care in Early Rheumatoid Arthritis (CareRA) trial demonstrated that remission induction with csDMARD combinations and step-down glucocorticoids (GCs) was not superior over methotrexate (MTX) monotherapy with step-down GCs (Cobra Slim) in RA patients with a high-risk profile (1). Moreover, Cobra Slim showed benefit over a tight step-up with MTX in monotherapy (TSU) in RA patients with a low-risk profile. Objectives: To compare the long term outcomes up to 5 years of different initial intensive treatment strategies in participants of the CareRA-plus study. Methods: In the CareRA trial, patients with DMARD naive early RA were stratified in a high-or low-risk group based upon the presence of serummarkers, disease activity and erosive status. High-risk patients were randomised to Cobra Classic (MTX+sulphasalazine with highly dosed GC remission induction scheme), Cobra Avant-Garde (MTX+leflunomide with moderately dosed GC scheme) or Cobra Slim. Low-risk patients were randomised to Cobra Slim or TSU. Patients completing this trial were eligible for the CareRA-plus observational study. Here, patients were evaluated 6-monthly over 3 years. Therapy adaptation was left to the treating physician. Efficacy was assessed by DAS28-CRP and HAQ and compared between the originally allocated treatment arms. The 5-year evolution from CareRA baseline of DAS28-CRP and HAQ was assessed via linear mixed models. All adverse events (AEs), considered to be clinically relevant by investigators, and DMARD/GCs therapy were registered. Results: Of 322 eligible patients, 252 (78%) were included in CareRA-plus, of which 203 (81%) completed the study. Characteristics and outcomes at the CareRA closing visit (year 2) did not differ between patients entering CareRA-plus or not. DAS28-CRP<2.6 at year 5 in high-risk patients was 72%, 77% and 64% in the Classic, Slim and Avant-Garde group respectively (p=0.403). In the longitudinal analyses, all treatment arms in the high-risk group had comparable DAS28-CRP (p=0.921) and HAQ scores over time (p=0.540). In the low-risk population, 83% of patients in the Slim and 82% in the TSU arm had DAS28-CRP<2.6 at year 5 (p=0.945). Low-risk patients starting Cobra-Slim had lower DAS28-CRP scores over 5 years than those receiving TSU (p= 0.002). HAQ score over time did not differ (p=0.129). In high-risk patients, the total numbers of AEs throughout CareRA-plus, were 70 in 36 Classic, 95 in 48 Slim and 80 in 36 Avant-Garde patients (p=0.182). In the low-risk group there were 18 AEs in 10 Slim and 36 in 17 TSU patients (p=0.048). During the 5-year study, biologics were initiated in 22% of all patients: 23% of Classic, 23% of Slim high-risk, 25% of Avant-Garde, 17% of Slim low-risk, and 15% of TSU patients. At the year 5 visit, 71%, 61% and 50% of high-risk patients were on csDMARD monotherapy (mostly MTX) in Classic, Slim and Avant-Garde respectively. Of the low-risk group, 65% in COBRA-Slim and 62% in TSU were taking a single csDMARD. At the year 5 visit, 9% of all participants received chronic oral GC therapy (>3 months). Conclusion: All intensive treatment strategies resulted in excellent long-term clinical outcomes. Initial Cobra Slim therapy showed comparable 5-year effectiveness as Cobra Classic and Avant-Garde in high-risk early RA patients and better efficacy and safety than conservative step up treatment in low-risk patients.
The Combinatietherapie Bij Reumatoide Artritis (CoBRA) trial was a milestone in the development of the present treatment paradigm for Rheumatoid Arthritis (RA). This study introduced the principle of fast remission induction by means of a combination of standard Disease Modifying AntiRheumatic Drugs (DMARDs) and a step down bridge therapy with high dose glucocorticoids in early Rheumatoid Arthritis.
The purpose of the present study is to compare different combinations of traditional DMARDs and glucocorticoids, based on the original CoBRA protocol, for treatment of early Rheumatoid Arthritis.
Besides the efficacy and effectiveness of these strategies, patient centered outcomes and potential implementation problems of such treatment strategies are evaluated.
