OBJECTIVES: 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.
METHODS: 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).
RESULTS: 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.
CONCLUSIONS: 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.
TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.
BACKGROUND: Treat-to-target therapy is effective for patients with rheumatoid arthritis (RA), but long-term results of continued targeted treatment are lacking.
OBJECTIVE: To evaluate long-term outcomes in patients with early RA after 10 years of targeted treatment in 4 treatment strategies.
DESIGN: Randomized trial. (Nederlands Trial Register: NTR262 and NTR265).
SETTING: The Netherlands.
PATIENTS: 508 patients with early active RA.
INTERVENTION: Sequential monotherapy (strategy 1), step-up combination therapy (strategy 2), or initial combination therapy with prednisone (strategy 3) or with infliximab (strategy 4), all followed by targeted treatment aiming at low disease activity.
MEASUREMENTS: Functional ability (Health Assessment Questionnaire [HAQ] score) and radiographic progression (Sharp-van der Heijde score) were primary end points. Survival in the study population was compared with the general population using the standardized mortality ratio.
RESULTS: 195 of 508 of patients (38%) dropped out of the study (28% in strategy 4 vs. 40% to 45% in strategies 1 to 3, respectively). At year 10, mean HAQ score (SD) was 0.57 (0.56); 53% and 14% of patients were in remission and drug-free remission, respectively, without differences among the strategies. Over 10 years, mean HAQ scores were 0.69, 0.72, 0.64, and 0.58 in strategies 1 to 4, respectively (differences not clinically relevant). Radiographic damage was limited for all strategies, with mean Sharp-van der Heijde estimates during follow-up of 11, 8, 8, and 6 in strategies 1 to 4, respectively (P = 0.15). Standardized mortality ratio was 1.16 (95% CI, 0.92 to 1.46) based on 72 observed and 62 expected deaths, with similar survival among the 4 strategies (P = 0.81).
LIMITATION: Dropout rate varied by strategy.
CONCLUSION: In patients with early RA, initial (temporary) combination therapy results in faster clinical improvement and targeted treatment determines long-term outcomes. Drug-free remission, with prevention of functional deterioration and clinically relevant radiographic damage, and normalized survival are realistic outcomes.
PRIMARY FUNDING SOURCE: Dutch College of Health Insurance Companies, Schering-Plough, and Janssen.
BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines.
METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137.
FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study.
INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards.
FUNDING: Roche Nederland BV.
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.
OBJECTIVE: The aim of this study was to explore the clinical utility of the clinical disease activity index (CDAI). We compared the disease control with protocolized treatment adjustment following a tight control strategy utilizing either the simplified disease activity index (SDAI) or the CDAI.
METHODS: In a prospective 12 month study, DMARD-naive RA patients were randomized to either a CDAI or SDAI arm and were treated with traditional DMARDs, increased on a monthly basis according to a predefined protocol to achieve low disease activity.
RESULTS: Of 102 patients (84 females, 96 Black Africans), the mean symptom duration was 3.0 years (s.d. 3.8) and the mean 28-joint DAS (DAS28) at baseline was 6.2 (s.d. 1.2). By 12 months, the proportion of patients in the CDAI and SDAI groups achieving low disease activity (30% and 32%) and remission (33 and 34%) were similar. There were no significant differences in the mean DAS28 or its components or in HAQ Disability Index or health-related quality of life scores. Baseline predictors of low disease activity at 12 months were shorter symptom duration (P = 0.03) and lower HAQ-DI score (P = 0.04).
CONCLUSION: Given that the CDAI performed as well as the SDAI, and considering the cost savings and convenience because no acute phase reactant test is necessary, we suggest the CDAI may be an appropriate tool for monthly disease activity monitoring as part of a tight control strategy in developing countries.
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 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.
Conferencia»ACR/ARHP Annual Meeting 2014. Published in: Arthritis & Rheumatology
Año»2014
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BACKGROUND/PURPOSE: Recent studies showed diverging results about mortality trends in patients with rheumatoid arthritis (RA). Our aim was to determine survival after 10 years of treat-to-target therapy in patients with early RA, to compare these survival rates with the general population and to define risk factors for mortality during the 10 years duration of the BeSt study.
METHODS: The BeSt study enrolled 508 Dutch patients with recent-onset active RA (1987 criteria) who were randomized to: sequential monotherapy, step-up therapy, initial combination including either prednisone or infliximab. During 10 years, all patients were treated-to-target, aiming at a disease activity score (DAS) ≤2.4. Kaplan-Meier curves and the log-rank test were used to compare survival rates in the four treatment strategies. Standardized mortality ratios (SMR) were calculated to compare the BeSt population to the general Dutch population, matched by age, gender and calendar year. Cox regression was used to calculate hazard ratios (HR) to determine baseline risk factors for increased mortality in the BeSt population.
RESULTS: During 10 years, 72 of 508 patients died at a mean age of 75 years. No difference in survival was observed between the treatment strategies (p=0.805) (figure), with 16/126, 15/121, 21/133 and 20/128 deaths in arm 1 to 4, respectively. Based on the general Dutch population, 62 deaths were expected and 72 deaths occurred, resulting in an overall SMR of 1.16 (95% confidence interval, CI 0.92 – 1.46). Comparing the general population to each of the treatment strategies resulted in a SMR (95% CI) of 1.00 (0.61 – 1.64), 1.02 (0.61 – 1.69), 1.30 (0.85 – 1.99) and 1.32 (0.85 – 2.04) in arm 1 to 4, respectively.
In the BeSt population, baseline age (HR 1.13, 95% CI 1.10-1.16), male gender (HR 1.78, 95% CI 1.06-2.99), smoking at baseline (HR 5.19, 95% CI 3.08-8.75) and health assessment questionnaire at baseline (HR 1.89, 95% CI 1.29-2.76) were associated with an increased risk of mortality. Randomization arm was not associated with an increased risk of mortality (arm 1 as reference category; arm 2 HR 0.99, 95% CI 0.49 – 2.00; arm 3 HR 1.27, 95% CI 0.66 – 2.44; arm 4 HR 1.25, 95% CI 0.65 – 2.41).
CONCLUSION: After 10 years of continued tight controlled treatment in patients with rheumatoid arthritis in the BeSt study, the survival rate was comparable to the general Dutch population, without differences between the treatment strategies. Higher age, male gender, smoking and worse functional ability were associated with an increased risk of mortality within our study population. These results suggest that treatment targeted at DAS ≤2.4 prevents increased mortality previously associated with RA, and that the medication used in these strategies does not increase mortality.
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.
METHODS:
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).
RESULTS:
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.
CONCLUSIONS:
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.
TRIAL REGISTRATION NUMBERS:
EudraCT-number 2008-007225-39 and NCT01172639; Results.
Diseño del estudio»Ensayo controlado aleatorizado (ECA)
