OBJECTIVES: To compare 10-year disease outcomes of RA patients who have continuous low disease activity and are on MTX with or without initial combination therapy with infliximab or prednisone and SSZ.
METHODS: Recent-onset RA patients from the Behandel Strategieen (BeSt) (Dutch acronym for Treatment Strategies) study with 10 years of follow-up were analysed. Treatment was tightly controlled, targeted at DAS ⩽ 2.4. The selected patients had low disease activity from 6 months until 10 years and therefore did not intensify treatment. Patients were grouped into those receiving MTX monotherapy and those receiving initial combination therapy. Between-group differences over time were compared, using (generalized) linear mixed model analyses, for the outcomes DAS, HAQ, ESR, visual analogue scale patient global health, percentage of patients in (drug-free) remission and percentage of patients with Sharp/van der Heijde score progression ⩾5.
RESULTS: At 10 years, 28/247 (11%) patients on MTX monotherapy (some tapered to drug free) had continued DAS ⩽ 2.4 compared with 68/261 (26%) patients on combination therapy (all tapered to monotherapy or drug free). No between-group differences in continuous responders were found over time, except for a higher percentage of patients in drug-free remission after MTX monotherapy. Significant group-time interactions were found for DAS, ESR and visual analogue scale patient global health, but the results seem clinically negligible.
CONCLUSION: More patients achieved continuous low disease activity on initial prednisone or infliximab combination therapy than on initial MTX monotherapy, but there appeared to be no additional benefits. Regardless of induction therapy, patients with continuous low disease activity have similar long-term outcomes, with only a higher proportion of patients in drug-free remission after MTX monotherapy.
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.
OBJECTIVE: To determine the most effective treatment strategy among anticitrullinated protein antibodies (ACPA)-negative patients with early rheumatoid arthritis.
METHODS: In the BeSt study, 184 ACPA-negative patients were randomised to: (1) sequential monotherapy, (2) step-up therapy, (3) initial combination including prednisone, (4) initial combination including infliximab. Treatment was targeted at the disease activity score (DAS) ≤2.4. Early response and 10-year outcomes were compared between the four strategy-arms in ACPA-negative patients.
RESULTS: ACPA-negative patients achieved more short-term functional improvement from initial combination therapy than when on monotherapy (at month 3, mean Health Assessment Questionnaire (HAQ) 0.71 vs 0.98, p=0.006; at month 6, 0.59 vs 0.87, p=0.004). Functional ability over time was comparable between the strategy-arms (p=0.551) with a mean HAQ of 0.6 at year 10 (p=0.580 for comparison across the strategy-arms). 10-year radiographic progression was negligible (median 0.5) and comparable between the 4 strategy-arms (p=0.082). At year 10, remission was achieved by 11/40 (28%), 9/45 (20%), 17/56 (30%) and 17/43 patients (40%) in strategy-arms 1-4, respectively (p=0.434). Over time, similar remission percentages were achieved in all strategy-arms (p=0.815). 18%, 16%, 20% and 21% in strategy-arms 1 to 4 (p=0.742) were in drug-free remission at year 10, with a median duration of 60 months across the arms.
CONCLUSIONS: Initial combination therapy with methotrexate, sulfasalazine and prednisone, or methotrexate and infliximab, is the most effective treatment strategy for ACPA-negative patients, resulting in earlier functional improvement than when on initial methotrexate monotherapy. After 10 years of targeted treatment, in all strategy-arms favourable clinical outcomes were achieved and radiographic progression was limited.
TRIAL REGISTRATION NUMBER: NTR262, NTR265.
OBJECTIVE: To identify risk factors for early study termination and motivators for adherence to a long-term followup trial and to improve completeness of long-term studies.
METHODS: Risk factors for early termination in 508 included patients were identified through Cox regression analysis. Patients completing the 10-year followup filled in a questionnaire on possible motives for continued study participation.
RESULTS: Risk factors for early termination were higher age (hazard ratio [HR] 1.03, 95% confidence interval [95% CI] 1.02-1.04), functional disability during the preceding year (HR 1.54, 95% CI 1.20-1.99), having achieved drug-free remission (HR 6.62, 95% CI 2.07-21.14), limited joint damage (HR 0.98, 95% CI 0.97-0.995 for actual damage; HR 0.83, 95% CI 0.73-0.94 for damage progression), and few adverse events (HR 0.35, 95% CI 0.26-0.47). A total of 288 of 313 patients (92%) attending the last visit answered the questionnaire. The majority mentioned contributing to scientific research (97% agreed), helping other patients (91%), and learning about new treatment strategies (84%) and their disease (85%) as reasons to continue participation. Next, patients mentioned tight control (202 of 278 patients), good treatment strategy (128 of 278), good medication (117 of 278), and good half-term results (102 of 278) as motivators. More than 95% of patients experienced participation "as expected" or "better than expected." Additional examinations during yearly visits (extra questionnaires, imaging) were mentioned as "worse than expected" (10%), as was answering routine questionnaires (7%).
CONCLUSION: Continued participation was relatively high in the Treatment Strategies for Rheumatoid Arthritis (BeSt) Study. Higher age, functional disability, drug-free remission, little joint damage, and few adverse events predicted early study termination. Main motives for continued participation were a willingness to contribute to research, help future patients, and because patients had good experiences with the study protocol.
INTRODUCTION: Personalized medicine is the holy grail of medicine. The EULAR recommendations for the management of rheumatoid arthritis (RA) support differential treatment between patients with baseline characteristics suggestive of a non-poor prognosis (non-PP) or poor prognosis (PP) (presence of autoantibodies, a high inflammatory activity and damage on radiographs). We aimed to determine which prognostic risk groups benefit more from initial monotherapy or initial combination therapy.
METHODS: 508 patients were randomized to initial monotherapy (iMono) or initial combination therapy (iCombo). Disease outcomes of iMono and iCombo were compared within non-PP or PP groups as determined on baseline characteristics
RESULTS: PP patients treated with iCombo after three months more often achieved ACR20 (70% vs 38%, P <0.001), ACR50 (48% vs 13%, P <0.001) and ACR70 response (24% vs 4%, P <0.001) than those treated with iMono, and had more improvement in HAQ (median decrease 0.75 vs 0.38, P <0.001). After 1 year, differences in ACR20 response and DAS-remission remained; PP patients treated with iCombo (vs iMono) had less radiographic progression (median 0.0 vs 1.5, P =0.001).
CONCLUSIONS: Since PP and non-PP patients benefit equally from iCombo through earlier clinical response and functional improvement than with iMono, we conclude that personalized medicine as suggested in the guidelines is not yet feasible. The choice of treatment strategy should depend more on rapid relief of symptoms than on prognostic factors.
TRIAL REGISTRATION: Netherlands Trial Register NTR262 (registered 7 September 2005) and NTR265 (8 September 2005).
Background Long term studies with treat-to-target therapy are essential to guide treatment strategies. Objectives To compare clinical and radiographic outcomes of 4 treatment strategies in early rheumatoid arthritis (RA) patients after 10 years. Methods The BeSt study enrolled 508 patients with early RA. Patients were randomized to: 1 sequential monotherapy, 2 step-up therapy, 3 initial combination with prednisone, 4 initial combination with infliximab. Treatment adjustments were based on 3-monthly disease activity score (DAS) measurements (DAS>2.4: next step; DAS≤2.4 for ≥6 months: taper to maintenance dose, next if DAS<1.6 for ≥6 months: stop last drug). Functional ability (Health Assessment Questionnaire, HAQ) over time was analyzed with a linear mixed model (LMM). Annual X-rays were scored ine one session by 2 blinded readers with the Sharp van der Heijde Score (SHS). SHS progression was categorized per year into “no” (<0.5), “little” (≥0.5 - ≤5) and “much” (>5) and analyzed over time with a generalized LMM. Results 10 year follow-up was completed by 313 patients (62%). Drop-out rates were lowest in arm 4. Mean age of completers was 61 years and 67% were female. Mean (SD) DAS was 1.6 (0.8) and mean (SD) HAQ was 0.6 (0.6). 82% had a DAS≤2.4, 53% had a DAS<1.6, 15% were in drug-free remission (DFR) with a mean (median) duration of 52 (58) months. After 10 years, 38% were still on the initial treatment step, others had changed medication at least once. Toxicity was similar in all arms. Table 1 shows outcomes per treatment arm. The initial functional improvement achieved during year 1 was maintained during 10 years. Over time HAQ was significantly lower in arm 4 than in arm 2 (0.52 vs 0.70, p=0.03, other differences non-significant). Ten year progression rates were low in all arms. Over time, patients in arm 3 less often developed progression compared to arm 1 (p=0.03, other comparisons non-significant). If progression was present, estimates were 8, 11, 8 and 5 SHS progression in 10 years in arm 1 to 4, respectively. (Table presented) Conclusions 10 year follow-up in the BeSt study shows the benefit of continued treat-to-target therapy, steering at low disease activity. After initial improvement functional ability remained stable. Of the completers, 53% and 15% were in DAS- and drug-free remission, respectively. Development of radiographic progression was comparable between groups, although more severe in initial monotherapy arms.
BACKGROUND: Treat-to-target therapy (T2T) is recommended in the treatment of rheumatoid arthritis (RA), but appears not yet fully implemented in daily practice. OBJECTIVES: To evaluate adherence to a T2T strategy and to determine the rheumatologist’s opinion about the study protocol steps, suppression of RA and performance of disease activity score (DAS). METHODS: During 10 year follow-up rheumatologists in 20 clinics treated 508 early RA patients enrolled in the BeSt study as part of their daily outpatient practice. The protocol required treatment adjustments based on 3-monthly DAS measurements, with treatment intensification aiming to achieve low disease activity (DAS ≤2.4) and tapering and discontinuation steps when the target was met and sustained. Rheumatologists filled in questionnaires about satisfaction with level of RA suppression, agreement with the next protocol step and the DAS as representation of disease activity. We checked adherence to the treatment protocol over time and investigated if questionnaire responses and hypothetical conditions (see results) where rheumatologists might disagree with the DAS were associated with protocol violations, using generalized estimating equations. RESULTS: Protocol adherence decreased over time from almost 100% in year 1 to ±60% per visit in year 10, with an average of 79% per visit over 10 years. Rheumatologists mostly agreed with DAS (80-90% of visits over time), and were satisfied with treatment steps in the protocol (75-90% over time) and the level of RA suppression (85-90% over time). Although even then the protocol was mostly followed, the odds for PV increased when the rheumatologist felt the DAS underestimated (Odds Ratio, OR 2.1, 95% confidence interval, CI 1.7-2.5) or overestimated (OR 2.0, 95% CI 1.7-2.3) true disease activity, when the rheumatologist disagreed with the study protocol (OR 2.5, 95% CI 2.1-2.9) or was dissatisfied with the level of RA suppression (OR 1.4, 95% CI 1.2-1.6). The odds for PV were also higher in some specific conditions: when swollen joint count (SJC) was ≤1 and erythrocyte sedimentation rate (ESR) was ≥28 (OR 1.3, 95% CI 1.1-1.5), or when the visual analogue scale of global health of the patient (VASpt) was ≥20 millimetre (mm) higher than the VAS of the physician (VASph) (OR 1.3, 95%CI 1.2-1.5). Other specified conditions as SJC ≤1 and tender joint count ≥2, or SJC ≤1 and VASpt ≥20 mm, or VASph ≥20 mm higher than the VASpt, did not increase the risk of PV. CONCLUSIONS: Rheumatologists adhered well to the treat-to-target strategy of the BeSt protocol, although over time adherence decreased. This may be because in later years, physicians started taking part in the study who had not taken part in designing the protocol. Rheumatologists mostly agreed with how the DAS represented disease activity and with the treatment protocol steps, and were satisfied with the level of RA suppression. However, when they did not agree or were dissatisfied, protocol deviation was more likely. These results prove the feasibility of DAS targeted treatment, steering at low disease activity: rheumatologists feel the DAS performs well in estimating disease activity and are willing to comply with DAS steered therapy adjustments.
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.
Objectives To compare clinical and radiological outcomes of 8 years targeted treatment with four treatment strategies in recent onset rheumatoid arthritis (RA) patients. Methods Patients (n=508) with recent onset RA were randomized to 4 treatment strategies: 1. sequential monotherapy, 2. step-up combination therapy, 3. initial combination with prednisone, 4. initial combination with infliximab. Treatment was DAS≤2.4 steered, with measurements every three months: DAS >2.4: next treatment step; DAS ≤2.4 during ≥6 months: taper to maintenance dose, next if DAS <1.6 during ≥6 months: stop anti-rheumatic treatment. Functional ability, measured with the Health Assessment Questionnaire (HAQ), was analyzed with a linear mixed model with time, treatment and time∗treatment as independent variables. Radiographs of baseline and years 1-8 were scored with the Sharp/vd Heijde Score (SHS), blinded for patient identity and in random order, to asses radiological damage progression. Results After 8 years, 347 patients were still in follow-up. A DAS ≤2.4 was achieved in 79% of these and 52% were in remission (DAS <1.6), without differences between the treatment groups (table). 18, 19, 17 and 15% of the patients in groups 1-4 were in drug-free remission with a median (mean) duration of 45 (39) months. Six patients lost and 12 patients achieved drug-free remission in year 8, while 8 patients with prolonged drug-free remission dropped out. After initial differences in years 1 and 2 between the 4 groups, yearly radiological damage progression rates were low and similar between all groups, reflecting the efficacy of DAS-steered therapy. Median (mean) total damage progression after 8 years was 3 (11) points SHS (n.s. between groups). Patients in sustained drug-free remission had a mean SHS progression of 0.1 (median (IQR) 0 (0-0.03)) per personyear drug-free. The initial improvement of function, which occurred earlier in groups 3 and 4 than in groups 1 and 2, was maintained without deterioration over 8 years in all groups. No differences were found for functional ability over time, with the exception of better functional ability in group 4, compared to group 2: mean HAQ: 0.57 and 0.71. Toxicity was comparable between the groups. Conclusions After 8 years DAS≤2.4 targeted treatment, radiological damage is still very low and following initial improvement (earlier with initial combination therapy than with initial monotherapy), functional ability was maintained in all groups without deterioration over time. A stabilization of the percentages of patients in clinical remission and in drug-free remission was observed. (Table Presented).
