Long-Term Outcomes of Patients With Recent-Onset Rheumatoid Arthritis After 10 Years of Tight Controlled Treatment: A Randomized Trial.

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.

Large-joint damage in patients with early rheumatoid arthritis and its association with treatment strategy and damage of the small joints.

OBJECTIVE: To determine the prevalence of large-joint damage and the association with small-joint damage in patients with RA after 8 years of low DAS (≤2.4)-targeted treatment with different treatment strategies. METHODS: Radiological data of 290 patients participating in the BeSt study, a randomized trial comparing initial monotherapy and initial combination therapy strategies, were used. Radiographs of large joints were scored using the Larsen score and of the small joints using the Sharp-van der Heijde score. With multivariate logistic regression analysis, an association between total damage of the small joints and of the large joints was investigated. RESULTS: After 8 years of treatment, damage was observed in 12% of shoulders, 10% of elbows, 26% of wrists, 13% of hips, 18% of knees and 7% of the ankles. Damage in one or more large joints was found in 64% of patients, with a median score of 1. No difference was found between initial monotherapy or combination therapy strategies. There was a significant association between damage progression in small joints and damage to one or more large joints (OR 1.02; 95% CI 1.00-1.04). CONCLUSION: After 8 years of DAS-targeted treatment in early RA patients, large-joint damage was found in 64% of patients and was associated with small-joint damage. Continued DAS-targeted treatment is probably more important in damage suppression than initial treatment strategy. Patients with more damage to hands and feet also have more damage to the large joints.

The impact of four dynamic, goal-steered treatment strategies on the 5-year outcomes of rheumatoid arthritis patients in the BeSt study.

OBJECTIVE: To compare clinical and radiological outcomes of four dynamic treatment strategies in recent-onset rheumatoid arthritis (RA) after 5 years follow-up. METHODS: 508 patients with recent-onset RA were randomly assigned into four treatment strategies: sequential monotherapy; step-up combination therapy; initial combination with prednisone; initial combination with infliximab. Treatment adjustments were made based on 3-monthly disease activity score (DAS) measurements (if DAS >2.4 next treatment step; if DAS ≤ 2.4 during ≥ 6 months taper to maintenance dose; if DAS <1.6 during ≥ 6 months stop antirheumatic treatment). Primary and secondary outcomes were functional ability, joint damage progression, health-related quality of life and (drug-free) remission percentages. RESULTS: After 5 years, 48% of patients were in clinical remission (DAS <1.6) and 14% in drug-free remission, irrespective of initial treatment. After an earlier improvement in functional ability and quality of life with initial combination therapy, from 1 year onwards clinical outcomes were comparable across the groups and stable during 5 years. The initial combination groups showed less joint damage in year 1. In years 2-5 annual progression was comparable across the groups. After 5 years, initial combination therapy resulted in significantly less joint damage progression, reflecting the earlier clinical response. CONCLUSION: Irrespective of initial treatment, an impressive improvement in clinical and radiological outcomes of RA patients can be achieved with dynamic treatment aimed at reducing disease activity, leading to 48% remission, 14% drug-free remission and sustained functional improvement. Starting with combination therapy resulted in earlier clinical improvement and less joint damage without more toxicity.

Erosions in the foot at baseline are predictive of orthopaedic shoe use after 10 years of treat to target therapy in patients with recent onset rheumatoid arthritis.

The objective of this study is to investigate if foot joint damage due to rheumatoid arthritis (RA) can predict whether patients will start wearing orthopaedic shoes (OS) within 10 years after treatment start. Data from recent onset RA patients with 10 years follow-up from the BeSt (Dutch acronym for treatment strategies) study were used. Treatment was tightly controlled, targeted at disease activity score (DAS) ≤2.4, according to 1 of 4 pre-specified treatment strategies. After 10 years of follow-up, orthopaedic shoe use was recorded in 285/508 patients (responders to questionnaires at 10 years). Between-group differences for orthopaedic shoe users and non-users were calculated at baseline, after 10 years, and change scores over the 10-year period were calculated. Predictors for orthopaedic shoe use were identified by univariable and multivariable logistic regression analyses. Orthopaedic shoe use was reported by 57/285 patients after 10 years. Orthopaedic shoe users had more joint damage, joint swelling and pain in the feet already at baseline and after 10 years. At both time points, DAS of orthopaedic shoe users and non-users was similar. Multivariable logistic regression showed that dichotomized foot erosions score (cut-off ≥1 erosion) (OR 2.42), anti-citrullinated protein antibodies (ACPA) (OR 4.64) and DAS (OR 1.77) were independent predictors of orthopaedic shoe use. Despite intensive targeted treatment, 57/285 recent onset RA patients started using orthopaedic shoes over 10 year of follow-up. Presence of foot erosions at treatment start predicts orthopaedic shoe use after 10 years. The risk of orthopedic shoe use increased for ACPA-positive patients and for those with higher baseline disease activity.

Continued participation in a ten-year tight control treat-to-target study in rheumatoid arthritis: why keep patients doing their best?

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.

Intra articular injection with corticosteroids in patients with recent onset rheumatoid arthritis: subanalyses from the BeSt study.

To investigate the association between intra-articular (IA) large joint corticosteroid injections and clinical outcomes in patients with recent onset rheumatoid arthritis (RA). We compared pain (visual analog scale (VAS)), the Disease Activity Score (44 joints) (DAS), and swollen and tender joint counts before and after IA injection. Using linear mixed models (LMM), the DAS and the Health Assessment Questionnaire (HAQ) score over time were compared in IA injected versus noninjected patients. In year 1, 93 joints were injected in 44 patients treated with initial methotrexate monotherapy and 16 in patients treated with initial combination therapy (p < 0.01). Three months later, swelling and tenderness were resolved in 58-50 % of the injected joints; but within 12 months after the injection, swelling recurred in 14 % and tenderness in 41 % of the injected joints. Mean (SD) DAS decreased from 4.0 (1.4) before to 3.2 (1.2) 3 months after injection (p < 0.01) and VAS for pain from 49 (26) to 40 (27) (p < 0.01). LMM showed a higher DAS and HAQ in patients injected in year 0-1 compared to those not injected, but no difference in subsequent years, and similar treatment adjustments. Eight-year radiographs showed similar damage in injected joints (17 %) and noninjected joints (14 %). IA corticosteroid injections are associated with symptom relief, sometimes only temporarily, in 50 % of cases. Initially DAS significantly improved, but over time DAS and HAQ were similar in injected versus non-injected patients. After 8 years there was no difference in joint damage.

Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis.

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).

A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study.

OBJECTIVE: To determine whether a multibiomarker disease activity (MBDA) score predicts radiographic damage progression in the subsequent year in patients with early rheumatoid arthritis. METHODS: There were 180 serum samples available in the BeSt study (trial numbers NTR262, NTR 265): 91 at baseline (84 with radiographs available) and 89 at 1-year followup (81 with radiographs available). Radiographs were assessed using the Sharp/van der Heijde Score (SvdH). Twelve serum biomarkers were measured to determine MBDA scores using a validated algorithm. Receiver-operating curves and Poisson regression analyses were performed, with Disease Activity Score (DAS) and MBDA score as independent variables, and radiographic progression as dependent variable. RESULTS: At baseline, MBDA scores discriminated more between patients who developed radiographic progression (increase in SvdH≥5 points) and patients who did not [area under the curve (AUC) 0.767, 95% CI 0.639-0.896] than did DAS (AUC 0.521, 95% CI 0.358-0.684). At 1 year, MBDA score had an AUC of 0.691 (95% CI 0.453-0.929) and DAS had an AUC of 0.649 (95% CI 0.417-0.880). Adjusted for anticitrullinated protein antibody status and DAS, higher MBDA scores were associated with an increased risk for SvdH progression [relative risk (RR) 1.039, 95% CI 1.018-1.059 for baseline MBDA score; 1.037, 95% CI 1.009-1.065 for Year 1 MBDA score]. Categorized high MBDA scores were also correlated with SvdH progression (RR for high MBDA score at baseline 3.7; low or moderate MBDA score as reference). At 1 year, high MBDA score gave a RR of 4.6 compared to low MBDA score. CONCLUSION: MBDA scores predict radiographic damage progression at baseline and during disease course.

Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial).

OBJECTIVE: To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomised controlled trial comparing four therapeutic strategies. METHODS: A questionnaire was sent to all 508 participants of the BeSt trial, treated for an average of 2.2 years with either sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Treatment adjustments were made every 3 months to achieve low disease activity (DAS < or =2.4). The questionnaire explored patients' preferences or dislikes for the initial therapy. RESULTS: In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1-4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment. CONCLUSIONS: Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.