Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry.

BACKGROUND: Treat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease-modifying antirheumatic drug combination approach (cohort II). METHODS: A total of 128 patients from cohort II were case-control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up. RESULTS: After 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36). CONCLUSIONS: The initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission.

Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three-year results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort.

OBJECTIVE: Treat-to-target (T2T) leads to improved clinical outcomes in early rheumatoid arthritis (RA). The question is whether these results sustain in the long term. Our objective was to investigate the 3-year results of a protocolized T2T strategy in daily clinical practice. METHODS: In the Dutch Rheumatoid Arthritis Monitoring remission induction cohort, patients newly diagnosed with RA were treated according to a T2T strategy aimed at remission (Disease Activity Score in 28 joints [DAS28] <2.6). Patients were treated with methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with anti-tumor necrosis factor α agents in case of failure. Primary outcomes were disease activity, Health Assessment Questionnaire (HAQ) score, Short Form 36 physical component summary (PCS) and mental component summary (MCS) scores, and the Sharp/van der Heijde score (SHS) after 3 years. Secondary outcomes were sustained DAS28 remission (≥6 months) and remission according to the provisional American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) definition. RESULTS: After 3 years (n = 342), 61.7% of patients were in DAS28 remission and 25.3% met the provisional ACR/EULAR definition of remission. Sustained remission was experienced by 70.5%, which in the majority was achieved with conventional disease-modifying antirheumatic drugs only. The median scores were 0.4 (interquartile range [IQR] 0.0-1.0) for the HAQ, 45.0 (IQR 38.4-53.2) for the PCS, 53.1 (IQR 43.2-60.8) for the MCS, and 6.0 (IQR 3.0-13.0) for the total SHS. CONCLUSION: In very early RA, T2T leads to high (sustained) remission rates, improved physical function and health-related quality of life, and limited radiographic damage after 3 years in daily clinical practice.

Frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in daily clinical practice.

OBJECTIVE: To describe the frequency and effectiveness of dose increase of adalimumab, etanercept, and infliximab in the treatment of rheumatoid arthritis (RA) in daily clinical practice. METHODS: All RA patients with a dose increase of tumor necrosis factor (TNF)-blocking therapy between January 1997 and January 2008 were selected from a register including data from RA patients starting a first TNF-blocking agent (the Dutch Rheumatoid Arthritis Monitoring registry). The primary outcome was change in Disease Activity Score in 28 joints (DAS28) at 3 months after dose increase. Secondary outcomes were the change in DAS28 at 6 months after dose increase, the European League Against Rheumatism response rates, and the percentages of patients reaching a DAS28 of ≤3.2 at 3 and at 6 months after dose increase. Furthermore, the effectiveness of dose increase was assessed for the different reasons for dose increase: nonresponse, loss of response, and partial response. RESULTS: During the study period, the dose was increased in 44 (12%) of the 368 adalimumab patients, 32 (8%) of the 420 etanercept patients, and 115 (36%) of the 323 infliximab patients. The change in DAS28 at 3 months and 6 months after dose increase was limited and only significant in etanercept patients at 3 months (-0.51; P = 0.035). Disease activity decreased significantly at 3 months from dose increase in the nonresponders and patients with loss of response (-0.66 and -0.99, respectively; both P = 0.001), but not in the partial responders. CONCLUSION: Although dose increase was applied in all 3 TNF-blocking agents in daily clinical practice, these results suggest that the effectiveness of dose increase is limited.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies.

OBJECTIVE: To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-alpha) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard to the percentage of responders and costs. METHODS: The response (>1.2 DAS28 decrease) in patients who started on anti-TNF-alpha treatment for the first time was evaluated at 3 and 6 months after initiation. How many patients continued or discontinued their initial anti-TNF-alpha treatment was evaluated. Possible alternative guidelines were evaluated by means of a decision tree, with regard to the expected percentage of successfully (responders) and unsuccessfully treated patients and expected costs. RESULTS: At 3 months 56% (N = 306) and 44% (N = 233) of all 539 evaluable patients were classified as responders or non-responders, respectively. Despite the guidelines, most (81%) (N = 189) of the non-responders continued treatment. 37% of the non-responders who continued anti-TNF-alpha treatment were eventually classified as responders at 6 months. Decision analytical modelling showed that with equal expected costs all alternative strategies would result in more responders than according to theoretical full adherence with the guidelines. "Continuation in case of partial response" had the best trade-off between successfully treated patients (64%) and unsuccessfully treated patients (17%). CONCLUSION: There was suboptimal adherence to the Dutch guidelines for treatment with anti-TNF-alpha for rheumatoid arthritis patients. This seemed to be justified by the fact that a delayed response up to 6 months was shown. If treatment is continued despite a non-response at 3 months, this is only recommended in patients with at least a partial response (at least 0.6 DAS28 improvement).

The effectiveness and medication costs of three anti-tumour necrosis factor alpha agents in the treatment of rheumatoid arthritis from prospective clinical practice data.

AIM: to evaluate the effects of adalimumab, etanercept and infliximab on disease activity, functional ability and quality of life and the medication costs in a naturalistic design. METHODS: All patients from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register starting on tumour necrosis factor (TNF)alpha-blocking agents for the first time were monitored and assessed by trained research nurses every 3 months. The primary outcome was the Disease Activity Score (DAS28) course over the 12 months follow-up, analysed by linear mixed models. Secondary outcomes were the Health Assessment Questionnaire (HAQ), EuroQol five dimensions (EQ-5D) and the Short-Form 36 items (SF36) scores, and medication-related total costs. RESULTS: The DAS28 and SF-36 physical component scale decreased in all three medication groups over 12 months, but the decrease was larger for adalimumab and etanercept in comparison to infliximab (p<0.001). The analyses of the HAQ and the EQ-5D scores showed the same (non-significant) trend, namely that at 12 months, the functionality and quality of life was better for adalimumab and etanercept patients. With regard to the medication costs, infliximab treatment resulted in significantly higher costs over the follow-up period than treatments with either adalimumab or etanercept. The comparison between adalimumab and etanercept showed a significant difference in the 12-month DAS28 course (p = 0.031). There were no additional indications for differences in effectiveness or costs between adalimumab and etanercept. CONCLUSION: The evaluation of the effectiveness and costs showed that adalimumab and etanercept are more or less equal and favourable compared to infliximab in the first year of treatment.

The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomised controlled trials and clinical practice.

BACKGROUND: Randomised controlled trials (RCTs) evaluating the efficacy of antagonists to tumour necrosis factor alpha (TNFalpha) showed high response percentages in the groups treated with active drugs. OBJECTIVE: To compare the efficacy of anti-TNF treatments for rheumatoid arthritis (RA) patients in RCTs and in daily clinical practice, with an emphasis on the efficacy for patients eligible and not eligible for RCTs of anti-TNF treatments. METHODS: First, randomised placebo-controlled trials written in English for etanercept, infliximab and adalimumab for patients with RA were selected by a systematic review. Second, the DREAM (Dutch Rheumatoid Arthritis Monitoring) register with patients starting for the first time on one of the TNF-blocking agents was used. Patient characteristics, doses of medication and co-medication as well as the ACR20 response percentages were compared between RCTs and DREAM data, stratified for trial eligibility. RESULTS: In 10 of 11 comparisons, the ACR20 response percentages were lower in daily clinical practice than in the RCT active drug group, which was significant in five of 11 comparisons. Only 34-79% of DREAM patients fulfilled the selection criteria for disease activity in the several RCTs examined. DREAM patients eligible for RCTs had higher response percentages than ineligible DREAM patients. ACR20 response percentages of eligible DREAM patients were comparable with the ACR20 response percentages of the RCT active drug group in 10 of 11 comparisons. CONCLUSION: The efficacy of TNF-blocking agents in RCTs exceeded the efficacy of these drugs in clinical practice. However, in clinical practice more patients with lower disease activity were treated with TNF-blocking agents compared with those treated in RCTs. For daily practice patients who were eligible for RCTs, responses were more similar to responses reached in RCTs.

Socio-economic consequences of rheumatoid arthritis in the first years of the disease.

OBJECTIVE: Few data have been presented to document the impact of rheumatoid arthritis (RA) on socio-economic well-being. In this study, exact figures on socio-economic consequences were assessed. METHODS: The socio-economic consequences were studied in an inception cohort (186 early RA patients, mean disease duration 3 yr) by measuring the change in work capability, income, rest during the daytime, leisure time activity, transport mobility, housing and social support occurring in the first years of the disease. RESULTS: For 89% of the patients, RA had an impact on one of the socio-economic items; for 58%, at least three of these items were affected simultaneously. Work disability appeared to be 4-15 times higher than in the general population. After 3 yr, 42% of the patients were registered as work disabled. Nearly a quarter of the patients experienced income reduction. Over 40% of the patients claimed extra rest during the daytime. Leisure activity changed towards activities with a lower joint load. There was a decline in transport mobility for 52% of the patients. Social support increased strongly. CONCLUSIONS: Socio-economic change already presents in the first years of RA and appears to be influenced by age, gender, marital status and work disability. Furthermore, physical limitation appeared to be predictive for work-related income reduction, reduced transport mobility and development of social dependency.

Radiographic damage in large joints in early rheumatoid arthritis: relationship with radiographic damage in hands and feet, disease activity, and physical disability.

An assessment of the onset of radiographic damage in the large joints (hip, knees, shoulders, elbows, ankles and tarsus) in patients with early rheumatoid arthritis, and the relationship of the progression of large joint damage with joint damage in hands and feet, with physical disability, and with cumulative disease activity, was performed in a prospective 6 yr follow-up study. Large joint damage appeared to be an early phenomenon with 20% of the patients having some damage in at least one large joint within 1 yr, and 50% of the patients within 6 yr after disease onset. Radiographic damage in large joints was significantly related to the damage in hands and feet, the physical disability index, and the cumulative disease activity. The initial disease activity at study entry was the only prognostic factor that reached significance.

Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis.

OBJECTIVE: The development and validation of Modified Disease Activity Scores (DAS) that include different 28-joint counts. METHODS: These scores were developed by canonical discriminant analyses and validated for criterion, correlational, and construct validity. The influence of disease duration on the composition of the DAS was also investigated. RESULTS: No influence of disease duration was found. The Modified DAS that included 28-joint counts were able to discriminate between high and low disease activity (as indicated by clinical decisions of rheumatologists). CONCLUSION: The Modified DAS are as valid as disease activity scores that include more comprehensive joint counts.

Validity and reliability of joint indices. A longitudinal study in patients with recent onset rheumatoid arthritis.

This prospective longitudinal study evaluates the validity and reliability of joint indices (JIs) used to measure disease activity in patients with RA. From seven traditional JIs (Ritchie Articular Index (RAI), Modified RAI, Thompson score, 28 JI, 36 JI, total tender and total swollen joints) 37 'new' JIs were computed by considering three different characteristics of joint inflammation, tenderness, swelling and the combination of tenderness and swelling, and by grading for tenderness and/or weighting for surface area of the joints. Several aspects of validity were investigated, the construct (correlation with radiographic damage), correlational (correlation with ESR, general health) and criterion validity (correlation with a Health Assessment Questionnaire, discrimination between high and low disease activity). It was found that the validity and reliability of traditional JIs do not differ substantially. Graded JIs are almost always more valid than ungraded JIs. Weighted JIs are almost always less valid and reliable than unweighted JIs. Therefore no JI proved to be superior for measuring the disease activity under consideration. Taking simplicity into account the 28 JI, not graded and not weighted, was preferable.