Radiographic progression in early rheumatoid arthritis patients following initial combination versus step-up treat-to-target therapy in daily clinical practice: results from the DREAM registry.

BACKGROUND: Early and intensive targeted treatment with disease modifying anti-rheumatic drugs (DMARDs) has been shown to lead to substantial reductions in disease activity and radiograph damage in patients with early rheumatoid arthritis (RA). The aim of this quasi-experimental study was to compare the first-year radiographic progression rates between a treat-to-target (T2 T) strategy with initial combination therapy (strategy II, started in 2012) versus an initial step-up monotherapy (strategy I, started in 2006). METHODS: A total of 128 patients from strategy II was individually matched with 128 patients from strategy I on sex, age (± 5 yrs.) and baseline disease activity (± 0.5 on the DAS28). Differences in radiographic progression (Sharp/van der Heijde) scores (SHS) and the number of patients experiencing a minimal clinically important difference (MCID; ≥ 5 SHS points) between both strategies were tested with Mann Whitney U and chi-square tests. Next, linear and logistic regression analyses were performed to examine which baseline variables were associated with radiographic progression scores and the probability of experiencing an MCID within 1 year. RESULTS: Patients with initial combination therapy had slightly higher baseline disease activity scores and pain scores, but better mental health scores. Patients with initial monotherapy had significantly more, and more frequently clinically relevant, radiographic progression after 1 year. Experiencing a MCID was independently associated with fewer tender joints (p = 0.050) and higher erythrocyte sedimentation rate (p = 0.015) at baseline. CONCLUSION: Treating early RA patients with initial combination therapy results in better radiographic outcomes than initial monotherapy in daily clinical practice. TRIAL REGISTRATION: Netherlands Trial Register NTR578, 12 January 2006.

Recently diagnosed rheumatoid arthritis patients benefit from a treat-to-target strategy: results from the DREAM registry.

Despite considerable evidence on the efficacy and safety of early aggressive treat-to-target (T2T) strategies in early rheumatoid arthritis (RA), a proportion of patients still fail to reach remission. The goal of this study is to examine remission rates and predictors of remission in a real life T2T cohort of consecutive patients with a recent diagnosis of RA. Baseline demographics, clinical, laboratory and patient-reported variables and 1-year follow-up disease activity data were used from patients with early RA included in the DREAM remission induction cohort II study. Survival analyses and simple and multivariable logistic regression analyses were used to examine remission rates and significant predictors of achieving remission. A total of 137 recently diagnosed consecutive RA patients were available for this study. During the first year after inclusion, DAS28 remission was achieved at least once in 77.2 % of the patients and the median time to first remission was 17 weeks. None of the examined baseline variables were robustly associated with achieving remission within 1 year and in the multivariable analysis only lower ESR (p = 0.005) remained significantly associated with achieving fast remission within 17 weeks. During the first year of their disease a high proportion of recently diagnosed RA patient achieved remission, with only a small percentage of patients needing bDMARD therapy. Combined with the absence of baseline predictors of remission, this suggests that clinicians in daily clinical practice may focus on DAS28 scores only, without needing to take other patients characteristics into account.

Adherence to a treat-to-target strategy in early rheumatoid arthritis: results of the DREAM remission induction cohort.

INTRODUCTION: Clinical trials have demonstrated that treatment-to-target (T2T) is effective in achieving remission in early rheumatoid arthritis (RA). However, the concept of T2T has not been fully implemented yet and the question is whether a T2T strategy is feasible in daily clinical practice. The objective of the study was to evaluate the adherence to a T2T strategy aiming at remission (Disease Activity Score in 28 joints (DAS28) < 2.6) in early RA in daily practice. The recommendations regarding T2T included regular assessment of the DAS28 and advice regarding DAS28-driven treatment adjustments. METHODS: A medical chart review was performed among a random sample of 100 RA patients of the DREAM remission induction cohort. At all scheduled visits, it was determined whether the clinical decisions were compliant to the T2T recommendations. RESULTS: The 100 patients contributed to a total of 1,115 visits. The DAS28 was available in 97.9% (1,092/1,115) of the visits, of which the DAS28 was assessed at a frequency of at least every three months in 88.3% (964/1,092). Adherence to the treatment advice was observed in 69.3% (757/1,092) of the visits. In case of non-adherence when remission was present (19.5%, 108/553), most frequently medication was tapered off or discontinued when it should have been continued (7.2%, 40/553) or treatment was continued when it should have been tapered off or discontinued (6.2%, 34/553). In case of non-adherence when remission was absent (42.1%, 227/539), most frequently medication was not intensified when an intensification step should have been taken (34.9%, 188/539). The main reason for non-adherence was discordance between disease activity status according to the rheumatologist and DAS28. CONCLUSIONS: The recommendations regarding T2T were successfully implemented and high adherence was observed. This demonstrates that a T2T strategy is feasible in RA in daily clinical practice.

A tight control treatment strategy aiming for remission in early rheumatoid arthritis is more effective than usual care treatment in daily clinical practice: a study of two cohorts in the Dutch Rheumatoid Arthritis Monitoring registry.

UNLABELLED: There is strong evidence from clinical trials that a 'treat to target' strategy is effective in reaching remission in rheumatoid arthritis (RA). However, the question is whether these results can be translated into daily clinical practice and clinical remission is a reachable target indeed. OBJECTIVE: The study aims to investigate whether in early RA a treatment strategy aiming at Disease Activity Score (DAS) 28 <2.6 is more effective than 'usual care' treatment for reaching clinical remission after 1 year. METHODS: Two early RA inception cohorts from two different regions including patients who fulfilled the American College of Rheumatology criteria for RA were compared. Patients in the tight-control cohort (n=126) were treated according to a DAS28-driven step-up treatment strategy starting with methotrexate, addition of sulphasalazine (SSZ) and exchange of SSZ by anti-tumour necrosis factor in case of failure. Patients in the usual-care cohort (n=126) were treated with methotrexate or SSZ, without DAS28-guided treatment decisions. The primary outcome was the percentage remission (DAS28<2.6) at 1 year. Time to first remission and change in DAS28 were secondary outcomes. RESULTS: After 1 year, 55% of tight-control patients had a DAS28<2.6 versus 30% of usual care patients (OR 3.1, 95% CI 1.8 to 5.2). The median time to first remission was 25 weeks for tight control and more than 52 weeks for usual care (p<0.0001). The DAS28 decreased with -2.5 in tight control and -1.5 in usual care (p<0.0001). CONCLUSION: In early RA, a tight control treatment strategy aiming for remission leads to more rapid DAS28 remission and higher percentages of remission after 1 year than does a usual care treatment.

Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study.

OBJECTIVE: Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not yet been implemented. The objective of this study was to develop, implement, and evaluate a treat-to-target strategy aimed at achieving remission in very early RA in daily clinical practice. METHODS: Five hundred thirty-four patients with a clinical diagnosis of very early RA were included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Treatment adjustments were based on the Disease Activity Score in 28 joints (DAS28), aiming at a DAS28 of <2.6 (methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with biologic agents in case of persistent disease activity). The primary outcome was disease activity after 6 months and 12 months of followup, according to the DAS28, the European League Against Rheumatism (EULAR) response criteria, and the modified American College of Rheumatology (ACR) remission criteria. Secondary outcomes were time to first DAS28 remission and outcome of radiography. RESULTS: Six-month and 12-month followup data were available for 491 and 389 patients, respectively. At 6 months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At 12 months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. The median time to first remission was 25.3 weeks (interquartile range 13.0-52.0). The majority of patients did not have clinically relevant radiographic progression after 1 year. CONCLUSION: The successful implementation of this treat-to-target strategy aiming at remission demonstrated that achieving remission in daily clinical practice is a realistic goal.

Ultrasound findings in rheumatoid wrist arthritis highly correlate with function.

PURPOSE: The wrist is almost invariably affected in rheumatoid arthritis (RA) and inflammation of the wrist can lead to impaired function and eventually to severe destruction. Classical signs of inflammation, pain, swelling and heat may often be observed in clinical examination of wrist arthritis and in ultrasound (US) investigation. We described the relation between clinical and ultrasound parameters of wrist arthritis and secondly their relation to function. PATIENTS AND METHODS: In 33 RA patients with wrist arthritis, clinical and US parameters were measured. Function was evaluated with the SODA-S (Sequential Occupational Dexterity Assessment-Short) and the DASH-DLV (Disabilities of the Arm, Shoulder and Hand-Dutch Language Version). Correlation coefficients were calculated and factor analysis was performed to describe the relation between the aforementioned measures. RESULTS: Correlation coefficients between clinical and ultrasound parameters of RA wrist inflammation in this study were fair to moderate. We found a good correlation between ultrasound and observed function. CONCLUSION: The classical signs of inflammation (pain, swelling, redness, heat and impaired function) seem to reflect different aspects of arthritis. Ultrasound correlates well with function, thus can give paramount information on wrist function, and might therefore be a valuable complementary tool in measuring wrist arthritis in RA.

[Practice guideline 'Diagnosis and treatment of rheumatoid arthritis']. / Richtlijn 'Diagnostiek en behandeling van reumatoïde artritis'.

Treatment early in the course of the disease, along with early diagnosis, has a positive influence on clinical outcome in patients with rheumatoid arthritis (RA). Therapeutic strategies, including the use of 'disease-modifying antirheumatic drug' (DMARD) combinations, have proved effective, with relatively few side effects. New insights into the pathophysiology of RA have lead to the development of novel therapeutic agents that have been demonstrated to be highly effective. Patients should be monitored intensively with respect to the effect of therapy on reduction of disease activity, followed by modification of therapeutic strategy in the case of a suboptimal treatment response. Various non-pharmacological interventions, such as exercise therapy and patient education, are available to help patients to cope with the consequences of the disease. Optimizing treatment of RA by means of this approach will help to realize the goal of current therapy: to achieve and sustain remission and, thereby, an optimal functional level.

Remission and rheumatoid arthritis: data on patients receiving usual care in twenty-four countries.

OBJECTIVE: To compare the performance of different definitions of remission in a large multinational cross-sectional cohort of patients with rheumatoid arthritis (RA). METHODS: The Questionnaires in Standard Monitoring of Patients with RA (QUEST-RA) database, which (as of January 2008) included 5,848 patients receiving usual care at 67 sites in 24 countries, was used for this study. Patients were clinically assessed by rheumatologists and completed a 4-page self-report questionnaire. The database was analyzed according to the following definitions of remission: American College of Rheumatology (ACR) definition, Disease Activity Score in 28 joints (DAS28), Clinical Disease Activity Index (CDAI), clinical remission assessed using 42 and 28 joints (Clin42 and Clin28), patient self-report Routine Assessment of Patient Index Data 3 (RAPID3), and physician report of no disease activity (MD remission). RESULTS: The overall remission rate was lowest using the ACR definition of remission (8.6%), followed by the Clin42 (10.6%), Clin28 (12.6%), CDAI (13.8%), MD remission (14.2%), and RAPID3 (14.3%); the rate of remission was highest when remission was defined using the DAS28 (19.6%). The difference between the highest and lowest remission rates was >or=15% in 10 countries, 5-14% in 7 countries, and <5% in 7 countries (the latter of which had generally low remission rates [<5.5%]). Regardless of the definition of remission, male sex, higher education, shorter disease duration, smaller number of comorbidities, and regular exercise were statistically significantly associated with remission. CONCLUSION: The use of different definitions of RA remission leads to different results with regard to remission rates, with considerable variation among countries and between sexes. Reported remission rates in clinical trials and clinical studies have to be interpreted in light of the definition of remission that has been used.

Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study.

INTRODUCTION: We analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care. METHODS: The study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models. RESULTS: Between January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries. CONCLUSION: In conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.

Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis.

OBJECTIVE: To study the bioavailability of a divided higher oral dose of methotrexate (MTX), in comparison to a single dose, in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 10 patients with RA taking a stable dose (25-35 mg weekly) of MTX. Separated by one week, a pharmacokinetic analysis was performed in each patient after an oral single dose, and after an equal but split dose separated by 8 hours. MTX serum concentrations were measured by a fluorescence polarization immunoassay technique. Analysis was performed by calculation of the area under the curve (AUC) by the trapezoidal rule and by means of an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. For the population analysis, data from 15 patients in our previous study comparing oral and subcutaneous administration of MTX were also used. RESULTS: The median MTX dose was 30 mg weekly (range 25-35 mg). The bioavailability of the split dose was 28% higher compared to the single dose (p = 0.007). In the population pharmacokinetic modeling, a 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after single-dose and split-dose MTX was 0.76 and 0.90, respectively, compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 oral administration regimens (p = 0.008). CONCLUSION: The bioavailability of oral higher dose MTX in adult patients with RA can be improved by splitting the dose.

Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis.

OBJECTIVE: To determine the bioavailability of higher oral doses of methotrexate (MTX) in adult patients with rheumatoid arthritis (RA). METHODS: A pharmacokinetic analysis was performed in 15 patients with RA taking a stable dose of MTX (> or = 25 mg weekly). Separated by 2 weeks, a pharmacokinetic analysis was performed in each patient after oral and subcutaneous administration of the same dose of MTX. MTX serum concentrations were measured by a fluorescence polarization immunoassay. Pharmacokinetic analysis was performed with an iterative 2-stage Bayesian population procedure, obtaining population and individual pharmacokinetic parameters. RESULTS: The median MTX dose was 30 mg weekly (range 25-40 mg). A 2-compartment model best described the serum MTX concentration versus time curves. The mean bioavailability after oral MTX was 0.64 (range 0.21-0.96) compared to subcutaneous administration. There was a statistically significant difference in the bioavailability of the 2 administration regimens. CONCLUSION: Bioavailability of a higher oral dose of MTX in adult patients with RA is highly variable, and on average two-thirds that of the subcutaneous administration. To improve efficacy of MTX at dosages of 25 mg weekly or more, a change to parenteral administration should be considered.

Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis.

OBJECTIVE: To study which factors are associated with longterm methotrexate (MTX) use in rheumatoid arthritis (RA). METHODS: All patients with RA who had started MTX after January 1, 1993, were selected from a regional hospital based registration system. Data on demographic and clinical features were retrieved through chart review. By means of life table analysis and Cox regression analysis, MTX survival and the relation between demographic variables, clinical features, and MTX survival were studied. RESULTS: A total of 1072 MTX treatment episodes in 1022 patients were analyzed. The cumulative MTX survival probability after 5 years was 64%, and after 9 years was 50%. Univariate analysis showed a significant relation between MTX survival probability and folic acid supplementation, attending rheumatologist, concurrent prednisolone use, concurrent sulfasalazine use, and the number of previous disease modifying drugs. In the multivariate analysis folic acid supplementation, attending rheumatologist, and concurrent prednisolone use remained significantly related to MTX survival. Age, disease duration, and creatinine clearance were not. CONCLUSION: In this retrospective study of 1022 patients with RA the cumulative MTX survival probability was 64% after 5 years and 50% after 9 years. Folic acid supplementation and to a lesser extent prednisolone were associated with a longer MTX survival. In addition, treatment strategies of individual rheumatologists influenced MTX survival.