Favourable effect of a 'second hit' after 13 weeks in early RA non-responders: the Amsterdam COBRA treat-to-target randomized trial.

OBJECTIVE: The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA. METHODS: Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 < 1.6 or EULAR good response at 26 weeks. At 13 weeks, non-responders were randomized to (open-label) intensification [high-risk patients: prednisolone 60 mg/day tapered to 7.5 mg/day, addition of SSZ (2 g/day) and HCQ (400 mg/day); low-risk patients: prednisolone 30 mg/day tapered to 7.5 mg/day] or continuation. RESULTS: In the high-risk group (n = 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P = 0.04]. In the low-risk group (n = 40), 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3, respectively, reached the target.Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification. CONCLUSION: Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult. TRIAL REGISTRATION: Netherlands Trial Register (NTR), NL4393, https://www.trialregister.nl/.

TNF inhibitor treatment is associated with a lower risk of hand osteoarthritis progression in rheumatoid arthritis patients after 10 years.

Objective: To investigate the effect of TNF inhibitors (TNFis) on incidental and progressive hand OA in recent-onset RA patients after a 10 year follow-up. Methods: Radiographs of 262 RA patients (mean age 52 years, 66% women) from the BeSt study were scored for osteophytes in DIP/PIP joints using the Osteoarthritis Research Society International atlas (0-3; summed score 0-54) and according to the Kellgren-Lawrence (KL) score (0-4; summed score 0-72) at baseline and 10 year follow-up. TNFi treatment was assessed on visits every 3 months. Associations between TNFi treatment and hand OA were analysed on the patient and joint level using generalized linear models and generalized estimating equations, respectively. Results: Fifty-eight percent of the patients were treated with TNFi, with a median duration of 42 months. A total of 143 patients (55%) had hand OA in any IP joint at baseline based on the Osteoarthritis Research Society International osteophyte score. On the patient level, TNFi treatment duration did not affect incidental hand OA. However, every month of TNFi treatment resulted in a reduced relative risk (RR) of hand OA progression in DIP joints [relative risk (RR) 0.987 (95% CI 0.978, 0.996)] but not in PIP joints. On the joint level, the effect on hand OA progression was observed in DIP joints [RR 0.996 (95% CI 0.991, 1.000)] but not in PIP joints. The results from the KL score analyses were comparable to the osteophyte score. Conclusion: TNFi treatment was associated with a reduced risk on radiographic hand OA progression in DIP joints but not in PIP joints after 10 years. Although the effect sizes are small, these results provide evidence for influence of TNF-α in hand OA pathogenesis.

Similar efficacy and safety of initial COBRA-light and COBRA therapy in rheumatoid arthritis: 4-year results from the COBRA-light trial.

Objective: To assess the efficacy and safety of initial COBRA-light vs COBRA therapy in RA patients after a 4-year follow-up period. Methods: In the COBRA-light trial, 162 consecutive patients with recent-onset RA were randomized to either COBRA-light (prednisolone and MTX) or COBRA therapy (prednisolone, MTX and SSZ) for 1 year. After 1 year, treatment was continued without protocol, and adjusted by the treating physician according to clinical judgement, preferably with a treat-to-target strategy. Four years after trial initiation, all patients were invited to participate in the COBRA-light extension study, in which patients were interviewed and physically examined, patient reported outcomes were assessed, radiographs were made and clinical records were examined for comorbidities and medication use. Results: In the extension study, 149 out of 162 (92%) original trial patients participated: 72 COBRA-light and 77 COBRA patients. Initial COBRA-light and COBRA therapy showed similar effect on disease activity, physical functioning, radiological outcome and Boolean remission over the 4-year follow-up period. In addition, both treatment groups showed similar survival and major comorbidities, although the power to detect differences was limited. Besides protocolled differences in prednisolone, MTX and SSZ use, the use of other synthetic and biologic DMARDs and intra-articular and intramuscular glucocorticoid injections was similar in both treatment groups over the 4-year period. Conclusion: Early RA patients initially treated with COBRA-light or COBRA therapy had similar efficacy and safety outcomes over a 4-year follow-up period.

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.

Repair of joint damage in patients with rheumatoid arthritis does not relate to previous suppression of inflammation: a subanalysis after 8 years treat-to-target in the BeSt-trial.

OBJECTIVES: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. METHODS: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. RESULTS: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. CONCLUSION: After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair.

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.

Sustained drug-free remission in rheumatoid arthritis after DAS-driven or non-DAS-driven therapy: a comparison of two cohort studies.

OBJECTIVES: To compare the prevalence of and predictors for sustained drug-free remission in two cohorts of patients with recent-onset RA treated with DAS-driven therapy or non-DAS-driven therapy. METHODS: Sustained drug-free remission was assessed after 5 years of follow-up in 508 patients treated with DAS-driven therapy (DAS ≤ 2.4) in a randomized treatment cohort, and in 424 patients who received non-DAS-driven therapy in a prospective inception cohort. The design of the DAS-driven cohort required systematic joint assessments with DAS-driven restart of therapy. Predictors for remission were identified by univariable and multivariable logistic regression in each cohort separately and in a combined multivariate logistic regression analysis corrected for propensity scores, including a sensitivity analysis on patients receiving initial monotherapy. RESULTS: Patients in the DAS-driven cohort had more active disease at baseline, but the prevalence of sustained drug-free remission was similar after DAS-driven (9.8%) and non-DAS-driven therapy (10.6%). Among patients with ACPA, drug-free remission was more frequently achieved after DAS-driven than after non-DAS-driven therapy (5.4 vs. 2.1%, OR = 2.68, 95% CI 0.97, 7.43). Absence of ACPA and short symptom duration were independent predictors for sustained drug-free remission in both cohorts. Initial treatment choice and inclusion period were not predictive. The sensitivity analysis yielded comparable results. CONCLUSION: Retrospectively comparing a DAS-driven to a non-DAS-driven therapy cohort, the occurrence and predictors of sustained drug-free remission were similar. The DAS-driven cohort had a more unfavourable prognosis. DAS-driven therapy may improve the chance of sustained drug-free remission in ACPA-positive patients with recent-onset RA.

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.

Blood pressure changes in patients with recent-onset rheumatoid arthritis treated with four different treatment strategies: a post hoc analysis from the BeSt trial.

OBJECTIVE: To evaluate the effect of disease activity and antirheumatic treatment on blood pressure (BP) in patients with recent-onset rheumatoid arthritis (RA). METHODS: 508 patients with RA were randomised to receive (1) sequential monotherapy, (2) step-up combination therapy, (3) initial combination with prednisone or (4) with infliximab. Systolic and diastolic BP (SBP, DBP), disease activity score (DAS) and body mass index (BMI) were evaluated every 3 months. A linear mixed model was used to model SBP and DBP in each treatment group during year 1, adjusting for baseline BP, changes in BMI, DAS and cardiovascular medication. RESULTS: In all groups, mean SBP and DBP were lower for patients with DAS < or =2.4 than for patients with DAS >2.4. In addition, patients initially treated with infliximab (group 4) had a larger decrease in SBP and DBP over time than patients in groups 1-3. The decrease in BP was also observed in patients treated with infliximab after failure on conventional disease-modifying antirheumatic drugs in groups 1-3. The decrease in BP associated with treatment with infliximab occurred irrespective of the DAS response. CONCLUSION: A lower DAS is associated with lower BP. An additional decrease in BP was observed in patients treated with infliximab. Further research is needed to confirm the effect of infliximab on BP.

Earlier is better when treating rheumatoid arthritis: but can we detect a window of opportunity?

OBJECTIVES: The window of opportunity (WOO) hypothesis suggests a limited time frame to stop rheumatoid arthritis (RA). We hypothesised that a WOO could either be represented by a hyperbolic ('curved') decline in the chance to achieve the outcome sustained drug-free remission (sDFR) over time, after which achieving sDFR is not possible anymore, or by a more gradual linear decline approaching zero chance to achieve sDFR. METHODS: Patients with RA (symptom duration <2 years) were included from two randomised trials: BehandelStrategieën (BeSt), n=508 and Induction therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early arthritic Disease (IMPROVED), n=479. Cox-regression was performed to assess the shape of the association between symptom duration and sDFR (Disease Activity Score<1.6, no disease-modifying anti-rheumatic drugs for ≥1 year) for patients starting slow-acting monotherapy (IMPROVED, BeSt) or fast-acting combination therapy (BeSt). Likelihood ratio tests were used to compare the fit of linear and non-linear models in both databases separately. Predictions from the best fitting models were used to assess whether the absolute risk to achieve sDFR approaches zero with increasing symptom duration. RESULTS: In BeSt and IMPROVED, 54/226 and 110/421 patients achieved sDFR with fast-acting treatment, and 53/243 (BeSt) with slow-acting treatment. Non-linear models did not fit better than linear models (fast-acting treatment BeSt p=0.743, IMPROVED p=0.337; slow-acting treatment BeSt p=0.609). After slow-acting monotherapy, linear models declined steeper. None of the models approached zero chance to achieve sDFR over time. CONCLUSIONS: The chance to achieve sDFR decreased gradually over time, and decreased fastest in patients starting slow-acting monotherapy. In both treatment groups, we found no evidence for a WOO within 2 years symptom duration.

The BeSt story: on strategy trials in rheumatoid arthritis.

PURPOSE OF REVIEW: To give an overview of recent strategy trials for the treatment of rheumatoid arthritis. RECENT FINDINGS: Strategy studies showed a clear benefit of dynamic result-driven treatment towards tight control of disease activity compared with 'usual care' in rheumatoid arthritis patients. In addition, treatment given after short symptom duration gives better outcomes than later initiation of treatment. In many trials, combination therapies, especially combinations with prednisolone or biologicals, were superior to monotherapies. Moreover, combination therapies were more effective if given early in the disease as compared with a delayed introduction, giving support to the window of opportunity hypothesis. In the BeSt study, initial combination therapy could be successfully discontinued in half of the patients, emphasizing that 'initial' would mean 'temporary'. Less evidence is available about initial combination in comparison with combination therapy with a shorter delay. Larger tight-controlled, goal-steered, dynamic strategy trials comparing initial combination therapy with a short-delay combination therapy will help to translate the use of initial (temporary) combination therapy into normal daily practice. SUMMARY: Treatment strategy trials have demonstrated that in the majority of patients with rheumatoid arthritis, the following approach is the most beneficial: goal-steered, dynamic treatment towards tight control of disease activity, including early introduction of (an) effective disease-modifying antirheumatic drug(s) in combination with prednisone or antitumor necrosis factor, which includes tapering of the medication if remission or low disease activity is achieved.

Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial.

BACKGROUND: In patients with early rheumatoid arthritis, initial combination therapies provide earlier clinical improvement and less progression of joint damage after 1 year compared with initial monotherapies (as demonstrated in the BeSt study). OBJECTIVE: To evaluate whether the initial clinical and radiographic efficacy of combination therapies could be maintained during the second year of follow-up in patients with early rheumatoid arthritis. DESIGN: Randomized, controlled clinical trial with blinded assessors. SETTING: 18 peripheral and 2 university medical centers in the Netherlands. PATIENTS: 508 patients with early active rheumatoid arthritis. INTERVENTION: 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). Trimonthly treatment adjustments were made to achieve low disease activity. MEASUREMENTS: Primary end points were functional ability (Health Assessment Questionnaire) and Sharp-van der Heijde score for radiographic joint damage. RESULTS: Groups 3 and 4 had more rapid clinical improvement during the first year; all groups improved further to a mean functional ability score of 0.6 (overall, P = 0.257) and 42% were in remission (overall, P = 0.690) during the second year. Progression of joint damage remained better suppressed in groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 in groups 1, 2, 3, and 4, respectively [P = 0.004]). After 2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through 4, respectively, were receiving single-drug therapy for initial treatment. There were no significant differences in toxicity. LIMITATIONS: Patients and physicians were aware of the allocated group, and the assessors were blinded. CONCLUSIONS: Currently available antirheumatic drugs can be highly effective in patients with early rheumatoid arthritis in a setting of tight disease control. Initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements. In addition, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies.

Comparison between low disease activity or DAS remission as treatment target in patients with early active rheumatoid arthritis.

OBJECTIVES: To compare outcomes of targeted treatment aimed at either low disease activity or remission in patients with early active rheumatoid arthritis (RA). METHODS: Five-year outcomes were compared in 133 patients with early active RA (1987), starting with methotrexate, sulfasalazine and tapered high dose of prednisone (arm 3 of the BehandelStrategieën (Treatment Strategies for Rheumatoid Arthritis) (BeSt) study), targeted at Disease Activity Score (DAS) ≤2.4 (low disease activity), and 175 patients with early RA, starting methotrexate and tapered high dose of prednisone, targeted at DAS <1.6 (selected from IMPROVED study who would have fulfilled inclusion criteria of the BeSt study). Association of treatment target with outcomes DAS <1.6, Boolean remission at year 1 and drug-free DAS remission (DFR) at year 5 were analysed by logistic regression analysis. RESULTS: At baseline, DAS <1.6 steered patients had a milder disease than DAS ≤2.4 steered patients (mean DAS 4.1±SD 0.7vs4.4±0.9, p=0.012) and less radiological damage. DAS decrease, functional ability and radiological damage progression over time were similar in both patient groups. DAS ≤2.4 was achieved in similar percentages in both patient groups, but more DAS <1.6 steered patients achieved DAS <1.6 and DFR. DAS <1.6 steered treatment was associated with achieving DAS <1.6 (OR 3.04 (95% CI 1.64 to 5.62)) and Boolean remission (3.03 (1.45 to 6.33)) at year 1 and DFR at year 5 (3.77 (1.51 to 9.43)). CONCLUSIONS: In patients with early active RA who start with comparable disease-modifying antirheumatic drug+prednisone combination therapy, subsequent DAS <1.6 steered treatment is associated with similar clinical and radiological outcomes over time as DAS ≤2.4 steered treatment; however, in the DAS <1.6 steered group, more patients achieved remission and drug-free remission.

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.

Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study.

INTRODUCTION: Flares in patients with rheumatoid arthritis are suggested to sometimes spontaneously resolve. Targeted therapy could then entail possible overtreatment. We aimed to determine the flare prevalence in patients who are treated-to-target and to evaluate associations between flares and patient-reported outcomes and radiographic progression. METHODS: In the BeSt study, 508 patients were treated-to-target for 10 years. After initial treatment adjustments to achieve disease activity score ≤2.4, a flare was defined from the second year of follow-up onwards, according to three definitions. The first definition is a disease activity score >2.4 with an increase of ≥0.6 regardless of the previous disease activity score. The other definitions will be described in the manuscript. RESULTS: The flare prevalence was 4-11 % per visit; 67 % of the patients experienced ≥1 flare during 9 years of treatment (median 0 per patient per year). During a flare, functional ability decreased with a mean difference of 0.25 in health assessment questionnaire (p < 0.001), and the odds ratios (95 % confidence intervals) for an increase in patients' assessment of disease activity, pain and morning stiffness of ≥20 mm on a visual analogue scale were 8.5 (7.3-9.8), 8.4 (7.2-9.7) and 5.6 (4.8-6.6), respectively, compared to the absence of a flare. The odds ratio for radiographic progression was 1.7 (1.1-2.8) in a year with a flare compared to a year without a flare. The more flares a patient experienced, the higher the health assessment questionnaire at year 10 (p < 0.001) and the more radiographic progression from baseline to year 10 (p = 0.005). CONCLUSION: Flares were associated with concurrent increase in patient's assessment of disease activity, pain and morning stiffness, functional deterioration and development of radiographic progression with a dose-response-effect, both during the flare and long term. This suggests that intensifying treatment during a flare outweighs the risk of possible overtreatment. TRIAL REGISTRATION: Dutch trial registry NTR262 (7 September 2005) and NTR265 (8 September 2005).

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.

Early local swelling and tenderness are associated with large-joint damage after 8 years of treatment to target in patients with recent-onset rheumatoid arthritis.

OBJECTIVE: To assess whether early swelling and tenderness in large joints in patients with rheumatoid arthritis (RA) is predictive of later local damage and whether this leads to functional disability. METHODS: Two-year clinical and 8-year radiological followup data from the BeSt study (trial numbers NTR262 and NTR265), a randomized controlled treat-to-target trial, were used. The association between early local joint swelling and/or tenderness (at least once, or for ≥ 2 consecutive visits) and later large-joint damage (Larsen score ≥ 1) was assessed using generalized estimating equations. The association between large-joint damage and functional ability [by Health Assessment Questionnaire (HAQ)] was assessed using logistic and linear regression analysis. RESULTS: Clinical and 8-year radiological data were available for 290 patients. Concomitant local joint swelling and tenderness at least once in the first 2 years was independently associated with damage of the large joints (OR 2.5, 95% CI 1.7-3.6), as was swelling without tenderness (OR 2.0, 95% CI 1.1-3.6). Stronger effects were seen for persistent swelling and/or tenderness. Other independent predictors for joint damage were baseline erythrocyte sedimentation rate (OR 1.01, 95% CI 1.01-1.02) and the presence of rheumatoid factor and/or anticitrullinated protein antibodies (OR 2.5, 95% CI 1.5-4.1; and OR 2.2, 95% CI 1.3-3.8, respectively). Patients with large-joint damage had a higher HAQ score after 8 years than patients without (difference 0.15). CONCLUSION: Early local swelling and tenderness are independent predictors of later joint damage in these joints after 8 years of Disease Activity Score-guided treatment in patients with RA. This suggests that suppression of local inflammation could help prevent local damage and functional disability.

[The Dutch College of General Practitioners' practice guideline on arthritis]. / De standaard 'Artritis' van het Nederlands Huisartsen Genootschap.

The Dutch College of General Practitioners' new practice guideline on arthritis combines arthritis and gout. One of the important improvements in this guideline is that it recommends that patients be referred to the rheumatologist as soon as 4 weeks after being seen, or earlier, if rheumatoid arthritis is likely or suspected. Obviously, these early referrals are related to the large increase in effective treatment options in rheumatoid arthritis, particularly after early treatment (window of opportunity). The new guideline relating to gout advocates the use of oral prednisone as the second choice in patients without an adequate treatment response or who do not tolerate NSAIDs: colchicine and intra-articular injections may be attractive alternatives.