P J S M Kerstens

Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis

Objectives: To compare the occurrence of drug-free remission, functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis (RA). Methods: Patients with recent-onset, active RA (n  =  508) were randomly assigned to four different treatment strategies: (1) sequential monotherapy; (2) step-up combination therapy; (3) initial combination therapy with prednisone and (4) initial combination therapy with infliximab. Treatment was adjusted based on 3-monthly disease activity score (DAS) assessments, aiming at a DAS ⩽2.4. From the third year, patients with a sustained DAS <1.6 discontinued treatment. Results: In total, 43% of patients were in remission (DAS <1.6) at 4 years and 13% were in drug-free remission: 14%, 12%, 8% and 18% of patients in groups 1–4, respectively. The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission. Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment, without significant differences between the groups. Significant progression of joint damage was observed in 38% and 31% of patients in groups 3 and 4 versus 51% and 54% of patients in groups 1 and 2 (p<0.05, group 4 versus groups 1 and 2, group 3 versus group 2). Conclusions: In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy.

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.

Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study

Objectives To determine the relapse rate after discontinuing treatment in patients with rheumatoid arthritis (RA) in sustained clinical remission, to identify predictors of a relapse and to evaluate treatment response after restarting treatment. Methods Five-year data from the BeSt study were used, in which 508 patients with recent-onset RA were randomised into four dynamic treatment strategies, aiming at a disease activity score (DAS) ≤2.4. When DAS was <1.6 for ≥6 months, the last disease-modifying antirheumatic drug (DMARD) was tapered and discontinued. If DAS increased to ≥1.6, the last DMARD was immediately reintroduced. Results During a 5-year period, 115/508 patients (23%) achieved drug-free remission. Of these, 53 patients (46%) restarted treatment because the DAS was ≥1.6 after a median of 5 months, 59 patients (51%) remained in drug-free remission for a median duration of 23 months and 3 (3%) were lost to follow-up. In those who restarted treatment, mean (SD) DAS increased from 1.13 (0.73) at remission before tapering to 2.18 (0.65) at restart, reflecting an increase in all four components of DAS. Multivariable predictors for restarting treatment were anti-cyclic citrullinated peptide (anti-CCP), last DMARD sulfasalazine, low baseline Health Assessment Questionnaire score and high mean DAS until remission. Of the 53 patients who restarted treatment, 39 (74%) again achieved remission 3–6 months after the restart. The median (IQR) damage progression in those who restarted treatment during the year of DAS increase was 0 (0–1) Sharp-van der Heijde units. Conclusion During 5 years DAS steered treatment, nearly 25% of patients with RA achieved drug-free remission; 46% restarted DMARD monotherapy because of a relapse, the majority of whom again achieved clinical remission within 3–6 months without showing radiological progression during the relapse.

Clinical and radiological efficacy of initial vs delayed treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis

Objectives: To compare the clinical and radiological efficacy of initial vs delayed treatment with methotrexate (MTX) and infliximab (IFX) in patients with recent onset rheumatoid arthritis (RA). Methods: In a post hoc analysis of the BeSt study (for Behandel Stratagieen, Dutch for treatment strategies), 117 patients who started initial MTX+IFX were compared with 67 patients who started MTX+IFX treatment after failing (disease activity score (DAS)>2.4; median delay to IFX: 13 months) on ⩾3 traditional DMARDs. If the DAS remained >2.4, the protocol dictated IFX dose increases to 6, 7.5 and 10 mg/kg. In case of a DAS ⩽2.4 for ⩾6 months, IFX was tapered and finally stopped. We aimed to correct for allocation bias using propensity scores. Functional ability was measured by the Health Assessment Questionnaire (HAQ), radiological progression by Sharp/van der Heijde scoring (SHS). Results: Baseline differences between the initial and delayed groups were no longer significant after propensity score adjustment. At 3 years after baseline, patients treated with initial MTX+IFX experienced more improvement in HAQ over time and were less likely to have SHS progression than patients treated with delayed MTX+IFX (p = 0.034). At 2 years after IFX initiation, more patients in the initial group compared with the delayed group could discontinue IFX after a good response (56% vs 29%, p = 0.008). Conclusions: The results of this post hoc analysis suggest that using MTX+IFX as initial treatment for patients with recent onset RA is more effective than reserving MTX+IFX for patients who failed on traditional DMARDs, with more HAQ improvement over time, more IFX discontinuation and less progression of joint damage.

DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis.

Objectives: To compare the efficacy of Disease Activity Score (DAS)-driven therapy and routine care in patients with recent-onset rheumatoid arthritis. Methods: Patients with recent-onset rheumatoid arthritis receiving traditional antirheumatic therapy from either the BeSt study, a randomised controlled trial comparing different treatment strategies (group A), or two Early Arthritis Clinics (group B) were included. In group A, systematic DAS-driven treatment adjustments aimed to achieve low disease activity (DAS ⩽2.4). In group B, treatment was left to the discretion of the treating doctor. Functional ability (Health Assessment Questionnaire (HAQ)), Disease Activity Score in 28 joints (DAS28) and Sharp/van der Heijde radiographic score (SHS) were evaluated. Results: At baseline, patients in group A (n = 234) and group B (n = 201) had comparable demographic characteristics and a mean HAQ of 1.4. Group A had a longer median disease duration than group B (0.5 vs 0.4 years, p = 0.016), a higher mean DAS28 (6.1 vs 5.7, p<0.001), more rheumatoid factor-positive patients (66% vs 42%, p<0.001) and more patients with erosions (71% vs 53%, p<0.001). After 1 year, the HAQ improvement was 0.7 vs 0.5 (p = 0.029), and the percentage in remission (DAS28 <2.6) 31% vs 18% (p<0.005) in groups A and B, respectively. In group A, the median SHS progression was 2.0 (expected progression 7.0), in group B, the SHS progression was 1.0 (expected progression 4.4). Conclusions: In patients with recent-onset rheumatoid arthritis receiving traditional treatment, systematic DAS-driven therapy results in significantly better clinical improvement and possibly improves the suppression of joint damage progression.

Progression of joint damage in early rheumatoid arthritis: Association with HLA–DRB1, rheumatoid factor, and anti–citrullinated protein antibodies in relation to different treatment strategies†

OBJECTIVE To determine the association of HLA-DRB1, rheumatoid factor (RF), and anti-citrullinated protein antibody (ACPA) status with progression of joint damage in early rheumatoid arthritis (RA) treated according to different treatment strategies. METHODS The present study was conducted using data from the BeSt study (Behandelstrategieën voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score [DAS] of < or =2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab (group 4), in 508 patients with early RA. Multivariate logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score over 2 years beyond the smallest detectable change [4.6]) according to the presence or absence of the shared epitope (SE), DERAA, RF, and ACPA, with correction for other baseline characteristics. RESULTS Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1, 2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0. DERAA carriership did not protect against progressive disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3, and 4, respectively). RF positivity and ACPA positivity predicted progressive disease in group 1 (odds ratio 4.7 [95% confidence interval 1.5-14.5] for RF and 12.6 [95% confidence interval 3.0-51.9] for ACPA), but not in groups 2-4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5-4.9], 1.0 [0.3-3.3], and 1.4 [0.4-4.8] in group 2, group 3, and group 4, respectively; for ACPA, odds ratio [95% confidence interval] 3.4 [0.8-14.2], 1.7 [0.5-5.4], and 1.8 [0.5-6.8] in group 2, group 3, and group 4). CONCLUSION In patients with early RA treated with the goal of tight control of the DAS, no significant association between HLA-DRB1 status and radiographic progression was found. RF and ACPA were predictive of progressive disease only in patients treated with sequential monotherapy. These observations suggest that effective treatment can prevent radiographic progression, even in patients with risk factors for severe damage.

Tight control and intensified COBRA combination treatment in early rheumatoid arthritis: 90% remission in a pilot trial

OBJECTIVE To investigate the efficacy and feasibility of an intensive combination treatment in early rheumatoid arthritis (RA) combined with monitoring both disease activity and cartilage degradation. METHODS In a pilot trial, 21 patients with active early RA (mean DAS28 5.3; mean disease duration 3 months) were treated with COBRA treatment comprising sulfasalazine, methotrexate and high-dose step-down prednisolone, intensified by adding hydroxychloroquine and continued low-dose prednisolone. In addition, based on measurements of disease activity or a marker of cartilage degradation (CTX-II), treatment adjustments were possible with methotrexate intensification after 8 or 21 weeks; and with infliximab after 21 weeks. RESULTS Nineteen of 21 patients (90%) were in remission (DAS28 <2.6) after 40 weeks (8 weeks, 57%; 21 weeks, 76%). American College of Rheumatology (ACR) criteria, ACR20, 50, 70 and 90 improvements rates were 100%, 95%, 71% and 43% respectively. CTX-II excretion decreased by mean (SD) 347(292) ng/mmol creatinine, but only 50% of patients reduced their CTX-II excretion below the cut-off point. The two monitoring groups showed no significant difference in remission according to DAS score or CTX-II excretion, despite a trend towards more intensive treatment in the CTX-II group. Treatment intensification was feasible according to protocol. CONCLUSIONS This small pilot study suggests that intensified and tightly controlled COBRA treatment is uniquely effective in early RA. TRIAL REGISTRATION NUMBER ISRCTN96372677.

Cost-Utility Analysis of Treatment Strategies in Patients With Recent-Onset Rheumatoid Arthritis

OBJECTIVE To evaluate societal costs and quality-adjusted life years (QALYs) of treatment strategies for patients with recent-onset active rheumatoid arthritis (RA). METHODS Patients (n = 508) were randomly allocated to 1 of 4 treatment strategy groups: sequential monotherapy, step-up combination therapy, initial combination therapy with prednisone, or initial combination therapy with infliximab. For 2 years, patients reported cost and utility measures. RESULTS Average QALYs (ideally 2.00) for groups 1-4 were 1.29, 1.31, 1.32, and 1.41, respectively, for the British EuroQol (P <or= 0.05 for group 4 versus groups 1-3); 1.41, 1.43, 1.44, and 1.52, respectively, for the Dutch EuroQol (P <or= 0.05 for group 4 versus groups 1-3); and 1.38, 1.38, 1.39, and 1.44, respectively, for the Short Form 6D (P <or= 0.05 for group 4 versus groups 1-3). The Time Trade-Off showed no significant differences. In the primary analysis, using the friction cost method to value productivity, the cost-utility ratio for group 4 against the next best alternative was estimated at euro 130,000 (95% confidence interval euro 27,000, euro 3,000,000) per QALY. Using the human capital method, the value of sustained productivity in group 4 largely compensated for the extra medication costs. CONCLUSION Initial combination therapy with infliximab for patients with recent-onset active RA resulted in significantly better quality of life than other strategies. Using the friction cost method, costs to achieve this improvement are generally considered too high, and initial combination therapy with prednisone should be preferred. However, depending on the extent to which productivity is valued, infliximab costs could be largely compensated for by savings on productivity. Since patterns of infliximab use had not yet stabilized after 2 years, longer followup may change the economic conclusions.

Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent-onset rheumatoid arthritis treated according to the Disease Activity Score

Objectives: To determine the efficacy of subsequent disease modifying antirheumatic drug (DMARD) therapies after initial methotrexate (MTX) failure in patients with recent onset rheumatoid arthritis (RA), treated according to the DAS for 2 years. Methods: In groups 1 and 2 of the BeSt study, 244 RA patients were initially treated with MTX 15–25 mg/week. Patients who discontinued MTX because of insufficient clinical response (disease activity score, DAS >2.4) or toxicity were classified as “MTX failures.” In group 1, these patients switched to sulfasalazine (SSA), then leflunomide and finally to MTX + infliximab (IFX). In group 2, “MTX failures” added SSA to MTX, then hydroxychloroquine (HCQ), then prednisone, and eventually switched to MTX + IFX. “MTX successes” were patients who achieved a DAS ⩽2.4 after 2 years while still on MTX monotherapy. Total Sharp/van der Heijde score (TSS) progression from 0–2 years was assessed in “MTX failures” versus “MTX successes.” Results: After 2 years, 162/244 patients (66%) had discontinued MTX because of insufficient response or toxicity. Of these, 78% also failed on SSA (adding or switching), 87% subsequently failed on leflunomide (in group 1), and 64% on MTX + SSA + HCQ (in group 2). 34 of 48 patients (71%) in groups 1 and 2 were successfully treated with MTX + IFX. After 2 years, regardless of the “success” on subsequent DMARDs, “ MTX failures” had a median TSS progression of 3 units (mean 9) versus 1 unit (mean 3) in “MTX successes” (p = 0.007). Conclusion: After failure on initial MTX, treatment with subsequent conventional DMARDs is unlikely to result in a DAS ⩽2.4 and allows progression of joint damage.

Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis

Objective To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression. Methods Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS-CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA). In addition, the recent ACR/EULAR clinical trial and practice remission was assessed 3-monthly with 28 and 68/66 joint counts. For each index, Generalized Estimating Equations analyses were performed to relate disease activity levels and the absence/presence of remission to 3-monthly assessments of physical functioning and annual radiological progression. Results From the composite indices, CDAI and SDAI were the most stringent definitions of remission and classified more patients as LDA. DAS28 and DAS28-CRP had the highest proportions of remission and MDA and a smaller proportion of LDA. ACR/EULAR remission percentages were comparable to CDAI/SDAI: remission percentages. The variant including CRP and 68/66 joint counts was the most stringent. For all indices, higher levels of disease activity were associated with decreased physical functioning and more radiological damage progression. Despite differences in classification between the indices, no major differences in relation to the two outcomes were observed. Conclusion The associations of nine composite indices and ACR/EULAR remission criteria with functional status and joint damage progression showed high accordance, whereas the proportions of patients classified in the disease activity levels differed.