Y P M Goekoop-Ruiterman

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.

Changes in hand and generalised bone mineral density in patients with recent-onset rheumatoid arthritis

Objectives: To evaluate changes in bone mineral density (BMD) in the hands, hip and spine after 1 and 2 years of follow-up, in relation to antirheumatic and antiresorptive therapies and disease and demographic variables in patients with recent-onset rheumatoid arthritis (RA). Methods: Changes in BMD measured in metacarpals 2–4 by digital x-ray radiogrammetry and in the hip and spine by dual energy x-ray absorptiometry were assessed at baseline and after 1 and 2 years of follow-up in 218 patients with recent-onset RA from the BeSt study, who received one of four treatment strategies: 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). Results: After 1 and 2 years, there was significant BMD loss in all locations, with significantly greater BMD loss in the hands than generalised BMD loss in the hip and spine. Initial combination therapy with prednisone or infliximab were associated with less hand BMD loss compared with initial monotherapy after 1 and 2 years (−0.9 and −1.6%, −0.6 and −1.4%, −1.7 and −3.3%, and −2.6 and −3.6% for group 4–1 after 1 and 2 years, overall p = 0.001 and p = 0.014, respectively). Progression in erosions was independently associated with increased BMD loss both in the hands and hip after 1 year. The use of bisphosphonates protected only against generalised BMD loss in the hip and spine. Conclusions: The association between joint damage progression and both hand and generalised BMD loss in RA suggests common pathways between these processes, with hand BMD loss occurring earlier in the disease course than generalised BMD loss.

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.

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.

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.

Changes in bone mineral density in patients with recent onset, active rheumatoid arthritis

Objectives: We examined the effects of four different treatment strategies on bone mineral density (BMD) in patients with recently diagnosed, active rheumatoid arthritis (RA) and the influence of disease-related and demographic factors on BMD loss after 1 year of follow-up in the BeSt trial. Methods: BMD measurements of the lumbar spine and total hip were performed in 342 patients with recent onset RA at baseline and after 1 year. Multivariable regression analyses were performed to determine independent associations between disease and demographic parameters and BMD loss after 1 year. Results: Median BMD loss after 1 year was 0.8% and 1.0% of baseline in the spine and the hip, respectively. No significant differences between the treatment groups, including corticosteroids and the anti-tumour necrosis factor-α infliximab, were observed with regard to BMD loss after 1 year of treatment. Joint damage at baseline and joint damage progression according to the Sharp–van der Heijde score were independently associated with more BMD loss after 1 year. The use of bisphosphonates independently protected against BMD loss. Conclusions: After 1 year of follow-up in the BeSt study, we did not find differences in BMD loss between the four treatment strategies, including high doses of corticosteroids and anti-tumour necrosis factor-α. Joint damage and joint damage progression are associated with high BMD loss, which emphasises that BMD loss and erosive RA have common pathways in their pathogenesis.

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

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

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 ≤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.

Patient-reported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis

OBJECTIVE To investigate the effectiveness of 4 different treatment strategies for recent-onset rheumatoid arthritis (RA) on 2-year patient-reported outcomes, including functioning and quality of life. METHODS A total of 508 patients with recent-onset RA were randomly assigned to 1) sequential monotherapy, 2) step-up combination therapy, both starting with methotrexate, 3) initial combination therapy, including a tapered high-dose prednisone, or 4) initial combination therapy with methotrexate and infliximab. Treatment was adjusted every 3 months if the Disease Activity Score (DAS) remained >2.4. The McMaster Toronto Arthritis Patient Preference Disability Questionnaire, the Short Form 36 (SF-36), and scores for pain, global health, and disease activity measured on a 100-mm visual analog scale (VAS) were compared between groups at baseline and every 3 months thereafter for 2 years. RESULTS After 2 years, all patient-reported outcomes had improved significantly from baseline, irrespective of the treatment strategy. SF-36 subscale scores approached population norms for 3 physical components, and achieved population norms (P > 0.05) for bodily pain and 4 mental components. Improvement in functioning, VAS scores, and physical items of the SF-36 occurred significantly earlier in patients treated with initial combination therapies (all comparisons after 3 months: overall P < 0.001; P < 0.05 for groups 1 and 2 versus groups 3 and 4). CONCLUSION All 4 DAS-driven treatment strategies resulted in substantial improvements in functional ability, quality of life, and self-assessed VAS scores after 2 years. Initial combination therapy led to significantly faster improvement in all patient-reported measures.