André J. Peeters

Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis

BACKGROUND The value of intensive combination therapy in early rheumatoid arthritis is unproven. In a multicentre, double-blind, randomised trial (COBRA), we compared the combination of sulphasalazine (2 g/day), methotrexate (7.5 mg/week), and prednisolone (initially 60 mg/day, tapered in 6 weekly steps to 7.5 mg/day) with sulphasalazine alone. METHODS 155 patients with early rheumatoid arthritis (median duration 4 months) were randomly assigned combined treatment (76) or sulphasalazine alone (79). Prednisolone and methotrexate were tapered and stopped after 28 and 40 weeks, respectively. The main outcomes were the pooled index (a weighted change score of five disease activity measures) and the Sharp/Van der Heijde radiographic damage score in hands and feet. Independent health-care professionals assessed the main outcomes without knowledge of treatment allocation. FINDINGS At week 28, the mean pooled index was 1.4 (95% CI 1.2-1.6) in the combined treatment group and 0.8 (0.6-1.0) in the sulphasalazine group (p < 0.0001). At this time, 55 (72%) and 39 (49%) patients, respectively, were improved according to American College of Rheumatology criteria. The clinical difference between the groups decreased and was no longer significant after prednisolone was stopped, and there were no further changes after methotrexate was stopped. At 28 weeks, the radiographic damage score had increased by a median of 1 (range 0-28) in the combined-therapy group and 4 (0-44) in the sulphasalazine group (p < 0.0001). The increases at week 56 (2 [0-43] vs 6 [0-54], p = 0.004), and at week 80 (4 [0-80] vs 12 [0-72], p = 0.01) were also significant. Further analysis suggests that combined therapy immediately suppressed damage progression, whereas sulphasalazine did so less effectively and with a lag of 6 to 12 months. There were fewer withdrawals in the combined therapy than the sulphasalazine group (6 [8%] vs 23 [29%]), and they occurred later. INTERPRETATION This combined-therapy regimen offers additional disease control over and above that of sulphasalazine alone that persists for up to a year after corticosteroids are stopped. Although confirmatory studies and long-term follow-up are needed, this approach may prove useful in the treatment of early rheumatoid arthritis.

Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis.

Background COBRA (for ‘COmbinatie therapie Bij Rheumatoide Artritis’) combination therapy is effective for the treatment of rheumatoid arthritis (RA), but long-term safety is unknown. This study evaluates survival, comorbidities and joint damage in the original COBRA trial cohort. Methods In the COBRA trial, 155 patients with early RA were treated with sulfasalazine (SSZ) monotherapy (SSZ group) or a combination of step-down prednisolone, methotrexate (MTX) and SSZ (COBRA group). The current 11-year follow-up study of the COBRA trial invited all original patients and performed protocollised scrutiny of clinical records, questionnaires, physical examination, laboratory and imaging tests. Results In all, 152 out of 155 patients yielded at least partial data. After a mean of 11 years follow-up, 18 (12%) patients had died, 6 COBRA patients and 12 SSZ patients, HR 0.57 (95% CI 0.21 to 1.52). Treatment for hypertension was significantly more prevalent in the COBRA group (p=0.02) with similar trends for diabetes and cataract. Conversely, hypercholesterolaemia, cancer and infection showed a trend in favour of COBRA. Other comorbidities such as cardiovascular disease and fractures appeared in similar frequency. Radiographic findings suggest as a minimum sustained benefit for COBRA therapy, that is, difference in joint damage but similar subsequent progression rates after 5 years. Imputation to compensate for selective dropout suggests increasing benefit for COBRA, that is, difference in yearly progression rates similar to that seen in the first 5 years of follow-up. Conclusions After 11 years, initial COBRA combination therapy resulted in numerically lower mortality and similar prevalence of comorbidity compared with initial SSZ monotherapy. In addition, lower progression of joint damage suggests long-term disease modification.

Remission induction therapy with methotrexate and prednisone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVED study)

Aim Classifying more patients as rheumatoid arthritis (RA) (2010 American College of Rheumatology/European League Against Rheumatism criteria for RA) may improve treatment outcomes but may cause overtreatment in daily practice. The authors determined the efficacy of initial methotrexate (MTX) plus prednisone treatment in patients with 1987 or 2010 classified RA and undifferentiated arthritis (UA). Method 610 recent onset RA or UA patients started with MTX 25 mg/week and prednisone 60 mg/day tapered to 7.5 mg/day in 7 weeks. Percentage remissions after 4 months were compared between RA (1987 or 2010 criteria) and UA. Predictors for remission were identified. Results With the 2010 criteria, 19% more patients were classified as RA than with the 1987 criteria, but similar remission rates were achieved: 291/479 (61%) 2010 classified RA and 211/264 (58%) 1987 classified RA patients (p=0.52), and 79/122 (65%) UA patients (p=0.46). Anticitrullinated protein antibodies (ACPA) positive RA patients achieved more remission (66%) than ACPA negative RA patients (51%, p=0.001), but also had a lower mean baseline Disease Activity Score (DAS) (3.2 vs 3.6, p<0.001). Independent predictors for remission were male sex, low joint counts, DAS and Health Assessment Questionnaire, low body mass index and ACPA positivity. Conclusion Initial treatment with MTX and a tapered high dose of prednisone results in similarly high remission percentages after 4 months (about 60%) in RA patients, regardless of fulfilling the 1987 or 2010 criteria, and in UA patients. Independent predictors indicate that initiating treatment while disease activity is relatively low results in more remission.

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.

Effect of self-efficacy and physical activity goal achievement on arthritis pain and quality of life in patients with rheumatoid arthritis

To examine physical activity and achievement of physical activity goals in relation to self‐reported pain and quality of life among patients with rheumatoid arthritis (RA).

Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis

Objectives: Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. Methods: BMD of the total hip and the lumbar spine was measured using dual-energy x ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score ⩽−2.5 SD and reduced BMD as Z score ⩽−1 SD. Multivariate logistic regression analyses were performed to detect associations of osteoporosis and reduced BMD with disease activity, functional disability, joint damage (Sharp–van der Heijde score) and demographic factors. Results: Osteoporosis and reduced BMD were found in the spine and/or the hip in 11% and 25%, respectively, of the patients. Longer symptom duration and presence of rheumatoid factor (RF) were the only RA-specific markers for osteoporosis and reduced BMD. Further, postmenopausal status in women, a low body mass index, familial osteoporosis, and, remarkably, male gender, were independently associated with osteoporosis and reduced BMD. Conclusion: In patients with recently diagnosed active RA who had never been treated with DMARDs or corticosteroids, BMD seems to be well-preserved and predominantly related to demographic factors. Longer symptom duration and a positive RF, but not higher disease activity or more joint damage, were related to osteoporosis and reduced BMD.

Heart conduction disturbance: an HLA-B27 associated disease.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.

Probability of continued low disease activity in patients with recent onset rheumatoid arthritis treated according to the disease activity score

Objective: To assess the duration and the probability of maintaining low disease activity once a low disease activity score (DAS) is achieved in recent onset rheumatoid arthritis (RA) patients. Methods: The BeSt study is a randomised trial comparing four different treatment strategies in patients with recent onset, active RA. Treatment adjustments were mandatory as long as the DAS was >2.4. If the DAS was ⩽2.4, treatment was continued and after 6 months, tapered to maintenance dose. We analysed thrice-monthly DAS calculations in order to assess the duration and the probability of maintaining a DAS ⩽2.4. Results: Patients treated with initial combination therapy achieved a DAS ⩽2.4 significantly earlier than patients treated with initial monotherapy. Independent of treatment strategy and without treatment adjustments, the probability of a next DAS ⩽2.4 3 months after a first DAS ⩽2.4 was 74%. The probability increased to 85% after two preceding DAS ⩽2.4 and to 88–97% after one to two preceding DAS<1.6. The median duration of a DAS ⩽2.4 was 12 months. Conclusion: Once recent onset RA patients achieve a low DAS, the probability of maintaining a low DAS without treatment adjustments is high. This may have implications for the monitoring of patients in daily practice.

Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study)

Objective To assess long-term disease outcome of undifferentiated arthritis (UA) after initial treatment with methotrexate (MTX) or placebo. Methods 110 patients with UA were randomised to receive MTX (n=55) or placebo (n=55) for 1 year. After 5 years the outcomes for diagnosis (rheumatoid arthritis, 1987 criteria (RA (1987)), UA or UA in remission) and radiographic progression were compared between treatment arms and anti-citrullinated protein antibody (ACPA)-positive and -negative patients. Outcomes were recalculated for patients who, with hindsight, might have been classified at baseline as having RA according to the 2010 criteria (RA (2010)). Results 25 patients in the MTX group and 29 in the placebo group progressed to RA (1987) (p=0.45). MTX delayed progression from UA to RA (1987) but only in ACPA-positive patients. Drug-free remission was achieved in 35 patients, 20 of whom were initially treated with MTX, and 32 were ACPA-negative. ACPA-positive patients had more radiographic progression, regardless of treatment. Forty-three patients (39%) could be reclassified as having had RA (2010) at baseline, 6/24 (25%) of whom achieved remission after placebo treatment. Conclusions After 5 years there is no lasting benefit of a 1 year initial course of MTX for patients with undifferentiated arthritis, compared with initial placebo. Progression to classifiable RA was not suppressed, drug-free remission not induced and the progression of radiological damage was similar in both groups. Reclassification at baseline with the 2010 criteria showed that 25% of patients with RA (2010) achieved spontaneous drug-free remission.

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.