Marieke M. ter Wee

Three-Year Clinical Outcome Following Baseline Magnetic Resonance Imaging in Anti–Citrullinated Protein Antibody–Positive Arthralgia Patients: An Exploratory Study

Advanced imaging may be useful in the detection of subclinical synovitis (i.e., synovitis that cannot be detected by clinical examination) in anti–citrullinated protein antibody (ACPA)–positive arthralgia patients, and it may contribute to timely assessment of which individuals will eventually develop rheumatoid arthritis (RA) (1,2). Therefore, in this pilot study we investigated whether magnetic resonance imaging (MRI) can visualize subclinical inflammation in the hands and/or wrists of ACPA-positive arthralgia patients, and we determined the relationship between baseline MRI and development of clinical arthritis during 3 years of followup. MRI scans in healthy volunteers were included for comparison. The study was embedded in a cohort study that recruited seropositive arthralgia patients at the rheumatology outpatient clinics of the VU University Medical Center and Jan van Breemen Research Institute Reade (3). During 26 months, all arthralgia patients with positive ACPA status (3) (independent of IgM–rheumatoid factor status) were consecutively asked to participate in the present MRI substudy. Inclusion and exclusion criteria have been reported previously (2,3). Baseline MRI was performed on 28 included patients and 4 healthy volunteers without a history of joint disorders or clinical arthritis. Development of clinical arthritis was monitored according to the schedule of the cohort study during at least 3 consecutive years. MRI sequences (Siemens Sonata 1.5T MR scanner) were chosen according to Outcome Measures in Rheumatology (OMERACT) guidelines (4). STIR and 3-dimensional T1-weighted magnetization-prepared rapid gradient-echo images were obtained before and after intravenous gadolinium administration. Synovitis and bone marrow edema were scored by 2 independent observers (NA, CD) according to the OMERACT RA MRI Scoring (RAMRIS) system (4). The MRI protocol included scanning of all proximal interphalangeal (PIP) joints (PIP joints 1–5), metacarpophalangeal (MCP) joints (MCP joints 1–5), and wrist joints of both hands. At the patient level, MRI positivity was defined as the presence of synovitis and/or bone marrow edema in at least 1 joint/bone. Individual cumulative MRI scores (range 0–288) were calculated by summing synovitis and bone marrow edema scores of each hand/wrist joint. At baseline, the median age of the 28 patients was 44 years (interquartile range [IQR] 37–53 years). Twenty-three patients (82%) were women. The median duration of arthralgia was 15 months (IQR 11–35 months). The median age of the 4 healthy controls (1 man, 3 women) was 31 years (IQR 26–56 years). At baseline, MRI abnormalities were frequently found. In 26 of 28 patients (93%), MRI synovitis was present in 1 joint of both hands/wrists (Figure 1A). Ten of 26 patients had a synovitis score of 2 in 1 joint. A synovitis score of 3 was not observed. Bone marrow edema was present in only 3 of 28 patients (11%). MRIs in all healthy controls showed signs of mild synovitis (score of 1) in 1 joint (range 3–23). A score of 2 for synovitis was found in 1 joint of 1 healthy control. Bone marrow edema was not observed on MRIs in healthy controls. The presence of MRI abnormalities at baseline was not associated with dichotomous outcome of development of clinical arthritis (yes/no). Twelve of 28 patients (43%) developed clinical arthritis and were subsequently diagnosed as having RA according to the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria (5). In 10 of 12 patients, arthritis was observed in hand and/or wrist joints. At the patient level, 11 of 12 patients who developed clinical arthritis and all 16 patients who did not develop clinical arthritis had a positive baseline Figure 1. A, Baseline T1-weighted contrast-enhanced magnetic resonance imaging (MRI) scan of the hand/wrist joints of an anti– citrullinated protein antibody (ACPA)–positive arthralgia patient who developed arthritis in hand/wrist joints during 3-year followup. Arrows indicate MRI signs of synovitis (score of 2). B, Cumulative MRI scores (including score of 1 for synovitis and bone marrow edema) of patients with and those without development of arthritis during 3-year followup. Symbols represent individual patients; horizontal bars show the median. C, Survival curves for all included patients, comparing the group with an MRI synovitis score of 2 in at least 1 joint (solid line) and the group with an MRI synovitis score of 1 in at least 1 joint (dashed line). Patients with a synovitis score of 2 developed arthritis faster than those with a synovitis score of 1. Plus sign indicates a censored patient. D, Cumulative MRI scores (including score of 1 for synovitis and bone marrow edema) in relation to age, in individual ACPA-positive arthralgia patients and individual healthy controls.

Reduction of Inflammation Drives Lipid Changes in Ankylosing Spondylitis

Objective. To investigate the effects of changing inflammation on lipid levels in ankylosing spondylitis. Methods. In a cohort of 230 patients, lipid levels were measured at baseline and after 52 weeks of treatment with tumor necrosis factor-α–blocking agents (anti-TNF). Results. Total cholesterol (TC; +4.6%), low-density lipoprotein cholesterol (+4.3%), and high-density lipoprotein cholesterol (HDL-C; +3.7%) increased upon treatment. Changes were most evident in patients with substantial reduction in inflammatory levels (TC +8.2% vs +1.6% and HDL-C +8.3% vs +2.2% in patients with C-reactive protein ≥ 10 mg/l normalizing upon treatment vs CRP < 10 mg/l throughout treatment period). Conclusion. Anti-TNF therapy results in lipid changes mostly when inflammation is appreciably modified.

The short-term effects of two high-dose, step-down prednisolone regimens on body composition in early rheumatoid arthritis

OBJECTIVE To investigate the effect of two different high-dose, step-down prednisolone regimens on body composition in early RA patients after 26 weeks of treatment. METHODS Prednisolone-naive patients with recent-onset RA (n = 108) were randomized to either COBRA (prednisolone 60 mg/day, tapered to 7.5 mg/day in 6 weeks; MTX and SSZ) or COBRA-light therapy (prednisolone 30 mg/day, tapered to 7.5 mg/day in 8 weeks and MTX). Body composition was assessed at baseline (before or soon after start of treatment) and after 26 weeks with DXA, and recorded as total body mass (TBM), total fat mass (FM), total lean mass (LM) and trunk/peripheral fat ratio. Log-ratio analyses assessed the proportional distribution of TBM (between LM, FM and bone mass) and FM (between trunk, extremities and head). The subgroup of patients with a DXA before start of treatment (n = 38) was analysed separately. RESULTS In the subgroup of patients with a DXA before start of treatment, TBM increased by 1.6 kg (P < 0.001) and total FM by 1.3 kg (P < 0.001). The trunk/peripheral fat ratio and the proportional distribution of TBM and FM remained stable over time. There were no differences between the treatment groups. Similar results were obtained in the study population as a whole. CONCLUSION Both high-dose, step-down prednisolone regimens caused increases in TBM, mainly caused by an increase in FM, but we found no fat redistribution from peripheral to central tissues. This absence in fat redistribution contradicts the widely held assumption of rapid adverse effects of prednisolone on body composition in RA. TRIAL REGISTRATION ISRCTNregistry, http://www.isrctn.com, ISRCTN55552928.

Short and sustained periods of ACR/EULAR remission predict good functional outcome, but do not predict good radiographic outcome in early rheumatoid arthritis patients with low overall damage progression

To investigate whether remission at single and consecutive visits predicts good outcome in early rheumatoid arthritis (RA).

Content validity of the Dutch Rheumatoid Arthritis Impact of Disease (RAID) score: results of focus group discussions in established rheumatoid arthritis patients and comparison with the International Classification of Functioning, Disability and Health core set for rheumatoid arthritis

BackgroundThe Rheumatoid Arthritis Impact of Disease (RAID) score was developed as a European League Against Rheumatism initiative to obtain a patient reported outcome score for clinical trials in patients with rheumatoid arthritis (RA), based on patients’ perception of the impact of the disease on several domains of health. The objective of this study was to assess the content validity of this score in Dutch RA patients.MethodsDuring three focus group discussions (n = 23), patients with RA reflected on comprehensiveness of the RAID to measure impact of RA on their life, relevance of the RAID domains and formulation of questions. Also, the domains of the RAID score were compared to the comprehensive International Classification of Functioning, Disability and Health core set for RA.ResultsPatients confirmed that RA had impact on five domains already incorporated in the RAID score: emotional well-being, pain, performing daily activities, fatigue and coping. There was variation in interpretation of some of the items of the RAID score, suggesting problems in comprehension. Patients indicated that the domains work, relationships with others (such as family and friends) and spare time/hobbies were missed in the RAID and could be added to obtain a more ‘complete’ picture of the impact of the disease.ConclusionThe RAID score has fairly good content validity. If confirmed as important in other patient groups, items in the above mentioned areas should be considered in a future upgrade.

Effective Treatment for Rapid Improvement of Both Disease Activity and Self-Reported Physical Activity in Early Rheumatoid Arthritis

To investigate the longitudinal relationship between disease activity and self‐reported physical activity (PA) in patients with early rheumatoid arthritis during the first year of treatment with combination therapy.

Initial validation and results of the Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire: a EULAR project

Objectives To describe the development and assess the psychometric properties of the novel ‘Symptoms in Persons At Risk of Rheumatoid Arthritis’ (SPARRA) questionnaire in individuals at risk of rheumatoid arthritis (RA) and to quantify their symptoms. Methods The questionnaire items were derived from a qualitative study in patients with seropositive arthralgia. The questionnaire was administered to 219 individuals at risk of RA on the basis of symptoms or autoantibody positivity: 74% rheumatoid factor and/or anticitrullinated protein antibodies positive, 26% seronegative. Validity, reliability and responsiveness were assessed. Eighteen first degree relatives (FDR) of patients with RA were used for comparison. Results Face and content validity were high. The test-retest showed good agreement and reliability (1 week and 6 months). Overall, construct validity was low to moderate, with higher values for concurrent validity, suggesting that some questions reflect symptom content not captured with regular Visual Analogue Scale pain/well-being. Responsiveness was low (small subgroup). Finally, the burden of symptoms in both seronegative and seropositive at risk individuals was high, with pain, stiffness and fatigue being the most common ones with a major impact on daily functioning. The FDR cohort (mostly healthy individuals) showed a lower burden of symptoms; however, the distribution of symptoms was similar. Conclusions The SPARRA questionnaire has good psychometric properties and can add information to currently available clinical measures in individuals at risk of RA. The studied group had a high burden and impact of symptoms. Future studies should evaluate whether SPARRA data can improve the prediction of RA in at risk individuals.

Cost-utility of COBRA-light versus COBRA therapy in patients with early rheumatoid arthritis: the COBRA-light trial

Objective To evaluate if COmbinatie therapie Bij Reumatoïde Artritis (COBRA)-light therapy is cost-effective in treating patients with early rheumatoid arthritis (RA) compared with COBRA therapy. Methods This economic evaluation was performed next to the open-label, randomised non-inferiority COBRA-light trial in 164 patients with early RA. Non-responders to COBRA or COBRA-light received etanercept (50 mg/week) for 3–6 months. The societal perspective analysis took medical direct, non-medical direct and indirect costs into account. Costs were measured with patient cost diaries for the follow-up period of 52 weeks. Bootstrapping techniques estimated uncertainty around the cost-effectiveness ratios, presented in cost-effectiveness planes. Results 164 patients were randomised to either COBRA or COBRA-light strategy. At week 52, COBRA-light proved to be non-inferior to COBRA therapy on all clinical outcome measures. The results of the base-case cost-utility analysis (intention-to-treat analyses) revealed that COBRA-light strategy is more expensive (k€9.3 (SD 0.9) compared with COBRA (k€7.2 (SD 0.8)), but the difference in costs were not significant (k€2.0; 95% CI –0.3 to 4.4). Also, both strategies produced similar quality-adjusted life-years (QALYs). The sensitivity analyses showed robustness of these results. In a per-protocol sensitivity analysis, in which costs of etanercept were assumed to be provided as prescribed according to protocol, both arms had much higher costs: COBRA-light: k€11.5 (8.3) compared with k€8.5 (6.8) for COBRA, and the difference in costs was significant (k€2.9; 0.6 to 5.3). Conclusions In the base-case cost-utility analysis, the two strategies produced similar QALYs for similar costs. But it is anticipated that if protocol had been followed correctly, the COBRA-light strategy would have been more costly due to additional etanercept costs, for a limited health gain. Given the limited added benefit and high costs of starting etanercept in the presence of low disease activity in our trial, such a strategy needs better justification than is available now. Trial registration number 55552928, Results.

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.