Annelies Boonen

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.

Ankylosing spondylitis: an overview

Ankylosing spondylitis (AS) is a complex, potentially debilitating disease that is insidious in onset, progressing to radiological sacroiliitis over several years. Patients with symptomatic AS lose productivity owing to work disability and unemployment, have a substantial use of healthcare resources, and reduced quality of life. The pathogenesis of AS is poorly understood. However, immune mediated mechanisms involving human leucocyte antigen (HLA)-B27, inflammatory cellular infiltrates, cytokines (for example, tumour necrosis factor α and interleukin 10), and genetic and environmental factors are thought to have key roles. The detection of sacroiliitis by radiography, magnetic resonance imaging, or computed tomography in the presence of clinical manifestations is diagnostic for AS, although the presence of inflammatory back pain plus at least two other typical features of spondyloarthropathy (for example, enthesitis and uveitis) is highly predictive of early AS. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently first line drug treatment. However, NSAID treatment has only a symptomatic effect and probably does not alter the disease course. For symptoms refractory to NSAIDs, second line treatments, including corticosteroids and various disease modifying antirheumatic drugs, are employed but are of limited benefit. Emerging biological therapies target the inflammatory processes underlying AS, and thus, may favourably alter the disease process, in addition to providing symptom relief.

Inequities in access to biologic and synthetic DMARDs across 46 European countries

Objectives We investigated access to biologic and synthetic disease modifying drugs (bDMARDs and sDMARDs) in patients with rheumatoid arthritis (RA) across Europe. Methods A cross-sectional study at national level was performed in 49 European countries. A questionnaire was sent to one expert, addressing the number of approved and reimbursed bDMARDs and sDMARDs, prices and co-payments, as well as acceptability of bDMARDs (barriers). Data on socio-economic welfare (gross domestic product per capita (GDP), health expenditure, income) were retrieved from web-based sources. Data on health status of RA patients were retrieved from an observational study. Dimensions of access (availability, affordability and acceptability) were correlated with the countrys welfare and RA health status. Results In total, 46 countries (94%) participated. Six countries did not reimburse any of the five sDMARDs surveyed, and in ten countries no bDMARDs were reimbursed. While the price of annual treatment with an average sDMARD was never higher than GPD, the price of one year treatment with a bDMARD exceeded GPD in 26 countries. Perceived barriers for access to bDMARDs were mainly found among financial and administrative restrictions. All dimensions of access were positively correlated with the countrys economic welfare (coefficients 0.69 to 0.86 for overall access scores). Conclusions Patients with RA in lower income European countries have less access to bDMARDs and sDMARDs, with particularly striking unaffordability of bDMARDs in some of these countries. When accepting that sDMARDs and bDMARDs are equally needed across countries to treat RA, our data point to inequities in access to pharmacological treatment for RA in Europe.

No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study

Aim To monitor joint inflammation and destruction in rheumatoid arthritis (RA) patients receiving adalimumab/methotrexate combination therapy using MRI and ultrasonography. To assess the predictive value of MRI and ultrasonography for erosive progression on CT and compare MRI/ultrasonography/radiography for erosion detection/monitoring. Methods Fifty-two erosive biological-naive RA patients were followed with repeated MRI/ultrasonography/radiography (0/6/12 months) and clinical/biochemical assessments during adalimumab/methotrexate combination therapy. Results No overall erosion progression or repair was observed at 6 or 12 months (Wilcoxon; p>0.05), but erosion progressors and regressors were observed using the smallest detectable change cut-off. Scores of MRI synovitis, grey-scale synovitis (GSS) and power Doppler ultrasonography decreased after 6 and 12 months (p<0.05), as did DAS28, HAQ and tender and swollen joint counts (p<0.001). Patients with progression on CT had higher baseline MRI bone oedema scores. The RR for CT progression in bones with versus without baseline MRI bone oedema was 3.8 (95% CI 1.5 to 9.3) and time-integrated MRI bone oedema, power Doppler and GSS scores were higher in bones/joints with CT progression (Mann–Whitney; p<0.05). With CT as the reference method, sensitivities/specificities for erosion in metacarpophalangeal joints were 68%/92%, 44%/95% and 26%/98% for MRI, ultrasonography and radiography, respectively. Median intraobserver correlation coefficient was 0.95 (range 0.44–0.99). Conclusion During adalimumab/methotrexate combination therapy, no overall erosive progression or repair occurred, whereas repair of individual erosions was documented on MRI, and MRI and ultrasonography synovitis decreased. Inflammation on MRI and ultrasonography, especially MRI bone oedema, was predictive for erosive progression on CT, at bone/joint level and MRI bone oedema also at patient level.

The impact of inflammatory bowel disease on labor force participation: Results of a population sampled case-control study

IntroductionInflammatory bowel diseases are chronic conditions that might cause a severe impact on social life. The aim of the study was to assess employment, chronic work disability, and sick leave in patients with inflammatory bowel disease. MethodsA postal questionnaire was sent to 984 patients with inflammatory bowel disease and 1504 controls. Age- and gender-adjusted employment and chronic work disability ratios and rates were calculated using indirect standardization. In subjects in paid employment, proportions of those having an episode of sick leave and lost workdays were analyzed. Logistic regression was used to assess the contribution of age, gender, education, and course of disease. ResultsThe results of 680 (69%) patients and 715 (48%) controls could be analyzed. For the entire group of patients, employment was 6.5% lower, compared with controls (95% CI: 4.0–9.0). Chronic work disability was 17.1% higher than expected (95% CI: 15.1–19.1). In those in paid employment, 62% of patients compared with 53% of controls had experienced one or more episodes of sick leave during the past year (p = 0.002). This resulted in 19.2 versus 11.8 days of sick leave per subject per year for patients and controls respectively (p = 0.002). Relative to controls, the risk of chronic work disability was more increased in younger (p = 0.02) and higher educated (p = 0.02) patients. Course of disease contributed to chronic work disability and sick leave. ConclusionIBD has a significant impact on labor force participation that is higher in CD compared with UC and highest in younger and more highly educated patients.

The burden of illness of rheumatoid arthritis

It is necessary to understand the full burden of illness of a disease before the value of interventions can be assessed. Rheumatoid arthritis (RA) has an impact on a variety of stakeholders, including patients, healthcare systems, and society as a whole. This overview discusses the societal and patient perspectives, distinguishing several domains of impact. Epidemiology is important from a societal perspective, as it affects the total impact on health and costs related to RA and influences healthcare organization priorities. Co-morbidities, such as cardiovascular disease, are important factors contributing to the impact of RA. The impact on health is, naturally, relevant to both patients and society as a whole, and is summarized by health-related quality-of-life measures from the point of view of the patient and by utilities from the societal perspective. Similarly, work participation is important for both patients and society. Withdrawal from the labor force and short- and long-term sick leave are extensively studied in RA and lead to substantial productivity costs at the societal level and to income loss for patients. In addition, the recent concept of presenteeism, which reflects the problems that patients experience while at work, is considered. Finally, the costs of illness of RA are summarized. Societal costs are mainly driven by the costs of drug treatment and inpatient care, including surgery. Patient and family costs are mainly driven by the need for formal and informal care. Overall, RA has a significant impact on the health of and costs to patients and society, suggesting that effective interventions to reduce the impact are of value.

The epidemiology of ankylosing spondylitis and the commencement of anti-TNF therapy in daily rheumatology practice

Objectives: This study aimed to describe the epidemiology of ankylosing spondylitis (AS) in rheumatology practice at the beginning of the anti-TNF (tumour necrosis factor) era, and to evaluate the initiation of anti-TNF therapy in a clinical setting where prescription is regulated by the authority’s imposed reimbursement criteria. Methods: Between February 2004 and February 2005, all Belgian rheumatologists in academic and non-academic outpatient settings were invited to register all AS patients who visited their practice. A random sample of these patients was further examined by an in-depth clinical profile. In a follow-up investigation, we recorded whether patients initiated anti-TNF therapy and compared this to their eligibility at baseline evaluation. Results: 89 rheumatologists participated and registered 2141 patients; 1023 patients were clinically evaluated. These 847 fulfilled the New York modified criteria for definite AS and 176 for probable AS. The profile of AS in rheumatology practice is characterised by longstanding and active disease with a high frequency of extra-articular manifestations and metrological and functional impairment. At a median of 2 months after the clinical evaluation, anti-TNF therapy was initiated in 263 of 603 (44%) evaluable patients with definite AS and in 22 of 138 (16%) evaluable patients with probable AS (total 38%). More than 85% of the patients who started anti-TNF therapy had an increased Bath Ankylosing Spondylitis Disease Activity Index despite previous NSAID (non-steroidal anti-inflammatory drug) use. Conclusions: Of a representative cohort of 1023 Belgian AS patients seen in daily rheumatology practice, about 40% commenced anti-TNF therapy. Decision factors to start anti-TNF therapy may include disease activity and severity.

Identifying core domains to assess flare in rheumatoid arthritis: an OMERACT international patient and provider combined Delphi consensus

Objective For rheumatoid arthritis (RA), there is no consensus on how to define and assess flare. Variability in flare definitions impairs understanding of findings across studies and limits ability to pool results. The OMERACT RA Flare Group sought to identify domains to define RA flares from patient and healthcare professional (HCP) perspectives. Methods Flare was described as a worsening of disease activity of sufficient intensity and duration to consider a change in therapy. International patients and HCPs participated in separate and combined rounds of Delphi exercises to rate candidate flare domains previously generated in patient focus groups. Core domains were defined as those with ≥70% ratings of being ‘essential’ according to the third/final Delphi exercise. Results The final Delphi included 125 RA patients from 10 countries and 108 HCPs from 23 countries who rated 14 domains. Patients had a mean (±SD) age of 56±12 years and disease duration of 18±12 years. HCPs included physicians from clinical practice/research and industry, allied health providers and researchers with 17±11 years experience. Core domains comprised: pain (93%), function (89%), swollen joints (84%), tender joints (81%), participation (81%), stiffness (79%), patient global assessment (76%) and self-management (75%). Fatigue (68%), which did not reach group consensus, will receive additional consideration. Conclusions As part of the process to develop a measure for RA flare, patients and HCPs agreed on eight core domains. Next steps include identifying items to assess domains and conducting studies to validate and refine a new measure.

Tumor Necrosis Factor α Inhibition in Radiographic and Nonradiographic Axial Spondyloarthritis: Results From a Large Observational Cohort

OBJECTIVE To evaluate the baseline characteristics of patients with radiographic axial spondyloarthritis (SpA; ankylosing spondylitis [AS]) and patients with nonradiographic axial SpA, to investigate determinants of anti-tumor necrosis factor (anti-TNF) agent prescription on the background of a nonrestrictive reimbursement policy, and to assess the response to TNF inhibition. METHODS We compared the characteristics of radiographic axial SpA and nonradiographic axial SpA in 1,070 patients from the Swiss Clinical Quality Management (SCQM) Cohort who fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axial SpA. By taking advantage of the situation that patients who are eligible for anti-TNF treatment are preferentially enrolled in the SCQM Cohort for patients with AS/axial SpA, we explored parameters leading to the initiation of anti-TNF treatment in single and multiple regression models and assessed treatment responses. RESULTS We confirmed a similar burden of disease (as determined by self-reported disease activity, impaired function, and quality of life) in patients with nonradiographic axial SpA (n = 232) and those with radiographic axial SpA (n = 838). Patients with radiographic axial SpA had higher median levels of acute-phase reactants and higher median AS Disease Activity Scores (ASDAS; 3.2 versus 3.0). Anti-TNF treatment was initiated in 363 patients with radiographic axial SpA and 102 patients with nonradiographic axial SpA, preferentially in those with sacroiliitis on magnetic resonance imaging, peripheral arthritis, a higher C-reactive protein (CRP) level, a higher ASDAS, and a higher Bath Ankylosing Spondylitis Disease Activity Index level. The ASAS criteria for 40% improvement responses at 1 year were higher in patients with radiographic axial SpA compared with those with nonradiographic axial SpA (48.1% versus 29.6%; odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.12-4.46, P = 0.02). The difference was smaller in the subgroups of patients with elevated baseline CRP levels (51.6% in patients with radiographic axial SpA versus 38.5% in those with nonradiographic axial SpA; OR 1.7, 95% CI 0.68-4.48, P = 0.29). CONCLUSION The indications for treatment with anti-TNF agents were comparable for patients with radiographic axial SpA and those with nonradiographic axial SpA. With the exception of patients with elevated CRP levels at baseline, higher rates of response to TNF inhibition were achieved in the group of patients with radiographic axial SpA than in the group with nonradiographic axial SpA.

Measuring Worker Productivity: Frameworks and Measures

Worker productivity is a combination of time off work (absenteeism) due to an illness and time at work but with reduced levels of productivity while at work (also known as presenteeism). Both can be gathered with a focus on application as a cost indicator and/or as an outcome state for intervention studies. We review the OMERACT worker productivity groups’ progress in evaluating measures of worker productivity for use in arthritis using the OMERACT filter. Attendees at OMERACT 9 strongly endorsed the importance of work as an outcome in arthritis. Consensus was reached (94% endorsement) for fielding a broader array of indicators of absenteeism. Twenty-one measures of at-work productivity loss, ranging from single item indicators to multidimensional scales, were reviewed for measurement properties. No set of at-work productivity measures was endorsed because of variability in the concepts captured, and the need for a better framework for the measurement of worker productivity that also incorporates contextual issues such as job demands and other paid and unpaid life responsibilities. Progress has been made in this area, revealing an ambivalent set of results that directed us back to the need to further define and then contextualize the measurement of worker productivity.