Evaluation of Disease Burden by (Separate) Patient-reported, Clinical, and Laboratory Factor Scores in Patients With Established Rheumatoid Arthritis: A Factor Analysis Replication

Rheumatoid arthritis (RA) can cause significant burden to patients. Some of these aspects are directly related to disease activity and are manageable with antirheumatic drugs, whereas others require nonpharmacological interventions.

How reliable is assessment of joint swelling and tenderness over socks or stockings in patients with established rheumatoid arthritis?

ABSTRACT Objectives Physicians tend to omit examinations of the foot and ankle in routine practice because it consumes a lot of time when working within tight time constraints. Although barefoot examination is critical to assess disease activity of rheumatoid arthritis (RA), we think occasional examination of foot over socks or stockings is better than not examining foot at all. The aim of this study was to assess the accuracy of foot examinations over socks or stockings in patients with RA. Methods Sixty patients with RA were enrolled in this study. A rheumatologist and a senior resident performed foot examinations on each patient over socks, over stockings, and on bare foot to assess swelling and tenderness. Concordance rates between the barefoot examination and the examinations over socks or stockings by each examiner were investigated. Results The rheumatologist had a concordance rate of 94.4% over socks and 98.8% over stockings. The senior resident had a concordance rate of 95.6% over socks and 98.5% over stockings. Conclusions Foot examinations over socks and stockings had high concordance rates with the barefoot examination, and it may be an option for decreasing foot and ankle examination time in RA patients.

Intensive therapy for moderate established rheumatoid arthritis: the TITRATE research programme

Background Rheumatoid arthritis is a major inflammatory disorder and causes substantial disability. Treatment goals span minimising disease activity, achieving remission and decreasing disability. In active rheumatoid arthritis, intensive management achieves these goals. As many patients with established rheumatoid arthritis have moderate disease activity, the TITRATE (Treatment Intensities and Targets in Rheumatoid Arthritis ThErapy) programme assessed the benefits of intensive management. Objectives To (1) define how to deliver intensive therapy in moderate established rheumatoid arthritis; (2) establish its clinical effectiveness and cost-effectiveness in a trial; and (3) evaluate evidence supporting intensive management in observational studies and completed trials. Design Observational studies, secondary analyses of completed trials and systematic reviews assessed existing evidence about intensive management. Qualitative research, patient workshops and systematic reviews defined how to deliver it. The trial assessed its clinical effectiveness and cost-effectiveness in moderate established rheumatoid arthritis. Setting Observational studies (in three London centres) involved 3167 patients. These were supplemented by secondary analyses of three previously completed trials (in centres across all English regions), involving 668 patients. Qualitative studies assessed expectations (nine patients in four London centres) and experiences of intensive management (15 patients in 10 centres across England). The main clinical trial enrolled 335 patients with diverse socioeconomic deprivation and ethnicity (in 39 centres across all English regions). Participants Patients with established moderately active rheumatoid arthritis receiving conventional disease-modifying drugs. Interventions Intensive management used combinations of conventional disease-modifying drugs, biologics (particularly tumour necrosis factor inhibitors) and depot steroid injections; nurses saw patients monthly, adjusted treatment and provided supportive person-centred psychoeducation. Control patients received standard care. Main outcome measures Disease Activity Score for 28 joints based on the erythrocyte sedimentation rate (DAS28-ESR)-categorised patients (active to remission). Remission (DAS28-ESR < 2.60) was the treatment target. Other outcomes included fatigue (measured on a 100-mm visual analogue scale), disability (as measured on the Health Assessment Questionnaire), harms and resource use for economic assessments. Results Evaluation of existing evidence for intensive rheumatoid arthritis management showed the following. First, in observational studies, DAS28-ESR scores decreased over 10–20 years, whereas remissions and treatment intensities increased. Second, in systematic reviews of published trials, all intensive management strategies increased remissions. Finally, patients with high disability scores had fewer remissions. Qualitative studies of rheumatoid arthritis patients, workshops and systematic reviews helped develop an intensive management pathway. A 2-day training session for rheumatology practitioners explained its use, including motivational interviewing techniques and patient handbooks. The trial screened 459 patients and randomised 335 patients (168 patients received intensive management and 167 patients received standard care). A total of 303 patients provided 12-month outcome data. Intention-to-treat analysis showed intensive management increased DAS28-ESR 12-month remissions, compared with standard care (32% vs. 18%, odds ratio 2.17, 95% confidence interval 1.28 to 3.68; p = 0.004), and reduced fatigue [mean difference –18, 95% confidence interval –24 to –11 (scale 0–100); p < 0.001]. Disability (as measured on the Health Assessment Questionnaire) decreased when intensive management patients achieved remission (difference –0.40, 95% confidence interval –0.57 to –0.22) and these differences were considered clinically relevant. However, in all intensive management patients reductions in the Health Assessment Questionnaire scores were less marked (difference –0.1, 95% confidence interval –0.2 to 0.0). The numbers of serious adverse events (intensive management n = 15 vs. standard care n = 11) and other adverse events (intensive management n = 114 vs. standard care n = 151) were similar. Economic analysis showed that the base-case incremental cost-effectiveness ratio was £43,972 from NHS and Personal Social Services cost perspectives. The probability of meeting a willingness-to-pay threshold of £30,000 was 17%. The incremental cost-effectiveness ratio decreased to £29,363 after including patients’ personal costs and lost working time, corresponding to a 50% probability that intensive management is cost-effective at English willingness-to-pay thresholds. Analysing trial baseline predictors showed that remission predictors comprised baseline DAS28-ESR, disability scores and body mass index. A 6-month extension study (involving 95 intensive management patients) showed fewer remissions by 18 months, although more sustained remissions were more likley to persist. Qualitative research in trial completers showed that intensive management was acceptable and treatment support from specialist nurses was beneficial. Limitations The main limitations comprised (1) using single time point remissions rather than sustained responses, (2) uncertainty about benefits of different aspects of intensive management and differences in its delivery across centres, (3) doubts about optimal treatment of patients unresponsive to intensive management and (4) the lack of formal international definitions of ‘intensive management’. Conclusion The benefits of intensive management need to be set against its additional costs. These were relatively high. Not all patients benefited. Patients with high pretreatment physical disability or who were substantially overweight usually did not achieve remission. Future work Further research should (1) identify the most effective components of the intervention, (2) consider its most cost-effective delivery and (3) identify alternative strategies for patients not responding to intensive management. Trial registration Current Controlled Trials ISRCTN70160382. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.

Increased Expression of Extracellular Vesicles Is Associated With the Procoagulant State in Patients With Established Rheumatoid Arthritis

This study sought to identify different subpopulations of extracellular vesicles (EVs) in plasma from female patients with established rheumatoid arthritis (RA) in relation to the activation of coagulation and fibrin formation in these patients. Forty women were included in the study, 20 patients and 20 age-matched healthy controls. The mean disease duration in patients was 13.0 (5.0–25.0) years, with medium to high disease activity despite ongoing treatment with low-dose prednisolone and methotrexate. There were no differences between the investigated groups regarding the presence of traditional cardiovascular risk factors. The concentration of phosphatidylserine-positive (PS+) EVs; platelet (CD42a+), leucocyte (CD45+), monocyte (CD14+), and endothelial (CD144+)-derived EVs; and EVs-expressing tissue factor (CD142+), P-selectin (CD62P+), and E-selectin (CD62E+) were determined by flow cytometry analysis. Overall hemostasis potential (OHP) was assessed to follow the hemostatic disturbances, including the parameters for overall coagulation potential (OCP) and overall fibrinolytic potential (OFP). Fibrin clot turbidity was measured together with clot lysis time, and scanning electron microscopy was performed. Increased concentrations of PS+, CD42a+, CD142+, CD45+, CD14+, and CD62P+ EVs were found in plasma from patients with RA compared to healthy controls, and the concentrations of PS+, CD42a+, CD14+, and CD62P+ EVs were positively correlated with the inflammatory parameters in RA patients. Positive correlations were also found between the levels of PS+ and CD42a+ EVs and OCP as well as between the levels of PS+, CD42a+, and CD62P+EVs and OHP. The levels of PS+, CD42a+, CD14+, CD62P+, and CD62E+ EVs were negatively correlated with OFP. Elevated levels of circulating EVs of different cell origins were found in patients with established RA, in relation to the inflammatory burden and coagulation activation in the disease.

Cumulative inflammatory burden and obesity as determinants of insulin resistance in patients with established rheumatoid arthritis: cross-sectional study

ObjectivesTo describe the prevalence of insulin resistance (IR) in patients with established rheumatoid arthritis (RA) and to analyse the contribution of cumulative inflammatory burden and other factors to its development.DesignObservational cross-sectional study.ParticipantsPatients with RA and controls matched for age, sex and Body Mass Index. We excluded patients with diabetes.SettingsPatients from an RA inception cohort at Hospital Regional Universitario de Málaga, Spain, were recruited between September 2016 and May 2018.Primary and secondary outcome measuresIR was evaluated using the homeostasis model assessment for IR and beta-cell function and the quantitative insulin sensitivity check index. Other variables included the cumulative 28-Joint Disease Activity Score (DAS28) with C reactive protein (CRP) body composition and cytokines. Two logistic regression models were constructed to identify factors associated with IR in patients with RA.ResultsEighty-nine patients with RA and 80 controls were included. The prevalence of IR was similar in both cases and controls. Inflammatory activity was controlled appropriately in patients during follow-up (mean DAS28 3.1 (0.8)). The presence of IR in patients with RA was associated with obesity (OR 6.01, 95% CI 1.9 to 8.7), higher cumulative DAS28-CRP values during follow-up (OR 2.8, 95% CI 1.3 to 6.0), and higher interleukin-1β levels (OR 1.6, 95% CI 1.1 to 2.4). The second model showed that the risk of IR increased by 10% for each kilogram of excess body fat.ConclusionIn patients with well-controlled, established RA, IR is associated mainly with poorer control of inflammation from diagnosis and with obesity, specifically total fat mass.

Physical activity in established rheumatoid arthritis and variables associated with maintenance of physical activity over a seven-year period – a longitudinal observational study

Background A large number of patients with RA do not adhere to the recommended levels of physical activity to enhance health. According to EULAR recommendations, physical activity should be part of standard care in people with rheumatic diseases. There have been few larger studies on maintenance of physical activity over longer periods of time. The aim was to study self-reported physical activity levels over 7 years in patients with established rheumatoid arthritis (RA). In addition, to determine variables associated with maintenance or change of physical activity behavior. Methods Questionnaires were sent to the BARFOT cohort in 2010 (n = 1525) and in 2017 (n = 1046), and 950 patients responded to both questionnaires. Patients were dichotomized according to meeting MVPA recommendations (physically active at a moderate level ≥ 150 min/week or at an intense level ≥ 75 min/week) or not. Body mass index, smoking habits, tender joint count (TJC), swollen joint count (SJC), Patient Global Assessment (PatGA), pain intensity and distribution, fatigue, physical function (HAQ), health-related quality of life (EQ. 5D), comorbidities, and medical treatment were assessed. We used logistic regression analysis to study variables associated with maintenance and/or change of MVPA behavior. Results Forty-one per cent (n = 389) of the patients met MVPA recommendations on both occasions. Patients who met MVPA recommendations over 7 years were younger and a higher proportion were never-smokers. There was a negative association with being overweight or obese, having cardiovascular or pulmonary diseases, pain, fatigue, and physical function, whereas there was a positive association between QoL and maintaining MVPA recommendations. Similar factors were positively associated with a deterioration in physical activity level over time. Conclusions Maintenance of physical activity over a long period of time is challenging for patients with established RA. Reports of high quality of life supported maintenance of physical activity while disease related and unhealthy lifestyle factors had a negative effect. Health professionals should consider the patient’s standpoint when encouraging maintenance of physical activity, preferably using coordinated lifestyle interventions.