James Dale

Targeting ultrasound remission in early rheumatoid arthritis: the results of the TaSER study, a randomised clinical trial

Objective To investigate whether an intensive early rheumatoid arthritis (RA) treat-to-target (T2T) strategy could be improved through the use of musculoskeletal ultrasound (MSUS) assessment of disease activity. Methods 111 newly diagnosed patients with RA or undifferentiated arthritis (symptom duration <1u2005year) were randomised to strategies that aimed to attain either DAS28-erythrocyte sedimentation rate (ESR)<3.2 (control) or a total power Doppler joint count≤1 during a combined DAS28-ESR/MSUS assessment (intervention). MSUS examination was indicated if: DAS28-ESR<3.2 or DAS28-ESR≥3.2 with two swollen joints. Step-up disease-modifying antirheumatic drug (DMARD) escalation was standardised: methotrexate monotherapy, triple therapy and then etanercept/triple therapy. American College of Rheumatology (ACR) core-set variables were assessed 3 monthly by a metrologist blinded to group allocation. MRI of dominant hand and wrist, and plain radiographs of hands and feet were undertaken at baseline and 18u2005months for grading by two readers using the Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis MRI Scoring System (RAMRIS) and van der Heijde/Sharp Score, respectively. The coprimary outcomes were mean change from baseline of DAS44 and RAMRIS erosion score. Results Groups were matched for baseline clinical, demographic and radiographic features. The intervention group received more intensive DMARD therapy. Both groups demonstrated significant improvements in DAS44 (mean change: control −2.58, intervention −2.69; 95% CI difference between groups −0.70 to 0.48; p=0.72). There were no significant between-group differences for any ACR core-set variables, except DAS44 remission after 18u2005months (control 43%, intervention 66%; p=0.03). There was minimal progression of MRI and radiographic erosions and no difference in imaging outcomes or serious adverse event rates. Conclusions In early RA, a MSUS-driven T2T strategy led to more intensive treatment, but was not associated with significantly better clinical or imaging outcomes than a DAS28-driven strategy. Trial registration number NCT00920478.

Tightening Up? Impact of Musculoskeletal Ultrasound Disease Activity Assessment on Early Rheumatoid Arthritis Patients Treated Using a Treat to Target Strategy

To determine the level of agreement and potential impact on disease‐modifying antirheumatic drug (DMARD) escalation decisions and of adding musculoskeletal ultrasound (MSUS) assessment of disease activity to the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA).

Optimising the strategy of care in early rheumatoid arthritis

In rheumatoid arthritis (RA), early use of disease-modifying anti-rheumatic drugs (DMARDs), intensive follow-up and treating to target to achieve low disease activity produce significant improvements in measures of disease activity, functional impairment and retard erosive radiographic progression. Step-up, parallel and step-down regimens are all significantly more effective than sequential monotherapy; although the most effective regimen has not been established. Minimising the period of exposure to synovitis, by including a rapidly acting agent (e.g., corticosteroids or tumour necrosis factor alpha (TNFalpha) inhibitor), may slow radiographic progression further. Biologic therapies, especially TNFalpha inhibitors, are effective in early RA; however, their exact role is unclear. Current measures may overestimate the number of patients in clinical remission; therefore, musculoskeletal ultrasound and/or novel biomarkers may also have a role. Pre-clinical immunological markers could possibly be used to trigger pre-emptive treatment in asymptomatic, at risk individuals. Potential treatment developments include combining biologic agents or targeting alternative immunological pathways.

Brief Report: Predicting Functional Disability: One‐Year Results From the Scottish Early Rheumatoid Arthritis Inception Cohort

To identify baseline prognostic indicators of disability at 1 year within a contemporary early inflammatory arthritis inception cohort and then develop a clinically useful tool to support early patient education and decision‐making.

PAR2 expression in peripheral blood monocytes of patients with rheumatoid arthritis

Objectives Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functio©nal significance of PAR2 expression on rheumatoid arthritis (RA)-derived leucocyte subsets. Methods Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR2 on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. Results Patients with RA had elevated but variable surface expression of PAR2 on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86–4.10%) vs 0.06% (0.03–0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR2 expression in patients with RA compared with controls (3.05% (0.36–11.82%) vs 0.08% (0.02–0.28%), p<0.0001). For both subsets, PAR2 expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR2 expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR2 expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR2 expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR2 agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). Conclusions These findings are consistent with a pathogenic role for PAR2 in RA.

How low to aim in rheumatoid arthritis? Learning from other disciplines

Treat-to-target strategies have been widely adopted as the standard of care for the management of patients with rheumatoid arthritis. The concept of ‘tight control’ is prevalent in other disciplines, particularly in diabetes and cardiovascular risk management. In these disciplines, evidence has accumulated that the utility of tight control strategies must be carefully weighed against the disutility that may arise from multiple interventions, particularly in patients at low risk. There is a lively debate in rheumatology circles about whether treatment should be targeted at achieving low disease activity, clinical remission or imaging remission. As rheumatologists we should learn the lessons from other disciplines, and ensure that we expand the evidence base to ensure our recommendations are securely underpinned by robust evidence.

PAR 2 expression in peripheral blood monocytes of patients with rheumatoid arthritis

Objectives Proteinase-activated receptor 2 (PAR2) is a G protein-coupled receptor activated by serine proteinases with proinflammatory activity. A study was undertaken to investigate the presence and functio©nal significance of PAR2 expression on rheumatoid arthritis (RA)-derived leucocyte subsets. Methods Venous blood was obtained from patients with RA and osteoarthritis (OA) as well as healthy control subjects. Surface expression of PAR2 on peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry and interleukin 6 (IL-6) generation by ELISA. Results Patients with RA had elevated but variable surface expression of PAR2 on CD14+ monocytes compared with control subjects (median (1st to 3rd quartiles) 1.76% (0.86–4.10%) vs 0.06% (0.03–0.81%), p<0.0001). CD3+ T cells showed a similar pattern with significantly higher PAR2 expression in patients with RA compared with controls (3.05% (0.36–11.82%) vs 0.08% (0.02–0.28%), p<0.0001). For both subsets, PAR2 expression was significantly higher (p<0.00001) in patients with high levels of disease activity: PAR2 expression for both CD14+ and CD3+ cells correlated to C reactive protein and erythrocyte sedimentation rate. Furthermore, in a cohort of patients with newly diagnosed RA, elevated PAR2 expression in both CD14+ and CD3+ cells was significantly reduced 3 months after methotrexate or sulfasalazine treatment and this reduction correlated significantly with the reduction in the 28-joint Disease Activity Scale score (p<0.05). PAR2 expression on cells from patients with OA was low, similar to levels seen in control subjects. Generation of IL-6 by monocytes in response to a selective PAR2 agonist was significantly greater in patients with RA than in patients with OA and control subjects (p<0.05). Conclusions These findings are consistent with a pathogenic role for PAR2 in RA.

Advances in the management of rheumatoid arthritis.

Modern early rheumatoid arthritis strategies are usually based upon a number of important overarching principles: 1. early diagnosis facilitates early commencement of disease modifying anti-rheumatic therapy; 2. early commencement of treatment reduces the long-term risk of erosive damage and functional decline; 3. composite disease activity measures should be used to quantify global rheumatoid arthritis disease activity; and 4. therapy should be intensified until a predefined disease activity target has been achieved. A substantial minority of rheumatoid arthritis patients (approximately 40%) will experience an adequate response to methotrexate monotherapy; however, the remainder may require disease modifying anti-rheumatic combination therapy, and/or biologic therapy, to achieve disease activity targets. Importantly, short term trials of methotrexate monotherapy do not appear to disadvantage outcomes provided treatment continues to be intensified if disease activity targets are not achieved.

The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank

BackgroundThe Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkersMethodsDemographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6xa0months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12xa0months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12xa0monthsResultsResults are available for 1073 patients; at baseline, 76xa0% were classified as RA and 24xa0% as UA. Median time from onset to first review was 163xa0days (IQR97-323). Methotrexate was first-line DMARD for 75xa0% patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24xa0months, however the proportion in any employment fell (51 to 38xa0%, pu2009=u20090.0005). 24xa0% patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9xa0%) patients exhibited rapid radiographic progression after 12xa0months. The SERA Biobank has accrued 60,612 samplesConclusionsIn routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis

Predicting functional disability: One year results from the Scottish Early Rheumatoid Arthritis Inception Cohort

To identify baseline prognostic indicators of disability at 1 year within a contemporary early inflammatory arthritis inception cohort and then develop a clinically useful tool to support early patient education and decision‐making.