Changes in Plasma Itaconate Elevation in Early Rheumatoid Arthritis Patients Elucidates Disease Activity Associated Macrophage Activation.

Changes in the plasma metabolic profile were characterised in newly diagnosed rheumatoid arthritis (RA) patients upon commencement of conventional disease-modifying anti-rheumatic drug (cDMARD) therapy. Plasma samples collected in an early RA randomised strategy study (NCT00920478) that compared clinical (DAS) disease activity assessment with musculoskeletal ultrasound assessment (MSUS) to drive treatment decisions were subjected to untargeted metabolomic analysis. Metabolic profiles were collected at pre- and three months post-commencement of nonbiologic cDMARD. Metabolites that changed in association with changes in the DAS44 score were identified at the three-month timepoint. A total of nine metabolites exhibited a clear correlation with a reduction in DAS44 score following cDMARD commencement, particularly itaconate, its derived anhydride and a derivative of itaconate CoA. Increasing itaconate correlated with improved DAS44 score and decreasing levels of C-reactive protein (CRP). cDMARD treatment effects invoke consistent changes in plasma detectable metabolites, that in turn implicate clinical disease activity with macrophages. Such changes inform RA pathogenesis and reveal for the first time a link between itaconate production and resolution of inflammatory disease in humans. Quantitative metabolic biomarker-based tests of clinical change in state are feasible and should be developed around the itaconate pathway.

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 <1 year) 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 18 months 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 18 months (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.

Introduction of a new observation chart and education programme is associated with higher rates of vital-sign ascertainment in hospital wards.

INTRODUCTION Local and national awareness of the need to improve the recognition and response to the clinical deterioration of hospital inpatients is high. The authors designed and implemented a programme to improve recognition of deteriorating patients in their hospital; a new observation chart for vital signs was one of the major elements. The aim of the study is to evaluate the impact of the new chart and associated education programme on the completeness of vital-sign recording in ward areas. METHODS The setting is a university-affiliated teaching hospital in Sydney, Australia. Three study periods, each lasting 14 days (preintervention, 2 weeks postintervention, 3 months postintervention), were carried out in three wards. The new observation chart was supported by an education programme. The primary outcome measures were the ascertainment rates of individual vital signs as a proportion of total observation sets. RESULTS Documentation of respiratory rate increased from 47.8% to 97.8% (p<0.001) and was sustained at 3 months postintervention (98.5%). Collection of a full set of vital signs also improved by a similar magnitude. Basic neurological observation for all patients was introduced in the new chart; the uptake of this was very good (93.1%). Ascertainment rates of blood pressure and oxygen saturation also increased by small but significant amounts from good baseline rates of 97% or higher. CONCLUSION The introduction of a new observation chart, and education regarding its use and importance, was associated with a major improvement in the recording of respiratory rate and other vital signs.

Effect of etanercept on serum amyloid A protein (SAA) levels in patients with AA amyloidosis complicating inflammatory arthritis.

We assessed changes in serum amyloid A protein (SAA) levels during treatment with etanercept in AA amyloidosis complicating inflammatory arthritis. Five women and four men with AA amyloidosis and inflammatory arthritis received etanercept. SAA levels were recorded before and after commencement of treatment. Previous immunosuppressive drugs included cyclophosphamide (four patients), azathioprine (three patients), methotrexate (two patients) and chlorambucil (in one patient). Two patients received no disease modifying drugs between the time of diagnosis of AA amyloidosis and commencement of etanercept. In seven out of nine patients the median SAA level during etanercept treatment was lower than levels before anti-tumour necrosis factor therapy. In five out of nine patients, the median post treatment level was <11 mg/l. There were no significant changes in serum creatinine or proteinuria during periods (median, 23 months; range, 1-24 months) of etanercept therapy. The etanercept was stopped in four patients because of: acute bacterial endocarditis, psoriasiform rash, psychosis and leukopenia. In two of these patients alternative biologics were commenced (adalimumab or anakinra) and one was restarted on etanercept. One patient died of cerebral haemorrhage during the study. Etanercept therapy was associated with a fall in SAA levels in seven of nine patients, five of whom achieved levels which might be expected to be associated with stable or regressing amyloid deposits. Etanercept represents a useful alternative to immunosuppressant therapy such as cyclophosphamide or chlorambucil. Further work is needed to establish whether organ damage related to AA amyloidosis is slowed by etanercept.

Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial.

BACKGROUND: Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs, but a minority of patients achieve a good response. We aimed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis--for sustained, tight control of disease activity--compared with routine outpatient care. METHODS: We designed a single-blind, randomised controlled trial in two teaching hospitals. We screened 183 patients for inclusion. 111 were randomly allocated either intensive management or routine care. Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response (defined as a disease activity score <2.4 and a fall in this score from baseline by >1.2). Analysis was by intention-to-treat. FINDINGS: One patient withdrew after randomisation and seven dropped out during the study. Mean fall in disease activity score was greater in the intensive group than in the routine group (-3.5 vs -1.9, difference 1.6 [95% CI 1.1-2.1], p<0.0001). Compared with routine care, patients treated intensively were more likely to have a good response (definition, 45/55 [82%] vs 24/55 [44%], odds ratio 5.8 [95% CI 2.4-13.9], p<0.0001) or be in remission (disease activity score <1.6; 36/55 [65%] vs 9/55 [16%], 9.7 [3.9-23.9], p<0.0001). Three patients assigned routine care and one allocated intensive management died during the study; none was judged attributable to treatment. INTERPRETATION: A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression, physical function, and quality of life at no additional cost.