Summary There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website ( https://peac.hpc.qmul.ac.uk/ ) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.

Background and Purpose-Carotid plaque area measured by ultrasound (cross-sectional area of longitudinal views of all plaques seen) was studied as a way of identifying patients at increased risk of stroke, myocardial infarction, and vascular death. Methods-Patients from an atherosclerosis prevention clinic were followed up annually for up to 5 years (mean, 2.5Ϯ1.3 years) with baseline and follow-up measurements recorded. Plaque area progression (or regression) was defined as an increase (or decrease) of Ն0.05 cm 2 from baseline. Results-Carotid plaque areas from 1686 patients were categorized into 4 quartile ranges: 0.00 to 0.11 cm 2 (nϭ422), 0.12 to 0.45 cm 2 (nϭ424), 0.46 to 1.18 cm 2 (nϭ421), and 1.19 to 6.73 cm 2 (nϭ419). The combined 5-year risk of stroke, myocardial infarction, and vascular death increased by quartile of plaque area: 5.6%, 10.7%, 13.9%, and 19.5%, respectively (PϽ0.001) after adjustment for all baseline patient characteristics. A total of 1085 patients had Ն1 annual carotid plaque area measurements: 685 (63.1%) had carotid plaque progression, 306 (28.2%) had plaque regression, and 176 (16.2%) had no change in carotid plaque area over the period of follow-up. The 5-year adjusted risk of combined outcome was 9.4%, 7.6%, and 15.7% for patients with carotid plaque area regression, no change, and progression, respectively (Pϭ0.003). Conclusions-Carotid plaque area and progression of plaque identified high-risk patients. Plaque measurement may be useful for targeting preventive therapy and evaluating new treatments and response to therapy and may improve cost-effectiveness of secondary preventive treatment.