Editors' ChoiceRheumatoid Arthritis

Synovial signatures signpost arthritis

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaax1725
DOI: 10.1126/scitranslmed.aax1725

Abstract

Cellular signatures define pathobiological endotypes in early rheumatoid arthritis, informing prognosis and treatment.

Advances in understanding the pathogenesis of rheumatoid arthritis (RA) have informed the development of highly effective therapeutics that inhibit joint damage and improve quality of life. However, 40% of patients with RA remain refractory to therapy. RA pathology is highly heterogenous, and it is unclear how heterogeneity relates to disease activity, prognosis, and therapeutic response. Incomplete patient drug responses are attributable to RA synovial tissue heterogeneity and diverse target expression. Disease stage and therapy can influence synovial pathobiology. This presents the requirement to access well-phenotyped patient tissues, providing a platform to elucidate the cellular basis of disease and therapy response.

Humby and colleagues performed a longitudinal investigation of 144 treatment-naïve patients with early-stage RA, collecting serial synovial tissue samples from symptomatic joints before treatment and 6 months after commencing disease-modifying antirheumatic drugs (DMARDs). They correlated the cellular and molecular characteristics of patient synovial pathotypes with patient clinical phenotypes including disease activity score and imaging assessments. Patients with early RA had 3 distinct pathotypes: (1) “lympho-myeloid”, dominated by lymphoid lineage infiltration; (2) “diffuse-myeloid”, with myeloid lineage predominance but B cell/plasma cell poor; and (3) “pauci-immune” pathotype, characterized by stromal cell predominance. Longitudinal correlation showed that genes expressed by the lympho-myeloid pathotype strongly correlated with disease activity and DMARD response at 6 months. Elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevated osteoclast-targeting genes and predicted radiographic joint damage at 12 months. In contrast, disease activity, radiographic progression, and therapeutic response were reduced in patients with pauci-immune pathology. Diverse synovial pathotypes are therefore a feature of early RA prior to potential drug-sensitive modification of synovial pathology. Distinct synovial pathotypes are associated with clinical phenotypes, disease outcome, prognosis, and radiographic progression, and specific molecular signatures predict therapy response.

Advancing understanding of RA synovial pathotypes will enrich response to current biological therapies though targeting cognate pathways expressed in distinct patient cohorts. This study emphasizes the importance of developing stratified and pathway-driven treatment approaches for patients with RA, analogous to cancer medicine. Identification of the cellular and molecular phenotypes of early RA signposts therapeutic approaches targeting specific phenotypes and endotypes. Now researchers are able to commence the quest to find new therapies targeting stromal cells that play a critical role in joint damage in early pauci-immune RA.

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