Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients

Abstract

ObjectivesTo unravel the hierarchy of cellular/molecular pathways in the disease tissue of early, treatment-naïve rheumatoid arthritis (RA) patients and determine their relationship with clinical phenotypes and treatment response/outcomes longitudinally.Methods144 consecutive treatment-naïve early RA patients (<12 months symptoms duration) underwent ultrasound-guided synovial biopsy before and 6 months after disease-modifying antirheumatic drug (DMARD) initiation. Synovial biopsies were analysed for cellular (immunohistology) and molecular (NanoString) characteristics and results compared with clinical and imaging outcomes. Differential gene expression analysis and logistic regression were applied to define variables correlating with treatment response and predicting radiographic progression.ResultsCellular and molecular analyses of synovial tissue demonstrated for the first time in early RA the presence of three pathology groups: (1) lympho-myeloid dominated by the presence of B cells in addition to myeloid cells; (2) diffuse-myeloid with myeloid lineage predominance but poor in B cells nd (3) pauci-immune characterised by scanty immune cells and prevalent stromal cells. Longitudinal correlation of molecular signatures demonstrated that elevation of myeloid- and lymphoid-associated gene expression strongly correlated with disease activity, acute phase reactants and DMARD response at 6 months. Furthermore, elevation of synovial lymphoid-associated genes correlated with autoantibody positivity and elevation of osteoclast-targeting genes predicting radiographic joint damage progression at 12 months. Patients with predominant pauci-immune pathology showed less severe disease activity and radiographic progression.ConclusionsWe demonstrate at disease presentation, prior to pathology modulation by therapy, the presence of specific cellular/molecular synovial signatures that delineate disease severity/progression and therapeutic response and may pave the way to more precise definition of RA taxonomy, therapeutic targeting and improved outcomes.

B Cell Synovitis and Clinical Phenotypes in Rheumatoid Arthritis: Relationship to Disease Stages and Drug Exposure

“…Overall, these data provide insights into the specific associations of immune cells with clinical phenotypes and highlight the relevance of B cells as markers of ongoing synovitis associated with a clinical phenotype of aggressive disease in early RA. However, alternative histologic scoring systems that aim to more comprehensively assess immune cell infiltration are available, including an integrated histologic scoring system that we have recently developed and that has been verified by combined histologic and ‐omics approaches . Although it is likely that in the near future integrated histologic and molecular analyses will identify novel or previously unrecognized pathways mediating treatment response or resistance, in order to translate those studies to routine clinical care there is a need for well‐validated histopathologic scores that can be easily applied for patient classification, such as the B cell synovitis score described herein, particularly if it were demonstrated to have clinical utility for stratifying patients to receive rituximab.…”

“…However, the degree of synovial B cell infiltrate is a highly variable phenomenon, ranging from complete absence to a dense distribution within organized infiltrates in up to 40% of patients and as such has been examined as a potential source of predictive and prognostic biomarkers in RA. Indeed, recent data from a large cohort of patients with untreated early RA have suggested that a B cell–rich lymphoid synovitis is associated with highly active disease and predictive of radiographic progression . However, comparison of these data with other cohorts that either support or refute this notion is challenging due to a lack of consistency in quantitative and qualitative assessment of B cell synovitis, the effects of concomitant diverse therapy, and examination of patients at variable disease stages and levels of disease activity.…”

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring

“…Patients were enrolled in the Pathobiology of Early Arthritis Cohort (PEAC, details at http://www.peac-mrc. mds.qmul.ac.uk/index.php) at the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London (REC 05/Q0703/198, London, UK), as previously described (Kelly et al, 2015;Humby et al, 2019;Lewis et al, 2019). All patients belonging to this cohort underwent baseline ultrasound-guided biopsy on the most inflamed accessible joint.…”

Metabolic Checkpoints in Rheumatoid Arthritis

“…Progressive disability and systemic complications are still a burden leading to socioeconomic costs and unmet needs. Indeed, current conventional and biologic disease modifying therapies produce good responses in only 60% of patients (Humby et al, 2019). Predictive biomarkers of prognosis, therapeutic response, and resistance to treatment, which currently include ACPA, RF, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR), remain inadequate from a clinical decision making perspective (McInnes and Schett, 2011;Dennis et al, 2014).…”