When inflammation is not the driver: Pauci-immune synovitis and the stromal basis of refractory arthritis.

Approximately 5% to 20% of patients with rheumatoid arthritis (RA) fail to respond to sequential biologic and targeted synthetic disease-modifying antirheumatic drugs, representing a major unmet clinical need. Increasing evidence indicates that a substantial proportion of these patients exhibit a pauci-immune (fibroid) synovial pathotype, characterised by sparse immune-cell infiltration and enrichment of fibroblast, extracellular matrix, and cell adhesion pathways rather than inflammatory immune signatures. Notably, this pathotype is present in up to one quarter of treatment-naïve patients with early RA. Clinically, it is associated with persistent disease activity and pain despite relatively low systemic inflammation and predicts poor therapeutic responses across multiple drug classes, including tumour necrosis factor inhibitors, rituximab, and tocilizumab. Recent advances in spatial transcriptomics and single-cell technologies have begun to elucidate the biological basis of this phenotype, identifying an endothelial-fibroblast signalling network driven by Notch and transforming growth factor beta pathways that spatially orchestrates fibrogenic responses. These studies have also defined distinct sublining fibroblast subsets, including DKK3⁺ fibroblasts associated with treatment refractoriness and CD200⁺ fibroblasts linked to resolution of inflammation. Together, these findings shift the pathogenic paradigm from immune-cell-driven inflammation to stromal cell dysfunction in a biologically distinct subset of RA, positioning stromal cells as promising therapeutic targets. This review synthesises the clinical, molecular, and mechanistic evidence supporting the pauci-immune synovial pathotype, and discusses its implications for precision medicine and treatment stratification.