Dissection of the immune landscape in Psoriatic Arthritis patients

Despite significant advancements in psoriatic arthritis (PsA) treatment modalities, a considerable proportion of patients continue to experience persistent joint inflammation and functional impairment, unresponsive to the armamentarium of biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase (JAK) inhibitors. The etiology of resistance in these cases is complex, likely involving intricate immunological and genetic factors which are currently mostly unknown. Identifying novel biomarkers and targets for refractory disease is urgently needed. Here, utilizing single-cell RNA-sequencing of synovial fluid from 41 PsA patients and 9 Osteoarthritis (OA) controls we map the comprehensive immune landscape of PsA. Our analysis reveals major perturbations within the myeloid compartment, identifying distinct cell subsets and altered gene programs in PsA patients. Notably, within the myeloid compartment, refractory patients exhibit elevated expression of interferon- gamma induced gene programs linked to the immunoproteasome and MHC class I antigen presentation, at both the gene and protein level. These results suggest a potential interaction of the immunoproteasome and MHC class I antigen presentation in refractory PsA patients with sustained inflammation. Our research imparts critical insights into PsA pathogenesis, paving the way for both molecular level patient classification and potentially new therapeutic interventions for currently treatment resistant patients.