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. Overall design: Patients diagnosed with psoriatic arthritis according to the Classification Criteria for Psoriatic Arthritis (CASPAR criteria) (51), who had a personal history of psoriasis and active knee involvement were recruited to the study from the rheumatology departments at Sourasky Medical Center in Israel between June 2018 until April 2023. A control group of nine patients with active knee osteoarthritis was also recruited, either from the rheumatology department or the orthopedics surgery department at Sourasky Medical center. Additionally, seven healthy volunteers were recruited to provide blood samples. The study was approved by the Institutional Review Boards of Weizmann Institution of Science, Rehovot, Israel. All participants provided a written informed consent (in accordance with the Helsinki declaration) prior to sample collection. PsA patients were followed for a minimum of six months from the time of sampling (range) with disease activity assessed using the Disease Activity in Psoriatic Arthritis (DAPSA) score (16) calculated at both the sampling time and during follow up visits. Patients were categorized into four groups based on their clinical response to treatment (assessed using the DAPSA score). (For treatment-naïve patients, we considered the response to the first bDMARD treatment administered following the initial sampling. In case of patients with longitudinal samples (n=6), we included the samples from the last visit. ): Responders, achieved remission during follow up visits (DAPSA = 4); Partial responders, exhibit low disease activity during follow up visits (4 ? DAPSA = 14); Non-responders, displayed moderate to high disease during follow up visits (DAPSA ?14); Refractory, displayed moderate to high disease (DAPSA>14) following three or more sequential bDMARDs/tsDMARD (specifically JAKi) with at least two different mode of action.