<scp>PEPITEM</scp> Regulates the Synovial Microenvironment During Immune‐Mediated Inflammatory Arthritis to Limit Disease

OBJECTIVE: Here we investigate the status of the adiponectin-PEPITEM pathway in early, treatment naive rheumatoid arthritis (RA) and psoriatic arthritis (PsA) and the therapeutic efficacy of PEPITEM administration in preclinical models. METHODS: Peripheral blood was isolated from patients with clinical suspect arthralgia and suspected inflammatory arthritis and analyzed by flow cytometry or Western blot. Effect of PEPITEM treatment on inflammatory arthritis was assessed in mice by histology, single-cell RNA sequencing, flow cytometry, or multiplex analysis. RESULTS: Patients newly diagnosed with RA and PsA had significantly reduced expression of adiponectin receptor 2 and its downstream signaling adapter protein APPL-1 on their peripheral-blood mononuclear cells, resulting in diminished response to adiponectin and local synovial concentrations of PEPITEM. Building on these observations, treatment with PEPITEM in three distinct inflammatory arthritis animal models significantly reduced arthritis severity, joint swelling, leukocyte infiltration, and expression of several pro-inflammatory mediators (eg, JE [CCL2], RANTES, interleukin-16) in the synovium. Mechanistically, PEPITEM treatment suppressed the cyclooxygenase 2 and NF-κB signaling pathways. Moreover, PEPITEM altered the composition of leukocyte subsets recruited into the joint. CONCLUSION: Collectively, these findings underscore the importance of understanding the dysregulation of the adiponectin-PEPITEM pathway in different immune-mediated inflammatory diseases (IMIDs), such as RA and PsA. The observed differences in expression and downstream signaling through adiponectin receptors suggest potential targets for therapeutic intervention to restore the balance of this regulatory pathway to mitigate chronic inflammation and disease progression in these patients, paving the way for its clinical use as an alternative and/or combination therapy for early IMIDs.