Abstract
Pain is a key symptom associated with rheumatoid arthritis (RA) and can persist even in the context of overall disease control by standard-of-care disease modifying anti-rheumatic drugs (DMARDs). Analgesic agents and corticosteroids are often used to supplement DMARDs for pain relief but lack disease modifying properties, and their sustained use carries adverse risks. In this work, we characterized the progression of pain sensitivity in the SKG mouse model of RA and evaluated the potential therapeutic interventions. Male and female SKG mice, after systemic mannan injection, developed a mechanical pain phenotype and joint swelling, with a strong inverse correlation between clinical arthritis scores and pain thresholds. To test potential interventions for pain alleviation, we evaluated all-trans retinoic acid (ATRA)-loaded poly(lactic-co-glycolic acid) microparticles (ATRA-PLGA MP) administered via intra-articular injection, which we have previously demonstrated to be disease-modifying. The pain and inflammation patterns assessed by the von Frey test and clinical scoring showed ATRA-PLGA MP monotherapy reduced inflammation and alleviated mechanical allodynia in arthritic SKG mice, an effect that was amplified by combination treatments with standard-of-care agents. In early-stage arthritis, co-administration with cytotoxic T-lymphocyte-associated protein (CTLA)-4-Ig, clinically known as abatacept, delayed disease progression and sustained the reduction of mechanical allodynia. In established arthritis, sequential treatment with the corticosteroid dexamethasone (Dex) reduced cumulative disease burden and reduced mechanical allodynia. These findings highlight the potential of combining ATRA-PLGA MP with standard-of-care treatments as a potential strategy to enhance the efficacy and durability of disease modification and pain alleviation for arthritis management.