Optimizing efficacy to safety ratio of glucocorticoids in rheumatoid arthritis models by leveraging PPARα agonism.

OBJECTIVES

Glucocorticoids remain essential therapies for immune- and inflammatory diseases such as rheumatoid arthritis (RA) but are notorious for their metabolic side effects. Given the anti-inflammatory and metabolically favorable actions of peroxisome-proliferator activated nuclear receptor (PPAR) agonists, we investigated whether PPARα agonism could enhance the therapeutic efficacy and/or mitigate the metabolic side effects of glucocorticoids.

METHODS

We evaluated the effects of the synthetic glucocorticoid dexamethasone and the PPARα agonist GW7647 across four model systems: TNFα-stimulated L929sA fibroblasts, primary human fibroblast-like synoviocytes (FLS) from osteoarthritis (OA) and RA patients, and collagen-induced arthritis mice.

RESULTS

Dexamethasone reduced the inflammatory TNFα response in L929sA cells, which was further potentiated by GW7647. In vivo, dexamethasone induced adiposity and hypertriglyceridemia, which GW7647 counteracted without affecting arthritis severity. In both OA-FLS and RA-FLS, dexamethasone and GW7647 cooperatively regulated metabolic genes expression. Proteomic profiling of TNFα-stimulated human OA-FLS revealed that combined use of dexamethasone and GW suppressed interferon-stimulated proteins. In line herewith, suppression of pro-inflammatory gene expression upon combined dexamethasone and GW7647 treatment was more outspoken in L929sA co-stimulated with TNFα and IFNβ, compared to TNFα alone.

CONCLUSION

GW enhances the anti-inflammatory effects of glucocorticoids in L929sA cells and mitigates metabolic side effects of dexamethasone in vivo, without compromising efficacy. In human OA-FLS and RA-FLS, this combination cooperatively regulates metabolic gene expression. Moreover, PPARα agonism permits to broaden its anti-inflammatory profile to interferon-driven pathways. As both glucocorticoids and PPAR agonists are already widely used in clinical practice, these findings offer a promising strategy to optimize glucocorticoid-based therapies.