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

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ABSTRACT Objectives Glucocorticoids remain essential therapies for several 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 (GW) across three RA model systems: L929sA fibroblasts, primary human fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA) mice. Results Dexamethasone reduced the inflammatory TNFα response in L929sA cells, which was further potentiated by GW. In vivo however, GW reduced the dexamethasone-induced adiposity and hypertriglyceridemia, but not arthritis severity. Curiously, GW alone induced several proinflammatory genes within arthritic synovium which were counteracted by glucocorticoids. Proteomic profiling of TNFα-stimulated human FLS revealed that combined use of dexamethasone and GW selectively suppressed interferon-stimulated proteins. In line herewith, co-stimulation with TNFα and IFNβ amplified the suppressive effect of combined dexamethasone and GW treatment on pro-inflammatory gene expression in L929sA versus TNFα alone. Conclusion GW enhances the anti-inflammatory effects of glucocorticoids in human FLS and L929sA, and mitigates metabolic side effects of dexamethasone in vivo, without compromising their efficacy. In addition, PPARα agonism permits to broaden its anti-inflammatory profile to interferon driven pathways. Given that both synthetic glucocorticoids and PPAR agonists are already widely used in (general) clinical practice, these findings offer a promising strategy to optimize glucocorticoid-based therapies. KEY MESSAGES What is already known on this topic Synthetic glucocorticoids such as dexamethasone are widely used as immunosuppressive drugs, but cause many (metabolic) side effects. Peroxisome-proliferator-activated nuclear receptor (PPAR) agonists are clinically primarily used to treat symptoms that resemble glucocorticoid-induced side effects, but they also exert (modest) immunosuppressive effects. What this study adds This study explores the therapeutic potential of a combination treatment with dexamethasone and PPARα agonist GW7647 (GW) in cellular and murine models of rheumatoid arthritis We reveal that GW attenuates dexamethasone-induced adiposity and hypertriglyceridemia in vivo, hereby improving glucocorticoid-related side effects. The therapeutic efficacy of dexamethasone is maintained or even enhanced by GW in murine and cellular models of rheumatic arthritis, respectively. We offer novel mechanistic insights in the proposed combination treatment by revealing the selective suppression of interferon signaling pathways in human FLS. How this study might affect research, practice or policy Given that both synthetic glucocorticoids and PPAR agonists are already used in clinical practice, this study offers a promising, translatable strategy to optimize glucocorticoid-based therapies with an improved efficacy/safety ratio.

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