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

ObjectivesGlucocorticoids 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 PPAR agonism could enhance the therapeutic efficacy and/or mitigate the (metabolic) side effects of glucocorticoids. MethodsWe evaluated the effects of the synthetic glucocorticoid dexamethasone and the PPAR agonist GW7647 (GW) across three RA model systems: L929sA fibroblasts, primary human fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA) mice. ResultsDexamethasone reduced the inflammatory TNF 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 TNF-stimulated human FLS revealed that combined use of dexamethasone and GW selectively suppressed interferon-stimulated proteins. In line herewith, co-stimulation with TNF and IFN{beta} amplified the suppressive effect of combined dexamethasone and GW treatment on pro-inflammatory gene expression in L929sA versus TNF alone. ConclusionGW 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, PPAR 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 MESSAGESO_ST_ABSWhat is already known on this topicC_ST_ABSO_LISynthetic glucocorticoids such as dexamethasone are widely used as immunosuppressive drugs, but cause many (metabolic) side effects. C_LIO_LIPeroxisome-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. C_LI What this study addsO_LIThis study explores the therapeutic potential of a combination treatment with dexamethasone and PPAR agonist GW7647 (GW) in cellular and murine models of rheumatoid arthritis C_LIO_LIWe reveal that GW attenuates dexamethasone-induced adiposity and hypertriglyceridemia in vivo, hereby improving glucocorticoid-related side effects. C_LIO_LIThe therapeutic efficacy of dexamethasone is maintained or even enhanced by GW in murine and cellular models of rheumatic arthritis, respectively. C_LIO_LIWe offer novel mechanistic insights in the proposed combination treatment by revealing the selective suppression of interferon signaling pathways in human FLS. C_LI How this study might affect research, practice or policyO_LIGiven 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. C_LI