Background: Glucocorticoids (GC) treatment in myositis is empirical and side effects are frequent. Both therapeutic and iatrogenic effects of GC are mediated by glucocorticoid receptor (GR) which is ubiquitously expressed. We have recently shown in experimental myositis (EM) induced in GR(i)skm-/- mice that prednisone (PDN) induces a myofibre-mediated anti-inflammatory phenotype in immune cells. Muscle transcriptomic analysis indicated that PDN induces myofibres release of epinephrine that could mediate therapeutic response. Epinephrine effect depends on its binding to the β-adrenergic receptors (β-AR). β2-AR are the most expressed in immune cells.

Objectives: The aim of this study was to investigate the importance of β-adrenergic pathway activation in the therapeutic response to PDN in preclinical models of myositis.

Methods: Human myotubes were treated with proinflammatory cytokines for 2 days. Then, PDN (or vehicle) was added with or without a GR inhibitor for 5 days. EM was induced at day 0 (D0) in 10-week-old mice through the immunisation against a polypeptide from skeletal muscle fast-type C protein. From D14 to D20, mice were treated with oral PDN at the dose of 1 mg/kg/day for 7 days (or vehicle), with or without a β-blocker at the same dose, or with an oral β2-agonist (6 mg/kg/day for 7 days). Muscle strength was assessed at D0, D14 and D20 before the sacrifice (D21). Serum creatine-kinase (CK) levels were assessed at D21.

Results: PDN increased by 2-fold the epinephrine level in the supernatant of human myotubes treated with proinflammatory cytokines. This effect of PDN was suppressed when a GR inhibitor was added. In vehicle-treated EM mice, a 20% decrease in muscle strength was found at D14 (p=0.0001) up to D20 (p=0.0001) compared to D0. PDN-treated EM mice recovered muscle strength at D20 (p=0.008 vs D14). This effect of PDN was abolished when a β-blocker was co-administered (p=0.0001 vs D0). At sacrifice, CK serum levels were 2 times higher in vehicle-treated EM mice compared to unimmunized mice (p=0.004). PDN normalized CK serum levels in EM mice. This effect of PDN was suppressed when a β-blocker was co-administered (p=0.008 vs unimmunized mice). Conversely, a treatment with a β2-agonist reproduced PDN therapeutic effect on muscle weakness as well as on CK level. These results show that PDN improves myositis in EM through myofibre production of epinephrine and β-adrenergic pathway activation.

Conclusion: Coadministration of β-blockers might decrease PDN therapeutic effect in myositis. Stimulation of β2-adrenergic pathway might represent a new therapeutic strategy for myositis.

REFERENCES: [1] Giannini M et al. DOI: 10.1136/annrheumdis-2023-eular.5217.

Acknowledgements: NIL.

Disclosure of Interests: None declared.