Mechanisms and Clinical Applications of Glucocorticoid Steroids in Muscular Dystrophy

Abstract

Glucocorticoid steroids are widely used as immunomodulatory agents in acute and chronic conditions. Glucocorticoid steroids such as prednisone and deflazacort are recommended for treating Duchenne Muscular Dystrophy where their use prolongs ambulation and life expectancy. Despite this benefit, glucocorticoid use in Duchenne Muscular Dystrophy is also associated with significant adverse consequences ranging from adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of muscular dystrophy like the limb girdle dystrophies, glucocorticoids are not typically used. Here we review the experimental evidence supporting multiple mechanisms of glucocorticoid action in dystrophic muscle including their role in dampening inflammation and myofiber injury. We also discuss alternative dosing strategies as well as novel steroid agents that are in development and testing, with the goal to reduce adverse consequences of prolonged glucocorticoid exposure while maximizing beneficial outcomes.

Hematopoietic Prostaglandin D Synthase Inhibitor PK007 Decreases Muscle Necrosis in DMD mdx Model Mice

“…Current treatment options for DMD include corticosteroids, such as prednisolone, which inhibit the upstream effectors of the arachidonic pathway COX-1/2 [ 34 ]. Inhibition of COX-1/2 not only inhibits pro-inflammatory PGD2—the immediate product of HPGDS, but, importantly, the inhibition of anti-inflammatory prostaglandins such as PGE2 and PGF2α [ 11 ].…”

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

“…Recently, several novel compounds have emerged which have been approved or await final approval by medicines agencies. This includes the FDA-approved novel corticosteroid Deflazacort that was shown to be associated with improved muscle strength [ 267 ] and agents with conditional approval such as Casimersen for skipping exon 45 resulting in the elevated production of dystrophin in skeletal muscle [ 301 ] and Eteplirsen for skipping of exon 51 which causes delayed loss of ambulation in some patients [ 211 ] and Golodirsen and Viltolarsen for skipping exon 53 resulting in increased dystrophin levels [ 49 , 102 ], as well as the oxadiazole drug named Ataluren, approved by the European Medicines Agency, which is supposed to help restore dystrophin by supressing nonsense mutations [ 22 ]. Ongoing clinical evaluations of further pharmacological interventions that focus on skeletal muscle abnormalities in dystrophinopathy include the anti-inflammatory substances Valmorolone and Cosyntropin, the anti-fibrotic drugs Givinostat and Pamrevlumab and the myostatin inhibitor RO7239361 [ 284 , 298 ].…”

Role of Immunoglobulins in Muscular Dystrophies and Inflammatory Myopathies

“…The majority of IIMs are firstly treated with immunotherapy but often secondary and also tertiary-line agents (chronic steroid-sparing immunosuppressive drugs, methotrexate, azathioprine, rituximab, immunoglobulins) are necessary to allow an amelioration of the pathological muscle signs ( 8 , 9 ). Corticosteroids are recommended for treating Duchenne Muscular Dystrophy (DMD) where their use prolongs ambulation and life expectancy ( 10 , 11 ). Despite this benefit, corticosteroid long-term use in DMD is associated with severe side effects, namely, adrenal suppression, growth impairment, poor bone health and metabolic syndrome.…”

“…Despite this benefit, corticosteroid long-term use in DMD is associated with severe side effects, namely, adrenal suppression, growth impairment, poor bone health and metabolic syndrome. For other forms of MD like the limb girdle muscular dystrophies (LGMDs), corticosteroids are not typically used and only a few clinical trials and anecdotal evidences indicate that some forms of LGMDs may be responsive to steroids ( 10 , 11 ). Intravenous immunoglobulins (IVIG) have been widely used in the treatment of autoimmune neuromuscular disease due to relatively few side effects (fever, myalgia, headache and nausea) and favorable therapeutic outcomes.…”