Corticosteroid at low dose may help with muscle damage, inflammation
Pilot study in Becker and limb-girdle MD of prednisone given once weekly
Once a week treatment with a corticosteroid was seen to lower some biomarkers of muscle damage and inflammation, helping to improve muscle function in people with some forms of muscular dystrophy, according to a pilot study in the U.S.
Prednisone was given once weekly for six months to 19 people with limb-girdle muscular dystrophy (LGMD), a disease type that primarily affects the hips and shoulders, and to one adult with Becker muscular dystrophy (BMD), which most often affects the legs. A study aim was to investigate whether such low-dose treatment provides the benefits of corticosteroids without the side effects of long-term use.
“Moving forward, it may be possible to design [blood] markers to more carefully tailor steroid regimens [that] optimize efficacy and minimize adverse consequences,” the researchers wrote in the study, “Serum protein and imaging biomarkers after intermittent steroid treatment in muscular dystrophy,” published in Scientific Reports.
Corticosteroids help treat muscular dystrophy, but side effects rise over time
A group of diseases, muscular dystrophy is caused by mutations that disrupt the activity of genes important for muscle health, leading to muscle weakness and wasting that progressively worsen over time.
Patients are often treated with corticosteroids, or glucocorticoids, to reduce inflammation, but long-term use is linked to obesity, insulin resistance, and osteoporosis, among other side effects. Previous studies in mouse models of muscular dystrophies showed that once-weekly glucocorticoid treatment enhanced muscle strength and reduced tissue fibrosis, or scarring.
Researchers, led by those at Northwestern University in Chicago, conducted the pilot Phase 2 trial Weekly Steroids in Muscular Dystrophy (NCT04054375) to evaluate the safety and efficacy of weekly treatment with prednisone in people with LGMD or BMD.
Patients, recruited from the university’s Muscular Dystrophy Association clinic between June 2019 and January 2020, had a mean age of 35 and most were male (65%). Nineteen had one of the five subtypes of LGMD — 2A/R1, 2B/R2, 2I/R9, 2J/R10, and 2L/R12 — and were at different disease stages, while one participant had BMD. Sex- and age-matched healthy adults were included as a control group for comparison.
All provided blood samples to identify differentially expressed proteins at baseline (study’s start) and, for patients, after six months of weekly treatment with prednisone at a dose of 0.75 to 1 mg/kg, depending on a person’s body mass.
A total of 507 proteins considered muscular dystrophy biomarkers were identified, with 109 found at higher baseline levels and 398 at lower baseline levels in patients than in controls. Proteins at increased levels were mainly associated with muscle tissue function and differentiation (when cells become specialized), in line with the leak of muscle proteins into the bloodstream due to muscle tissue breakdown.
Conversely, proteins at lower levels were associated with cell attachment to neighbor cells, organization and stabilization of cellular structures, and regulation of calcium levels inside cells. For example, ANXA1, “a membrane-stabilizing and immunosuppressive biomarker,” was lower in patients than controls, the researchers noted.
Intermittent steroid use led to expected changes in protein levels
Six months of intermittent glucocorticoid treatment significantly increased the levels of 24 proteins and decreased those of 132 others, largely in line with the known effects of glucocorticoids on the immune system. Among proteins at lower levels were several responsive in the TNF-alpha and interferon-gamma inflammatory pathways, which are implicated in the progression of muscular dystrophies.
Proteins whose levels increased after treatment mainly were associated with muscle growth, regeneration, and repair.
“Overall, these findings indicate that this relatively low, once-weekly dose of prednisone modulated inflammatory pathways in [patients],” the researchers wrote.
Treatment also led to shifts toward normalized levels of several muscular dystrophy-associated proteins. For instance, MMP3 and MMP8 — proteins involved in cell regeneration — rose significantly after 24 weeks of prednisone, while CCL21 and CCL22, associated with immune pathways, significantly declined.
According to the researchers, “this ‘normalizing’ effect of once weekly prednisone was similar to higher doses used in the DMD [Duchenne muscular dystrophy] patients and may indicate these biomarkers are especially relevant to mitigating the muscular dystrophy process.”
Thirteen patients underwent MRI evaluation for fat fraction in leg muscles — muscle tissue that is replaced by fat as a result of muscle breakdown. Most showed a “small trend” toward a greater fat fraction during the study, which negatively correlated with measures of muscle function.
Possibility of muscle repair with low-dose corticosteroid use for 6 months
Results further showed a maintenance or increase in lean mass and reduced creatine kinase — a marker of muscle damage.
“The change in CKM [creatine kinase] over the 6 months of prednisone treatment suggested that those with greater reduction in CKM had greater gain in functional status, so that change in CKM over this short time frame may reflect improved muscle repair or membrane stability,” the scientists wrote.
Overall, once-weekly steroid dosing was well tolerated with few side effects over six months.
Study findings “can help guide larger and more informative studies to use glucocorticoids to treat muscular dystrophy beyond DMD,” the scientists concluded.
Among the study’s limitations, they mentioned its small number of patients, their varying mutations, and variability in their functional status, “including younger individuals who were nonambulatory and older participants who retained ambulation.”
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