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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant, 4q35-linked, slowly progressive muscular dystrophy with no known effective treatment. Since prednisone improves strength in Duchenne dystrophy, we performed a pilot, open-label trial of prednisone in eight subjects fulfilling strict diagnostic criteria for FSHD. Prednisone (1.5 mg/kg/day; maximum 80 mg/day) was administered for 12 weeks. Manual muscle testing, maximum voluntary isometric contraction testing, and muscle mass estimations by dual energy x-ray absorptiometry and urinary creatinine excretion were performed at baseline and at 12 weeks. There were no significant changes in strength or muscle mass. We conclude that prednisone given for 12 weeks does not produce major improvement in strength or increase muscle mass in FSHD. The study did not have sufficient power or length of follow-up to address the possibility that prednisone might arrest or slow disease progression.

Prednisone improves strength in Duchenne dystrophy and changes the natural history of the disease. We studied the in vivo effects of prednisone (0.75 mg.kg-1.day-1) on muscle and whole body protein metabolism in six patients with Duchenne dystrophy and three patients with Becker dystrophy. Patients were admitted to the Clinical Research Center for study and consumed a constant flesh-free diet. Strength was measured by manual and quantitative muscle testing. Fractional muscle protein breakdown was estimated by the ratio of 3-methylhistidine to creatinine excretion determined in three consecutive 24-h urine collections. Whole body protein kinetics were studied in the postabsorptive state using a primed continuous infusion of L-[1-13C]leucine. Fractional muscle protein synthesis was determined from tracer incorporation into noncollagen muscle protein obtained by needle biopsy. After 6-8 wk of prednisone treatment, average muscle strength increased by 15% (P < 0.04), and 24-h creatinine excretion (an index of muscle mass) increased by 21% (P = 0.002). 3-Methylhistidine excretion decreased by 10%, but the change was not statistically significant. The ratio of 3-methylhistidine to creatinine excretion decreased by 26% (P < 0.04). Fractional muscle protein synthesis and whole body protein synthesis and breakdown did not change significantly. We conclude that the beneficial effect of prednisone on strength in Duchenne dystrophy appears to be associated with an increase in muscle mass, which may be mediated by inhibition of muscle proteolysis rather than stimulation of muscle protein synthesis.

Prednisone improves strength and function in patients with Duchenne dystrophy. Although the mechanism of this effect is uncertain, prior studies suggested that the benefit might result from immunosuppressive effects on T lymphocytes invading muscle. A recent randomized, double-blind, controlled trial of prednisone and azathioprine demonstrated that azathioprine had no effect in Duchenne dystrophy, raising questions about the role of immunosuppression in mediating clinical improvement. The goal of this current study was to compare the effects of prednisone and azathioprine on mononuclear infiltrates from biopsies performed at the end of the controlled clinical trial (reported separately in the article by Griggs et al on page 520). We studied 14 patients from the prednisone group (0.75 mg/kg/d), 10 from the combination therapy group (prednisone 0.3 mg/kg/d and azathioprine 2.5 mg/kg/d), and 13 from the azathioprine group (2.5 mg/kg/d), and used monoclonal antibodies for cell typing. There were no significant differences between the groups for total T cells, T-cell subsets, B cells, natural killer cells, total mononuclear cells, necrotic muscle fibers, or fibers focally invaded by mononuclear cells. These data indicate that azathioprine decreases mononuclear subsets infiltrating muscle to a similar degree as does prednisone, although azathioprine-treated patients do not show a clinical improvement. This implies that immunosuppressive actions on cellular infiltrates in muscle are probably not the primary mechanism of prednisone-induced clinical improvement.

Prednisone has been shown to improve strength in Duchenne dystrophy. Azathioprine often benefits corticosteroid-responsive diseases and can reduce the dose of prednisone needed. The present study reports a randomized, controlled trial of prednisone and azathioprine designed to assess the longer-term effects of prednisone and to determine whether azathioprine alone, or in combination with prednisone, improves strength. Ninety-nine boys (aged five to 15 years) with Duchenne dystrophy were randomized to one of three groups: (I) placebo; (II) prednisone 0.3 mg/kg/d; or (III) prednisone 0.75 mg/kg/d. After 6 months, azathioprine 2 to 2.5 mg/kg/d was added in groups I and II and placebo added in group III. The study showed that the beneficial effect of prednisone (0.75 mg/kg/d) is maintained for at least 18 months and is associated with a 36% increase in muscle mass. There was weight gain, growth retardation, and other side effects. Azathioprine did not have a beneficial effect. This study suggests that prednisone's beneficial effect is not due to immunosuppression.

Two successive, 6-month, randomized, double-blind, controlled trials of prednisone showed that 0.75 mg/kg/d was the optimal dose to improve strength in boys with Duchenne muscular dystrophy (DMD). We attempted to maintain 93 boys on that dose for an additional 2 years. During the 3 years of observation, the decline in average muscle strength scores of all boys taking prednisone was 0.072 units/yr, as compared with an expected decline of 0.341 units/yr from natural history controls. The occurrence of side effects in some boys prevented maintenance of the full dose, which may have lessened the response. At the time of last visit, dosages ranged from 0.15 mg/kg to 0.75 mg/kg. In addition to maintaining their strength, several of the boys actually improved their performance in lifting kilogram weights and in some timed function tests. Treatment of DMD with prednisone significantly slows the progression of weakness and loss of function for at least 3 years.

We previously reported the results of a randomized, double-blind 6-month trial of prednisone therapy in which 102 boys aged 5 to 15 years with Duchenne muscular dystrophy received daily doses of 1.5 and 0.75 mg/kg per day and were compared with those receiving placebo. The strength and function in both prednisone-treated groups improved equally and were significantly better than in the placebo group. To compare alternate-day and daily dosing of prednisone with respect to benefits and adverse side effects, the placebo group was started on alternate-day prednisone therapy, and the treatment group regimens were changed to equivalent doses of alternate-day prednisone without breaking the double-blind nature. At the end of 6 months, the group that was changed from daily to alternate-day therapy had declined in strength back to levels observed 12 months previously, at the start of daily therapy. The group in which alternate-day therapy was started showed a significant improvement in strength at 3 months, similar in magnitude to the response of boys treated with daily therapy. However, their strength declined significantly in the subsequent 3 months compared with boys who received daily therapy. The frequency of side effects was not significantly different for alternate-day therapy compared with daily therapy. We conclude that alternate-day prednisone therapy effectively increases strength but does not sustain the improvement to the same extent as daily therapy or mitigate side effects.

A randomized, controlled trial of daily prednisone was conducted in 99 boys (aged 5 to 15 years) with Duchenne dystrophy to define the time course of improvement and the dose response to treatment. Prednisone at 0.3 mg/kg (n = 33), prednisone at 0.75 mg/kg (n = 34), and placebo (n = 32) were administered for 6 months. Patients were examined using manual muscle and myometry testing, timed functional testing, pulmonary function testing, and laboratory measurements at 10 days, 1 month, 2 months, 3 months, and 6 months of treatment. Boys treated with prednisone had stronger average muscle strength scores, than did boys treated with placebo as early as 10 days after starting therapy. At the 3-month visit, the boys in the group given 0.75 mg/kg of prednisone were significantly stronger than those in the group given 0.3 mg/kg of prednisone, indicating a dose response. At 6 months, significant side effects occurred in the group treated with 0.75 mg/kg of prednisone, including weight gain, cushingoid appearance, and excessive hari growth. Only weight gain was observed in the group taking prednisone at a dose of 0.3 mg/kg. Importantly, no side effects were evident at 10 days or 1 month of treatment, despite improvement in muscle strength and function. We conclude that prednisone produces a rapid increase in muscle strength in patients with Duchenne dystrophy and that this improvement is maximal at a prednisone dosage of 0.75 mg/kg or less.

We investigated the effect of high-dose prednisone therapy in 33 boys with Duchenne muscular dystrophy. The drug was given daily in doses of 1.5 mg/kg of body weight (to a maximum of 80 mg) for six months. Muscle strength, joint contractures, timed functional tests, functional ability, and pulmonary function were measured at the beginning and end of the treatment period. The trial was designed using natural history controls, and the power of the study was 0.80 to detect a slowing of 50% in the rate of progression. During the period of the trial, muscle strength, functional grades, timed functional tests, and pulmonary function improved. Contractures followed the expected natural history of the illness.

We performed a randomized, double-blind, controlled six-month trial of prednisone in 103 boys with Duchenne's muscular dystrophy (age, 5 to 15 years). The patients were assigned to one of three regimens: prednisone, 0.75 mg per kilogram of body weight per day (n = 33); prednisone, 1.5 mg per kilogram per day (n = 34); or placebo (n = 36). The groups were initially comparable in all measures of muscle function. Both prednisone groups had significant improvement of similar degree in the summary scores of muscle strength and function. Improvement began as early as one month and peaked by three months. At six months the high-dose prednisone group, as compared with the placebo group, had improvement in the time needed to rise from a supine to a standing position (3.4 vs. 6.2 seconds), to walk 9 m (7.0 vs. 9.7 seconds), and to climb four stairs (4.0 vs. 7.1 seconds), in lifting a weight (2.1 vs. 1.2 kg), and in forced vital capacity (1.7 vs. 1.5 liters) (P less than 0.001 for all comparisons). There was an increase in urinary creatinine excretion (261 vs. 190 mg per 24 hours), which suggested an increase in total muscle mass. However, the prednisone-treated patients who had required long-leg braces (n = 5) or wheelchairs (n = 11) continued to require them. The most frequent side effects were weight gain, cushingoid appearance, and excessive hair growth. We conclude from this six-month study that prednisone improves the strength and function of patients with Duchenne's muscular dystrophy. However, further research is required to identify the mechanisms responsible for these improvements and to determine whether prolonged treatment with corticosteroids may be warranted despite their side effects.

Daily regimens of prednisone (PDN), deflazacort (DFZ) and vamorolone (VAM) have all been shown to be efficacious in treatment of Duchenne Muscular Dystrophy (DMD) by improving muscle function. The objective of this analysis is to compare the effect of PDN, DFZ and VAM on muscle function after 1 year of treatment in DMD patients aged 4 to <7 years at the time of treatment initiation. Data were analyzed from two randomized, double-blind studies (FOR-DMD and VISION-DMD). Two groups from the FOR-DMD study (daily PDN 0.75 m/kg/day and daily DFZ 0.9 mg/kg/day) were compared to patients treated with VAM 6.0 mg/kg/day in the VISION-DMD study. Data between the studies were matched based on propensity scores which were calculated using baseline age, time to stand (TTSTAND) velocity, NSAA score, weight z-score and height z-score. The data on TTSTAND velocity and other measures of motor function were compared using Mixed Model for Repeated Measures (MMRM) with propensity score weighting. Based on the propensity scores, 39 PDN and 47 DFZ treated patients were extracted from the FOR-DMD study and 27 VAM treated patients from the VISION-DMD study. All patients were glucocorticoid naïve at baseline with an average (SD) age of 5.4 (0.6), 5.4 (0.8) and 5.5 (0.9) years for PDN, DFZ and VAM groups, respectively. After 48 to 52 weeks of treatment, the least square mean (LSM) TTSTAND velocity increased in all treatment groups by 0.04 rises/sec, with no significant LSM difference between PDN vs VAM (0.002; 95% CI -0.033 to 0.037; p=0.929) or DFZ vs VAM (0.002; 95% CI -0.029 to 0.032; p=0.923). In other efficacy measures (6-minute walk test, NSAA score, time to run/walk 10 meters velocity), comparable increases were seen in all three treatment groups, with no statistically significant differences between PDN vs VAM or DFZ vs VAM. These data show that daily regimens of prednisone, deflazacort and vamorolone have comparable effect in improving motor function in patients with DMD. [ABSTRACT FROM AUTHOR]

Daily glucocorticoid treatment has an impact on height and weight in patients (pts) with DMD. The objective of this analysis is to compare the effect of prednisone (PDN), deflazacort (DFZ) and vamorolone (VAM) on height and body mass index (BMI) in DMD pts aged 4 to <7 years at the start of treatment. Boys treated with PDN 0.75 mg/kg/day(n=55) or daily DFZ 0.9 mg/kg/day (n=49) from the FOR-DMD study were compared to pts treated with VAM 2.0 (n=28) or 6.0 mg/kg/day (n=28) in the VISION-DMD study (up to 48-weeks) or treated with 2-6 mg/kg/d flexible dosing in the VBP15-LTE study (n= 46) (up to 2.5 years). Height and BMI z-scores were calculated using the CDC growth data and annualized slopes of changes over 1 year (FOR-DMD versus VISION-DMD) and over 2.5 years (FOR-DMD versus VBP15-LTE) were analyzed. At Week 48-52, H z-score decreased -0,30 SDS in the FOR-PDN and -0,50 SDS in the FOR-DFZ group while it increased +0,16 SDS in the VIS-VAM 2 and +0,29 in the VIS-VAM 6 cohorts. After 30 months of treatment. the H z-score decreased -0,69 SDS in the FOR-PDN and -1,0 SDS in the FOR-DFL boys and increased 0,09 SDS in the LTE-VAM patients At Week 48-52 and at 2.5 years, most of the pts (>70%) in all groups had higher BMI z-scores than at baseline. After 2.5 years of treatment, large increases of BMI (>0.5, >0.75 or >1.0 SDS) were seen most frequently in DFZ and PDN groups and the change in BMI z-score was less with VAM than with PDN and DFL when the baseline BMI was taken into account (conditional BMI change analysis). In conclusion, this between study comparisons suggest that daily vamorolone has less effect of height and BMI than daily prednisone or deflazacort. [ABSTRACT FROM AUTHOR]

Vertebral fractures (VF) cause excess morbidity in glucocorticoid (GC)-treated DMD. Vamorolone (VAM/VBP15) is a dissociative steroid that retains anti-inflammatory properties with reduced positive transcriptional activity, leading to fewer side effects in pre-clinical studies compared with classic GC. We determined VF burden in VAM-treated boys vs. boys treated with daily deflazacort (DEFLAZ DAILY), daily prednisolone (PRED DAILY), and intermittent prednisolone (PRED INT). 39 boys from VBP15-LTE study were compared to 68 boys from FOR-DMD (all ambulatory, steroid-naïve). In VBP15-LTE, boys 4 to <7 years-old initiated VAM 0.25, 0.75, 2.0, or 6.0 mg/kg/d for 6 months, followed by permitted dose escalations/de-escalations for 2 years. In FOR-DMD, boys 4 to <8 years-old were randomized to DEFLAZ DAILY (0.9mg/kg/d), PRED DAILY (0.75mg/kg/d) or PRED INT (0.75mg/kg/d 10 days on/off). VF were read centrally on x-rays (Genant method, T4 to L4) after 30 (VAM) or 36 (classic GC) months. In the VAM group, VF parameters were adjusted (adj) for shorter duration by a factor of 1.2 (36/30 months), as appropriate. Mean age of boys on classic GC was 8.8±1.1 and on VAM 8.0±1.0 years. VF burdens: 1. VF prevalence: PRED DAILY 7/24 boys (29.2%), DEFLAZ DAILY 4/21 (19.0%), VAM 4/39 (10.3%; 12.3% adj), PRED INT 0/23; 2. Highest fracture severity: DEFLAZ DAILY moderate (n=1, 9.5%), PRED DAILY mild (N=7, 100%), VAM mild (n=4; 100%), and PRED INT N/A; 3. Average number of VF/child with VF: PRED DAILY 1.3, DEFLAZ DAILY 1.3, VAM 1.0; 1.2 adj and PRED INT 0; 4. Maximum Spine Deformity Index (SDI, sum of VF Grades): DEFLAZ DAILY 6, PRED DAILY 4, VAM 1; PRED INT 0; and 5. Average SDI/child with VF: DEFLAZ DAILY 3.0, PRED DAILY 2.7, VAM 1.0; 1.2 adj, and PRED INT 0. VF burden was higher on PRED DAILY and DEFLAZ DAILY than VAM but lowest on PRED INT. VAM may be a bone-sparing strategy to improve muscle strength. Longer-term follow-up is needed to assess comparative effects on VF burden relative to muscle strength. [ABSTRACT FROM AUTHOR]