Corticosteroid therapy for Duchenne muscular dystrophy

Review question

Is there new evidence for benefit from corticosteroids for prolongation of walking, and improving muscle strength and functional abilities in Duchenne muscular dystrophy (DMD), particularly over the long term (more than two years)? Are different corticosteroids, or different regimens equally effective, with similar side effect profiles?

Background

DMD is an incurable disease beginning in childhood that almost exclusively affects boys. Muscle wasting and loss of walking lead to wheelchair dependence and early death. Randomised controlled trials (RCTs) have shown that corticosteroids improve muscle strength and function for up to six months and strength up to two years (evidence on function at two years is limited). Data from other study types suggest that corticosteroids produce better function over a five-year period in many patients. Overall, long-term benefit remains unclear, and has to be weighed against long-term side effects. It is also unclear whether different corticosteroids differ greatly in side effects. Earlier versions of this review found insufficient evidence to determine whether an intermittent regimen is as effective as a daily regime, or produces fewer side effects.

Study characteristics

We found 12 studies of corticosteroid treatment in DMD, involving a total of 667 randomised boys; two other studies are ongoing. Among the 12 completed studies, the treatments were: a corticosteroid versus inactive medicine (placebo) (in nine trials); daily versus weekend-only prednisone (in one trial); and deflazacort versus prednisone (in three trials). Some studies included more than one comparison; some were not fully reported or provided results that could not be analysed.

Key results and quality of the evidence

One trial, a two-year study comparing a corticosteroid (deflazacort) with placebo, assessed the effects of corticosteroids on the ability to continue walking, but the data were not suitable for analysis. Most studies did not report ability to continue walking.

At the usual 0.75 mg/kg/day dose, corticosteroids improved muscle strength and function over six months compared to placebo. These results are based on combined data (up to 152 participants) from four trials, which provided moderate quality evidence. Improvements were seen in timed tests (eg. timed walk or run, time to stand, stair climb), ability to lift weights, a leg function grade, and a measure of the strength of muscles used in breathing. Evidence from single trials showed 0.75 mg/kg/day prednisone to be superior to 0.3 mg/kg/day on most strength and function tests, with little evidence of greater benefit at 1.5 mg/kg/day. Changes in appearance and hair growth were more common at 0.75 mg/kg/day than 0.3 mg/kg/day.

One RCT (n = 66) also reported better strength, function and quality of life at 12 months with daily 0.75 mg/kg/day prednisone. The two-year RCT, which had 28 participants, showed that deflazacort stabilised muscle strength for up to two years compared to placebo. This study did not show benefit on timed tests at two years; however, these results are imprecise and at high risk of bias, with less than half the original participants contributing data.

One trial found that changes in muscle strength and function were similar with daily and weekend-only prednisone regimens over a 12-month period (low to moderate quality evidence).

Two small RCTs compared daily prednisone 0.75 mg/kg/day with daily deflazacort 0.9 mg/kg/day, but trial methods did not allow comparisons of muscle strength or function.

Previous versions of this review have found adverse events such as excessive weight gain, abnormal behaviour, changes in appearance, and abnormal hair growth to be more common with corticosteroids than with placebo. We assessed the quality of evidence for abnormal behaviour and weight gain for this review and found it to be moderate. The newer study of daily versus weekend-only prednisone showed that both groups gained weight. The body mass index (BMI; a measure of weight for height) did not show any clear difference between the regimens (low quality evidence). The weekend-only group had a greater increase in height. According to very low quality evidence from two studies, deflazacort appeared to cause less weight gain at one year than prednisone, and no significant difference in numbers with behaviour change. Data were insufficient to assess the risk of fractures or cataracts.

The evidence is up to date to February 2016.

Authors' conclusions: 

Moderate quality evidence from RCTs indicates that corticosteroid therapy in DMD improves muscle strength and function in the short term (twelve months), and strength up to two years. On the basis of the evidence available for strength and function outcomes, our confidence in the effect estimate for the efficacy of a 0.75 mg/kg/day dose of prednisone or above is fairly secure. There is no evidence other than from non-randomised trials to establish the effect of corticosteroids on prolongation of walking. In the short term, adverse effects were significantly more common with corticosteroids than placebo, but not clinically severe. A weekend-only prednisone regimen is as effective as daily prednisone in the short term (12 months), according to low to moderate quality evidence from a single trial, with no clear difference in BMI (low quality evidence). Very low quality evidence indicates that deflazacort causes less weight gain than prednisone after a year's treatment. We cannot evaluate long-term benefits and hazards of corticosteroid treatment or intermittent regimens from published RCTs. Non-randomised studies support the conclusions of functional benefits, but also identify clinically significant adverse effects of long-term treatment, and a possible divergence of efficacy in daily and weekend-only regimens in the longer term. These benefits and adverse effects have implications for future research and clinical practice.

Read the full abstract...
Background: 

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood. Untreated, this incurable disease, which has an X-linked recessive inheritance, is characterised by muscle wasting and loss of walking ability, leading to complete wheelchair dependence by 13 years of age. Prolongation of walking is a major aim of treatment. Evidence from randomised controlled trials (RCTs) indicates that corticosteroids significantly improve muscle strength and function in boys with DMD in the short term (six months), and strength at two years (two-year data on function are very limited). Corticosteroids, now part of care recommendations for DMD, are largely in routine use, although questions remain over their ability to prolong walking, when to start treatment, longer-term balance of benefits versus harms, and choice of corticosteroid or regimen.

We have extended the scope of this updated review to include comparisons of different corticosteroids and dosing regimens.

Objectives: 

To assess the effects of corticosteroids on prolongation of walking ability, muscle strength, functional ability, and quality of life in DMD; to address the question of whether benefit is maintained over the longer term (more than two years); to assess adverse events; and to compare efficacy and adverse effects of different corticosteroid preparations and regimens.

Search strategy: 

On 16 February 2016 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL Plus, and LILACS. We wrote to authors of published studies and other experts. We checked references in identified trials, handsearched journal abstracts, and searched trials registries.

Selection criteria: 

We considered RCTs or quasi-RCTs of corticosteroids (e.g. prednisone, prednisolone, and deflazacort) given for a minimum of three months to patients with a definite DMD diagnosis. We considered comparisons of different corticosteroids, regimens, and corticosteroids versus placebo.

Data collection and analysis: 

The review authors followed standard Cochrane methodology.

Main results: 

We identified 12 studies (667 participants) and two new ongoing studies for inclusion. Six RCTs were newly included at this update and important non-randomised cohort studies have also been published. Some important studies remain unpublished and not all published studies provide complete outcome data.

Primary outcome measure: one two-year deflazacort RCT (n = 28) used prolongation of ambulation as an outcome measure but data were not adequate for drawing conclusions.

Secondary outcome measures: meta-analyses showed that corticosteroids (0.75 mg/kg/day prednisone or prednisolone) improved muscle strength and function versus placebo over six months (moderate quality evidence from up to four RCTs). Evidence from single trials showed 0.75 mg/kg/day superior to 0.3 mg/kg/day on most strength and function measures, with little evidence of further benefit at 1.5 mg/kg/day. Improvements were seen in time taken to rise from the floor (Gowers' time), timed walk, four-stair climbing time, ability to lift weights, leg function grade, and forced vital capacity. One new RCT (n = 66), reported better strength, function and quality of life with daily 0.75 mg/kg/day prednisone at 12 months. One RCT (n = 28) showed that deflazacort stabilised muscle strength versus placebo at two years, but timed function test results were too imprecise for conclusions to be drawn.

One double-blind RCT (n = 64), largely at low risk of bias, compared daily prednisone (0.75 mg/kg/day) with weekend-only prednisone (5 mg/kg/weekend day), finding no overall difference in muscle strength and function over 12 months (moderate to low quality evidence). Two small RCTs (n = 52) compared daily prednisone 0.75 mg/kg/day with daily deflazacort 0.9 mg/kg/day, but study methods limited our ability to compare muscle strength or function.

Adverse effects: excessive weight gain, behavioural abnormalities, cushingoid appearance, and excessive hair growth were all previously shown to be more common with corticosteroids than placebo; we assessed the quality of evidence (for behavioural changes and weight gain) as moderate. Hair growth and cushingoid features were more frequent at 0.75 mg/kg/day than 0.3 mg/kg/day prednisone. Comparing daily versus weekend-only prednisone, both groups gained weight with no clear difference in body mass index (BMI) or in behavioural changes (low quality evidence for both outcomes, one study); the weekend-only group had a greater linear increase in height. Very low quality evidence suggested less weight gain with deflazacort than with prednisone at 12 months, and no difference in behavioural abnormalities. Data are insufficient to assess the risk of fractures or cataracts for any comparison.

Non-randomised studies support RCT evidence in showing improved functional benefit from corticosteroids. These studies suggest sustained benefit for up to 66 months. Adverse effects were common, although generally manageable. According to a large comparative longitudinal study of daily or intermittent (10 days on, 10 days off) corticosteroid for a mean period of four years, a daily regimen prolongs ambulation and improves functional scores over the age of seven, but with a greater frequency of side effects than an intermittent regimen.

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