Emma Matthews, Ruth Brassington, Thierry Kuntzer, Fatima Jichi, Adnan Y Manzur
MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.
Cochrane Database Syst Rev. 2016 May 5;2016(5):CD003725. doi: 10.1002/14651858.CD003725.pub4.
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.
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.
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.
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.
The review authors followed standard Cochrane methodology.
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.
one two-year deflazacort RCT (n = 28) used prolongation of ambulation as an outcome measure but data were not adequate for drawing conclusions.
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.
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.
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.
杜氏肌营养不良症（DMD）是儿童期最常见的肌营养不良症。这种无法治愈的疾病具有X连锁隐性遗传特征，若不治疗，其特点是肌肉萎缩和行走能力丧失，到13岁时会完全依赖轮椅。延长行走时间是治疗的主要目标。随机对照试验（RCT）的证据表明，皮质类固醇在短期内（六个月）能显著提高DMD男孩的肌肉力量和功能，在两年时能提高力量（关于功能的两年数据非常有限）。皮质类固醇现已成为DMD护理建议的一部分，虽在很大程度上已常规使用，但关于其延长行走时间的能力、何时开始治疗、长期的利弊平衡以及皮质类固醇或治疗方案的选择等问题仍然存在。我们扩大了此次更新综述的范围，以纳入不同皮质类固醇和给药方案的比较。
评估皮质类固醇对DMD患者行走能力延长、肌肉力量、功能能力和生活质量的影响；解决长期（超过两年）获益是否能维持的问题；评估不良事件；比较不同皮质类固醇制剂和方案的疗效及不良反应。
2016年2月16日，我们检索了Cochrane神经肌肉专业注册库、CENTRAL、MEDLINE、EMBASE、CINAHL Plus和LILACS。我们写信给已发表研究的作者和其他专家。我们检查了已识别试验中的参考文献，手工检索了期刊摘要，并检索了试验注册库。
我们考虑了对确诊为DMD的患者给予皮质类固醇（如泼尼松、泼尼松龙和地夫可特）至少三个月的随机对照试验或半随机对照试验。我们考虑了不同皮质类固醇、方案以及皮质类固醇与安慰剂的比较。
综述作者遵循Cochrane标准方法。
我们识别出12项研究（667名参与者）和两项新的正在进行的研究以纳入。本次更新新纳入了6项随机对照试验，一些重要的非随机队列研究也已发表。一些重要研究仍未发表，并非所有已发表研究都提供完整的结局数据。
一项为期两年的地夫可特随机对照试验（n = 28）将行走时间延长作为结局指标，但数据不足以得出结论。
荟萃分析表明，皮质类固醇（0.75 mg/kg/天泼尼松或泼尼松龙）与安慰剂相比，在六个月时可改善肌肉力量和功能（来自多达四项随机对照试验的中等质量证据）。单项试验的证据表明，在大多数力量和功能指标上，0.75 mg/kg/天优于0.3 mg/kg/天，几乎没有证据表明1.5 mg/kg/天有进一步获益。从地板起身时间（Gowers时间）、定时步行、四阶楼梯攀爬时间、举重能力、腿部功能分级和用力肺活量均有改善。一项新的随机对照试验（n = 66）报告，每日0.75 mg/kg/天泼尼松在12个月时力量、功能和生活质量更佳。一项随机对照试验（n = 28）表明，地夫可特与安慰剂相比在两年时可稳定肌肉力量，但定时功能测试结果不够精确，无法得出结论。一项双盲随机对照试验（n = 64），在很大程度上偏倚风险较低，比较了每日泼尼松（0.75 mg/kg/天）与仅周末使用泼尼松（5 mg/kg/周末日），发现在12个月时肌肉力量和功能无总体差异（中等至低质量证据）。两项小型随机对照试验（n = 52）比较了每日0.75 mg/kg/天泼尼松与每日0.9 mg/kg/天地夫可特，但研究方法限制了我们比较肌肉力量或功能的能力。
先前已表明，体重过度增加、行为异常、库欣样外貌和毛发过度生长在使用皮质类固醇时比使用安慰剂更常见；我们将证据质量（针对行为改变和体重增加）评估为中等。毛发过度生长和库欣样特征在0.75 mg/kg/天比0.3 mg/kg/天泼尼松更频繁。比较每日与仅周末使用泼尼松，两组均体重增加，体重指数（BMI）或行为改变无明显差异（两项结局均为低质量证据，一项研究）；仅周末使用组身高线性增长更大。极低质量证据表明，地夫可特在12个月时体重增加少于泼尼松，行为异常无差异。数据不足以评估任何比较中骨折或白内障的风险。非随机研究支持随机对照试验的证据，表明皮质类固醇可改善功能获益。这些研究表明长达66个月持续获益。不良反应常见，尽管通常可控制。根据一项对每日或间歇（10天用药，10天停药）皮质类固醇平均为期四年的大型比较纵向研究，每日用药方案可延长七岁以上患者的行走时间并改善功能评分，但副作用发生率高于间歇用药方案。
随机对照试验的中等质量证据表明，DMD患者使用皮质类固醇治疗在短期内（十二个月）可改善肌肉力量和功能，在两年时可改善力量。基于现有关于力量和功能结局的证据，我们对0.75 mg/kg/天或更高剂量泼尼松疗效的效应估计相当有信心。除了非随机试验外，没有证据证实皮质类固醇对延长行走时间的作用。短期内，皮质类固醇的不良反应比安慰剂明显更常见，但临床症状不严重。根据一项单项试验的低至中等质量证据，仅周末使用泼尼松方案在短期内（12个月）与每日泼尼松一样有效，BMI无明显差异（低质量证据）。极低质量证据表明，治疗一年后地夫可特导致的体重增加少于泼尼松。我们无法从已发表随机对照试验评估皮质类固醇治疗或间歇用药方案的长期益处和危害。非随机研究支持功能获益的结论，但也确定了长期治疗的临床显著不良反应，以及长期来看每日与仅周末用药方案在疗效上可能存在差异。这些益处和不良反应对未来研究和临床实践具有启示意义。
