NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, Great Ormond Street Hospital Trust, University College London, London, UK; Solid Biosciences, London, UK.
NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, Great Ormond Street Hospital Trust, University College London, London, UK; Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, Great Ormond Street Hospital Trust, London, UK.
Neuromuscul Disord. 2019 Apr;29(4):261-268. doi: 10.1016/j.nmd.2019.02.002. Epub 2019 Feb 19.
The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5-18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI [-7.44,-0.72], p = 0.02 in ambulant; 4.81, 95% CI [-6.79,-2.82], p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI [-6.48,-4.45], p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI [-4.79,3.47], p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force -5.51%, 95% CI [-6.54,-4.48], p < 0.001 in ambulant and a slower decline -2.86%; 95% CI -3.29,-2.43, p < 0.001, in non-ambulant; pinch force: -2.66%, 95% CI [-3.82,-1.51], p < 0.001 in ambulant and -2.23%, 95% CI [-2.92,-1.53], p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.
在过去的十年中，许多治疗靶点改变了杜氏肌营养不良症（DMD）的转化研究领域，这些靶点主要在能行走的患者中进行研究。缺乏针对疾病非行走阶段和行走与非行走阶段过渡的研究。在这项前瞻性自然史研究中，我们报告了在 3 个欧洲国家中对 89 名 DMD 男孩进行的一组全面评估的结果，这些男孩接受了广泛的年龄范围（5-18 岁）和功能能力的治疗，包括能行走（n=60）和不能行走（n=29）。尽管使用了糖皮质激素，但使用呼气峰流速百分比预测值（PEF%）仍可在早期行走阶段检测到呼吸下降（能行走者平均每年下降 4.08%（95%CI [-7.44，-0.72]，p=0.02）；不能行走者平均每年下降 4.81%（95%CI [-6.79，-2.82]，p<0.001））。FVC%在不能行走的 DMD 患者中捕获了疾病进展，每年损失 5.47%（95%CI [-6.48，-4.45]，p<0.001）。使用上肢运动表现（PUL 1.2）测量的上肢功能显示非行走队列每年损失 4.13 分（95%CI [-4.79，3.47]，p<0.001）。当以上肢力量的百分比预测值报告时，上肢力量（握力-5.51%，95%CI [-6.54，-4.48]，p<0.001，在能行走者中；握力下降速度较慢-2.86%；95%CI -3.29，-2.43，p<0.001，在不能行走者中；捏力-2.66%，95%CI [-3.82，-1.51]，p<0.001，在能行走者中；捏力-2.23%，95%CI [-2.92，-1.53]，p<0.001，在不能行走者中）。此外，我们还探索了通过结合呼吸、上肢功能和力量域来构建复合终点的新概念：我们能够识别出在只有这些域中的一个单独测量无法评估每年变化的情况下，患者中明显的临床进展。我们的研究为 DMD 的自然史领域做出了贡献，将疾病的行走和非行走阶段联系起来，并表明应进一步探索复合评分。
