Leary Siobhan M, Thompson Alan J
Institute of Neurology, University College London, Queen Sqaure, London, UK.
CNS Drugs. 2005;19(5):369-76. doi: 10.2165/00023210-200519050-00001.
Approximately 10% of patients with multiple sclerosis (MS) run a primary progressive course characterised by an accumulation of neurological deficits without relapse or remission. Designing therapeutic trials in primary progressive MS (PPMS) has presented several problems. Patient recruitment may be difficult because of the relative rarity of PPMS and historically has been hindered by the lack of specific diagnostic criteria. There has been a limited choice of validated outcome measures, although, in recent studies, the MS functional composite measure and magnetic resonance imaging measures of lesion load and atrophy have been widely used. Despite these problems, several trials have been designed specifically for PPMS, including exploratory randomised controlled trials of interferon-beta-1a and interferon-beta-1b and mitoxantrone, a phase III trial of glatiramer acetate, and an open-label study of riluzole. Patients with PPMS have also been included in randomised controlled trials of azathioprine, methotrexate, cladribine, intravenous immunoglobulin and cyclophosphamide, and open-label studies of haematopoietic stem cell transplantation and pirfenidone in progressive MS. However, no treatment has been proven definitively to modify the course of the disease. Looking to the future, therapeutic agents should aim to target the underlying pathogenic mechanisms in PPMS. As a result of the relative lack of inflammation in PPMS, neuroprotective agents that target neuronal loss directly, rather than inflammation, may be more worthwhile. However, further investigation into the pathogenic mechanisms in PPMS is required to guide the development of future therapeutic agents.
约10%的多发性硬化症（MS）患者呈原发性进行性病程，其特征为神经功能缺损不断累积，无复发或缓解。在原发性进行性MS（PPMS）中设计治疗试验存在若干问题。由于PPMS相对罕见，患者招募可能困难，而且历史上一直因缺乏特异性诊断标准而受阻。尽管在最近的研究中，MS功能综合测量以及病灶负荷和萎缩的磁共振成像测量已被广泛使用，但经过验证的结局测量方法选择有限。尽管存在这些问题，仍设计了多项专门针对PPMS的试验，包括干扰素-β-1a、干扰素-β-1b和米托蒽醌的探索性随机对照试验、醋酸格拉替雷的III期试验以及利鲁唑的开放标签研究。PPMS患者也被纳入了硫唑嘌呤、甲氨蝶呤、克拉屈滨、静脉注射免疫球蛋白和环磷酰胺的随机对照试验，以及造血干细胞移植和吡非尼酮治疗进行性MS的开放标签研究。然而，尚无治疗方法被明确证明可改变疾病进程。展望未来，治疗药物应旨在针对PPMS的潜在致病机制。由于PPMS中炎症相对缺乏，直接针对神经元丢失而非炎症的神经保护药物可能更有价值。然而，需要对PPMS的致病机制进行进一步研究，以指导未来治疗药物的开发。
