Giovannoni Gavin, Cutter Gary, Sormani Maria Pia, Belachew Shibeshih, Hyde Robert, Koendgen Harold, Knappertz Volker, Tomic Davorka, Leppert David, Herndon Robert, Wheeler-Kingshott Claudia A M, Ciccarelli Olga, Selwood David, di Cantogno Elisabetta Verdun, Ben-Amor Ali-Frederic, Matthews Paul, Carassiti Daniele, Baker David, Schmierer Klaus
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
Department of Biostatistics, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
Mult Scler Relat Disord. 2017 Feb;12:70-78. doi: 10.1016/j.msard.2017.01.007. Epub 2017 Jan 17.
Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms. However, anti-inflammatory therapies may modify these damaged pathways, but with a therapeutic lag that may take years to manifest. Based on these observations we propose that clinically apparent neurodegenerative components of progressive MS may occur in a length-dependent manner and asynchronously. If this hypothesis is confirmed it may have major implications for the future design of progressive MS trials.
除了最近针对原发性进行性多发性硬化症（MS）的抗CD20疗法和继发性进行性MS中的S1P调节剂西尼莫德外，抗炎疗法在非复发性进展性MS试验中一直呈顽固的阴性结果。我们认为，这可能是因为试验时间过短，且专注于评估神经元通路，而作为主要结局核心组成部分的储备能力不足。由先前炎症引发的延迟性神经轴突退变预计不会对针对MS特异性机制的疾病修饰疗法产生反应。然而，抗炎疗法可能会改变这些受损通路，但治疗延迟可能需要数年才能显现。基于这些观察结果，我们提出进行性MS临床上明显的神经退行性成分可能以长度依赖性方式异步发生。如果这一假设得到证实，可能会对未来进行性MS试验的设计产生重大影响。
