Selmaj Krzysztof, Hartung Hans-Peter, Mycko Marcin P, Selmaj Igor, Cross Anne H
Department of Neurology, University of Warmia & Mazury, Olsztyn, Poland.
Center of Neurology, Lodz, Poland.
J Neurol. 2024 Oct;271(10):6426-6438. doi: 10.1007/s00415-024-12584-x. Epub 2024 Aug 2.
Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.
几乎所有目前获批用于治疗多发性硬化症（MS）的疾病修正疗法（DMTs）即便不需要终身使用，也需要长期给药。然而，随着人们年龄的增长，免疫系统的反应性会逐渐降低，即免疫衰老。许多MS DMTs会降低免疫系统的反应性，增加感染甚至癌症的风险。随着MS患者（pwMS）年龄的增长，炎症性MS活动会下降，这一点已得到公认。多项研究探讨了在特殊情况下对复发型MS患者减少DMTs用药剂量的问题。在此，我们综述了将减少DMTs用药剂量作为一种策略的证据，该策略对老年pwMS患者尤为重要。治疗减量可涉及多种策略，如延长给药间隔或减少剂量、从风险较高的高效DMTs转换为风险较低的中度有效DMTs，或停止治疗。研究表明，对于那他珠单抗，延长给药间隔可维持临床疗效，同时降低进行性多灶性白质脑病（PML）的风险。奥瑞珠单抗延长给药间隔可减轻免疫球蛋白水平的下降。回顾性和观察性停药研究表明，年龄是药物疗效的重要调节因素。老年患者停止MS治疗与疾病进程稳定相关，而年轻患者停止治疗后更易出现新的临床活动。最近一项针对260例年龄大于55岁的稳定pwMS患者进行的为期2年的随机对照停药研究发现，停药后临床多发性硬化症病情稳定，仅新发MRI活动风险略有增加。对于年龄大于55岁的MS患者，减少DMTs用药剂量或停药可能并不劣于继续使用健康风险更高的免疫抑制剂治疗。然而，尽管有几项小型研究，但要得出关于老年pwMS患者治疗减量的确切结论，仍需要规模更大、时间更长的研究。理想情况下，应通过前瞻性随机对照试验对DMTs减量、继续用药和停药进行比较，纳入足够数量的受试者，以便对不同年龄组（如55 - 59岁、60 - 65岁、66 - 69岁等）的男女MS患者进行比较。最佳的是，此类研究应持续3年或更长时间，并应纳入对免疫衰老特异性标志物（如T细胞受体切除环）的检测，以考虑个体的不同衰老情况。
