Background: Multiple Sclerosis (MS), an autoimmune disease affecting millions worldwide, is characterized by its variable course, in which some patients will experience a more benign disease course and others a more active one, with the latter leading to permanent neural damage and disability. Methods: This study uses a Markov Chain model to demonstrate the probability of movement across different states on the Expanded Disability Status Scale (EDSS) and attempted to define worsening, improvement, cycling, and stability of these different pathways. Most importantly we were interested in assessing the lack of impermanence of confirmed disability worsening and if it could be estimated from the Markov model. Results: The study identified only 8.1% were considered worsening, 5.6% consistent improving and 86% cyclers and less than 1% consistently stable. More importantly we also found that many (approximately 30%) of participants with confirmed disability worsening (CDW) regressed to stages that were not considered worsening, on subsequent visits after CDW. Conclusions: These finding are similar to what has been reported previously as predictors of worsening, and also for a lack of durability of CDW, but our results suggest that clinical trial endpoints may need to be modified to more accurately capture differences between the treatment and control groups. Further, this suggests that the rate of worsening in trials that use time to CDW are overestimating the extent of CDW. The trials remain valid since the regressing applies to both treatment and control groups, but that the results may be underestimating the treatment benefit due to misclassification.

翻译：背景：多发性硬化症（MS）是一种影响全球数百万人的自身免疫性疾病，其病程具有高度变异性：部分患者病程较为良性，而另一部分则呈现活动性进展，后者会导致永久性神经损伤与功能障碍。方法：本研究采用马尔可夫链模型，量化患者在扩展残疾状态量表（EDSS）不同状态间转移的概率，并尝试定义这些不同路径中的恶化、改善、循环及稳定模式。我们重点关注如何评估已确认残疾恶化（CDW）的非持久性现象，并探究其是否可通过马尔可夫模型进行估计。结果：研究发现仅8.1%的患者呈现持续恶化轨迹，5.6%表现为持续改善，86%为循环波动轨迹，不足1%保持持续稳定。更重要的是，约30%经历CDW的受试者在后续随访中会退回到非恶化状态。结论：这些发现与既往报道的恶化预测因子及CDW非持久性特征相符，但结果表明临床试验终点指标可能需要调整，以更精准捕捉治疗组与对照组的差异。此外，使用"至CDW时间"作为终点的试验可能高估了CDW的实际程度。虽然回归现象在治疗组和对照组中均存在使得试验仍具有效性，但错误分类可能导致对治疗获益的低估。