The Danish Multiple Sclerosis Registry, Department of Neurology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.
National Institute of Public Health, University of Southern Denmark in Copenhagen, Denmark.
Mult Scler Relat Disord. 2019 Jul;32:1-8. doi: 10.1016/j.msard.2019.04.017. Epub 2019 Apr 15.
In multiple sclerosis (MS) the quantitative role of relapses in Expanded Disability Status Scale (EDSS) worsening beyond the recovery phase is not well known. Most studies have examined the predictive role of early relapses in more distant endpoints. Relapses and worsening may be associated because they could be independent effects of the same underlying disease characteristics without causal relationship. With the design of the present study we aim to estimate the direct effect on disability of relapses.
We used data from the obligatory bi-annually registration in the Danish Multiple Sclerosis Registry of relapses and EDSS for all patients treated with disease modifying drugs for relapsing/remitting MS from 1996 to 2015 with exclusion of patients in whom no relapses had ever been recorded during treatment. We paired two consecutive control periods into study intervals which were the actual study units. Study intervals were qualified and included if they were at length 12-24 months, with EDSS ≤ 5.5 at start, and if a preceding relapse had been no closer than nine months to the EDSS assessment at the start or end of the study interval to eliminate relapse-related temporary EDSS worsening. We compared EDSS worsening in study intervals with and without relapses. The same patients could contribute with study intervals with and without relapses. For statistical analyses we used Generalized Estimating Equations to account for intra-patient correlations.
We analysed 5187 study intervals from 2015 MS patients. The mean of EDSS increase was 0.205 units in qualifying study intervals with relapses and 0.065 without relapses when adjusted for length of study interval, sex, and EDSS at start of interval; p < 0.0001. However, the effect of relapses on EDSS was absent in male patients (p = 0.521), and when EDSS was ≥ 4.0 at start of the study interval (p = 0.726).
Relapses play an independent and significant role for worsening of MS in patients under disease-modifying therapy (DMT) and eliminating relapses would not only free the patients from the temporary perils of relapses but would also reduce the worsening of the disease.
在多发性硬化症（MS）中，恢复期后扩展残疾状况量表（EDSS）恶化中复发的定量作用尚不清楚。大多数研究都检查了早期复发对更远端终点的预测作用。复发和恶化可能相关，因为它们可能是同一潜在疾病特征的独立影响，而没有因果关系。通过本研究的设计，我们旨在估计复发对残疾的直接影响。
我们使用了从 1996 年至 2015 年，所有接受疾病修正药物治疗的复发性缓解型 MS 患者在丹麦多发性硬化症登记处强制性每两年登记一次的复发和 EDSS 数据，排除了在治疗期间从未记录过复发的患者。我们将两个连续的对照期配对成研究间隔，作为实际的研究单位。如果研究间隔长度为 12-24 个月，起始时 EDSS≤5.5，且在前一个复发与研究间隔开始或结束时的 EDSS 评估之间至少相隔 9 个月，以消除与复发相关的暂时 EDSS 恶化，则将研究间隔定义为合格并纳入。我们比较了有和无复发的研究间隔中 EDSS 的恶化情况。同一患者可能会为有和无复发的研究间隔做出贡献。为了进行统计分析，我们使用了广义估计方程来考虑患者内相关性。
我们分析了来自 2015 年 5187 名 MS 患者的 5187 个研究间隔。在调整了研究间隔长度、性别和间隔开始时的 EDSS 后，有复发的合格研究间隔中 EDSS 增加平均值为 0.205 单位，无复发的为 0.065 单位；p<0.0001。然而，在男性患者中，复发对 EDSS 的影响不存在（p=0.521），并且当研究间隔开始时 EDSS≥4.0 时（p=0.726），复发对 EDSS 的影响也不存在。
在接受疾病修正治疗（DMT）的患者中，复发对 MS 的恶化起着独立且显著的作用，消除复发不仅可以使患者免受复发的暂时危险，还可以降低疾病的恶化程度。
