Salter Amber, Lancia Samantha, Kowalec Kaarina, Fitzgerald Kathryn C, Marrie Ruth Ann
Department of Neurology, Section on Statistical Planning and Analysis, UT Southwestern Medical Center, Dallas, Texas.
Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas.
JAMA Neurol. 2024 Sep 18;81(11):1170-7. doi: 10.1001/jamaneurol.2024.2920.
Multiple studies suggest that comorbidity worsens clinically relevant outcomes in multiple sclerosis (MS), including the severity of disability at diagnosis and rate of disability worsening after diagnosis. However, less is known regarding the association of comorbidity with measures of disease activity, such as relapse rate and magnetic resonance imaging lesion accrual, which are relevant to clinicians and clinical trialists.
To evaluate the association of comorbidities with disease activity in clinical trials of disease-modifying therapies (DMTs) in populations with MS.
DESIGN, SETTING, AND PARTICIPANTS: A 2-stage meta-analytic approach was used in this cohort study of individual participant data from phase 3 clinical trials of MS DMTs that had 2 years of follow-up and were conducted from November 2001 to March 2018. Data were analyzed from February 2023 to June 2024.
Comorbidity burden and individual comorbidities present at trial enrollment, including hypertension; hyperlipidemia; functional cardiovascular disease, ischemic heart, cerebrovascular, and peripheral vascular disease; diabetes; autoimmune thyroid and miscellaneous autoimmune conditions; migraine; lung and skin conditions; depression; anxiety; and other psychiatric disorders.
The main outcome was evidence of disease activity (EDA) over 2 years of follow-up, defined as confirmed relapse activity, disability worsening, or any new lesions on magnetic resonance imaging.
A total of 16 794 participants with MS were included from 17 clinical trials (67.2% female). Over the 2-year follow-up, 61.0% (95% CI, 56.2%-66.3%; I2 = 97.9%) of the pooled trials had EDA. After adjusting for multiple factors, the presence of 3 or more comorbidities was associated with an increased hazard of EDA (adjusted hazard ratio [AHR], 1.14; 95% CI, 1.02-1.28) compared with no comorbidity. Presence of 2 or more cardiometabolic conditions was also associated with an increased hazard of EDA (AHR, 1.21; 95% CI, 1.08-1.37) compared with no cardiometabolic comorbidity. Presence of 1 psychiatric disorder was associated with an increased hazard of EDA (AHR, 1.07; 95% CI, 1.02-1.14).
In this study, a higher burden of comorbidity was associated with worse clinical outcomes in people with MS, although comorbidity could potentially be a partial mediator of other negative prognostic factors. Our findings suggest a substantial adverse association of the comorbidities investigated with MS disease activity and that prevention and management of comorbidities should be a pressing concern in clinical practice.
多项研究表明，合并症会使多发性硬化症（MS）的临床相关结局恶化，包括诊断时的残疾严重程度以及诊断后残疾恶化的速率。然而，关于合并症与疾病活动度指标（如复发率和磁共振成像病变累积）之间的关联，我们了解得较少，而这些指标对临床医生和临床试验人员来说是相关的。
在MS患者的疾病修饰治疗（DMT）临床试验中，评估合并症与疾病活动度之间的关联。
设计、设置和参与者：本队列研究采用两阶段荟萃分析方法，对来自2001年11月至2018年3月进行的、有2年随访期的MS DMT 3期临床试验的个体参与者数据进行分析。数据于2023年2月至2024年6月进行分析。
试验入组时存在的合并症负担和个体合并症，包括高血压；高脂血症；功能性心血管疾病、缺血性心脏病、脑血管疾病和外周血管疾病；糖尿病；自身免疫性甲状腺疾病和其他自身免疫性疾病；偏头痛；肺部和皮肤疾病；抑郁症；焦虑症；以及其他精神障碍。
主要结局是随访2年期间疾病活动的证据（EDA），定义为确诊的复发活动、残疾恶化或磁共振成像上出现任何新病变。
17项临床试验共纳入了16794名MS患者（67.2%为女性）。在2年随访期内，汇总试验中有61.0%（95%CI，56.2%-66.3%；I2=97.9%）出现了EDA。在对多个因素进行调整后，与无合并症相比，存在3种或更多合并症与EDA风险增加相关（调整后风险比[AHR]，1.14；95%CI，1.02-1.28）。与无心脏代谢合并症相比，存在2种或更多心脏代谢疾病也与EDA风险增加相关（AHR，1.21；95%CI，1.08-1.37）。存在1种精神障碍与EDA风险增加相关（AHR，1.07；95%CI，1.02-1.14）。
在本研究中，较高的合并症负担与MS患者更差的临床结局相关，尽管合并症可能是其他负面预后因素的部分介导因素。我们的研究结果表明，所研究的合并症与MS疾病活动度之间存在显著的不良关联，并且合并症的预防和管理应成为临床实践中迫切关注的问题。
