Chronic stress amplifies multidimensional disease activity in multiple sclerosis patients: A year-long within-person...

Chronic psychological stress is suspected to intensify disease activity in multiple sclerosis (MS), yet longitudinal real-world evidence remains limited. This study aims to determine whether the first year of the war in Israel during 2023-2024, a period of sustained nationwide stress, was associated with increased composite evidence of disease activity (EDA-3) in people with MS (pwMS).

We conducted a retrospective case-control study of 930 pwMS followed at Hadassah Medical Center who had ≥1 annual visit across three consecutive years. Within-person comparisons were made between the war year (P3, 07/10/2023-06/10/2024) and the preceding year (P2). The primary outcome was EDA-3 (clinical relapse, confirmed EDSS worsening, or magnetic resonance imaging [MRI] activity). Each component of EDA-3, as well as treatment modifications, was also evaluated independently.

EDA-3 prevalence was significantly higher during the war year (17.42%, 162/930) than pre-war (13.87%, 129/930; odds ratio [OR]=1.34, 95%-confidence interval [CI]: 1.02-1.76, p=0.034). Effects were more pronounced in males (OR=1.72, 95%-CI: 1.07-2.83; p=0.024) and in patients with EDSS≥4 (OR=1.77, 95%-CI: 1.20-2.63; p=0.0034). MRI activity increased from 11.77% to 17.54% (OR=1.83, 95%-CI: 1.14-2.98; p=0.011). Annualized relapse rate (ARR) showed a non-significant increase (p=0.068), and treatment modification rates were stable (switches: p=0.92; escalations: p=0.42). Results persisted after excluding pre-war DMT switchers (OR=1.55, 95%-CI: 1.147-2.122; p=0.004).

Sustained war-related stress coincided with clinically significant, multidimensional increases in MS disease activity, predominantly driven by MRI activity, with disproportionate impacts on males and higher-disability patients. These findings position chronic stress as a modifiable risk factor, advocating for integrated stress mitigation and proactive enhanced monitoring in MS care during prolonged crises.