To identify the leading conditions contributing to MS-related mortality in the U.S. (1999-2020), assess temporal and racial trends, and project future mortality rates through 2030.

Multiple sclerosis (MS) is a chronic, immune-mediated CNS disorder that heightens morbidity and mortality risk through associated comorbidities. Existing mortality studies are limited and outdated, whereas underutilized multiple-cause-of-death (MCOD) data provide a more comprehensive assessment of disease burden and future healthcare needs.

We conducted a population-based analysis of MCOD data from the CDC WONDER database, including all U.S. deaths from 1999 to 2020 coded using ICD-10. Demographic variables included age, sex, race/ethnicity, and year of death. Crude and age-adjusted mortality rates (AAMRs per 100,000, standardized to the 2000 U.S. population) were calculated. Temporal trends were assessed using Joinpoint regression to estimate annual percent change (APC) and average APC (AAPC). Future mortality through 2030 was projected using ARIMA, ETS, and linear regression models fitted to annual AAMR trends, generating point estimates with 95% prediction intervals in R.

Deaths due to MS and cancer increased steadily (AAMR 0.13 to 0.18). Aspiration pneumonia showed a consistent decline (AAMR 0.14 to 0.08). Lung cancer mortality rates remained low but rose slightly (AAMR 0.02 to 0.03). Sharp increases were observed for neurological conditions (AAMR 0.10 to 0.22) and musculoskeletal conditions (0.02 to 0.09). Chronic kidney and bladder disease mortality rose from 0.08 to 0.14, particularly after 2018. Across all categories, females consistently had higher AAMRs. Forecasts indicate a modest but continued decline in overall MS-related mortality through 2030.

MS-related mortality in the U.S. is increasingly driven by comorbidities such as cancer, neurological, musculoskeletal, and renal diseases, while aspiration pneumonia deaths have declined. Mortality is projected to gradually decrease through 2030, with persistently higher rates in females, highlighting the need for sex-specific management and planning.