Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system (CNS), characterized by multifocal inflammatory demyelination affecting both white and grey matter (Travers et al., 2022). Although its pathogenesis remains incompletely understood, neuroinflammation and neurodegeneration are widely recognized as the major pathological processes (Katz Sand, 2015). Clinically, MS is classified into three main phenotypes: relapsing-remitting MS (RRMS), defined by acute neurological attacks followed by full or partial recovery; primary progressive MS (PPMS), characterized by steady neurological decline from onset, typically without relapses but with occasional plateaus; and secondary progressive MS (SPMS), which initiates as RRMS but transitions to progressive disability affecting ambulatory, autonomic, and cognitive functions (Kuhlmann et al., 2023; Lublin et al., 2014; Pozzilli et al., 2023). Neurodegeneration, most prominent in progressive MS subtypes, makes MS the leading cause of non-traumatic neurological disability among young adults (Benedict et al., 2020). Globally, MS affects an estimated 2.3 million individuals, with onset predominantly occurring in young adulthood, between the ages of 20 and 40 years (Doshi and Chataway, 2016; Haki et al., 2024). Despite advances in treatment, 50–60 % of patients develop significant physical impairment within 15-30 years of onset, stressing its high lifetime risk of disability (Anat et al., 2018). A striking sex disparity exists, with females affected 2-3 times more frequently than males, and this gap appears to be widening in certain regions (Oh et al., 2018). Given its high prevalence and life-long progression, MS imposes a substantial burden in terms of physical disability, reduced quality of life and healthcare expenditures.

The etiology of MS arises from the interaction between genetic predisposition and environmental exposures (Amato et al., 2018). While heritability risk account for approximately 25 %, the remaining susceptibility involves dynamic environmental influences, epigenetic modifications, and intricate gene-environment interactions (Olsson et al., 2017). Among modifiable risk factors, Epstein-Barr virus (EBV) infection, ultraviolet B (UVB) exposure, vitamin D deficiency, obesity, and smoking have been strongly implicated (Dobson and Giovannoni, 2019). Notably, both smoking and vitamin D deficiency may also accelerate disease progression following onset (Amato et al., 2018). Current treatment strategies primarily aim to manage acute relapses, alleviate symptoms, and reduce inflammatory activity through disease-modifying therapies (DMTs) (Hauser and Cree, 2020). However, despite these approaches, no available therapy can completely halt disease progression or achieve a cure (Duan et al., 2023). As MS becomes a chronic condition with prolonged survival, integrated long-term management strategies are increasingly important for mitigating disability progression and reducing the overall burden of disease (Rae-Grant et al., 2018; Lublin et al., 2022).

Previous studies on the burden of MS have provided a valuable foundation for understanding its global epidemiological trends. Research on autoimmune diseases, including MS, has revealed substantial heterogeneity in disease burden worldwide, with pronounced variations in age and sex distribution as well as temporal trends from 1990 to 2019 (Li et al., 2023). Several existing studies have been geographically limited to specific countries (Cayuela et al., 2025; Zhang et al., 2024; Xiao et al., 2025). Besides, a separate study examined global MS trends using age-period-cohort analysis, revealing temporal patterns in disease burden based on the 2019 Global Burden of Disease (GBD) date (Qian et al., 2023). Another analysis focused on incidence trends in adults aged 2054 from 1990 to 2021 and projecting to 2035 (Wang et al., 2025). However, these studies were limited by the absence of global scope, comprehensive age coverage, long-term projections, inequality evaluations, and decomposition analyses of burden drivers. Given ongoing changes in population aging, risk factor exposure, and disease surveillance, a more comprehensive and forward-looking evaluation of MS burden is warranted. Moreover, understanding future trends in disability-adjusted life years (DALYs) is essential to anticipate demands for long-term care, rehabilitation resource allocation, and community reintegration strategies.

This study analyzes the global burden of MS from 1990-2021 using GBD data, assessing incidence, deaths, and DALYs by age, sex, and SDI region. We evaluate SDI-related inequalities, project disease burden through 2040 using BAPC modeling, decompose the drivers of epidemiological changes, and estimate the burden attributable to smoking. These findings aim to inform equitable and effective health policy interventions and guide future planning in rehabilitation services to meet the growing needs of MS patients.