Abstract
BACKGROUND: Multiple sclerosis (MS) is a major cause of disability, particularly among young adults, with fatigue affecting up to 95% of patients. Despite the availability of disease-modifying therapies (DMTs), their impact on MS-related fatigue (MSF) remains uncertain. This study investigates changes in fatigue levels among individuals with relapsing-remitting MS (RRMS) following the initiation of highly effective therapies (HETs). METHODS: A systematic search of MEDLINE, PubMed, Scopus, and PsycINFO identified studies involving adults with RRMS treated with HETs and assessed using validated fatigue measures at baseline and follow-up. Data on demographics, MS duration, DMT type, and fatigue scores were extracted. Meta-analyses using a random-effects model calculated standardized mean differences (SMD) in fatigue scores post-treatment. RESULTS: Eighteen studies comprising 4138 RRMS patients and 3806 person-years of follow-up were included. The overall SMD was -0.34 (95% CI -0.47 to -0.21), indicating a small but significant reduction in fatigue. Continuous treatments (e.g., natalizumab, ocrelizumab, fingolimod) showed significant improvements, while immune reconstituting therapies (e.g., alemtuzumab) did not. Among fatigue domains, only physical fatigue showed a significant reduction, particularly with natalizumab (SMD = -1.25; 95% CI -2.43 to -0.06) and when assessed using the fatigue scale for motor and cognitive functions scale (SMD = -1.52; 95% CI -2.87 to -0.17). CONCLUSION: MS-related fatigue levels, especially in its physical aspect, decrease after the initiation of HET. This finding reinforced the role of neuroinflammation in driving fatigue and highlighted the need for domain-specific research and treatment strategies.