BACKGROUND: In both the general population and people with multiple sclerosis (PwMS), physical exercise is associated with improved mental well-being. Moreover, there is evidence of the possible protection of physical activity against disease progression in multiple sclerosis (MS). However, the question arises if acute or regular exercise has any impact on the immune system in PwMS. To answer this question, we performed a systematic review and meta-analysis on both plasma and serum cytokine levels (IL-6 and TNF-alpha) before and after acute and regular exercise among PwMS and compared to healthy controls. METHOD: We performed an online search via PubMed, Embase, SCOPUS, Web of Science, and Cochrane Library till September 2021 to identify original studies on IL-6 and TNF-alpha changes after acute and regular exercise in PwMS and controls. Following the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA), 11 original studies were included in the meta-analysis. Sensitivity analyses were used to identify the origins of heterogeneity. R 4.0.4 was used to perform the meta-analysis of IL-6 and TNF-alpha levels before and after acute and regular exercise in PwMS, compared to controls. This study does not qualify for a clinical trial number. RESULTS: IL-6 levels did neither increase nor decrease after acute and regular exercise in PwMS, and compared to controls (pre- versus post-intervention standardized mean difference (SMD) -0.09, 95% CI -0.29 to 0.11, p-value = 0.37, PwMS versus control SMD -0.08, 95% CI -0.33 to 0.16, p-value = 0.47). In PwMS, TNF-alpha levels decreased after regular exercise and when TNF alpha levels of both acute and regular exercise were pooled (pre- versus post-intervention SMD -0.51, 95% CI -0.91 to 0.11, p value = 0.01, PwMS versus control SMD -0.23, 95% CI -0.66 to 0.18, p-value = 0.26). TNF-alpha levels did neither increase nor decrease after acute and regular exercise in PwMS, when compared to controls. CONCLUSION: This systematic review and meta-analysis show that exercise does not lead to significant changes in peripheral levels of IL-6 in PwMS in contrast to the observed response in healthy subjects and other medical contexts. However, regular exercise had a specific anti inflammatory effect on blood TNF-alpha levels in PwMS. It remains to be investigated why PwMS display this different exercise-induced pattern of cytokines.

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