Cerebrospinal Fluid and Blood Cytokines as Biomarkers for Multiple Sclerosis: A Systematic Review and Meta-Analysis of 226 Studies With 13,526 Multiple Sclerosis Patients

Background: Multiple sclerosis (MS) biomarker identification is important for pathogenesis research and diagnosis in routine clinical practice. Cerebrospinal fluid (CSF) and blood cytokines as potential biomarkers that can inform MS pathogenesis, diagnosis and response to treatment have been assessed in numerous studies. However, there have been no comprehensive meta-analyses to pool cytokine data and to address their diagnostic performance. We systematically reviewed literature with meta-analyses to assess the alteration levels of cytokines and chemokines in MS. Methods: We searched PubMed and Web of Science for articles published between January 1, 1990 and April 30, 2018 for this systematic review and meta-analysis. Data were extracted from 226 included studies encompassing 13,526 MS patients and 8,428 controls. Biomarker performance was rated by a random-effects meta-analysis based on the standard mean difference between cytokine concentration in patients with MS and controls, or patients before and after treatments. Results: Of the 26 CSF cytokines and 37 blood cytokines for potential differentiation between MS patients and controls, the random-effects meta-analysis showed that 13 CSF cytokines and 21 blood cytokines were significantly increased in MS patients in comparison to the controls. Interestingly, TNF-α, CXCL8, IL-15, IL-12p40, and CXCL13 were increased in both blood and CSF of MS patients. For those cytokines analyzed in at least 10 studies, differentiation between case and control was strong for CSF CXCL13, blood IL-2R, and blood IL-23; CSF CXCL8, blood IL-2, and blood IL-17 also performed well in differentiating between MS patients and controls, whereas those of CSF TNF-α and blood TNF-α, CXCL8, IL-12, IFN-γ were moderate. Furthermore, CSF IL-15, CCL19, CCL11, CCL-3, and blood CCL20, IL-12p40, IL-21, IL-17F, IL-22 had large effective sizes when differentiating between MS patients and controls but had a relatively small number of studies (three to seven studies). Conclusion: Our findings clarified the circulating cytokine profile in MS, which provide targets for disease modifying treatments, and suggest that cytokines have the potential to be used as biomarkers for MS.