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Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subset of PMS with more active inflammatory disease. The effects of natalizumab and methylprednisolone on intrathecal inflammation and the association of IgM OCBs with other biomarkers in PMS is uncertain. In the current study, we investigated the cerebrospinal fluid (CSF) proteome of untreated patients with PMS, effects of natalizumab and methylprednisolone, and associations of IgM OCBs with disease activity and CSF biomarkers. We found a reduction of BCMA, SLAMF7, granzyme A, IgG, and desmoglein-2 with both therapies, as well as natalizumab-specific reductions of VCAM-1, CD48, MDC, MMP-9, sE-selectin, and CHIT1, and methylprednisolone-specific reductions of DR3, IgD, RTN4, and increases of sCD206, LYVE1, sCD163 and MMP-3. IgM OCBs were associated with reduced levels of PIGR, higher levels of NFL and VEGF, and more contrast-enhancing lesions. The study suggests T and B cell activity biomarkers as treatment-responsive CSF biomarkers in PMS. Additionally, we found natalizumab to reduce adhesion molecules and methylprednisolone to increase myeloid biomarkers. 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MK contributed to this work as a former employee of the National Institutes of Health, and the opinions expressed in this work do not represent her current affiliation (Eli Lilly Japan K.K., Kobe, Japan). HHC reports non-financial support from Merck, Teva, Biogen, and Roche outside the submitted work. RR is now employed by Lundbeck, but she had no conflicts of interest at the time of trial conductance. HRS has received honoraria as speaker and consultant from Lundbeck AS, Denmark, and as editor (Neuroimage Clinical) from Elsevier Publishers, Amsterdam, The Netherlands. He has received royalties as book editor from Springer Publishers, Stuttgart, Germany, Oxford University Press, Oxford, UK, and from Gyldendal Publishers, Copenhagen, Denmark. LMV has served on scientific advisory boards for, received support for congress participation or received speaker honoraria from Amgen, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. Her laboratory has received research support from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. PK, JLVG, CGM, BB and JRC have no relevant conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"98"}}