Abstract: Described herein are methods of treating multiple sclerosis (MS), such as secondary progressive MS (SPMS), by intrathecally administering a B cell depleting agent, such as rituximab, alone or in combination with intravenous administration of a B cell depleting agent. Also described is the use of IL-12p40, CXCL13, or both as CSF biomarkers for selecting a patient with progressive MS as a candidate for treatment with an intrathecal immunomodulatory therapy, and for identifying a progressive MS patient as having meningeal inflammation. The present disclosure also describes a method of evaluating the effectiveness of a therapy for treating progressive MS by measuring the level of IL-12p40, CXCL13, or both in the CSF of the patient before and after treatment. A decrease in the level of IL-12p40, CXCL13, or both after treatment indicates the therapy is effective for treating progressive MS.