Intrathecal methotrexate in progressive multiple sclerosis: a phase 1 open-label study with long-term follow-up.

Progressive multiple sclerosis (PMS) remains challenging to treat effectively. Intrathecal methotrexate (ITMTX) has emerged as a potential therapy for alleviating PMS symptoms. This study aimed to assess the safety, tolerability, and efficacy of ITMTX in PMS patients over short- and long-term periods. A 1-year, open-label, phase 1 study was conducted, administering ITMTX quarterly to eligible PMS patients. Primary endpoints included changes in Expanded Disability Status Scale (EDSS) scores, 25-Foot Walk (25FW), and Symbol Digit Modalities Test (SDMT) from baseline to 1 year. Secondary endpoints encompassed 6-month clinical changes, cerebrospinal fluid immune cell profiling, and MRI measures. Long-term follow-up included retrospective review of patients continuing ITMTX treatment beyond the initial study period. Twenty-two patients were initially enrolled, with 17 completing the 12-month treatment. ITMTX was well-tolerated, with post-LP headache being the most common adverse event (31.8%). No significant changes were observed in EDSS, 25FW, SDMT, CSF IgG levels, or immune cell counts over 12 months. Long-term follow-up of ten patients receiving ITMTX for 2-9 years (mean 4.1 ± 3.1 years) showed stable EDSS in seven patients, with three experiencing minimal worsening (0.5 points). The therapy was well-tolerated long-term, with no evidence of disease progression in most patients. These findings support ITMTX as a promising therapeutic approach for PMS, particularly for patients progressing despite approved disease-modifying therapies or unable to tolerate them. Further large-scale studies are warranted to confirm these results. Clinicaltrials.gov identifier: NCT02644044, year: 2015.