Intrathecal Methotrexate for Progressive Multiple Sclerosis: An Open Label Single Arm Study

Summary

Multiple sclerosis (MS) is characterized pathologically by demyelination, axonal loss, and glial scar formation. Clinically, most patients have a relapsing-remitting course of MS (RRMS) that over time may become progressive without remissions - a secondary progressive MS (SPMS). About 15% of patients have a progressive course from onset which is called primary progressive (PP). Currently, there is no approved treatment for PPMS and for SPMS only therapy with mitoxantrone showed mild effect. Thus, more effective therapies need to be developed for treatment of SPMS and PPMS. Methotrexate (MTX), an anti-metabolite, has been in clinical use since 1948 when it was found to produce temporary remission of acute childhood leukemia. There are accumulating evidences that in progressive MS patients there are follicular lymphoid structures in the meninges and in the Virchow-Robin spaces. Therefore, intrathecal therapy may target the pathological follicular lymphoid activity. The safety of intrathecal MTX (ITMTX) has been demonstrated by its widespread use in treating lymphoproliferative diseases and leptomeningeal metastases. Sadik et. Al. reported about the feasibility and safety of using intrathecal methotrexate (ITMTX) as a treatment for unresponsive patients with progressive forms of MS. In their open label study they found that ITMTX may have a beneficial effect in progressive forms of MS and that it was well tolerated with no serious adverse events. The investigators aim is to evaluate the efficacy , safety and tolerability of intrathecal methotrexate administration every 3 months in progressive 30 patients with progressive MS. The investigators will evaluate clinical, laboratory evaluation of the blood and cerebrospinal fluid as well as the MRI scans of the participants. Each patient will be treated 4 times for 1 year with the option to continue for another 1 more year with the same protocol.

Timeline

Start

2016-01

Primary completion

2017-12

Completion

2018-01

Publications

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• Background American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002 Feb;46(2):328-46. doi: 10.1002/art.10148. No abstract available.
• Background Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon beta-1alpha: A randomized controlled trial. J Res Med Sci. 2011 Apr;16(4):457-62.
• Background Currier RD, Haerer AF, Meydrech EF. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8. doi: 10.1136/jnnp.56.11.1217.
• Background Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007 Apr;130(Pt 4):1089-104. doi: 10.1093/brain/awm038.
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• Background Sadiq SA, Simon EV, Puccio LM. Intrathecal methotrexate treatment in multiple sclerosis. J Neurol. 2010 Nov;257(11):1806-11. doi: 10.1007/s00415-010-5614-4. Epub 2010 Jun 10.
• Kolb H, Shachaf Y, Fainberg K, Golan M, Regev K, Vigiser I, Fuchs L, Gadoth A, Kestenbaum M, Omer N, Shopin L, Ash EL, Artzi M, Ben Bashat D, Aizenstein O, Karni A. Intrathecal methotrexate in progressive multiple sclerosis: a phase 1 open-label study with long-term follow-up. J Neurol. 2025 May 4;272(5):374. doi: 10.1007/s00415-025-13114-z.

Drugs

Indications

No indication recorded.