Methotrexate in progressive MS

M

ProfG has argued that if hand-function was the major endpoint of clinical trials then you would have had an approved treatment for progressive MS over a decade ago. In this study they look at the influence of intrathecal methotrexate. Methotrexate is an anti-proliferative agent

Safety of long-term intrathecal methotrexate in progressive forms of MS. Stark JW, Josephs L, Dulak D, Clague M, Sadiq SA. Ther Adv Neurol Disord. 2019 Dec 3;12:1756286419892360. doi: 10.1177/1756286419892360. eCollection 2019

BACKGROUND:There are few treatment options for multiple sclerosis (MS) patients with advanced disability [expanded disability status scale (EDSS) ⩾ 6.0]. In 2010, we reported initial results of using intrathecal methotrexate (ITMTX) in patients with progressive MS. We now report on long-term use of ITMTX. We performed a retrospective chart analysis of patients who have had 18 or more treatments to establish the ongoing safety and tolerability of ITMTX. Thus, the objective of this study was to establish the safety and tolerability of long-term therapy with (ITMTX) in patients with treatment-resistant, progressive forms of MS.

METHODS:We studied 83 patients (67 secondary and 16 primary progressive) who received ITMTX 12.5 mg every 8-11 weeks for 3-10 years (range: 18-57 treatments). All patients were evaluated neurologically, and their EDSS was assessed at every treatment. In addition, all adverse events, frequency of infections, and any hospitalizations, were noted.

RESULTS: There were no deaths, hospitalizations, or other serious adverse effects related to ITMTX. Headaches occurred at least once in 12% of patients, and transient fatigue occurred in 53% of patients. As determined by EDSS, there was no significant change from baseline status to post-treatment scores in both primary progressive MS (PPMS) and secondary progressive (SPMS) patients.

CONCLUSIONS: Pulsed ITMTX was well tolerated for up to 10 years in PPMS patients with no serious adverse effects. Although this was an open-label, retrospective analysis, and efficacy could not be studied, there was evidence of disease stabilization in many patients receiving ITMTX. It appears that long-term ITMTX is a safe therapeutic option in advanced progressive MS.

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10 comments

  • In the paper: “ clinically definite, progressive MS (PPMS or SPMS), previously failed treatment with at least 3 FDA-approved medications for at least 1 year each”

    What are 3 FDA-approved medications for progressive MS?

  • So why is this not being used more regularly for progressive MS?
    Why instead are people with progressive forms of MS being left to stress about the restrictive prescribing for ocrelìzumab or waiting for or trials on cladribine?

    • Because people don’t accept the data, most neuros have an EDSS fixation. You have to wait for trials of cladribine because of the NIHR (UK government) Because of them I am going to have to get my running shoes and rattling tin out. We are gonna need some help from the community

  • Thanks for the reply. Which drug is seen as more effective for progressive Methotrexate or cladribine and just as you are planning a trial for cladribine in progressive MS why hasa trial for Methotrexate in progressive MS not been done?

    • Economics…..You also need a champion, if you were to ask ProfK whether he would spend 8-9 years trying to get a study of a generic off the ground again, remembering that he has failed. I can guess the answer.

      Neuros are too frightened to rock the pharma boat so they won’t enter that space. But they could innovate and do methotrexate plus another neuroprotective agent. I have gone horse saying this but you are about to get more monotherapy trials.

      I guess they think I’m a A-hole and don’t listen to me, no wonder I like to have a rant and do odd things

  • This is my medical group. I switched to their practice about 6 years ago for the sole purpose of starting ITMX. I experienced headaches (from the methotrexate, never from the lumbar punctures), nausea (vomiting on one occasion) and fatigue following the treatment. I had this treatment for 2 1/2 years and despite the side effects, I would have continued if it stopped the progression of my SPMS. It did not. I suspect I was not included in this data set. I encountered many people who did see a stabilization of their disease from this treatment.

  • Very interesting. One has to wonder if big pharma and/or cost has anything to do with it not being prescribed today.

    • Yet too cheap to care about. Companies are not interested if the trial is going to cost millions and they only get pence back.
      Sad but true

  • Hope you will answer the following three questions

    First question When Methotrexate has been given apart from how a patient with progressive MS seems to be affected is there are data from subsequent MRI scans or or neurofilament levels?

    Second question how does Methotrexate perform for progressive patients compared to such drugs as cladribine? I understand that this is only your observation as neither have been trialled clinically

    Third question how does Methotrexate work and are there any drugs which work in a similar way as a comparison?

    • Neurofilaments tests were largely invented after the original trials but there are many questions to be answered do you need intrathecal verses oral, how good is it
      Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon β-1α: A randomized controlled trial. J Res Med Sci. 2011 Apr;16(4):457-62.

      It says that methotrexate is worse than beta interferon in RRMS, what does it do on memory B cells, well it is pants as an inhibitor (Glaesener et al. Arthritis Rheumatol. 2014 Sep; 66(9): 2590–2600. So again it rather supports the arguements that we have been making.

      Published online 2014 Aug 26. doi: 10.1002/art.38736
      PMCID: PMC4288311
      PMID: 24909567
      Distinct Effects of Methotrexate and Etanercept on the B Cell Compartment in Patients With Juvenile Idiopathic Arthritis
      Stephanie Glaesener,1 Tâm D Quách,1 Nils Onken,2 Frank Weller-Heinemann,2 Frank Dressler,1 Hans-Iko Huppertz,2 Angelika Thon,1 and Almut Meyer-Bahlburg1

      Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs.
      Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, Van Dyke C. Neurology. 1996 Nov;47(5):1153-7.
      This paper shows benefit on hand function

      As an immune modulator cladribine will wipe the floor with it, in progressive MS

      Methotrexate is an antimetabolite of the antifolate type so it is antiproliferative but it acts after DNA synthesis. It is used extensively in arthritis perhaps to limit the anti-body response that happens with an anti-TNF

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