OffLabel: methotrexate

Essential MS drugs in resource poor environments: methotrexate. #MSBlog #MSResearch #OffLabel

“Before interferon-beta was licensed I used to manage a couple of patients under Ian McDonald who were insistent on being on a DMT. The rationale was better to be on something rather than nothing. At the time there was some evidence that methotrexate was effective in MS and as it was relatively safe, so we acquiesced. As you may be aware there is class 1 evidence that it works in RA and some evidence that it works in MS (see below). In the era of treat-2-target of NEDA (no evident disease activity) it would seem reasonable in resource poor settings to try oral methotrexate and if there was breakthrough disease to switch to another agent. T2T-NEDA changes the dynamictead of leaving someone on an ineffective therapy we move onto something else. However, T2T-NEDA does mean that resources need to be found to do annual MRI studies to monitor for a treatment response; I suspect this may be a problem.”

“Yes, I am saying if that if I was working in the state system in South Africa and had no access to licensed therapies I would consider a trial of low dose oral methotrexate appropriate as a first-line therapy in active RRMS. It better to do something than nothing. Low dose oral methotrexate is therefore the first drug on my essential drug list for treating MS if patients do not have access to licensed therapies. Interestingly, I know several US neurologists who do exactly this for patients in their care who don’t have medical insurance coverage.”

“I don’t expect methotrexate to be very effective; probably in the moderate efficacy zone. But if it works in some patients so be it.”

Goodkin et al. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40.

Objectives: A randomized, double-blinded, placebo-controlled, clinical trial of low-dose, weekly, oral methotrexate was performed in 60 patients with clinically definite chronic progressive multiple sclerosis (MS) attending a referral-based outpatient MS clinic. 

Methods: Study patients were 21 to 60 years old with a disease duration of longer than 1 year. Patients’ Expanded Disability Status Scale scores were 3.0 to 6.5 (ambulatory with moderate disability). Patients were first stratified by Expanded Disability Status Scale scores, 3.0 to 5.5 and 6.0 to 6.5, and then were randomized to receive methotrexate or placebo treatment. Treatment consisted of weekly, oral, low-dose (7.5 mg) methotrexate or identical placebo for 2 years, followed by observation for as long as 1 year. A composite outcome measurement instrument was used and consisted of (1) Expanded Disability Status Scale, (2) ambulation index, (3) Box and Block Test, and (4) 9-Hole Peg Test. Failure of therapy was indicated by a designated change that was sustained for more than 2 months in one or more components of this composite measure. 

Results: Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity. 

Conclusion: We conclude that low-dose, weekly, oral methotrexate offers a new, relatively nontoxic treatment option for patients with chronic progressive MS.

Goodkin et al. Low-dose oral methotrexate in chronic progressive multiple sclerosis: analyses of serial MRIs. Neurology. 1996 Nov;47(5):1153-7.

Background: Methotrexate is a platform therapy for managing patients with rheumatoid arthritis. There is anecdotal evidence that it may work in MS.

Methods: We monitored 56 patients with chronic progressive multiple sclerosis (MS) who participated in a clinical trial of weekly, low-dose oralmethotrexate with annual gadolinium-enhanced MRIs of the brain (Gd + MRI). Not of these patients had clinical exacerbations during the 8 months preceding study entry. We also monitored 35 ofheu the patients with serial Gd + MRIs every 6 weeks for 6 months. 

Results: We observed a treatment effect, measured by absolute change in T2-weighted total lesion area (T2W-TLA), in the cohort that completed 6-week scans. We found change in T2W-TLA in this cohort to be significantly related to sustained change in performance on the nine-hold peg test but not to sustained change on the Expanded Disability Status Scale. Gadolinium enhancement of lesions on 6-week and annual scans was uncommon. Prestudy exacerbation frequency appears to be an important consideration in designing future clinical trials in patients with secondary and primary progressive MS.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • I really wouldn't want to take Methotrexate my cousin is on it for arthritis and she is developing so many side effects I can't believe it.

    • The problem is the classics were off patent before we learnt how to do MS trials. The fact they are not licensed and there is poor class 1 evidence doesn't mean they don't work. At least T2T-NEDA provides a framework for assessing response. I am not sure praying does; but it could be an add-on. A Cochrane meta-analysis on prayer therapy was equivocal.

    • Oh yes classics like prayer. Now I know where I've been going wrong. Prayer is the obvious answer … The problem is I have no faith so even as a placebo it is unlikely to work. The only way I could see this potentially working is as a placebo and that 'prayer therapy' results are equivocal, it doesn't even seem to be a particularly good placebo to my adamantly atheist mind. Oh well I guess I will just have to 'rely' on science. Ho hum, I'm off to find a witch to burn.

    • Methotrexate is an interesting option, but I would like to point out that most RA patients are on higher MTX dose than a measly 7,5mg weekly. The trend in rheumatology is to quickly raise the dose to 15-20 mg/week and continue on it for some time if the drug is well tolerated.
      If MTX had some effect in MS, then it is really regrettable that bigger studies have not been done. J

    • My cousin is on 7.5mg, for RA, she is monitored closely for the side effects, but it can't be the answer. Surely SPMS sufferers have got enough problems without adding to them.

    • Treatments are never "one pill fits all", there are plenty of patients who cannot take paracetamol because of side effects. Methotrexate is not for everybody, but most people who start on it can continue for years without any trouble. Maybe your cousin should try something else?

  • It seems like it has always been very much easier to get on disease modifiers for rheumatoid arthritis – is there any evidence of a more benign course of MS in those treated for rheumatoid?

    It always seems so unfortunate that it's so much more difficult to assess disease activity in MS than rheumatological conditions, especially given the absolutely critical nature of the system involved and the success of disease modifiers in RA. But doctors like to objectively measure things before they do anything about them… roll on better measures of MS disease activity (when will they ever come?).

  • It even seems intrathecal Methotrexate may be a viable option for progressive disease:

    Use of Long-Term Intrathecal Methotrexate in Progressive Forms of MS (P04.139)

    "Conclusions: ITMTX was remarkably well tolerated over a period of 3-6 years in progressive MS patients with no serious adverse effects noted. Although this study was not controlled there was evidence of disease stabilization given the poor natural history of severe progressive MS. These findings support the use of ITMTX treatment as an inexpensive and relatively safe treatment for progressive MS."

  • The initial posting mentions progressive MS – are you saying it may be worth trying methotrexate for PPMS + SPMS? Thanks

    • Same question as Bouncy: is it worth trying to get onto methotrexate for PPMS/SPMS?
      Seems it may be – why should progressive MSers be left untreated when there's evidence something inexpensive may help them

    • methotrexate is an immunosuppressive drug, which have so far not made a massive impact in non-relapsing/gadolinium progressive MS and is about 95% excluded from the healthy CNS.

    • Does it have to be in the CNS to have some effect – what if it just reduced the numbers of lymphocytes or made them less reactive?

  • I have already brought this up with my Neuro. The answer was no. They felt there was not enough evidence and could not justify using it. I don't think it's my place to convince them otherwise anymore. They should feel comfortable prescribing something and convince me that there is a good reason for me to use it. As a rapidly progressing PPMS'er, I don't really expect much anymore from the medical community. They just don't know how to make me better. It's hard dealing with that fact, but it's better then being given false hope I guess.

    • I'm so sorry to hear this. I don't know if you have the energy to fight this but I feel the decision is not a one way street and as it is your life, it most certainly is your place to ask. It's not about false hope, false hope would be thinking this would cure you or make a big difference, but hoping it might help somewhat is not false hope but proactively trying to manage the MS. I'd go further and kick up a huge fuss (metaphorically speaking) but we're all different and what I'm comfortable with, you may not be. However, you could get your MP (if you are in the UK) involved, I did this last year for my brother who was denied treatment (not MS) and what had taken 18 frustrating months , through the NHS 'by-the-book-process'- was sorted within a week of his involvement. Please don't give up, your life is worth fighting for.

    • Get a second opinion. I am in a similar situation. My neuro was thoughtful enough to refer me to get a second opinion on his diagnosis of aggressive PPMS. The second opinion came back PRMS. I'm now on natalizumab, with fingolimod as Plan B. Your options may be few, but there's a neuro somewhere with the same risk tolerance to treatment that you have. Live or die, I'm going to fight MS on MY terms. Hang in there!

By Prof G



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