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.

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