Off-label methotrexate

Prior to interferon-beta being licensed, I used to manage several patients under Prof. W. Ian McDonald who were insistent on being on treated with some form of 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 Prof. McDonald acquiesced. In retrospect, I have no idea if these patients responded or not as we didn’t monitor them clinically nor with MRI. How things have changed since then. 

As you may be aware there is class 1 evidence that methotrexate works in RA and some evidence that it works in MS as well (see below). I suspect it works rather well and in an 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 dynamic of how we use DMTs; instead of leaving someone on a suboptimal or ineffective therapy we move onto something else. However, T2T-NEDA does mean that resources need to be found to do annual MRI studies or potentially peripheral blood neurofilament levels to monitor for treatment response. This I suspect will be a problem in resource-poor countries, but even then clinicians could fall back onto clinical monitoring, which is better than nothing. 

What I am saying is yes, if I was working in a healthcare system with limited access to licensed high-cost therapies I would consider low dose oral methotrexate appropriate as one of the off-label first-line DMTs in active relapsing MS. This is why low dose oral methotrexate is on the Barts-MS essential off-label DMT list for treating MS. 

Interestingly, several US neurologists are still using low-dose oral methotrexate for patients in their care who don’t have medical insurance coverage. It is quite interesting to note that we all want to do the best for our patients and adapt our prescribing behaviour to achieve this aim. 

This is why when a neurologist in Venezuela recently asked me for advice about how to manage one of her patients with active MS we settled on low-dose methotrexate; in reality, it was the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine the other 1st-line DMTs on our essential off-label DMT list.

I don’t expect methotrexate to be highly effective, but probably it will fit in the moderate efficacy zone. The important thing is that works in some patients without causing catastrophic health expenditure or ruinous poverty.

Please note the low-dose methotrexate trial in chronic progressive MS (SPMS & PPMS) is the one study that we use as an example to support our length-dependent axonopathy study. Approximately two-thirds of the subjects in this trial had already lost most of their lower limb function (EDSS 6.0 or 6.5), which is why the trial was positive in the upper limbs, but not the lower limbs. 

What is needed is for an MS champion to do a trial of low-dose methotrexate vs. an active comparator or to simply collect real-world data on the number of subjects rendered NEDA on the drug. The investigators should also include regular blood sampling to measure peripheral blood neurofilament levels. In fact, we may be able to use an area-under-the-curve analysis of peripheral blood NFL levels to see how effective methotrexate and other off-label DMTs are in the real world. 

If you are interested in using methotrexate or other off-label DMTs in resource-poor settings please sign-up to our Grass Roots Off-Label DMT Initiative (GROLDI).

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 oral methotrexate 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 of 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.

Currier et al. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8.

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

CoI: multiple