Saturday, 22 October 2016

#ClinicSpeak & #ResearchSpeak: time to step-up or shut-up

Why did we allow the baby to be thrown-out with the bathwater? Successful, but unsuccessful, treatments for progressive MS. #ClinicSpeak #ResearchSpeak

There are so many killjoys out there who think progressive MS is an intractable problem and that we have no treatments that work. Incorrect! I would like to remind these killjoys of the cyclosporine and methotrexate studies from over 25 years ago in people with chronic progressive MS (SP & PPMS). Both these studies were positive and had an impact on disability progression. Cyclosporine was dropped because of renal toxicity and hypertension and methotrexate was dropped because most people think that protecting the upper limbs in people with progressive MS is not worth doing. 


I suspect, however, if methotrexate had been a innovative compound with a long patent-life it would have been taken forward into larger and more definitive trials. If these trials were done with modern insights we would have had a licensed DMT for progressive MS decades ago. What killed methotrexate as a treatment for MS was that it was a cheap generic drug. It is because of the trial below that I have included methotrexate on our essential off-label list of DMTs. If you had progressive MS would you consider methotrexate?  

The problem is that most pwMS and their families, and some in the neurological community, have unrealistic expectations of what to expect from an effective DMT for progressive MS. An anti-inflammatory therapy is unlikely to stop progression immediately, as this has been primed by previous damage and is destined to run its course over the next few years. What is more likely to occur is the slowing, or flat-lining, of progression over 2-5 year period; this delayed effect is what we refer to as therapeutic lag. The more neuronal reserve you have, i.e. the ability to recover function, the sooner you notice a therapeutic effect. 

With the natalizumab in SPMS, or ASCEND, trial there was no impact on EDSS and T25FW in 2 years, but a significant effect on the 9HPT. I suspect that if the trial went on longer for say 3 years then the EDSS and T25FW curves would have opened-up and we would have had a positive trial. There is a chance we may find-out if this actually happened; a large number of the original ASCEND population got to 3-years in the follow-up study of ASCEND before Biogen stopped the extension study. I predict that the study subjects who received natalizumab throughout the study (2 years of blinded study and one year of extension) will do better than those who were on placebo (2 years placebo and 1 year natalizumab). If I was a betting man I would put money down on this prediction.

The above is water under the bridge, right now we should be celebrating the recent results of ocrelizumab in PPMS and siponimod in SPMS, results. The killjoys say these results are not good enough. What do you want? Please remember a  25% difference in progression rates at 
at 2-3 years of follow-up may be 50% at 5 years and 75% at 10 years. I agree that if you have progressive MS these results are not what you want; you want to get back to normal. However, these drugs are not designed to restore function; for that to occur we need new therapies to add-on to anti-inflammatory therapies. Please be positive and celebrate the recent successes in progressive MS. The tragedy is we had similar successes over 25 years ago and we didn't build on them. This time we need to seize the day; carpe diem!


The Multiple Sclerosis Study Group. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. Ann Neurol. 1990 Jun;27(6):591-605.


Methods: Patients with clinically definite multiple sclerosis, mild to moderately severe neurological disability (entry score on the Expanded Disability Status Scale (EDSS) between 3.0 and 7.0), and a progressive course defined by an increase in the EDSS of between 1 and 3 grades in the year prior to entry were randomized to receive either cyclosporine (n = 273) or placebo (n = 274) in a 2-year, double-blinded, multicenter trial. Treatment groups at entry proved balanced for age, gender, duration of illness, and neurological disability. Cyclosporine dosage was adjusted for toxicity and a median trough whole-blood level was maintained between 310 and 430 ng/ml. 

Results: The mean increase in EDSS score was 0.39 +/- 1.07 grades for cyclosporine-treated patients and 0.65 +/- 1.08 grades for placebo-treated patients from entry until the time of early withdrawal or completion of the study (p = 0.002). Of three primary efficacy criteria, cyclosporine delayed the time to becoming wheelchair bound (p = 0.038; relative risk, 0.765), but statistically significant effects were not observed for "time to sustained progression" or on a composite score of "activities of daily living." Active treatment did have a favorable effect on several secondary measures of disease outcome. A large and differential withdrawal rate (44% for cyclosporine-treated patients, 32% for placebo-treated patients) complicated the analysis but did not appear to explain the observed effect of cyclosporine in delaying disease progression. Multivariate analysis did not show institutional effects but did demonstrate substantial effects of baseline neurological disability on outcome. Nephrotoxicity and hypertension were common troublesome toxicities and accounted for most of the excess loss of patients in the cyclosporine arm of the study. 

Conclusion: Thus, chronic cyclosporine therapy was associated with a statistically significant but clinically modest delay of progression of disability in a group of patients with multiple sclerosis selected for moderately severe and progressive disease. Close supervision by physicians familiar with cyclosporine is mandatory to minimize known adverse effects, particularly nephrotoxicity, when considering the use of this immunosuppressant. 

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.

Methods: 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. 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. 


Results: 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. 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

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

CoI: multiple

14 comments:

  1. You are a hero not just in the neurological community but in the medical world generally for this kind of public engagement. It matters.

    As someone with PPMS, I'm listening to this message. My concern is not unrealistic expectations regarding efficacy. As a single mother in her 40s, I am concerned about malignancies with Ocrevus. How to consider the balance of risk and benefit when a patient is willing to end up in a wheelchair -- isn't the mean for PPMS 50-50% in 20 years -- than significantly raise my risk for cancer and leave my child without a caregiver because of an intervention I chose.

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    1. Prof G is med-mad. He believes that pill-popping remedies all, and side effects are worth it all.

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    2. Yep...because that view is supported by data.

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    3. I thought the mean time to the wheelchair is 20 years from onset for RRMS and not PPMS?

      Could someone verify this?

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    4. I was referring to some natural history studies. Here is one: https://www.researchgate.net/publication/262341244 Mt. Sinai in NY recently published a study of their PPMS patients showing even slower progression rates. This is interesting for all of us who will be thinking about risks and benefits and new treatments are approved.

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  2. "Methotrexate was well tolerated at the low doses used in the research. Longer-term use may be associated with serious side effects, including lung and liver problems, and the suppression of bone marrow. As a result, methotrexate is not a first line treatment for multiple sclerosis."

    https://www.mstrust.org.uk/a-z/methotrexate-maxtrex#sideeffects

    "If you had progressive MS would you consider methotrexate?"

    I have PPMS and personally, no, I would not. It seems it would maybe be a case of choose your poison - PPMS alone, or PPMS with methotrexate. Not a good choice - the devil or the deep blue sea sort of thing.

    I'm not celebrating Ocrelizumab, at least not at the moment. Safety issues concern me.

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  3. I was on the ASCEND trial. At the time my problems were mobility and I did not notice any flatlining to my progression. Now I am on MS-SMART trial since Jan 2017. I have noticed tasks with my hands such as writing are becoming a lot more difficult and also my mobility declining. Without FES I would definitely be in a wheelchair. Watching my decline does not make me a happy bunny

    Utopia to me would be treatment that will flatline progression

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    1. Sorry to hear that you feel you are deteriorating but we have to rememebr
      MS-SMART is a placebo controlled trial and so 1 in 4 people get the placebo and as ProfG has suggested drugs may not flatline but change the slope of worsening.

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    2. What kind of FES are you using Patrick?

      It's new to me and since my spastic leg is causing problems I'd like a tip how to improve it.

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    3. I am using a two channel FES. It is a bit of aa faff to setup correctly and it takes a bit of practice and experience. I sugggest you go back to the clinic that issued it to you and talk to them.

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  4. The trouble with treatments for progression is that Prof G and co think a slowing down, possible flatlining is great. I want something more than just watching myself deteriorate at a slightly slower pace. Are you really that pleased with the efficacy of treatments in the pipeline for progressive MS? If someone is diagnosed with PPMS tomorrow there is NO treatment that can be offered. Yet Prof G thinks everything is hunky dory and we should stop moaning. How brave people are who don't have have to face watching themselves deteriorate.

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    1. HSCT has stopped progression in PPMS. They are now offering it in London if you have active lesions. Other places will offer it without active lesions.

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    2. This claim needs a privio, the data is that progressive MS is less likely to respond to HSCT, so not all people will get total benefit. Those with active lesions are more likely to benefit.

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  5. I did four doses of methotrexate – – one year. I could not tell that it affected the course of my disease at all and I suffered with the side effects (nausea) plus the time and unpleasant experience of being infused. The costs are real and the benefits are very blurry.

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