MS is classified into different subtypes which dictates what treatments you are eligible for. These MS disease subtypes are not supported biologically and I am of the opinion that MS is one disease.
What can a neuro offer a patient with SPMS without relapses? There must be many patients in this position, but no licensed therapies. Can a neuro prescribe off-label treatments eg Simvastatin (which is in trial as a potential neuro-protective agent) or Metformin (which is in trial as a potential remyelination agent)?
Also please note that the results for simvastatin on its own are less than impressive and metformin is already taken by a lot of MS patients to manage diabetes, so if it had a spectacular effect someone would have noticed by now. Both of these therapies are likely to only have small add-on benefits if they do anything at all. I would not put my faith in either of them.
I agree in principle, but the treatment effects may be larger when added on top of effective anti-inflammatory therapies. At the moment the trials have not been add-on studies, which makes no biological sense.
It is difficult to prescribe statins, metformin, etc. without firmer evidence they work. This is why we need definitive trials. If we prescribed these medications off-label to all non-relapsing or inactive progressive patients we would open ourselves to claims of quackery.
I don’t think any patient would accuse their neuro of quackery for prescribing therapies which have not gone through ‘definitive trials’ (do we ever get these in progressive MS?), but which offer the ‘possibility’ of some positive impact on the unrelenting loss of their brain tissue. We are told that time is brain, but when MS progression really gets going (eg inactive SPMS / PPMS) the patient is left untreated!
This is a form of cognitive dissonance; when is there enough evidence to say take this knowing that the evidence is not good enough to be sure there is a treatment effect or not, not to mention the potential for adverse events; primum non-nocere or "first, do no harm"?
I would argue that since you and other doctors are the gatekeepers that determine access to medications, sitting back and doing nothing for a disease as bad and as guaranteed to continue getting worse as progressive MS /is/ a form of harm. If people could make their own decisions and just walk into the pharmacy and purchase medications for themselves it would be a different story and doctors would have the right to refuse to provide treatment they disagreed with, but when the medical profession takes upon itself control of drug distribution, I think that comes with duties as well as privileges. I don't think you should be denying anyone access to drugs that might help them when there are no other options, your job as a gatekeeper should only be to make sure that people have all the information and are making an informed decision before they get the drug.
This is why we are doing trials such as the CladriPlus, Sizomus, Proximus, Clad-B, MS-Stat2, O-HAND, Chariot-MS, etc. is to try and develop treatments that work in progressive MS.
I hate the use of Latin phrases by medics! The “first, do no harm” position doesn’t fit with a disease such as MS where the brain and spinal cord are being shredded. Doing nothing is a cop out. I know of patients who order drugs on line eg metformin, Simvastatin, minocycline as they want to do something to try to slow the disease process. These are relatively safe drugs and it would be better if their neuros were involved in some way. Your fellow Italian got it right: Benito Mussolini — 'It is better to live one day as a lion than 100 years as a sheep.” We need more neuros who are lions. We need more patients who are Lions ie demanding more from the neuros who send them on their way without any treatment or hope. As the drivers of the real MS become apparent, it’s unethical (given patients are experiencing brain atrophy ie we are not dealing with in-growing toe nails or a mild case of vitiligo) for current patients not to be given the option of trying some therapy which has some chance of helping their condition. To Do is to Dare (I’m not a medic so won’t use the Latin phrase for this).
Depends on how progressive your neurologist is and how much their actions are or are not restricted by national health systems and/or insurance companies. However, all MS DMTs modify progressive MS, even interferon beta (see: https://jamanetwork.com/journals/jamaneurology/article-abstract/1107912). An excellent option for SPMS if you can't get coverage is subcutaneous cladribine (very effective and very cheap). I know there are neurologists in the US offering this to their patients. Call around.
I only raised this as Aaron Boster MD ran an online Q&A on Sunday and mentioned that he has prescribed a few of his PPMS patients with Metformin. Another possible therapy (for men) is testosterone - many male MSers have low testosterone so can be prescribed something to increase their testosterone which has been shown to provide a level of neuro-protection / slow down disability progression. Oral cladribine (Chariot MS) is being used in people with advanced MS (in wheelchairs) to slow / halt accumulating disability - so those behind the study must think it does something for progression. Too many patients with SPMS / PPMS without active inflammation are pushed out the door with no treatment offered - should this be happening in 2022?
Yes, I don't even agree that there is any such thing as "inactive" MS. AFAIK essentially 100% of MS patients have active inflammation in their brains when autopsies are done post-mortem, regardless of the disease subtype they were diagnosed with. I think one of the problems with metformin, and any other neuroprotective, for progressive MS is that they are kind of pointless if you don't shut down inflammation first. Too many neurologists still don't seem to get this. I think of it like trying to rebuild a house that's still on fire. If people are treating progressive MS with only neuroprotective agents because they believe that unchanged MRIs mean no inflammatory activity, they are going to have a hard time seeing any effect.
I agree with using testosterone and even metformin, but the priority has to be a powerful anti-inflammatory.
Depends on your definition of active. In the large Amsterdam Brain Bank study, ~80% of people with end-stage progressive MS had chronic active lesions in their brains and/or spinal cords at post-mortem.
Luchetti et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018 Apr;135(4):511-528.
What can a neuro offer a patient with SPMS without relapses? There must be many patients in this position, but no licensed therapies. Can a neuro prescribe off-label treatments eg Simvastatin (which is in trial as a potential neuro-protective agent) or Metformin (which is in trial as a potential remyelination agent)?
Also please note that the results for simvastatin on its own are less than impressive and metformin is already taken by a lot of MS patients to manage diabetes, so if it had a spectacular effect someone would have noticed by now. Both of these therapies are likely to only have small add-on benefits if they do anything at all. I would not put my faith in either of them.
I agree in principle, but the treatment effects may be larger when added on top of effective anti-inflammatory therapies. At the moment the trials have not been add-on studies, which makes no biological sense.
It is difficult to prescribe statins, metformin, etc. without firmer evidence they work. This is why we need definitive trials. If we prescribed these medications off-label to all non-relapsing or inactive progressive patients we would open ourselves to claims of quackery.
I don’t think any patient would accuse their neuro of quackery for prescribing therapies which have not gone through ‘definitive trials’ (do we ever get these in progressive MS?), but which offer the ‘possibility’ of some positive impact on the unrelenting loss of their brain tissue. We are told that time is brain, but when MS progression really gets going (eg inactive SPMS / PPMS) the patient is left untreated!
This is a form of cognitive dissonance; when is there enough evidence to say take this knowing that the evidence is not good enough to be sure there is a treatment effect or not, not to mention the potential for adverse events; primum non-nocere or "first, do no harm"?
I would argue that since you and other doctors are the gatekeepers that determine access to medications, sitting back and doing nothing for a disease as bad and as guaranteed to continue getting worse as progressive MS /is/ a form of harm. If people could make their own decisions and just walk into the pharmacy and purchase medications for themselves it would be a different story and doctors would have the right to refuse to provide treatment they disagreed with, but when the medical profession takes upon itself control of drug distribution, I think that comes with duties as well as privileges. I don't think you should be denying anyone access to drugs that might help them when there are no other options, your job as a gatekeeper should only be to make sure that people have all the information and are making an informed decision before they get the drug.
This is why we are doing trials such as the CladriPlus, Sizomus, Proximus, Clad-B, MS-Stat2, O-HAND, Chariot-MS, etc. is to try and develop treatments that work in progressive MS.
I hate the use of Latin phrases by medics! The “first, do no harm” position doesn’t fit with a disease such as MS where the brain and spinal cord are being shredded. Doing nothing is a cop out. I know of patients who order drugs on line eg metformin, Simvastatin, minocycline as they want to do something to try to slow the disease process. These are relatively safe drugs and it would be better if their neuros were involved in some way. Your fellow Italian got it right: Benito Mussolini — 'It is better to live one day as a lion than 100 years as a sheep.” We need more neuros who are lions. We need more patients who are Lions ie demanding more from the neuros who send them on their way without any treatment or hope. As the drivers of the real MS become apparent, it’s unethical (given patients are experiencing brain atrophy ie we are not dealing with in-growing toe nails or a mild case of vitiligo) for current patients not to be given the option of trying some therapy which has some chance of helping their condition. To Do is to Dare (I’m not a medic so won’t use the Latin phrase for this).
Depends on how progressive your neurologist is and how much their actions are or are not restricted by national health systems and/or insurance companies. However, all MS DMTs modify progressive MS, even interferon beta (see: https://jamanetwork.com/journals/jamaneurology/article-abstract/1107912). An excellent option for SPMS if you can't get coverage is subcutaneous cladribine (very effective and very cheap). I know there are neurologists in the US offering this to their patients. Call around.
I only raised this as Aaron Boster MD ran an online Q&A on Sunday and mentioned that he has prescribed a few of his PPMS patients with Metformin. Another possible therapy (for men) is testosterone - many male MSers have low testosterone so can be prescribed something to increase their testosterone which has been shown to provide a level of neuro-protection / slow down disability progression. Oral cladribine (Chariot MS) is being used in people with advanced MS (in wheelchairs) to slow / halt accumulating disability - so those behind the study must think it does something for progression. Too many patients with SPMS / PPMS without active inflammation are pushed out the door with no treatment offered - should this be happening in 2022?
Yes, I don't even agree that there is any such thing as "inactive" MS. AFAIK essentially 100% of MS patients have active inflammation in their brains when autopsies are done post-mortem, regardless of the disease subtype they were diagnosed with. I think one of the problems with metformin, and any other neuroprotective, for progressive MS is that they are kind of pointless if you don't shut down inflammation first. Too many neurologists still don't seem to get this. I think of it like trying to rebuild a house that's still on fire. If people are treating progressive MS with only neuroprotective agents because they believe that unchanged MRIs mean no inflammatory activity, they are going to have a hard time seeing any effect.
I agree with using testosterone and even metformin, but the priority has to be a powerful anti-inflammatory.
Depends on your definition of active. In the large Amsterdam Brain Bank study, ~80% of people with end-stage progressive MS had chronic active lesions in their brains and/or spinal cords at post-mortem.
Luchetti et al. Progressive multiple sclerosis patients show substantial lesion activity that correlates with clinical disease severity and sex: a retrospective autopsy cohort analysis. Acta Neuropathol. 2018 Apr;135(4):511-528.
So helpful, thank you.