Theories: "Auto-Immune" vs. Not

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby DenverCO » Thu May 26, 2005 12:08 pm

Bromley

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Postby HarryZ » Thu May 26, 2005 1:03 pm

Robin,

If you read Denver's recent message and the fact that one researcher has stated that it appears MS is several different kinds of disease, it could be very possible that MS is part auto-immune, part viral and part whatever which possibly makes some of the old and new theories both right in their perspective area.

The reason that Prineas and Barrett's autopsy work has caused such a stir in MS circles is because it is the first time that someone has actually been able to scientifically look at a lethal lesion so quickly after the patient died. They were able to see something very different to what the researches have thought for years.

Dr. Behan went a lot further than stating the EAE mouse model was not very good at studying MS in humans. He said that EAE isn't anything like MS in humans and that's why there has never been a treatment that worked in that poor mouse that has worked in humans.

I also don't think anyone is totally dismissing the auto-immune theory in MS. What I think many are saying is that the myelin being attacked by the immune system is a "result of" as opposed to a "caused by" scenario. In other words, something is causing damage to the myelin, inflammation is a result of this and the immune system is rushing to attack the inflammation and then causing more damage.

We often hear that a cure is "just around the corner" for MS but I start to wonder now that the recent research has served to open up even more questions about the disease.

Harry
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Postby finn » Fri May 27, 2005 5:46 am

Sorry, time to leave the board.

-finn
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Postby HarryZ » Fri May 27, 2005 6:22 am

Finn,

As usual, your message starts the thinking process in all of us :D And please don't excuse your written English capabilities...they are as good as or better than most of ours whose first language is English!

Instead, I'll ask a couple of questions:[list][*]If inflammation is the primary cause of the damage, why there is more permanet disability when there is less noticeable inflammation (RRMS vs. SPMS/PPMS)?

Perhaps there is something else, totally unknown at this time, that is the real problem.

[*]Current disease modifying therapies (DMT) have been used for almost 15 years. A lot of post marketing studies have been made, but why there is no reliable unbiased data about the ability of DMTs to prevent the permanent damage?


According to Dr. George Ebers who currently works in England but previously headed the MS Clinic here in London, Canada, there has never been an established program to gather accurate data on the CRAB drugs after they started to get used in the general population. He and his colleagues about two years ago were supposed to try and create some kind of program to address this but I don't know if anything concrete has been done as yet. The only data we seem to get on this comes from the drug companies themselves who conduct open label trials against placebo or head-to-head trials against the competitors' MS drugs.

[*]If axonal degeneration is the primary disease process, why our system decides to attack against myelin and oligodendrocytes?


Supposedly it's the oligodendrocytes breaking down that first alert the immune system that something very wrong is going on. The immune system goes to their aid and mistakingly causes more damage. Is it this action that causes the axonal damage or is it something related to this?

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Short and Long Term Effects

Postby reed » Fri May 27, 2005 3:39 pm

Finn wrote:

here's another quote concerning current therapies: "The disease modifying therapies recombinant betainterferons and glatiramer acetate are now widely used in the treatment of RRMS, but questions remain concerning their efficacy in preventing long term disability. The reduction in relapses of around 30% is undoubted as it was seen in all trials, both those studying RRMS and those with SPMS. However, the effect on disability is less clear, as a small effect was seen in only half the trials. In fact, even when an effect on permanent disability was reported, this assumed relapses last less than three or six months.Removing inflammation with immunotherapy may simply convert relapsing-remitting MS into primary progressive disease."[quote]


Now there's something to think about: "Step right up. For a thousand dollars a dose plus a little pain and some unpleasant side effects, you may be able to convert your remitting disease to secondary progressive form."

I have always wondered about this personal historical fact: When I had my first serious overall exacerbation (many years ago), my doctor told me immediately that the administration of steroids might well cause the symptoms to remit (and they did), but that the drug would not effect the overall course of the disease. I think that is the standard observation doctors make, and it is uncontroversial. But many years of data must have been available and studied in order to make this pronouncement. (For example, based only on my particular actual experience, I might well have concluded that the steroidal medication would reverse symptoms completely--or close to it--over the course of many years.) Now substitute the CRAB drugs for the large doses of steroids in my example. How do we know, given the limited time the CRAB drugs have been utilized, that the results won't prove to be similar to those of the steroids after, say, 25 years of use?--i.e., it's only with that magnitude of experience that scientists will be able to make reasonably confident pronouncements (predictions) about the likely effectiveness of long term use. Or so I fear.


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Postby raven » Sat May 28, 2005 5:54 am

As far as I can see the only effective measure for disease progression is brain parenchymal fraction. However during the RR stage of the disease brain volume is seen to decrease without corresponding increases in disability. This may be explained by brain plasticity compensating for the axonal loss. The transition to SPMS may well be due to the brains ability to compensate for the damage being exhausted. Once the SPMS stage is reached parenchmyal fraction correlates very closely with increasing disabilty.

In this review, data is summarized supporting the hypothesis that axonal loss is a major pathologic process responsible for irreversible neurologic disability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brain atrophy in the earliest stages of multiple sclerosis. Brain atrophy increases during the relapsing-remitting disease stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function, despite progressive brain tissue loss during the early stages of the disease. Beyond a threshold, however, further axonal loss leads to continuously progressive neurologic disability. We hypothesize that the rate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the disease. This view of disease pathogenesis has several important implications. First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parenchymal fraction, a precise measure of whole-brain atrophy, as an attractive candidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occurred. Third, neuroprotective drugs should be tested in combination with anti-inflammatory drugs in multiple sclerosis patients. Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention.


<shortened url>

If the above hypothesis is accepted I can take a stab at answering Finn's questions

If inflammation is the primary cause of the damage, why there is more permanet disability when there is less noticeable inflammation (RRMS vs. SPMS/PPMS)?


Possibly because self-repair mechanisms have been exhausted (SPMS) or do not function correctly (PPMS). It is possible that RRMS is the most destructive phase of the disease with the true effects being masked by self repair.

Current disease modifying therapies (DMT) have been used for almost 15 years. A lot of post marketing studies have been made, but why there is no reliable unbiased data about the ability of DMTs to prevent the permanent damage?


Studies have been done that show the interferons reduce the rate of parenchymal volume loss.

OBJECTIVE: To determine the time course of brain atrophy during treatment with once-weekly IM interferon beta-1a (IFNbeta-1a). METHODS: The MRI cohort (n = 386) of the European IFNbeta-1a dose comparison study in relapsing multiple sclerosis (MS) was analyzed. In addition to baseline and three annual scans, a frequent subgroup (n = 138) had two scans before treatment initiation and scans at months 4, 5, 6, 10, and 11. Brain parenchymal fraction (BPF), a normalized measure of whole-brain atrophy, and volume of Gd-enhancing lesions (T1Gd) and T2 hyperintense lesions (T2LL) were evaluated. RESULTS: BPF decrease was -0.686% (first year), -0.377% (second year), and -0.378% (third year). Analysis of the frequent subgroup showed that 68% of the first-year BPF decrease occurred during the first 4 months of treatment. This change was paralleled by a drop in T1Gd and T2LL. In the frequent subgroup, an annualized atrophy rate was determined by a regression slope for the pretreatment period and from month 4 of treatment onward. Annualized pretreatment rate (-1.06%) was significantly higher than the under-treatment rate (-0.33%). CONCLUSIONS: In the first year of treatment with anti-inflammatory agents, atrophy measurements are possibly confounded by resolution of inflammatory edema or more remote effects of previous damage to the CNS. The atrophy rate reduction observed after treatment month 4 may reflect a beneficial but partial effect of interferon beta-1a and was sustained over the 3-year study period.


<shortened url>

If axonal degeneration is the primary disease process, why our system decides to attack against myelin and oligodendrocytes?


Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease.

It is of course only theory but one that I feel best explains the processes seen in MS. I do not believe that suppressing inflammation results in a faster transition from RRMS to SPMS.

Robin
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Theory and Practice

Postby reed » Sat May 28, 2005 7:03 am

raven wrote:. It is of course only theory but one that I feel best explains the processes seen in MS. I do not believe that suppressing inflammation results in a faster transition from RRMS to SPMS.

Robin


Thanks for your instructive comment. Is it possible to test the hypothesis expressed in your last sentence? Is any research work being done to try to assess the answer, so far as you know? Thanks again.

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Postby raven » Sat May 28, 2005 7:22 am

Hi Reed

Unfortunately as you've probably found out there are no hard and fast answers with MS. I enjoy discussions such as the one above because they help me to refine my own thinking and make my own treatment decisions. I certainly do not pretend to have all the answers and do not attempt to convince others that their treatment choices are right or wrong.

As far as testing the hypothesis goes I suppose that I'm undergoing such a test on myself. I have undergone a treatment that profoundly suppresses inflammation. At the moment I am slowly regaining functionality rather than progressing. Whether that will continue is a question for time.

You may also wish to check out Lab Rat's testimonials in the Campath forum. He has had the treatment for 2 years and has almost completely recovered rather than progressing. The full trial data will not be published until 2007 though.

Robin
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Postby finn » Sun May 29, 2005 4:12 am

Sorry, time to leave the board.

-finn
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Postby HarryZ » Sun May 29, 2005 7:09 am

Finn,

Btw, Harry, thanks for your kind comments, but I do know my limitations. I'm really convincing only in Finnish ;-)


You are being far too modest :D Your current post indicates to me that you are more than fluent in English.

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Postby cleo » Sun May 29, 2005 10:28 am

I don't have anything to back up my theory that MS is inherited, or at least that an individual can inherit a predisposition to it, except for the fact that in my family, of the five materal granddaughters, three have had cancer (one died due to the cancer) and two have had MS (one also has died, I'm the other one). All immune system diseases.

My sister is the one who passed away from cancer. We were raised in Texas, and have lived here all our lives. The other three women all belong to my mother's sister's family, and were raised all over the world. So, no environmental connection. My mother died from Parkinson's Disease, as did her father. My paternal grandmother did from Leukemia, but that wouldn't have any bearing on my mother's side of the family, just my sister and myself.

Another thought, since women with MS who are pregnant seem to be free of exacerbations during their pregnancies, wouldn't that lead you to conclude that MS has a hormonal connection? Perhaps the men who are diagnosed with MS have lower testosterone levels than the average male.


Just thoughts.
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Postby raven » Sun May 29, 2005 10:30 am

Hi Finn

It's always good to share a discussion with you.

I have one question, if axonal degeneration is the primary event; why do we see functioning yet demyelinated axons within MS lesions?

But we do agree that the data available can be interpreted in many different ways. Not only by us laymen but also by neurologists. The following is a quote from Alasdair Coles

The critical issue for the treatment of multiple sclerosis is whether this death of nerve cells can be prevented. At present, all we have available to us are drugs that act on the immune system to suppress inflammation and demyelination. Now, we believe that nerve cells die off in multiple sclerosis because they have lost the beneficial effects of their myelin wrapping. In which case, if we can suppress inflammation early enough, and prevent too much demyelination, we should be able to stop nerve cell death. This is a hypothesis only. Some neurologists think multiple sclerosis is primarily a disease where nerve cells are destined to die, and that the inflammation we see in the brain is secondary; in which case no anti-inflammatory treatment will prevent the progressive phase of multiple sclerosis.


When the mystery is finally solved we should all get together and have a drink (provided the solution comes in our lifetime that is!)

Thanks

Robin
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Postby bromley » Sun May 29, 2005 11:47 am

Robin,

I'll join you and Finn for that drink if they ever solve the mystery (HarryZ can join us too as long as he doesn't mention Tysabri).

I've set out some thoughts from three of the UK's top MS experts below - all drawn from the UK MS Society website. There's a mixture of views on why axons degenerate / what causes the demyelination / the effect of suppressing inflamation etc.

Professor Neil Scolding:

'Drugs causing even the most intense suppression of inflammation do not stop disability progressing in MS. This is probably because other, non-inflammatory mechanisms cause progressive axon loss. We believe that perhaps the main cause of axon loss is persistent loss of oligodendrocytes and myelin: these appear to protect and support axons, as well as providing insulation. Their absence results in slow but steady axon death. For this reason, replacing myelin and oligodendrocytes might have beneficial effects not only in the short term, but also for the long term prevention of axon degeneration'.


Professor Kenneth Smith:

'I have tried to find out how demyelination changes the properties of nerve fibres, causing them to generate the symptoms of MS. Research from several laboratories has revealed that demyelination initially blocks conduction, causing symptoms such as visual problems, weakness and numbness, depending on which groups of nerve fibres are affected. However, nerve fibres can adapt to the demyelination and then conduction can be restored, leading to recovery from the symptoms.

Recovery does not always occur sufficiently, and then some residual symptoms can persist. Sometimes demyelinated nerve fibres can become hyperexcitable, and then they can generate tingling sensations, which are sometimes initiated by body movements. The demyelinated nerve fibres are sometimes repaired by remyelination, and when this happens normal function can be restored.

Together with my colleagues in the research community, I have tried to uncover why and how these changes in function occur. Most recently we have tried to understand why nerve fibres degenerate in MS. Once degeneration has occurred, function is likely to be permanently damaged because nerve fibres do not regrow in the brain and spinal cord. It is therefore very important to try to find ways to protect the nerve fibres from degeneration'.


Professor Alan Thompson

'Now, that’s all I’m saying about suppressing or modulating or interfering with inflammation with the immune system. I really want to come back to the key point that was made by Richard and that I made earlier on, that if we’re going to make a real difference to this condition we have got to have a much broader approach to it. And we’ve got to think about protecting the axon and we’ve got to think about encouraging repair. I think effecting or influencing the immune system has a limited impact and may only have a limited impact, even if you start early'.



All of these quotes come from the last 12 months. I think there's a recognition that this disease is much more complicated than was originally thought.

I keep shifting from being an auto-immune supporter (i.e. the immune system goes wrong and attacks the myelin, for some unknown reason, and this leads to axonal degeneration and disability), and being a neuro-degenerative disease supporter (the nerves are dying off for some reason and sometimes the immune system gets involved - probably trying to help out).

The evidence of course is very mixed and confusing. It now appears that grey matter as well as white matter (myelin) is involved in ms. Axonal degeneration might not necessarily be linked to lesions - some work suggests that atrophy in the spinal cord is not just happening where there are lesions. What about bacteria and viruses? Much evidence appears to support the involvement, in some way, of the Epstein Barr Virus. Are bacteria or viruses the cause of an underlying neuro-degeneration, or are they the reason why the immune system gets involved and causes damage?

My main worry is more to do with who is really pulling all this research together. Everyday there are more and more ms research papers published and more research is commissioned. Many of these papers examine very specific issues but it's not clear how the findings across the board are being pulled together to finally solve the mystery. Drugs companies have done very well out of the CRAB drugs but will they be issuing refunds if we find in the future that they made no difference to the course of the disease? Some are now suggesting that inflammation may have neuro-protective qualities - so should we not be taking steroids after a relapse? Can I buy a bottle of inflammation from the chemist? Why have some patients of Campath experienced susbstantial improvements in disability ratings if the real problem was underlying neuro-degeneration and not an auto-immune disease?


MRI scanners, ms tissues banks, super-computers, lesion projects, autopsies of ms patients who have died etc etc (and heaven knows how many mice). PLEASE, PLEASE, PLEASE will some researcher get to the bottom of this disease soon.

Bromley (currently feeling quite well but sick of the mystery of ms)
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Postby HarryZ » Sun May 29, 2005 12:07 pm

Ian,

I'll join you and Finn for that drink if they ever solve the mystery (HarryZ can join us too as long as he doesn't mention Tysabri).


You are a tough negotiator but I'll tell you what....I won't mention Tysabri as long as you buy the first round :D



All of these quotes come from the last 12 months. I think there's a recognition that this disease is much more complicated than was originally thought.


There must be more to it than what we know now because if it was as simple matter of preventing inflammation due to myelin degeneration, the CRAB drugs would be far more effective than the limited capability that they have shown.

The evidence of course is very mixed and confusing. It now appears that grey matter as well as white matter (myelin) is involved in ms.


MRI's can't see into the grey matter from what I've read. Yet we know there are MS patients who demonstrate several symptoms without having any lesions in their white matter. Can this be the result of axonal damage in this area?


Cleao mentioned that pregnant women enjoy a reprieve from their symptoms and this has been shown time and time again. Yet on Brain Talk the other day, I read a thread where a women who has 2 children and is pregnant again, is greatly concerned because she suffered large exacerbations during her previous pregnancy. Every time you think something is definite with this disease, it throws you another curve by doing something out of the ordinary.

No wonder the researchers haven't come up with the magic bullet as yet!

Harry
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Postby reed » Sun May 29, 2005 12:45 pm

[/quote] When the mystery is finally solved we should all get together and have a drink (provided the solution comes in our lifetime that is!)

Thanks

Robin[/quote]


I'd like to buy, provided, of course, that drink is not the one thing we're not allowed to do! (It figures.)

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