We are extremely proud to present the following article, written by our very own community member, Finn. In it, Finn broadly discusses current MS research and its implications on possible causes and therapies. Finn also critically analyzes the standard CRAB treatments in light of new developments. The author has spent a great deal of time poring over the literature, and this read is enlightening and informative.

This is MS is an entirely unbiased site, and we want to encourage all of our members to feel free to share their thoughts about MS with us and the community at large. MS is receiving a great deal of attention in the medical field, and piecing together the various studies to create a cohesive theory, as Finn has done, is an extremely helpful task. We welcome submissions from all of our community members-- if there's a topic that interests you, please send us a note and we'd be happy to work with you to pull it together and get it published.

Without further ado, the article:

"Consensus opinion is that MS-research has been progressing rapidly during the past ten years. As an MS-sufferer myself I would like to believe it. But if the amount of research projects is compared to the results achieved so far, one might want to ask oneself if there have been any major breakthroughs during that time..."

Please click "read more" to read the entire piece.

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Controversial thoughts about MS-research

Consensus opinion is that MS-research has been progressing rapidly during the past ten years. As an MS-sufferer myself I would like to believe it. But if the amount of research projects is compared to the results achieved so far, one might want to ask oneself if there have been any major breakthroughs during that time.

Better drugs?

The four major MS treatments Avonex, Betaseron, Copaxone and Rebif (ABCRs) have been available for years now, and their lack of efficiency has been proven both in clinical trials and in practise (1, 2). However, this has not changed the course of MS-research very much. Still most of the disease-modifying agents studied in clinical trials are immunomodulators, either immunosuppressants or monoclonal antibodies. Many of those agents are already used in treating cancer or organ transplant rejection. It is safe to say, that the research with them is more or less done with the same "trial and error" method as ever before. Results speak for themselves: Campath-1H managed to halt the progression of disability in 17 patients with early RRMS for over a year, but in 36 SPMS-patients it could only reduce relapse rate and new MRI lesion formation (3). In a relatively large (213 patients) phase II -trial of Antegren, treated patients had fewer MRI lesions and relapses, but there was no difference seen in the progression of disability between them and the placebo group during the six month trial period (4). As a comparison, in a small open label trial a common cholesterol lowering drug Simvastatin was also found to be more effective in lessening the number of new MRI lesions than ABCR's. On the other hand, it did not show any benefit in disability of treated patients, either (5).

As much as I hope that even one of those drugs would do the trick, I am afraid that none of them will be able to change the long term clinical progression of MS better than the current drugs. They may work relatively well for a short period of time in the early phases of disease, but they probably will not be able to slow down its - often debilitating - progression for a longer period of time. Dr. Alasdair Coles, co-developer of Campath, has stated a possible reason for it: "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." (3)

Better cost-effectiveness?

We are used to the fact that all therapies for MS are expensive and loaded with potential side effects. But like the trial with Simvastatin has showed, it does not necessarily need to be that way. In addition to statins, there are other commonly used substances that have already shown to have an effect on MS.

First is vitamin D. Its major source is sunshine. It has been known for a long time that the more sun one gets during childhood, the less likely it is that one will get MS. Recently, it has also been shown in two large clinical trials, that women who take vitamin D supplements through multivitamins are 40 percent less likely to develop MS than women who do not take supplements (6). But then again, even if vitamin D is able to prevent the disease to some extent, its ability to halt the progression of MS is questioned. To gain therapeutic effect might require very high, potentially toxic doses of vitamin D.

Secondly, there is a probable connection between hormones and MS. Women with MS experience fewer relapses during pregnancy, when progesterone levels are elevated, and have more episodes post-partum, when their progesterone levels decline. In a small, early-phase clinical trial of estriol, women with RRMS showed decreases in the numbers and volume of MRI lesions and significant improvements in cognitive function scores. When treatment was stopped, lesion numbers returned to pre-treatment levels, and then decreased again when the treatment was resumed. Unfortunately, similar results were not obtained in SPMS-patients (7).

Third: a relatively safe substance, which might have a good therapeutic effect on MS, is the antibiotic Minocycline. It has been studied here in Finland for over a decade now with laboratory models of ALS and stroke, and it has been found to be both an anti-inflammatory and a neuroprotective agent. Because it anecdotally appeared to improve the condition of MS patients who were using it for acne relief, a Canadian group of researchers decided to study Minocycline in a small clinical trial. The trial will last for 3 years, and the group has already found out that minocycline inhibits matrix metalloproteinases (MMPs), enzymes involved in the remodeling of the body's extracellular matrix (8). Preliminary results of the trial presented in the AAN-meeting last spring were very interesting: all 10 treated patients with previously active MS had remained without new or active MRI lesions for as long as 9 months. No change in their clinical condition was reported (9).

Better immune system?

I believe that I'm not the only one who would like try a treatment that might be able to make MS-symptoms disappear for good. Maybe that has also been the motive to those MS-patients who have been treated in a couple of small clinical trials with autologous stem cell transplantation (ASCT). It is originally an aggressive leukemia treatment and it is potentially dangerous; the risk of fatality in ASCTs has been around 5-8 percent. Basically, it is simple procedure: first stem cells are harvested from a patient's own bone marrow. Then the patient's immune system is “reset”—in other words, wiped clean—with high dose chemotherapy and low dose radiation. After that step, the stem cells are infused back to regenerate the now decimated immune system.

So far the treatment has produced mixed results. In some patients MS-symptoms may have stabilized, while others have been continuing to deteriorate. But there are two reported exceptions: a 57-year old man with leukemia and progressive MS was treated with allogeneic (not autologous) stem cell transplantation, in which the bone marrow comes from a donor. At 3 years follow-up, he is in complete remission of leukemia with a marked improvement in neurological condition (10). Also a clinical trial of high dose chemotherapy alone - without the bone marrow transplant - has shown positive results. It was used to treat six patients with progressive MS. Much of the patient's symptoms disappeared in three to six weeks (11). It might indicate that treatment has affected the unknown cause of MS. On the other hand, at least one patient experienced a single "flare up" of MS-symptoms after the treatment, which definitely raises some questions.

Better theory?

If one must name a single break through in MS-research, it might as well turn out to be this one. One and a half years ago a Scottish team of researchers published a paper about the "wrong MS-theory". In the paper they claimed that MS cannot be an autoimmune disease, that EAE does not work as an animal model of MS, and that the effect of ABCR's can be considered equal to placebo effect (12). The paper was silenced to death by MS-communities, but now the same issues are being discussed again. This time arguments are not based on hypothesis only. An Australian study did not find any evidence of immune system activity in the brains of 12 MS-sufferers, who had died shortly after a relapse. Instead it came to a conclusion that myelin producing cells had begun to die before there were any signs of inflammation (13). If its results are proven valid, the study will wreck the theory of MS being an autoimmune disease.

By coincidence, another study was published at the same time, where an antibody that kills myelin producing cells was found in the CSF of MS-patients (14). So a possible improvement in MS-research could be that researchers would try to develop a way to evaluate treatments by comparing the changes in the amount of those antibodies. Anyway, MS-research might need more creative thinking. Professor Norbert R. Myslinski has said: "we must keep testing our view of the world, and if it fails, replace it with a better one. We must remain flexible in our beliefs, just as our brains remain flexible in their structure and function." (15)

-finn

References:

(1) Therapy with glatiramer acetate for multiple sclerosis (Cochrane Review)
http://www.update-software.com/abstracts/AB004678.htm

(2) Interferon in relapsing-remitting multiple sclerosis (Cochrane Review)
http://212.49.218.202/abstracts/ab002002.htm

(3) The Story of Campath
http://www.mssociety.org.uk/research/news_in_research/campath_story.html

(4) ECTRIMS: Antegren (Natalizumab) Shows Promise In Multiple Sclerosis, Crohn's Disease
http://www.mult-sclerosis.org/news/Sep2001/AntegrenPromisingPhaseIIResults.html

(5) AAN News release
http://www.myelin.org/aanstatins033103.htm

(6) Taking Vitamin D Supplements Lovers Risk of Multiple Sclerosis
http://www.docguide.com/news/content.nsf/news/8525697700573E1885256E1A004DBD08?OpenDocument&c=&count=10&id=48DDE4A73E09A969852568880078C249

(7) NMSS On Estriol Study
http://www.mult-sclerosis.org/news/Oct2002/NMSSOnEstriolStudy.html

(8) MMPs in Multiple Sclerosis
http://www.mmpsinms.ca/index.html

(9) Emerging Therapies for MS
http://www.mult-sclerosis.org/news/May2003/EmergingTherapiesforMS.html

(10) Allogeneic hematopoietic stem cell transplantation in a patient affected by large granular lymphocyte leukemia and multiple sclerosis.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14648027&dopt=Abstract

(11) Strong Chemotherapy May Treat Advanced MS
http://www.thisisms.com/article76.html

(12) The Pathogenesis of Multiple Sclerosis Revisited
http://www.rcpe.ac.uk/publications/articles/journal_32_4/3_pathogenesis_of_MS.pdf

(13) Multiple Sclerosis May Not Be an Auto-immune Disease
http://www.thisisms.com/article63.html

(14) Antibody Present in MS'ers Attacks Myelin-Producing Cells
http://www.thisisms.com/article61.html

(15) The Future of The Brain
http://www.worldandi.com/specialreport/neuro/neuro.html