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ImmunoSuppressants

Since the Myelin damage in MS is believed to be caused by an Auto-Immune Response, some medications used to help shorten attacks or slow the progression of MS work by suppressing the Immune System. Others, like Steroids, treat the Inflammation that accompanies DeMyelination.



ChemoTherapy

The literal meaning of the term *Chemo-Therapy* is 'to treat with a chemical agent'; however, it generally refers to the potent Cytotoxic (Cell Killing) agents that are prescribed for some forms of Cancer. These drugs not only kill Tumor Cells, but can destroy the body's own normal cells as well.

The cells that are most vulnerable to Cytotoxic agents are those which grow and divide rapidly. Among those affected are Cancer Cells, Hair and Intestinal Cells, Blood Cells, and White Blood Cells of the Immune System.

The rationale for the use of ChemoTherapy to treat MS stems from the fact that MS is considered to be an AutoImmune Disease, whereby an abnormal, heightened Immune action of certain White Blood Cells mounts an attack on Myelinated Nerves of the Central Nervous System.


ChemoTherapeutic agents diminishes the numbers of White Blood Cells, and therefore (theoretically) should slow down or halt this destruction.

The following ChemoTherapeutic agents used to treat Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis are: Azathioprine (Imuran), Cyclophosphamide (Cytoxan), Cyclosporine (Sandimmune), and Methotrexate (Felex; Mexate).

The results of many trials with these agents have not conclusively shown them to be of definite value, and their use in treating Relapsing/Remitting MS remains highly controversial.

Mitoxantrone (Novantrone) had a statistically significant impact on relapse rate and disability in SP Multiple Sclerosis.

These results were presented September 10th 1998, at the 14thcongress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)
(See: Novantrone Update & FDA Approved 10-13-2000).

Novantrone is not intended for use as a treatment for people with Primary/Progressive Multiple Sclerosis. The FDA recommendation is that Novantrone is only used by those with normal Cardiac function, and for no more than a total cumulative dose of 140mg/m2 because of possible cumulative Cardiac toxicity.

Side-Effects of these agents include Nausea, Vomiting, Hair Loss, Danger Of Infection and an increased Long-Term Risk of developing certain Malignancies.


Azathioprine (Imuran), an ImmunoSuppressive agent, commonly used in ChemoTherapeutic regimens for Cancer patients and to treat Rheumatoid Arthritis, has also been evaluated as a treatment for MS to stabilize the patient's clinical course.

Imuran is a medication which suppresses the Immune System. It is given orally to patients whose MS is progressing slowly and is sometimes given in combination with Solu-Medrol treatment.

It is not recommended for women who plan to have children. Imuran can cause Liver problems and Nausea - Long-term use of the drug may also result in an increased risk of Leukemia and Lymphoma.

There have been numerous clinical trials of Azathioprine as a treatment for MS over the past 20 years both in the US and abroad. The results have not been uniform, and the use of this agent as a treatment for MS remains controversial.

One reason for this is that the potential Side-Effects of Azathioprine include Severe Anemia or Leukopenia (shortage of White Blood Cells), Liver Damage, or long-term increased risk of developing malignancies such as Leukemia or Lymphoma. Some patients have not been able to take Azathioprine because of severe Nausea.

A summary of the results of 20 different trials of Azathioprine over the past 20 years using different patient populations, different doses and different protocols, yields mixed results. Some benefit, as noted by slowed progression or fewer relapses, was noted in 60% of the trials. There was no apparent benefit in the other trials.

The decision to use Azathioprine is a complicated one, and should be made by the physician and the patient together, after a discussion of the potential risks and benefits.

Abstracts
Azathioprine (Imuran)


Cyclophosphamide (Cytoxan) is an ImmunoSuppressive drug that is usually given to treat Cancer. Its use in the treatment of MS stems from evidence that MS is an AutoImmune process directed against the Central Nervous System.

An ImmunoSuppressive drug would therefore be expected to slow down or stop the DeMyelinating process without, however, being able to reverse damage or improve symptoms.

In 1983, the report of a 4 year study of Cyclophosphamide for the treatment of Chronic/Progressive MS was published in the New England Journal of Medicine. This study demonstrated stabilization of the disease process in about 80% of the patients for periods of up to one year, compared to stabilization in 20% of patients who received only ACTH.

A subsequent study of 44 patients with Chronic/Progressive MS who were treated with either Cyclophosphamide or a placebo, failed to show any benefit in the treated group. Other studies have either confirmed a beneficial effect of Cyclophosphamide, or have failed to show benefit from this treatment.

At least one study has shown continued stabilization of disease with 'booster' doses of Cyclophosphamide given every other month. The results of a multicenter trial in Canada indicated that patients who received either IntraVenous or Oral Cyclophosphamide combined with Prednisone did no better than a similar group of patients who received placebo.

In this study the placebo response was 75%. The Side-Effects of Cyclophosphamide treatment include Nausea, Vomiting, and Bladder Cancer. The use and efficacy of Cyclophosphamide as a treatment for MS remains experimental and controversial.

Long-Term side effects include Sterility, Mutations, and the Increased Risk of Cancer.

Abstracts
  1. Cyclophosphamide (Cytoxan)

  2. Cyclophosphamide
    Research by: John Hopkins Health Innformation


Cyclosporine (Sandimmune) is a powerful ImmunoSuppressive drug that first came to attention when it was shown to significantly reduce rejection rates in organ transplantation. Unlike most ImmunoSuppressive drugs, it appears to have a specific action against primarily one type of white blood cell, the Helper T-Cells.

Since there is some evidence that these cells are abnormally active during acute exacerbations of MS, and since it has been shown to be effective in treating other AutoImmune Diseases and EAE (the animal model of MS), Cyclosporine was tried in a multicenter double blind, placebo controlled trial, in patients with Progressive MS.

The study enrolled almost 600 men and women and followed them for two years. Half received Cyclosporine, and half received placebo, with neither the doctors nor the patients being aware of the type of treatment.

Many variables were studied, such as clinical status, functional abilities, blood, spinal fluid, and MRI parameters. Those patients who received Cyclosporine had a slightly (but statistically significant) slower rate of disease progression than the placebo group.

There were no differences in activities of daily living, and no change in MRI or spinal fluid parameters. Additionally, there were serious Side-Effects associated with Cyclosporine use, namely Kidney Damage and High Blood Pressure.

Another study done in Germany compared Cyclosporine to another ImmunoSuppressive agent, Azathioprine. Over 80 patients in each treatment group completed a two year double blind protocol. No significant differences between the two groups were apparent at the end of the study.

The Cyclosporine group had twice as many Side-Effects as the Azathioprine-treated patients. It has been concluded therefore, that the benefit vs. risk of Cyclosporine administration for the treatment of MS did not justify its use under most circumstances.


Methotrexate is an effective and safe treatment for Rheumatoid Arthritis, a disease with similarities to MS, findings presented at the May 1994 meetings of the American Academy of Neurology indicate that Methotrexate may delay progression of impairment, especially in the upper extremities, in certain individuals with Primary/Progressive MS.

For people with Progressive MS and moderate disability, weekly low-dose oral Methotrexate may safely help to delay progression of impairment. Upper extremity function seems to be most affected by the medication, while lower extremity function - including ambulation - is not affected.

Methotrexate is a well known, widely available and affordable chemotherapy agent that has been used successfully for years in the treatment of certain Leukemias, Lymphomas and other Cancers, as well as in Rheumatoid Arthritis.

In spite of the potential for toxicity, Methotrexate has been safely used in these conditions for many years. The mechanism of action of Methotrexate in MS is not clear, but the drug is known to regulate and suppress Immune function and to fight inflammation.

While it is unfortunate that disability relating to ambulation did not seem to benefit from this treatment, the study did indicate that treatment could help preserve upper-extremity functions for a longer period of time, which has important consequences for activities of daily living and for mobility.


The Medical Advisory Board of the National Multiple Sclerosis Society considers the benefit from Methotrexate to be limited only to those with moderate disability and a Progressive course of disease.

Larger studies of Methotrexate for MS are warranted. Individuals who are concerned about the use of Methotrexate to treat MS should consult their personal physicians.


Also See:
Steroids, Interferons, & Copaxone

NMSS's
ChemoTherapy & AutoImmune Information


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