MS, Tysabri and PML

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The disease:

Multiple sclerosis (MS) is an auto-immune disease characterized by episodes of multi-focal inflammation and demyelination of the brain and spinal cord, leading to recurrent and unpredictable neurologic compromise (relapses or exacerbations), usually alternating with periods of disease inactivity (remissions).

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The drug:

Tysabri (natalizumab) is a monoclonal antibody that binds to the cell adhesion molecules involved in the white blood cell movement from the blood stream into the central nervous system across the  “blood-brain barrier”.

Keeping these cells out of the brain and spinal cord can help prevent the immune-mediated inflammation and demyelination that leads to clinical relapses in multiple sclerosis.

Studies have shown that patients taking Tysabri have a 64% reduced risk of disability progression and  >80% fewer exacerbations (relapses) compared to placebo.  More than 1/3 patient who take the drug are clinically free of disease activity.

Tysabri is administered by iv infusion once  a month.

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The problem:

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More than 50% of people have been infected with the JC or John Cunningham) virus (JCV), most during childhood or adolescence, often with no symptoms at all or just a minor febrile illness.

Once infected, the virus then lies dormant in the central nervous system, like a Tojan horse, totally inactive and innocuous.

However, if the infected person becomes immune suppressed, for example from HIV infection (AIDS) or from taking a immune presupposing medication, the virus can become reactivated and lead to a very serious brain infection known as Progressive multifocal leukoencephalopathy (PML).  PML leads to large confluent areas of brain infection and demyelination (below), causing disability and death,

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Large confluent areas of demyelination in PML.

When a few Tysabri patients developed PML during the initial clinical trials, the FDA temporarily pulled the drug, but then re-introduced it with more careful monitoring (the TOUCH porgram).

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I’m taking Tysabri, what’s my risk of PML?

There have now  been >350 cases of PML in MS patients taking Tysabri, and this constitutes an overall risk of about 1.5 cases per 1000 (or 0.15%) of those taking the drug.

The risk is higher for patients who have already been been exposed to (and test positive for) JCV, have taken other immunosupressive drugs, or have taken Tysabri for longer times:

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So, if you take Tysabri but test -ve for JCV, your PML risk is 0.07 per 1000, or 0.007% or 1 in 14,000.

Even if you test positive for JCV but haven’t taken prior immunosupressive meds (like azathioprine, methotrexate or mycophenolate) your PML risk is only 0.6 per 1000 or 0.06% or 1 in 1,700.

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So, what should I do?

If you take Tysabri, you should know your JCV status.  If your negative, you should get re-tested every 6-months since there are false negative results and some people do seroconvert every year.

If (or once) you test positive, you don’t need any further blood tests, but you should carefully weigh the risk benefits of continuing to take Tysabri beyond 2 years, particularly if you have had prior exposure to other immunosupressive drugs.

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Click here to find out more about Tysabri and PML from the MS society.

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Rituximab for Secondary Progressive MS?

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Multiple sclerosis comes in different varieties:

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Many patients with MS have discrete relapses, which then resolve either partially or completely resolve, and are separated by periods of disease inactivity.  We call this relapsing-remitting (a) or progressive-relapsing (b) disease.

Most of the “disease modifying” drugs currently used in MS work by preventing discrete relapses (and by preventing relapses) they will prevent the progressive acquisition of disability which can accompany each relapse in these types of MS.

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However, there are other MS patients develop progressive disability without discrete relapses.  This can occur after a relapsing remitting phase, so-called secondary progressive MS (c).  Or patients can start right out with progressive disease without any history of discrete relapses, so-called primary progressive MS (d).

Most disease modifying drugs are of little benefit for progressive disease, and treatment has been predominantly symptomatic, with dalfampridine and symptomatic treatments for spasticity.

The chemotherapy drug mitoxantrone was found to have some efficacy for treating secondary progressive MS, but the duration of therapy is limited to 2 years because of toxicity.

New data presented at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis this week suggests that the chemotherapeutic agent rituximab may also stabilize or even reverse disability in secondary progressive MS.

 

Oral Drugs for MS

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There are now 2 FDA approved oral drugs available for the treatment of relapsing remitting MS, teriflunomide (Aubagio, Genzyme/Sanofi) and fingolimod (Gilenya, Novartis).

In the past disease modifying treatments for relapsing-remitting MS all needed to be delivered by injection, and many patients went untreated because of fear of needles, or because of injection site reactions or other side effects with each dose of the mediction, sometimes felt to be worse than symptoms from the underlying disease.

Fingolimod was approved by the FDA in Sept 2010, based studies showing less brain lesions on serial imaging studies, and reduced rates of clinical relapses and progression of disability in patients treated with the drug compared to those on placebo and interferon beta. Patients starting fingolomid do need heart rate monitoring after their first dose, eye exams at basele and after 3 months to detect macular edema (a rare side effect of the drug), and zoster vaccination for those who are not already immune.

Teriflunomide showed less brain lesions on serial imaging studies and reduced clinical relapse rates compared to placebo in clinical trials. The most common side effects were diarrhea, abnormal liver tests, nausea, and hair loss. Treated patients need liver function tests at basleine and periodically during treatment.

Unoftunately, we don’t have head-to-head trials directly comparing the efficacy of these two drugs.

So which drug would I choose? Well, I might be more inclined to recommend teriflunomide for patients with a history of cardiac arythmia or for those taking blood pressure medications such as propranolol or verapamil which can also lower the heart rate. I might be more inclined to use fingolimod in patients who taking other drugs that can affect the liver.

Neither drug is approved for use during pregnancy, although teriflunomide has a stronger warning (category X) of teratogenicity from the FDA.

In sum, we now have two oral medications available for MS patients who have previously been unable or too afraid to get treated with an injectable medication, and this can only continue to improve the long term prognosis for this disease.