To better understand if Tysabri therapy is good for you, it is informative to take a short walk down memory lane. When Tysabri first returned to the market place in 2006 and MS specialists started treating patients under the TOUCH program, the risk of PML was estimated at 1/1000. Very quickly we learned about additional risks factors for PML; these new risk factors included,
- Duration of therapy greater than 2 years and
- Prior treatment with an immunosuppressant drug (such as cyclophosphamide, mitoxantrone, azathioprine or Imuran, methotrexate, mycophenolate or cellcept)
This was followed by the development of a blood test to determine if your body was making antibodies against the virus that is associated with the development of PML, called the JC virus. Initially, results from the this blood test were reported as either positive or negative; those with a positive test (56% of people) seemed to have almost all the risk of developing PM, whereas those who were negative on this test (44%) had a negligible risk of developing PML. To make matters slightly more complicated, those who were negative on the JC virus antibody test could become positive later (about a 2% yearly conversion rate over the short term). The initial testing showed that about 40% of people with MS were negative on this test and 60% positive. For many neurologist and patients who were risk adverse, this eliminated Tysabri as a treatment option in at least 60% of patients who they felt were good candidates by other criteria.
Around this time other highly effective therapies were becoming available for people with MS with their own set of risk factors, particularly Fingolimod (Gilenya) with its risk of cardiac complications, macular edema and reactivation of herpetic infections like shingles. We now have Tecfidera that appears relatively safe and effective, but associated with some unpleasant GI side effects in about 20% of people at the start of treatment.
Thankfully, we have further refined the risk stratification for people wishing to consider Tysabri therapy and the FDA recently approved the use of Tysabri as a first line agent (people with no prior disease modifying therapy) in well selected relapsing MS patients. The main change in our risk stratification is based on a free test that measures the actual amount of antibodies your body makes against the JC virus, called the JC Virus antibody index. We no longer consider patients as simply positive or negative for JC antibodies. This new information on stratifying risk by JC virus index in addition to the prior known risk factors, which include duration of therapy and prior immunosuppressant use, forms the basis of assessing your risk of developing PML on Tysabri therapy. More importantly, the new risk stratification scheme reclassifies approximately 25% of the patients previously considered JC virus antibody positive as a relatively lower risk group who may now consider Tysabri therapy.
Please see the attached figure to see the entire stratification scheme. Once you know your JC Virus index value (which you can get from your doctor) you can determine whether it is too risky for you to consider Tysabri by simply looking at the chart. First some highlights:
- If you are JC virus antibody negative the index value is not reported and your risk of PML is extraordinarily low (< 1 in 10,000). You are definitely the type of patient who should consider Tysabri as an option right from the start. Other factors will determine the best choice of the therapy.
- If you are JC Virus positive with any index level and you previously received immunosuppressant treatment, your risk of PML is very high after 2 years, and you should only consider Tysabri under extraordinary circumstances.
- JC Virus index levels less than 1.5 in patients with no prior history of immunosuppressant use confers a variable risk of PML over time. Generally, JC virus index levels less than 1.0 are associated with a low enough risk of PML for me to consider Tysabri as a first line treatment in my patients with risk factors for short term MS disease progression. I generally consider Tysabri only a second line therapy for those with antibody index values between 1 and 1.5, and only as a last option for those with consistent JC virus index values greater than 1.5.
So how do I make these judgments? First, I think it is reasonable to consider an MS therapy as first line in almost all patients if a severe risk of that therapy occurs in less than 1 in 10,000 people. I would consider the therapy first line in selected patients with significant MS disease activity if the risk of PML were less than 1 in 2500 (see table. This would mean a JC virus index value of < 0.9). This is mostly because we have other therapies available that may work and have a lower risk profile. For higher risks of PML, I am inclined to consider therapy only as second or third line but will still use Tysabri in selected cases.
So what is your risk profile? What are your thoughts on the risks associated with either Tysabri or any other MS disease modifying therapy?
-- Dr. Kinkel
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