Probability assessment

JC virus

The John Cunningham virus (JCV) is a human polyomavirus that is common in the general population. It is not fully known how it is transmitted and there are no symptoms associated with infection, so people do not know when they become infected. About 50–70% of the general population in EU is estimated to have been infected by JCV, but the number varies from country to country.1 JCV infection is not directly related to MS, but since it may affect people living with MS, it is important to be aware of potential implications of having JCV in the setting of some treatments for MS.  

Most people will never know if they have JCV.  However, if the usual immune system control of JCV is impaired, the virus changes and in some individuals, this can result in a rare opportunistic brain infection known as progressive multifocal leukoencephalopathy (PML). PML is a serious and potentially fatal lytic infection of oligodendrocytes resulting in the widespread destruction of myelin but can also affect other central nervous system cells.1 Some of the disease modifying drugs used to treat MS are associated with an increased probability of developing PML due to how they affect immune system function.3

When a person is infected with a virus, they develop antibodies to that specific virus. Antibodies can be detected by blood tests. A validated test for Tysabri (natalizumab) treated patients called STRATIFY JCV DxSelect ™ can detect the presence of serum antibodies against JCV (called anti-JCV antibodies).5 (Please note that the test is only validated for Tysabri (natalizumab) treated patients and is part of the risk-management plan). If no JCV antibodies are detected, you get a negative test result.  Conversely if JCV antibodies are detected, you get a positive test result. Since PML is caused by JCV, JCV antibody positivity is a factor known to increase the probability of developing PML. The test result does not indicate if you will or will not get PML, but JCV antibody positive patients are at an increased probability of developing PML compared to antibody negative.1 In patients who have not been previously exposed to immunosuppressants, the probability of PML can be  further stratified by the levels of antibodies (also known as “index”), and higher levels are associated with a higher probability of PML. Two other factors increase the probability of PML development during Tysabri treatment: treatment duration (especially beyond two years) and prior immunosuppression treatment. Patients who have all three risk factors have a high probability of PML.6

”The probability of developing PML when treated with Tysabri is low if you are JCV negative (less than 1 in 10,000).”

Prior to starting Tysabri treatment, it is recommended to test for serum JCV antibodies.  Since it is possible that a person may become infected with JCV after starting treatment, the blood test should be repeated every six months even if JCV negative at the start.  Repeat testing, 6 monthly, is also recommended for patients with low index levels, especially beyond two years of treatment.  It is also recommended to perform a baseline MRI and continued MRI monitoring to screen for PML during Tysabri treatment e.g. consult the SmPC and PID for full monitoring guidelines.1

The probability of developing PML when treated with Tysabri is low when JCV negative (1 in 10,000). With different combinations of the three risk factors the probability of developing PML ranges from low (1 in 10,000) to high (100 in 10,000). That is why you should always consult the PML risk stratification algorithm before initiating treatment and when evaluating the benefit/risk profile of continuing treatment with Tysabri.1

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the brain caused by JC virus. Symptoms and signs of PML can be absent entirely (i.e. asymptomatic presentation) or can result in a range of symptoms and signs depending on the anatomical site of the lesion. The symptoms and signs may look the same as some MS symptoms such as weakness, visual problems and cognitive problems. PML is a serious infection and may be fatal, but fortunately, PML is rare.1 Unlike PML, JCV infection is common, however, most people carrying the virus will never develop PML.3 PML can be seen in people with diseases that are associated with a suppressed immune system and in patients on treatments that suppress the immune system. 

”Unlike PML the JCV infections are quite common. However, most people carrying the virus will never develop PML.3

Symptoms

After the primary JCV infection, which is completely symptom-free, the virus remains clinically latent in the kidneys and other areas of the body. When the immune system is weakened, the virus can be reactivated, transported to the brain and cause PML.2

Initially, the symptoms of PML may be asymptomatic or have symptoms difficult to distinguish from MS. However, over time other neurological symptoms and signs can develop. Patients can suffer from increased motor weakness, become paralyzed, have vision and speech disorders, and become increasingly confused. If PML is suspected, Tysabri should be suspended until PML can be ruled out.1

Diagnosis

The diagnosis of PML is made by virologic techniques detecting the JCV DNA in the cerebrospinal fluid (or sometimes brain tissue), supported by typical changes in the brain that can be seen on MRI and clinical features.1,2 Asymptomatic diagnosis has been associated with improved outcomes in PML affected Tysabri treated patients, supporting the basis for vigilant clinical and MRI monitoring of patients at risk of PML.1

Treatment

Early detection of any sign of PML in Tysabri (natalizumab)-treated patients is crucial. The usual way to manage PML is to immediately stop the Tysabri treatment, and plasma exchange has been used to accelerate Tysabri clearance to restore immune surveillance in the brain.1

Here you can find important information documents for Tysabri (natalizumab) to use when you prescribe Tysabri. 

  • PID (Physician and management guidelines for Multiple Sclerosis patients on Tysabri treatment) Version 18, 2019

  • Patient alert card

  • Treatment initiation form

  • Treatment continuation form

  • Treatment discontinuation form

     

     

References

  1. Physician* Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI therapy (Version 18) (*TYSABRI therapy is to be initiated and supervised by specialized physicians experienced in the diagnosis and treatment of neurological conditions in centres with timely access to MRI)
  2. Folkhälsomyndigheten: Sjukdomsinformation om progressiv multifokal leukoencefalopati (PML) 2019-02-01
  3. Referensgruppen för Antiviral Terapi (RAV): JC-virusinfektion och progressiv multifokal leukoencefalopati (PML) – bakgrundsdokumentation 
  4. Tysabri (natalizumab) Summary of product characteristics 04/2020
  5. Lee et al. Journal of Clinical Virology. A second-generation ELISA (STRATIFY JCV™ DxSelect™) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. 2013.  https://www.ncbi.nlm.nih.gov/pubmed/23465394
  6. Ho et al. The Lancet Neurology: https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(17)30282-X/fulltext

Probability is the likelihood that an event will or will not occur 
 


Do you choose heads or tails when flipping a coin?

The movement of a coin when it’s thrown into the air is something we can’t control, nor if it becomes heads or tails. If we throw the coin enough times, the coin will land heads up half of the time and tails up half of the time. This can be due to chance, but one can calculate the probability that a certain outcome will occur. This can be done if you have the required information. Let's look at some probabilities.

What is the probability of finding a pearl in an oyster?

You might find a pearl in 1 oyster out of about 10,000.1

Do you know anyone who has a twin sister or brother? Well, perhaps you do, since the probability of having twins, once you are pregnant is close to 1 in 100 pregnancies.2

What about triplets?

The probability is 1 in 4400 pregnancies.3 So it may not be certain that you do know anyone with triplets.

MS - is a serious disease, where the probability of disease progression is significant. As disease-modifying treatments of MS reduces the probability of progression, they also come with probability of treatment related adverse events. So, as always, when you decide about a treatment regime you have to make a fair and rational assessment where you balance the benefits against the probabilities or risks of adverse events of the treatment.

Tysabri(natalizumab)

Tysabri, natalizumab, is a treatment for adult patients with highly active relapsing remitting MS. It is given as an infusion every four weeks and has been approved for over a decade.4

Tysabri treatment comes with benefits shown in both clinical trials and clinical practice to reduce number of relapses and inflammation in the brain. However, as any other therapy, it also comes with the probability of developing adverse events. One rare but serious adverse event is PML (Progressive Multifocal Leukoencephalopathy). The probability of PML looks different for different patients and can be estimated by using the algorithm that has been developed from a large number of available patient data.5

Factors that impact the probability of PML are5

  • presence of anti-JCV-antibodies, and their concentration in the blood (JCV-index)
  • Tysabri treatment duration
  • and prior use of immunosuppressants before starting Tysabri for JCV positive patients.

 

 

An analysis conducted in over 6,000 MS patients has demonstrated that 45% of MS patients are JCV negative and 55% are JCV positive.5

It is important to know your patient’s JCV index value to be able to stratify for the probability of PML.4

The probability of PML in the first 2 years of Tysabri treatment is low, however, patients who were treated with immunosuppressants in the past have somewhat higher probability of developing PML.5 For JCV negative patients, the PML risk estimates are based on post-marketing data from 125,000 Tysabri exposed patients.5

JCV negative patients

The probability of PML for JCV negative patients is 1 in 10,000,5 like the probability of finding a pearl in an oyster.1 Or that the probability of not getting PML is 9999 in 10,000 patients.

This does not mean that there is no risk, the JCV value may change over time due to a new JCV infection or fluctuating antibody status or a false negative test result. This is a reason for re-testing all JCV negative patients every six months, when treated with Tysabri.5

JCV positive patients

Estimates for JCV positive patients are based on pooled cohort of 21,696 patients from four clinical trials.5 The probability of PML for JCV positive patient depends on the JCV index.

Patients with an index level below or equal to 0,9  have low probability of developing PML. It varies from 1 to 6 in 10,000 patients during a treatment period from 1 to 6 years.5  It also shows that the probability of not getting PML is between 9994 and 9999 in 10,000 patients. 

How does it look for patients with an index above 1.5?

As for all patients, in the first 2 years of treatment the probability is low.5 It increases over time and after 5 to 6 years of treatment the probability is 100 in 10,000 patients.5 Or that the probability is that 9900 out of 10,000 patients will not get PML.

Probability is the likelihood that an event will or will not occur

So, when assessing Tysabri treatment, look at both the probability for PML and the probability of not getting PML to be able to create a fair objective picture of the situation.

When treating your patients with Tysabri.

  • Test for JCV on a regular basis (every six months)
  • and use the stratification algorithm to monitor the probability of PML for each individual patient5

References

  1. https://www.spey.com/2017/04/05/the-odds-of-finding-a-pearl/
  2. https://twinsuk.co.uk/twinstips/18/189/multiple-birth-statistics,-facts-&-trivia/what-are-the-chances-of-having-twins.triplets-or-quads-/
  3. https://twinsuk.co.uk/twinstips/18/189/multiple-birth-statistics,-facts-&-trivia/what-are-the-chances-of-having-twins.triplets-or-quads-/
  4. Tysabri (natalizumab) Summary of product characteristics 04/2020
  5. Physician* Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI therapy (Version 18) (*TYSABRI therapy is to be initiated and supervised by specialized physicians experienced in the diagnosis and treatment of neurological conditions in centres with timely access to MRI)

Keep on learning

Probability tool

The probability of developing PML when treated with Tysabri depends on the presence or absence of anti-JCV antibodies in the blood (JCV-positive or JCV-negative), the level of anti-JCV antibodies in those patients that are JCV-positive (JCV-index), treatment duration and prior use of immunosupressants (e.g. mitoxantrone, cyclophosphamide, azathioprine).

 

How to assess probability

Everything you do and everything you deal with have potential risks. Living your life is to constantly assess risks in relation to benefits and necessity. In order to make it easier for ourselves to make important decisions, we generalize and simplify. When probabilities become big numbers, sometimes hard to understand, we sometimes to fall back on emotional decisions and to act in a way that we usually do.

Biogen 52787/052020

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