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, and if the virus changes, 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 cells¹.  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 group level probability of developing PML compared to antibody negative.¹  In patients who have not been previously exposed to immunosuppressants, the group level 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 group level 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 group level probability of PML.⁶

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 group level 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 group level 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. Clinical 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.

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, although plasma exchange has not been shown to clearly beneficial to the patients’ recovery from PML.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) (the latest version)

-       Patient alert card

-       Treatment initiation form

-       Treatment continuation form

-       Treatment discontinuation form

Biogen-08861 januari 2023
Senast uppdaterad: 2023-02-07

_References

_{1) Physician* Information and Management Guidelines for Multiple Sclerosis patients on TYSABRI therapy (Version 19) (*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 fass.se}

_{5) Lee et al. Journal of Clinical Virology. A second-generation ELISA (STRATIFY JCVTM DxSelectTM) 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}