Natalizumab (Tysabri▼): progressive multifocal leukoencephalopathy—updated advice to support early detection (2023)

Updated risk estimates are available as a result of an EU review of natalizumab.

Advice for healthcare professionals:

Before starting natalizumab treatment

New advice:

  • Perform a baseline quantitative serum anti-JCV antibody test—including the index value—to support risk stratification for progressive multifocal leukoencephalopathy (PML)

Reminder of previous advice:

  • Before starting treatment, a recent (usually within 3 months) MRI should be available as a reference
  • Counsel patients and carers on the risk of PML — an updated Treatment Initiation Form will be available in due course
  • Advise patients and carers on symptoms to watch out for and to get medical advice urgently if they occur

During natalizumab treatment

New advice:

  • Perform a quantitative serum anti-JCV antibody test—including the index value—every 6 months for the patients specified in the algorithm below (see figure 2)
  • For high-risk patients (see below), consider the following extra precautions:
    • more frequent MRI screening for PML, such as every 3–6 months using an abbreviated protocol (FLAIR, T2-weighted, and DW imaging): earlier detection of PML in asymptomatic patients may be associated with improved PML outcome
    • If you suspect PML, extend the MRI protocol to include contrast-enhanced T1-weighted imaging and consider testing for JCV DNA in the cerebrospinal fluid using ultrasensitive polymerase chain reaction (PCR)

Reminder of previous advice (for all patients):

  • If you suspect PML at any time, stop natalizumab treatment and investigate appropriately until PML has been excluded
  • Perform a quantitative serum anti-JCV antibody test—including the index value—for any patient with unknown antibody index (all patients should be tested at least once)
  • Perform a full cranial MRI scan at least yearly for the entire duration of treatment, to have up-to-date reference images
  • Monitor patients for signs and symptoms or appearance of new neurological dysfunction (eg motor, cognitive, or psychiatric symptoms), bearing in mind that PML can present with features similar to multiple sclerosis
  • Consider PML in the differential diagnosis of any patient presenting with neurological symptoms or new brain lesions in their MRI scan – cases of asymptomatic PML, diagnosed based on MRI scans and positive JCV DNA in the cerebrospinal fluid, have been reported
  • After 2 years of treatment, remind patients of the risk of PML with natalizumab using the updated Treatment Continuation Form, which will be available in due course

After stopping natalizumab treatment:

New advice:

  • Advise patients and carers to continue to watch out for signs and symptoms of PML for 6 months after the last dose—use the new Treatment Discontinuation Form, which will be available in due course, to aid this discussion
  • Continue the same monitoring protocol for 6 months after the last dose, as PML has been reported during this time

Natalizumab (Tysabri) is a single disease-modifying therapy for adults with multiple sclerosis who have high disease activity despite treatment with beta-interferon, or who have rapidly evolving severe relapsing remitting disease.

Natalizumab is associated with a risk of PML— a rare, progressive, and demyelinating disease of the central nervous system that can be fatal. It is caused by activation of John Cunningham virus (JCV), which usually remains latent and typically only causes PML in immunocompromised patients.

Up to August 2015, there had been 582 reports worldwide from clinical practice of PML in patients receiving natalizumab. Up to 30 March 2016, we had received 33 Yellow Card reports of PML in patients receiving natalizumab in the UK. Evidence from these reports and several studies has led to new advice to reduce the risk of PML. This advice is summarised above, along with a reminder of the previous advice which still applies.

Clinically asymptomatic PML: importance of early detection

Recent analyses suggest that earlier detection of PML is associated with improved outcomes. Cases of asymptomatic PML, diagnosed based on MRI scans and positive JCV DNA in the cerebrospinal fluid, have been reported. PML which is clinically asymptomatic at diagnosis has more localised or unilobar lesions on MRI scans compared with symptomatic patients. Occasionally, particularly in patients with small lesions, exclusively grey matter involvement of PML has been observed on MRI scans.

Note that these analyses have important potential limitations, including lead time bias and length time bias. There was also information missing on MRI frequency in symptomatic PML cases, preventing comparison with PML cases asymptomatic at onset.[footnote 1]

Therefore the risk-proportionate MRI screening protocol for PML described in this article is recommended for patients receiving natalizumab. It is also important that patients do not have any signs or symptoms of PML before switching to other disease-modifying treatments (see other articles in this issue on dimethyl fumarate and fingolimod).

PML risk factors

The risk of PML in patients receiving natalizumab is already known to be higher in patients who:

  • are serum anti-JCV antibody positive
  • have had immunosuppressant therapy
  • have been receiving natalizumab for a long time (especially for more than 2 years)

Recent data show that in patients who have not had immunosuppressant therapy and are serum anti-JCV antibody positive, the risk of PML rises with increased serum anti-JCV antibody index (see figure 1).

Natalizumab (Tysabri▼): progressive multifocal leukoencephalopathy—updated advice to support early detection (1)

Image of diagram showing anti-JCV antibody status.

Figure 1: PML risk estimates in serum anti-JCV antibody positive patients were derived using Life Table method based on the pooled cohort of 21,696 patients who participated in the STRATIFY-2, TOP, TYGRIS, and STRATA studies. Further stratification of PML risk by serum anti-JCV antibody index interval for patients with no history of immunosuppressant use were derived from combining the overall yearly risk with the antibody index distribution. The risk of PML in serum anti-JCV antibody negative patients was estimated based on data from clinical practice from approximately 125,000 exposed patients.

Figure 1 shows that the risk of PML is low at index values ≤0.9, and increases substantially at index values >1.5 in patients who have been receiving natalizumab for more than 2 years.

Therefore, the following groups of patients have been defined as being at high risk of PML:

  1. those who have all three risk factors for PML (ie immunosuppressant therapy, serum anti-JCV antibody positive, and more than 2 years of natalizumab exposure)
  2. those who have not had immunosuppressant therapy but have a high serum anti-JCV antibody index and more than 2 years of natalizumab exposure

For these high-risk groups, consider the extra precautions listed in the ‘during natalizumab treatment’ section above, and in figure 2 below.

6-monthly serum anti-JCV antibody testing

Perform a quantitative serum anti-JCV antibody test—including the index value—every 6 months in the following patients (see algorithm below):

  • those who test negative for serum anti-JCV antibodies
  • those who have low serum anti-JCV antibody index values, less than 2 years of natalizumab exposure, and who have not had immunosuppressant therapy

It is important to test these patients every 6 months because their serum anti-JCV antibody status might fluctuate, they might develop a new JCV infection, or they might have had a false negative finding. Also, patients who had a low serum anti-JCV antibody index at baseline may change to a high serum anti-JCV antibody index during treatment.

Natalizumab (Tysabri▼): progressive multifocal leukoencephalopathy—updated advice to support early detection (2)

Image of diagram showing anti-JCV antibody status.

Figure 2: Algorithm of recommended patient monitoring (figure reproduced with permission from Biogen)

Risk of PML with other multiple sclerosis treatments

Other multiple sclerosis treatments—fingolimod (Gilenya) and dimethyl fumarate (Tecfidera)—have also been linked to a risk of PML.

Post-publication note – January 2018

On 30 January 2018, following a query from a reader, we corrected the second bullet point in the section “Advice for healthcare professionals: Before starting natalizumab treatment” to clarify that the baseline cranial MRI scan should be done before initiation of natalizumab treatment rather than within 3 months of treatment initiation. This amended version is consistent with advice in the March 2010 Drug Safety Update and the Summary of Product Characteristics for natalizumab as of January 2018.

Further information

Letter sent to health professionals in March 2016

European Medicines Agency announcement February 2016

Article citation: Drug Safety Update Vol 9 issue 9 April 2016: 2.

  1. Dong-Si et al. Outcome and survival of asymptomatic PML in natalizumab-treated MS patients. Ann Clin Transl Neurol 2014; 1: 755–64.

Published 18 April 2016



What are the chances of getting PML while on Tysabri? ›

PML is a rare brain infection that usually leads to death or severe disability. It is a possible side effect of taking TYSABRI. The estimated risk of developing PML is less than 1%.

How many years can you stay on Tysabri? ›

You can take Tysabri for as long as you want providing you tolerate it well, have not developed any serious side effects, and Tysabri is still preventing relapses if you have multiple sclerosis (MS) or reducing symptoms, if you have Crohn's disease.

What are the long term effects of Tysabri? ›

Headache, feeling tired, urinary tract infection, joint pain, lung infection, depression, pain in your arms or legs, diarrhea, vaginitis, rash, nose and throat infections, nausea, stomach area pain.

Can you take Tysabri if you are JCV positive? ›

People who carry the JC virus are susceptible to PML, but most don't develop it. However, Tysabri and some other therapies that suppress the immune system are known to increase the risk of PML for those who are JCV-positive after a certain period.

How many people died from Tysabri? ›

O multiple sclerosis drug Tysabri developed the serious brain infection known as PML last month and there were reports of four more deaths, according to a monthly update by the U.S. biotechnology company. The new cases of potentially fatal progressive multifocal leukoencephalopathy, or PML, were detected between Jan.

Is Tysabri a form of chemotherapy? ›

Tysabri isn't a kind of chemotherapy, but it is an immunosuppressant. Chemotherapy drugs are used to treat cancer. They work by stopping cells in your body from multiplying, especially cells that grow quickly (such as cancer cells). Immunosuppressants such as Tysabri work differently than chemotherapy drugs.

How much does one infusion of Tysabri cost? ›

The cost for Tysabri intravenous concentrate (300 mg/15 mL) is around $8,654 for a supply of 15 milliliters, depending on the pharmacy you visit. Quoted prices are for cash-paying customers and are not valid with insurance plans.

Does Tysabri make you gain weight? ›

Weight gain is a possible side effect of Tysabri. However, this side effect was rarely reported in clinical trials. Weight loss was also a rare side effect in people who took Tysabri.

How will I feel after a Tysabri infusion? ›

Headache, feeling tired, urinary tract infection, joint pain, lung infection, depression, pain in your arms or legs, diarrhea, vaginitis, rash, nose and throat infections, nausea, stomach area pain.

Can Tysabri make MS worse? ›

No, Tysabri shouldn't make your MS worse. Studies have shown this medication to be effective for treating certain types of MS. (For details, see the “Who is Tysabri prescribed for?” section below.) If you're receiving Tysabri and you stop treatment, you may have worsening MS symptoms.

Does Tysabri affect your teeth? ›

Yes, Tysabri can cause toothaches or tooth infections in some people. These teeth-related side effects occurred during studies of the drug, but they weren't common. Toothaches can be a symptom of an infection.

Is Tysabri good for MS? ›

TYSABRI is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML).

Does Tysabri weaken your immune system? ›

Official answer. Yes, treatment with Tysabri can weaken your immune system. This may increase your risk of getting an unusual or serious infection. Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), a rare brain infection.

What happens if you are JCV positive? ›

If the blood test finds JC virus (JCV positive), this indicates that you are at a higher risk of developing PML, although for most people the risk is still small.

Does Tysabri make you tired? ›

Reactions more common in the TYSABRI-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors.

Why was Tysabri taken off the market? ›

But in February 2005 it was withdrawn by its maker, Biogen Idec, and distributor, Elan, after three patients in clinical trials developed progressive multifocal leukoencephalopathy (PML), a rare viral infection of the brain. Two of the cases were fatal.

When should I stop taking Tysabri? ›

For patients who are on Tysabri, a positive JC virus test does not mean that PML will develop, but it places patients in a high risk group. In these situations, many will need to stop Tysabri after ~2 years of treatment, the time period after which PML risk rises.

Is Tysabri stronger than Ocrevus? ›

Results showed that annual relapse rates were lower for Tysabri than Ocrevus, and patients on Tysabri were significantly less likely to have had any relapse after 12 or 24 months of treatment. Further analyses indicated that patients on Tysabri were at an approximately 30% lower risk of any relapse.

Can you drink alcohol on Tysabri? ›

You may make alcohol safer if you're receiving infusions of Tysabri if you: Limit alcohol. Moderate use can lower your risk for the problems that alcohol can cause. That means one drink a day for women and 2 for men.

Does Tysabri affect your liver? ›

There have been reports of liver injury in patients receiving Tysabri. The term 'liver injury' is used to describe any side effect seen in a patient that could be a sign of the liver malfunctioning, such as raised levels of liver enzymes, yellowing of the skin or inflammation of the liver.

Does Tysabri stop MS progression? ›

Treatment with Tysabri was found to be highly effective at reducing MS relapses, lowering their annual frequency by 80.5% at two years of treatment, and by 97.5% at 10 years. While on Tysabri, patients' EDSS scores tended to remain stable.

Does Tysabri improve walking? ›

Data indicated that Tysabri-treated patients experienced less disability worsening on mobility and arm function tests than placebo-treated patients. In contrast, there was no difference in EDSS changes between the groups.

Does Tysabri help with walking? ›

PHILADELPHIA, Pennsylvania — Results of a new analysis show that patients with relapsing-remitting multiple sclerosis (RRMS) who had confirmed improvement in walking speed (CIWS) had better self-reported physical functioning, and treatment with natalizumab (Tysabri, Biogen Idec) improved the probability of achieving a ...

Can you take ibuprofen with Tysabri? ›

Interactions between your drugs

No interactions were found between ibuprofen and Tysabri.

What happens if I miss my Tysabri infusion? ›

If I can't attend can I miss a dose? Tysabri® is a therapy that needs to be given every 4 weeks. It has been demonstrated that if you miss a dose you have an increased risk of a serious infusion reaction occurs that means you can no longer receive therapy.

Can Tysabri cause leukemia? ›

Tysabri isn't likely to cause you to develop cancer. In clinical trials of Tysabri, cancer wasn't a side effect. Research has found an increased risk of certain types of cancer in the intestines of people with Crohn's disease.

How can I control MS without medication? ›

Instead of medicines, you can try physiotherapy, occupational therapy, and steroid shots to help you manage your symptoms. It's hard to know the course that your MS will take. Doctors can't know for sure if your MS will get worse. A small number of people with MS have only mild disease and do well without treatment.

Does having MS make you high risk for Covid? ›

Current evidence shows that simply having MS does not make you more likely than the general population to develop COVID-19, become severely ill or die from the infection. However, certain factors have been shown to increase the risk of a severe case of COVID-19: Progressive MS. Older age.

Can MS make your teeth fall out? ›

The Effect of MS Medications on the Mouth

One common side effect is dry mouth. “Dry mouth usually goes along with tooth decay that is very difficult to treat,” says Kashani. “It can progress very quickly to the nerve, and if you don't catch it in time, the patient can lose the tooth.”

What is the risk of Tysabri? ›

What are the risks of Tysabri? As with most drugs, there are risks linked to the long term use of Tysabri. The main risk is a potentially fatal brain infection, called progressive multifocal leukoencephalopathy (PML).

Does MS burn itself out? ›

Some people living with MS eventually reach a point that their disease progression appears to stop. From there, they experience only mild symptoms without developing major disability. This mild disease course is sometimes called benign or burned-out MS, although controversy surrounds these terms and what they mean.

What are the safest MS treatments? ›

The results are in, and according to a recent report comparing the safety records of all multiple sclerosis (MS) drugs on the market, Tecfidera took the top safety prize. The report reveals that newer MS drugs received high marks for safety, while older interferon drugs had more reported side effects.

What is the new cure for MS? ›

There's currently no cure for multiple sclerosis (MS), but treatment can help manage it. In recent years, new medications have become available to help slow the progression of the disease and relieve symptoms.

How do you know if Tysabri is working? ›

In general, you should expect to visit your doctor every three months and get a magnetic resonance imaging (MRI) brain scan every 12 months to find out if your disease-modifying drug is working. Some things your doctor will consider: How many relapses you've had. How severe the relapses were.

Can JCV be cured? ›

Can JC Virus Be Treated? There is no way to cure JC virus or PML if it develops. However, there are some ways that providers can try to treat it and give a person the best chance at recovery. If you take medication to suppress your immune system, such as steroids, your provider will want you to stop taking them.

Does PML ever go away? ›

For some people, plasma exchange may slow the progression of PML and slightly increase their life expectancy, but the benefits are uncertain. Even after stopping a medication or having plasma exchange, many people experience lingering PML symptoms. Others may develop neurological disabilities.

What is a high JCV level? ›

Previously, different anti-JCV antibody index categories have been defined for PML risk stratification and the cut points 0.9 and 1.5 included in the label of natalizumab [8, 21]–in the following termed as low (≤0.9), medium (>0.9 and ≤1.5) and high (>1.5) JCV index category.

How quickly does PML develop? ›

Typical symptoms associated with PML are diverse, since they are related to the location and amount of damage in the brain, and evolve over the course of several days to several weeks.

How common is PML in MS patients? ›

Progressive multifocal leukoencephalopathy (PML) has been associated with several disease-modifying therapies (DMTs), including DMF in treating MS. We present detailed clinical characteristics of nine PML cases and show that the PML incidence in DMF-treated patients is 0.02 per 1000 patients.

What is the mortality rate of PML? ›

In general, PML has a mortality rate of 30 to 50 percent in the first few months following diagnosis. Those who survive the disease may be left with severe neurological disabilities. Clinical trials are studies that allow us to learn more about disorders and improve care.

Does Tysabri stop progression? ›

Treatment with Tysabri was found to be highly effective at reducing MS relapses, lowering their annual frequency by 80.5% at two years of treatment, and by 97.5% at 10 years. While on Tysabri, patients' EDSS scores tended to remain stable.

What are the first signs of PML? ›

Symptoms of PML

The first symptoms may be clumsiness, weakness, or difficulty speaking or thinking. As the disorder progresses, many people develop dementia and become unable to speak. Vision may be affected. People with progressive multifocal leukoencephalopathy eventually become bedbound.

Can a person recover from PML? ›

Treatment. In people with HIV/AIDS, treatment to strengthen the immune system can lead to recovery from the symptoms of PML. No other treatments have proved effective for PML. Medicines to treat PML are being developed and may be available in the near future.

How do I get rid of PML? ›

There is no cure for PML. Treatment includes immediate termination of current medication. In some cases treatment may include treatment with antiretroviral medication or other experimental approaches.

What is the life expectancy of someone with primary progressive MS? ›

This can lead to a shorter life expectancy. A study published in 2017 reported that the average life expectancy for people with PPMS was 71.4 years . In contrast, the average life expectancy for people with relapsing-remitting MS was 77.8 years.

Is PML a disability? ›

PML qualifies you for social security disability benefits under the Social Security Administration's guidelines. If you or a loved one has been diagnosed with PML, then you are considered disabled for at least 24 months from the date of diagnosis.

What is the life expectancy of leukoencephalopathy? ›

Affected Populations

Life expectancy ranges from 2 to over 30 years, with an average life expectancy of 8 years after symptom onset.

What triggers PML? ›

PML is caused by lytic infection of oligodendrocytes and astrocytes resulting in multiple areas of demyelination in the CNS.

Can you see PML on MRI? ›

MRI has been able to detect PML-related changes 3 to 4 months before development of symptoms. Because prompt detection and treatment of PML in the presymptomatic phase has been shown to improve outcomes, appropriate surveillance of patients taking natalizumab is essential.

Will an MRI show PML? ›

The PML findings on brain MRI scans are described as bilateral, asymmetric subcortical-predominant lesions that appear hyperintense on T2-weighted and FLAIR sequences and hypointense on T1-weighted sequences. Mass effect is typically absent or mild, but not invariably.

How does Tysabri make you feel? ›

Common side effects include dizziness, nausea, urticaria (a skin rash) and shivering. Treatment with Tysabri may increase the risk of progressive multifocal leukoencephalopathy (PML), an uncommon brain infection that can lead to severe disability or even death.

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