PML: a rare side effect of some DMTs

What causes PML?

A virus called the John Cunningham (JC) virus causes PML. This virus spreads in saliva and pee. Over half of all people have been infected by this virus without knowing. This includes people with MS.

If your immune system is working normally, JC virus is harmless. It stays inactive and never causes symptoms. But a weakened immune system can’t keep the virus under control. Then it becomes active and changes (‘mutates’) in a way that lets it attack the brain and cause PML.

Some DMTs affect your immune system, causing a drop in how many white blood cells you have. These blood cells (called T and B cells) look out for and destroy viruses and bacteria. Without enough of these cells, the JC virus can become active, mutate, then trigger PML.

How serious is PML?

If nothing is done about PML in its early stages, the JC virus will cause damage to the brain. PML can kill around one in four people with MS who get it. Those who survive it are left with disability that ranges from mild to severe.

The good news is that over the years doctors have got better at managing PML risk. That’s why people at risk of PML are now less likely to get it.

Which disease modifying therapies (DMTs) have a risk of PML?

The following DMTs have some risk of PML:

• natalizumab (Tysabri and Tyruko)

This DMT has the highest PML risk. The main reason people stop taking natalizumab is to avoid PML. When taking this drug your risk of getting PML in any one year can range from around 1 in 100 to 1 in 10,000. This will depend on things like whether you have the JC virus or not, and how long you take the drug for.

People on natalizumab have a range of tests to keep an eye on their PML risk. Your MS team will keep you updated on your risk during your treatment. This site from Barts hospital in London helps you calculate your PML risk.

Very rarely cases of PML can also happen with:

• fingolimod (Gilenya) – a risk of less than 1 in 10,000
• dimethyl fumarate (Tecfidera) – a risk of around 1 in 50,000
• ocrelizumab (Ocrevus) – rare and mostly seen in people who earlier took natalizumab
• alemtuzumab (Lemtrada) – a handful of cases
• ozanimod (Zeposia)
• siponimod (Mayzent) – only two cases so far

Some people have developed PML but not because of the DMT they’re on now. They got PML because in the recent past they took a different DMT that has a risk of PML. That DMT is usually natalizumab.

With the following DMTs there have been no cases of PML when they’re used to treat MS. But because of how they affect your immune system, in theory there’s a risk PML might happen:

• cladribine (Mavenclad) – so far only seen in people taking this drug for other conditions, not MS
• diroximel fumarate (Vumerity)
• ofatumumab (Kesimpta)
• ublituximab (Briumvi)

PML is very rare in DMTs that don’t cause a long-term drop in your levels of white blood cells (B and T cells). This includes alemtuzumab (Lemtrada), cladribine (Mavenclad) and HSCT.

Who’s most at risk of PML?

There’s only a real risk of a DMT causing PML if you have the JC virus. If you don’t have it, PML is extremely rare (for example, less than 1 in 10,000 with natalizumab).

Some DMTs have no risk of PML. Others have hardly any risk. The biggest risk is with natalizumab (Tysabri or Tyruko). There’s no difference in risk between these two brands of natalizumab.

The following make your risk of PML higher:

• you have the JC virus
• you’ve been on a DMT with a risk of PML for a longer period of time. If you have the JC virus and take natalizumab, your PML risk goes up after two years
• you’ve taken a drug in the past that suppressed your immune system

The following are examples of drugs that suppress the immune system:

• mitoxantrone (used to treat MS or cancer)
• azathioprine (a treatment for rheumatoid arthritis)
• cyclophosphamide (a chemotherapy drug used against cancer)
• methotrexate (used in autoimmune conditions like rheumatoid arthritis and psoriasis)

If I’ve got the JC virus, must I avoid DMTs with a risk of PML?

No, you can still take a DMT that has a risk of PML if you have the JC virus. This includes the highest risk drug natalizumab (Tysabri and Tyruko).

When you catch the JC virus, your body makes antibodies to fight it, which show up in a blood test. So antibodies are a sign that you’ve been infected with this virus. The blood test shows how high your levels of antibodies are. Low levels mean your immune system is keeping the virus under control, with no risk of PML. Higher levels are a sign the virus is active. 

If your antibody levels go over a certain point, your risk of PML is now too high. Your neurologist will take steps to avoid PML.

What are the signs and symptoms of PML?

The signs and symptoms of PML can look and feel like an MS relapse. This is because both PML and MS damage myelin. This is the protective covering around nerves in the brain.

Symptoms of PML can develop over weeks or months, and include:

• worsening weakness in your arms or legs
• clumsiness and coordination difficulties
• eyesight problems
• problems with speaking or thinking
• loss of memory or mental confusion
• sometimes changes in your personality

A seizure is also a sign of PML, especially if it happens alongside any of the symptoms above.

Is there a treatment for PML?

There’s currently no cure or treatment that will undo any permanent damage caused by PML. The most important step is to straight away take the person off the DMT that caused PML. You won’t be able to go back on this drug.

With natalizumab doctors might use something called plasma exchange. This is when they take out liquid (plasma) from your blood and replace it with plasma from a blood donor. This gets the drug out of your body faster. 

Once the DMT leaves your system, your immune system will get back its ability to control the JC virus. PML symptoms often slowly improve. But any brain damage and disability that PML has caused will be permanent. For up to one in four people PML will be fatal.

How can you prevent PML?

Tests and scans

There’s no treatment or vaccine that can stop you picking up the JC virus. And once you have it, no treatment can get rid of it from your body.

If you’re about to start taking natalizumab (Tysabri and Tyruko), you’ll have a blood test. This will show if you have the JC virus. If the test finds antibodies to the JC virus, it's called a 'positive' result. It means you’ve been infected. If the test finds no antibodies, it's called a 'negative' result. It means you don’t have the JC virus.

Once you start natalizumab, you'll have a JC virus blood test every six months. This will check to see if you’ve picked the virus up since your last negative test. You'll keep having these tests even if you already know you have the virus. That's because the test tells your neurologist how high your antibody levels are. This helps to work out your PML risk so that your doctor knows when to take steps to prevent PML.

If you have the virus and take natalizumab, you'll have regular MRI scans of your brain to look for early signs of PML. But only if your antibody levels are high enough. You might have scans every three months to every six or 12 months depending on how high those levels are.

If you take natalizumab, your MS team will tell you what PML symptoms to look out for. They'll tell you what to do if you notice anything that might be PML.

Our page about Tysabri and Tyruko has more about tests for the JC virus, and how you might get different results from them.

If you're not on natalizumab, but your DMT has some risk of PML, your MS team will keep an eye on any symptoms that could be PML. They’ll also check how your immune system is working. For example, regular blood tests tell them if you have enough white blood cells to protect you from the JC virus.

Changes to your medication

With natalizumab (Tysabri and Tyruko), you may need to switch to a different DMT. That might happen once your levels of the JC virus antibody reach a certain level.

Another option could be that you stay on natalizumab. But your doses go down to every six weeks instead of every four. This can lower the risk of PML by around 90%.

If you’re on another DMT, your neurologist can switch you to an alternative drug if they’re worried about PML.

All these steps have been successful in lowering the risk of PML. For example, PML cases in people on natalizumab are not as common as in the past.

Why take natalizumab (Tysabri and Tyruko) when it might cause PML?

PML is a rare side effect with natalizumab (Tysabri and Tyruko). And for people who don’t have the JC virus the risk is extremely small (around a 1 in 10,000 risk). Each individual will weigh the risks of this DMT against the advantages it can bring them. They'll do this with their MS team.

Despite the risk of PML, natalizumab is a drug that works very well if your MS is very active. It was the first DMT to show a high level of effectiveness. For quite a few years it was the only drug available to treat very active MS. The rare risk of PML wasn’t seen as enough reason to take away natalizumab as an option.

If your MS is very active and you want to get pregnant, natalizumab can be a good DMT to take. Natalizumab is relatively low risk for pregnancy and breastfeeding. That isn't true for the other very effective DMTs.

Over the years neurologists have learnt how to reduce the risk of PML with natalizumab. Each person on this drug will agree with their doctor an individual approach to their risk of PML. You can manage your PML risk through:

• regular JC virus testing to calculate your PML risk
• more frequent MRI scans to look for early signs of PML
• spacing drug doses further apart to reduce risk
• switching to a different DMT if needed

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