Progressive Multifocal Leukoencephalopathy Risk from Immunosuppressants: What You Need to Know

What Is Progressive Multifocal Leukoencephalopathy (PML)?

PML is a rare but deadly brain disease caused by the reactivation of the JC virus. Most people carry this virus without knowing it - about 50 to 70% of adults have been exposed. Normally, your immune system keeps it under control. But when you take strong immunosuppressants, that control can break down. The virus starts attacking the white matter of your brain, destroying the fatty coating (myelin) around nerve cells. This leads to irreversible damage, and symptoms can show up fast: weakness on one side of the body, trouble speaking, vision loss, confusion, or loss of coordination. Once symptoms appear, the damage is often already advanced.

Which Immunosuppressants Carry the Highest Risk?

Not all immunosuppressants are created equal when it comes to PML risk. The biggest red flag is natalizumab (Tysabri), used for multiple sclerosis and Crohn’s disease. Among patients on natalizumab, the overall PML risk is about 0.12%, but it jumps dramatically if you have three things: a positive JC virus antibody test, prior use of another immunosuppressant like azathioprine or methotrexate, and treatment lasting more than two years. In that high-risk group, the chance of PML hits 4.1 cases per 1,000 patients.

Other drugs with notable risk include:

• Fingolimod (Gilenya): 0.4 cases per 1,000 patient-years
• Rituximab (Rituxan): 0.8 cases per 1,000 patient-years
• Dimethyl fumarate (Tecfidera): 0.2 cases per 1,000 patient-years

Drugs like interferon beta and glatiramer acetate have never been linked to confirmed PML cases. If you’re on one of the high-risk drugs, knowing your exact risk level isn’t just helpful - it’s critical.

How Is PML Risk Measured?

The main tool doctors use is the JC virus antibody test. It tells you if you’ve ever been exposed to the virus. But it’s not perfect. About 2 to 3% of people who test negative still carry the virus - false negatives happen. That’s why a negative test doesn’t mean zero risk.

For patients on natalizumab, labs also report a JC virus antibody index. This number shows how strong your immune response is to the virus. A low index (below 0.9) means very low risk - under 0.1% over four years. But if your index is above 1.5, your risk jumps to nearly 11% after four years of treatment. That’s why many neurologists stop natalizumab at the 24-month mark for patients with high index values, even if their MS is well-controlled.

Why Prior Immunosuppressant Use Matters

If you’ve ever taken another immunosuppressant before starting natalizumab, your PML risk triples. This isn’t just a small bump - it’s a major red flag. Studies show patients who used drugs like mitoxantrone, azathioprine, or methotrexate before switching to natalizumab have a 2.5 times higher chance of developing PML than those who didn’t. That’s why the FDA now requires doctors to ask: “Have you ever taken an immunosuppressant before?” before prescribing natalizumab. Many patients don’t realize that even a short course of prednisone or cyclophosphamide years ago can count. Your full medication history matters.

What Are the Early Warning Signs?

PML symptoms often mimic MS relapses, which is why so many cases are missed at first. About 37% of early PML cases are wrongly labeled as a flare-up. That’s dangerous. Unlike a typical MS relapse, PML symptoms usually get worse slowly over weeks, not days. Look out for:

• One-sided weakness or numbness
• Slurred speech or trouble finding words
• Blurred or double vision
• Loss of balance or clumsiness
• Changes in thinking, memory, or personality

There’s no single test that catches PML early. That’s why regular brain MRIs are essential. Neurologists recommend scans every 3 to 6 months for high-risk patients. Early PML lesions show up as small, bright spots on diffusion-weighted MRI sequences - something only trained radiologists can spot reliably. It takes 15 to 20 hours of specialized training to tell the difference between an MS plaque and the earliest signs of PML.

What Happens After PML Diagnosis?

Once PML is confirmed, the first step is always stopping the immunosuppressant. But that’s not enough. In 50 to 60% of cases, the immune system comes back too hard and starts attacking the brain itself - this is called IRIS, or immune reconstitution inflammatory syndrome. IRIS can cause swelling, seizures, or even death. Treatment often involves high-dose steroids like methylprednisolone to calm the overactive immune response.

Mortality rates for PML still hover between 30 and 50%. Survivors often live with permanent disabilities - trouble walking, speaking, or caring for themselves. But there’s hope. New treatments are emerging. In a 2024 pilot study, a T-cell therapy called DIAVIS cut PML deaths by 68%. Some patients have also responded to immune checkpoint inhibitors like pembrolizumab. These aren’t standard yet, but they’re changing the game.

How Are Doctors Managing This Risk Today?

Top medical centers have strict protocols. At places like Cleveland Clinic and Northwestern, every patient starting natalizumab gets:

1. A JC virus antibody test - before the first dose
2. Baseline brain MRI - to compare future scans
3. Monthly neurological checkups
4. Repeat antibody testing every 6 months
5. MRIs every 3 to 6 months - especially after 24 months of treatment

Doctors are also learning to watch for lymphopenia - low white blood cell counts. Patients with an absolute lymphocyte count below 0.8 x 10⁹/L have a 4.3 times higher risk of PML. That’s why blood counts are tracked closely. The FDA requires prescribers to complete 2 hours of training and renew it every two years. Still, only 92% of academic hospitals have full protocols in place. In community clinics, that number drops to 67%.

What Are Patients Really Feeling?

Behind the statistics are real people living in fear. On MS forums, 78% of patients on natalizumab say they feel extreme anxiety about PML. One Reddit user wrote: “I had a negative JC test, but my MRI showed early PML lesions. That 2-3% false negative rate? It’s real.” Another user, who caught PML early and stopped treatment, said: “I lost 90% of my motor function - then got back 90% after IRIS treatment. My MRI saved me.”

Because of this fear, 42% of patients have switched therapies even when their MS was stable. Since 2015, prescriptions for natalizumab have dropped 22% in patients with prior immunosuppressant use. More are choosing alternatives like ocrelizumab, which has no confirmed PML cases so far.

What’s Changing in the Future?

Research is moving fast. The Cleveland Clinic is running a Phase II trial (NCT05678901) testing maraviroc, an HIV drug, to prevent PML in high-risk natalizumab patients. Early results suggest it might block the JC virus from entering brain cells. Meanwhile, diagnostic tools are improving. The global PML testing market is expected to grow from $287 million in 2023 to $412 million by 2028. Better blood tests, AI-assisted MRI analysis, and faster antibody index readings are coming.

By 2030, experts predict PML risk with natalizumab could drop to 0.5 cases per 1,000 patient-years - low enough that it might become a first-line option again for select patients. But until then, vigilance is everything.

What Should You Do If You’re on an Immunosuppressant?

Here’s what to ask your doctor:

• Have I been tested for JC virus antibodies? What’s my index value?
• Have I ever taken another immunosuppressant? Does that change my risk?
• How often should I get an MRI? What kind?
• What symptoms should I report immediately?
• Is there a safer alternative if my risk is too high?

Don’t wait for symptoms. PML doesn’t give you a second chance. If you’re on a high-risk drug, stay proactive. Keep your appointments. Track your symptoms. Know your numbers. Your brain is worth it.