Understanding What Drugs Cause PML (Progressive Multifocal Leukoencephalopathy)

October 11, 2025 •

3 min read

An estimated 70-80% of the adult population is latently infected with the ubiquitous JC virus, which normally remains dormant. However, when immune-suppressing treatments are used, the virus can reactivate and cause progressive multifocal leukoencephalopathy (PML), a rare but often fatal brain infection.

Quick Summary

Certain immunosuppressive medications, particularly some monoclonal antibodies and chemotherapy agents, can reactivate the JC virus, leading to PML. The risk varies by drug, with factors like treatment duration and prior therapy influencing susceptibility. High-risk patients require careful monitoring and risk stratification.

Key Points

Immune System Suppression: PML is caused by the reactivation of the JC virus, which occurs in individuals with weakened immune systems, often due to medications.
High-Risk Monoclonal Antibodies: Natalizumab (Tysabri) poses the highest risk of PML among therapies for multiple sclerosis, particularly with prolonged use and prior immunosuppression.
Variable Drug Risk: The risk of developing PML varies greatly among different drugs and classes, ranging from very high with natalizumab to very rare with other immunomodulatory agents.
Combination Risk Factors: PML risk with many drugs is elevated when combined with other immunosuppressants, or in the presence of an underlying immune-compromising condition.
Critical Monitoring: High-risk patients, such as those on natalizumab, are closely monitored through regular JC virus antibody testing and brain MRI scans for early detection.
Treatment Approach: The primary strategy for treating drug-induced PML is to discontinue the offending medication and allow the immune system to recover.
Risk Mitigation: For drugs like natalizumab, healthcare providers use risk stratification strategies based on JCV antibody status, treatment duration, and prior immunosuppressant use to manage PML risk.

What Is Progressive Multifocal Leukoencephalopathy (PML)?

Progressive multifocal leukoencephalopathy (PML) is a severe, often fatal demyelinating disease of the central nervous system caused by the reactivation of the JC virus (JCV). Most adults are infected with JCV without harm, but in those with weakened immune systems, the virus can become active. This leads to the destruction of oligodendrocytes, the cells that form the myelin sheath around nerve fibers, resulting in progressive neurological decline.

How Drugs Trigger PML

Certain drugs can weaken the immune system, allowing dormant JCV to reactivate. The virus can then travel to the brain and replicate within glial cells, causing demyelination. While mechanisms vary, the core issue is reduced immune surveillance in the central nervous system. Some drugs prevent immune cells from entering the brain, others deplete specific immune cells like B-lymphocytes, and some cause general immune suppression.

Specific Drug Classes and Examples

Immunomodulatory and immunosuppressive drugs are most commonly linked to increased PML risk. The risk depends on the specific drug, the patient's condition, and other factors.

Monoclonal Antibodies

This class, used for autoimmune diseases and cancers, includes drugs with a notable association with PML.

Natalizumab (Tysabri): Primarily used for multiple sclerosis (MS), this drug is most frequently linked to PML. It blocks immune cells from entering the brain. Risk factors include anti-JCV antibodies, treatment duration over 24 months, and prior immunosuppressant use.
Rituximab (Rituxan): Used for various autoimmune conditions and cancers, it depletes B-lymphocytes. The PML risk is lower than with natalizumab but is often seen in patients with existing immune compromise or those receiving other immunosuppressants.
Alemtuzumab (Lemtrada): An MS treatment causing prolonged lymphocyte depletion, associated with PML risk.
Ocrelizumab (Ocrevus) and Ofatumumab (Kesimpta): These anti-CD20 therapies have been linked to rare PML cases.

Immunosuppressants and Chemotherapies

These agents are used in transplant patients, cancer treatment, and severe autoimmune disorders.

Fingolimod (Gilenya): An MS drug that prevents lymphocytes from reaching the CNS. PML has been reported in patients on fingolimod.
Fumarates (Dimethyl Fumarate - Tecfidera; Diroximel Fumarate - Vumerity): Oral MS drugs linked to rare PML cases, often with prolonged severe lymphopenia.
Mitoxantrone: An older chemotherapy and MS drug known to increase PML risk, especially before using other therapies like natalizumab.
Other Immunosuppressants: Drugs like azathioprine, cyclophosphamide, and mycophenolate mofetil used in autoimmune diseases and transplantation increase PML risk, particularly in combination.

PML Risk Comparison for Selected Drugs


Drug (Brand Name)	Class of Drug	Primary Use	Relative PML Risk	Mechanism and Risk Factors
Natalizumab (Tysabri)	Monoclonal Antibody	Multiple Sclerosis, Crohn's Disease	Highest documented risk among MS therapies	Blocks immune cell entry into CNS; risk increases with treatment duration, prior immunosuppressant use, and JCV antibody status.
Rituximab (Rituxan)	Monoclonal Antibody	Autoimmune diseases (RA, SLE), Cancers	Low, but higher than general population	Depletes B-cells; risk often confounded by underlying disease or co-therapy.
Fingolimod (Gilenya)	Immunomodulator	Multiple Sclerosis	Very Rare	Traps lymphocytes in lymph nodes; cases often preceded by long-term lymphopenia.
Dimethyl Fumarate (Tecfidera)	Immunomodulator	Multiple Sclerosis	Very Rare	Immunomodulatory; rare cases linked to sustained lymphopenia.
Alemtuzumab (Lemtrada)	Monoclonal Antibody	Multiple Sclerosis, Cancers	Rare	Causes profound lymphocyte depletion.
Mycophenolate Mofetil	Immunosuppressant	Organ Transplant, Autoimmune Diseases	Rare	Broad immunosuppression; risk increased by combination with other agents.

Monitoring and Management

Due to the severity of PML, monitoring high-risk patients for early detection is crucial.

Monitoring Strategies

JCV Antibody Testing: Helps stratify risk for drugs like natalizumab.
MRI Scans: Regular brain MRIs can detect early lesions.
Clinical Vigilance: Monitoring for new neurological symptoms by patients and providers.

Management and Treatment

There is no cure for PML; treatment focuses on restoring immune function.

Discontinue the Drug: The essential step is stopping the medication causing immunosuppression.
Immune Reconstitution: Techniques like plasma exchange can speed up immune recovery for certain drug-induced PML.
IRIS Management: Immune reconstitution inflammatory syndrome (IRIS) can occur during recovery, sometimes requiring corticosteroids.

Conclusion

PML is a serious but rare complication linked to several immunosuppressive drugs. The risk varies by drug and patient factors like JCV antibody status and treatment duration. While concerning, the benefits of these drugs often outweigh the risks for severe conditions. Vigilant monitoring, patient education, and prompt intervention are vital for risk management.

Frequently Asked Questions

The primary cause of PML is the reactivation of the John Cunningham (JC) virus, a common virus that is harmless in most healthy individuals. Reactivation occurs when the immune system becomes weakened, allowing the virus to multiply and attack the brain's white matter.

Natalizumab (brand name Tysabri) is the drug most frequently associated with PML, especially in patients with multiple sclerosis.

Natalizumab increases PML risk by preventing immune cells, specifically T-cells, from crossing the blood-brain barrier. This inhibits the immune system's surveillance of the central nervous system, allowing the JC virus to reactivate and spread.

Yes, drugs for other autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) can cause PML. Rituximab and methotrexate, for example, have been associated with PML risk, particularly in combination therapies.

Key risk factors include the presence of JC virus antibodies, longer duration of treatment with the causative drug, and prior use of other immunosuppressants. The underlying disease being treated also plays a significant role.

The main approach to treating drug-induced PML is to immediately discontinue the immunosuppressive medication responsible. This allows the patient's immune system to recover and fight off the infection, which is currently the most effective management strategy.

Yes, risk mitigation involves careful patient selection and monitoring. For high-risk medications, regular testing for JCV antibodies helps stratify risk, and frequent MRI scans can detect early signs of infection. This allows for prompt discontinuation of the drug if PML is suspected.

Symptoms of PML are neurological and vary depending on the area of the brain affected. They can include progressive weakness, clumsiness, vision and speech disturbances, memory loss, and personality changes.

While there's no way to prevent initial exposure to the JC virus, the risk of developing PML can be minimized. This involves using the lowest effective dose of immunosuppressants for the shortest duration necessary and carefully monitoring high-risk patients.

PML is a serious and potentially life-threatening condition. While not always fatal, it can lead to severe disability. The prognosis often depends on how quickly the infection is diagnosed and how effectively the immune function can be restored.