Can Rituximab Cause Progressive Multifocal Leukoencephalopathy (PML)?
Yes, rituximab can cause progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal demyelinating brain infection caused by JC virus reactivation. This risk is explicitly recognized in the FDA black box warning for rituximab and across multiple clinical guidelines 1.
Established Risk and Incidence
The FDA label carries a black box warning specifically for PML, stating that "Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving RITUXAN" 1. This represents the highest level of safety concern for this medication.
Disease-specific risk varies considerably:
- Rheumatoid arthritis: Approximately 4 per 100,000 patients treated with rituximab, representing a 10-fold increased risk compared to the baseline RA population risk of 0.4 per 100,000 2, 3
- Systemic lupus erythematosus: Similar risk of 4 per 100,000, with 40% of lupus-associated PML cases occurring during low-dose glucocorticoid therapy alone 2
- Hematologic malignancies: Higher baseline risk due to underlying disease and concurrent chemotherapy 4, 5
- Other autoimmune conditions: Rare cases documented across pemphigus vulgaris, vasculitis, and other indications 6
Clinical Recognition and Diagnosis
PML typically presents as a progressive neurological disorder with:
- Behavioral changes, confusion, or cognitive decline 6
- Motor deficits including weakness, gait disturbance, or spastic quadriparesis 5
- Speech difficulties (dysarthria, slurred speech) 5
- Visual disturbances 6
- Coordination problems or ataxia 5
Diagnostic confirmation requires:
- MRI brain showing hyperintense white matter lesions on T2-weighted images, typically involving subcortical and deep white matter without mass effect 5, 7
- PCR detection of JC virus DNA in cerebrospinal fluid (gold standard) 6, 2
- Brain biopsy when CSF PCR is negative but clinical suspicion remains high 2, 3
Critical Risk Factors
The following factors substantially increase PML risk with rituximab:
- Prolonged B-cell depletion: Rituximab causes extended B-lymphocyte suppression, creating conditions for JC virus reactivation 4
- Low CD4+ T-cell counts: Pre-treatment CD4+ counts below 200 cells/μL dramatically increase risk 5
- Concurrent or prior immunosuppression: Combination with methotrexate, cyclophosphamide, or other immunosuppressants amplifies risk 2, 3
- Duration of therapy: Risk increases with cumulative rituximab exposure 4
- Underlying disease severity: More aggressive disease requiring intensive immunosuppression carries higher risk 3
Prognosis and Management
PML associated with rituximab carries a grave prognosis:
- Most patients die within months of diagnosis or develop severe permanent neurological disability 2
- No proven effective treatments exist 6, 2
- Immediate discontinuation of rituximab and all immunosuppressants is mandatory upon diagnosis 1
- Inflammatory PML may paradoxically occur during immune reconstitution, even while CD20 counts remain suppressed 3
Mandatory Pre-Treatment Screening
Before initiating rituximab, the following screening is required:
- Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) to assess HBV reactivation risk 1
- Complete blood count with differential to establish baseline lymphocyte counts 8
- Immunoglobulin levels 8
- Latent tuberculosis screening 8
Consider measuring baseline CD4+ T-cell counts in high-risk patients, particularly those with prior extensive immunosuppression or hematologic malignancies 5.
Patient Counseling Requirements
Patients must be informed that PML is an extremely rare but devastating complication of rituximab therapy 2. They should be instructed to report immediately any new neurological symptoms including confusion, difficulty walking, vision changes, or speech problems 6. The risk-benefit discussion should acknowledge that while PML is rare (approximately 1 in 25,000 for RA patients), it is nearly always fatal or severely disabling when it occurs 3.
Comparative Context
While PML risk with rituximab is real and serious, it remains substantially lower than the risk associated with natalizumab (3.96 per 1,000 patients), another monoclonal antibody used in multiple sclerosis 6. The 20-year pharmacovigilance data confirms rituximab-associated PML as a rare clinical event requiring concurrent causal factors rather than an inevitable consequence of therapy 4.