Rheumatoid arthritis treatment with rituximab (Rituxan) carries a modest risk of progressive multifocal leukoencephalopathy (PML) at approximately 1 case per 25,000 individuals treated, researchers found.
Four such cases in an estimated population of 129,000 exposed to rituximab for rheumatoid arthritis were reported by David B. Clifford, MD, of Washington University in St. Louis, Mo., and colleagues online in the Archives of Neurology.
The drug's manufacturer and the FDA have put physicians on notice about this risk based on a few prior cases of the infection, which causes often fatal inflammation of the brain from reactivation of latent JC virus.
Some other biologic drugs that suppress components of the immune system have also been linked to PML, notably natalizumab (Tysabri) with a rate of about one per 1,000 patients receiving the drug for two years.
The case series from Clifford's group further supports that the risk is real, representing "the most decisive evidence available," according to the group.
Most cases of PML have occurred in the context of a well-known concomitant risk of PML.
"This factor, as well as the absence of a clear denominator for exposure, and probable missed cases of PML have made it challenging even for interested professionals collecting all available data to decide if any increased risk exists," they explained in the paper.
All four cases PML cases they documented with rituximab in rheumatoid arthritis patients were HIV-negative women over 50 years of age (median 67) with a history of treatment for joint disease ranging from three to 14 years.
The autoimmune condition Sjögren syndrome was common among these women. Two may have had enhanced PML risk due to cancer: breast cancer treated with surgery and chemotherapy in one case, and superficial squamous cell carcinoma of the oropharynx treated with chemotherapy and irradiation after rituximab but before developing PML in the other.
One of the women hadn't received any biologic and got minimal immunosuppressive therapy prior to rituximab.
All the cases presented with PML as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. The frequent development of inflammatory PML during the course of the disease was confirmed by MRI and and tissue evaluation.
Two patients died within a year after PML diagnosis. Of the two who remain alive after treatment withdrawal, one had no progression of neurological symptoms while the other is cognitively impaired though able to walk again.
JC virus status has been suggested as a predictor of PML risk for natalizumab, but Clifford's group cautioned that levels of the CD20 antigen targeted by rituximab varied in related PML cases in rheumatoid arthritis, suggesting that these may not be predictive.
In the four PML cases they documented with rituximab in rheumatoid arthritis patients, some CD20-positive cells were found on one brain autopsy but no CD20-positive cells appeared in a diagnostic biopsy sample taken early in the course of PML in another case.
Clifford's group urged physicians considering rituximab for rheumatic diseases to consider the risk of PML in their choice of treatments given the steep rates of morbidity and mortality associated with the infection and to inform patients as well.
For patients who are treated with the biologic agent, "aggressive evaluation of new and progressing neurological deficits is very important to allow early diagnosis," the researchers wrote in the paper. "No further rituximab should be used if a suspicious neurological symptom or sign appears until the diagnosis is successfully excluded."