Physicians considering the use of rituximab treatment of rheumatic diseases including rheumatoid arthritis should be aware that there is "a potential, albeit modest, risk of developing progressive multifocal leukoencephalopathy," according to a report published online May 9 in Archives of Neurology.
In addition, rheumatology patients who are already taking the drug should undergo "aggressive evaluation of new and progressing neurologic deficits ... to allow early diagnosis" of progressive multifocal leukoencephalopathy (PML), said Dr. David B. Clifford, professor of neurology and medicine at Washington University in St. Louis, and his associates.
PML is a serious, often fatal demyelinating infection of the brain, usually caused by reactivation of latent JC virus in people who are immunocompromised. It also has been reported as a complication of treatment with monoclonal antibodies such as natalizumab and efalizumab, among patients taking the drugs for disorders including multiple sclerosis, inflammatory bowel disease, and chronic plaque psoriasis.
The mechanism by which these agents facilitate the development of PML is not yet known, but it is presumed that some suppressive effect they exert on the immune system allows latent JC virus to reactivate. Primary JC virus infection usually occurs unnoticed during childhood and is very widespread; most adults are seropositive for JC virus, and many carry latent virus in kidney epithelial cells, lymphoid tissues, bone marrow, and possibly the brain.
"Until very recently, treatment of RA with rituximab had not been associated with development of PML," the investigators wrote. There was one case reported in 2009, but that "was complicated by a history of malignancy that had been treated with chemotherapy and irradiation a short time before PML onset," so the connection with rituximab was unclear, the researchers noted.
Dr. Clifford and his colleagues now report four additional cases of PML in RA patients treated with rituximab. To characterize the disorder in this patient population, they summarized their findings along with those for the previously reported case.
All of the patients were women aged 51-73 years who had moderate to severe RA of at least 3 years’ duration. All began taking rituximab after failing to respond adequately to other interventions including methotrexate, other biologics, or corticosteroids.
In all cases, rituximab was given at the recommended dose for refractory RA: Each course comprised two 1,000-mg infusions administered 2 weeks apart. Two patients received only a single course, and the maximal number of courses was five.
In two cases, patients may have been at increased risk of PML because of cancer. One woman had a history of breast cancer treated with surgery and chemotherapy; the other was the previously reported case in which the patient developed superficial squamous cell carcinoma of the oropharynx and received chemotherapy and irradiation after rituximab had been administered.
Symptom onset occurred at 5-7 months after a rituximab infusion in three cases. This timing is "interesting" because it occurs during the process of immune reconstitution, rather than earlier, when CD20 cells reach their nadir.
In a fourth case, PML onset was delayed until 16 months after rituximab infusion. However this also proved to be during immune reconstitution, as this patient had an unusually prolonged interval of CD-cell suppression. This suppression "only began to normalize after PML onset, when a clear immune reconstitution inflammatory syndrome (IRIS) was well documented on MR scans," the investigators said.
It appears that the immune reconstitution inflammatory syndrome may often complicate rituximab-associated PML, as it developed in three of these five cases. "This factor is critical for clinicians, since it impacts diagnosis and management," they added.
These five patients presented with a variety of central nervous system symptoms including dysesthesias, ataxia, dysphasia, cognitive decline, focal dystonic tremor, and segmental myoclonus.
JC virus DNA frequently was not detectable in the cerebrospinal fluid at presentation, "and was found only after repeated lumbar punctures as the disease progressed." In fact, one case required a brain biopsy to confirm PML.
Genentech, the maker of rituximab, estimates that these five cases of PML occurred against a background of approximately 129,000 exposures among RA patients. This puts the incidence of rituximab-associated PML at 1 in 25,000 exposed RA patients, Dr. Clifford and his associates said (Arch. Neurol. 2011 May 9 [doi:10.1001/archneurol.2011.103]).
This may be an underestimate because it’s likely that more patients have not been accurately diagnosed or reported to the company, they added.
This "modest" incidence is lower than that reported for natalizumab-associated PML (1 in 1,000 patients exposed for more than 2 years) or for efalizumab-associated PML (1 in 400 exposed patients).
The need for effective treatments of rituximab-associated PML is "urgent." Antiviral therapy has not been shown to be effective. Some clinicians still try using cytosine arabinoside and cidofovir, "in spite of significant evidence that they are not effective."