Introduction
There have been several case series reporting progressive
multifocal leukoencephalopathy (PML) in patients with a
variety of autoimmune diseases treated with biologic agents,
including natalizumab, rituximab, and efalizumab as well as
in patients taking mycophenolate mofetil.[1-4] On the basis
of these reports, PML is of particular concern to
rheumatologists treating patients with rheumatoid arthritis
(RA), systemic lupus erythematosus (SLE), or other rheumatic
diseases with rituximab and/or mycophenolate mofetil. PML is
a demyelinating disease caused by reactivation of the JC
virus. Latent JC virus infection is common, and it is
thought that the virus may reactivate in settings of
immunosuppression induced by disease, such as HIV, or
medications. PML typically presents with altered mental
status, visual changes, and ataxia. Brain imaging may show
patchy areas of demyelination, usually without edema.
Diagnosis may be made by demonstration of JC virus in
cerebrospinal fluid (CSF) or on brain biopsy (gold
standard). When PML occurs in rheumatic diseases,
immunosuppression is typically stopped, and prescribers may
try agents, such as cytarabine, mirtazapine, and cidofovir,
although there are no controlled trials demonstrating
benefit and prognosis is poor, with life expectancy after
diagnosis in non-HIV cases of only a few months.
Study Summary
To generate estimates of the rate of PML in US patients
with rheumatic diseases, the study authors investigated the
frequency of PML using the US Nationwide Inpatient Sample
database, which contains data from approximately 300 million
hospital discharges between 1998 and 2005; 9675 cases of PML
were identified, with the following rates of PML (per
100,000 discharges): 4 for SLE; 0.4 for RA; and 2 for other
connective tissue diseases, which included Sjögren's
syndrome, dermato- and polymyositis, and scleroderma. These
rates differ from a background rate of PML (after excluding
HIV, cancer, or organ transplant) in 0.2 per 100,000
discharges. PML was not associated with seronegative
spondyloarthropathies or systemic vasculitic syndromes. Of
note, for PML associated with SLE, there were no other
associated disease risk factors for PML (HIV, cancer, or
transplantation); however, in RA-associated PML, 60% of
cases had at least 1 additional disease risk for PML. The
study authors concluded that PML may occur more commonly in
SLE than other rheumatic diseases, perhaps due to
disease-specific issues; however, due to limitations of the
database they could not identify particular treatment
regimens that were more likely to be associated with PML.
Viewpoint
On the basis of these data, PML, although rare, does
appear to have increased frequency in rheumatic diseases,
particularly SLE. Unfortunately, this study does not tell us
what particular aspects of rheumatic disease -- disease
pathogenesis and/or treatments -- may lead to increased risk
for PML. Of importance, the authors stated that diagnosis of
PML may be difficult in patients with rheumatic diseases
because neurologic symptoms may be attributed to other
causes, especially CNS SLE. As such, given the increased
risk for PML, we should be aware of the possibility of this
disease and be sure to exclude it if suspected in patients
with CNS dysfunction. Of note, the JC virus may not be
detectable by polymerase chain reaction (PCR) in CSF, and
brain tissue may need to be obtained for diagnosis. Going
forward, we'll need studies to determine exact mechanisms
for PML in rheumatic diseases, and to construct clear
recommendations for risk for PML on the basis of therapies
in patients with rheumatic diseases, and hopefully
treatments for this devastating disease.
CONCLUSION: This study was confined to hospitalized
patients with rheumatic diseases, and it was also limited by
the lack of information regarding immunosuppressive therapy.
Nevertheless, the findings suggest that, although rare
overall, PML occurs more commonly in SLE than in other
rheumatic diseases. |
