PML and rheumatology: The contribution of disease and drugs
ABSTRACTProgressive multifocal leukoencephalopathy (PML), a rare, typically fatal, opportunistic infection caused by the JC virus, is becoming relevant to physicians in multiple specialties, including those who prescribe biologic agents for the treatment of autoimmune disorders. Reports of PML have led to US Food and Drug Administration alerts and warning letters regarding four immunosuppressive agents in recent years (natalizumab, rituximab, efalizumab, and mycophenolate mofetil). Consequently, informed clinical decision-making requires understanding the risk of PML associated with these therapies. An estimate of the relative frequency of PML associated with specific rheumatic conditions has been generated. Systemic lupus erythematosus appears to be associated with susceptibility to PML that cannot be fully explained by the intensity of immunosuppressive therapy. Further, the use of rituximab in patients with rheumatic disease has raised concerns. However, definitive attribution of cause is precluded by the limitations of the currently available data. All patients with rheumatic disease, regardless of the intensity of their current immunosuppressive therapy, should be considered potentially at risk of PML. With an evolving understanding of a greater clinical heterogeneity of PML, advances in diagnostic methods, and significant implications for therapy, PML should be considered in the differential diagnosis of neurologic manifestations of rheumatic diseases.
DISCUSSION
Dr. Simpson: To what extent are these lesions in the brain being attributed to the underlying vasculitis, particularly in SLE, as opposed to pursuing a PML diagnosis, and how might this result in dramatic underreporting of the complication?
Dr. Molloy: We found that PML is almost certainly underdiagnosed, particularly in SLE patients. If a patient succumbs to assumed neuropsychiatric SLE, how often is an autopsy undertaken? One telling paper from Sweden documented four cases of PML in SLE patients.14 In one of these, the diagnosis was made retrospectively from autopsy tissue that had been banked 20 years previously. It undoubtedly is underdiagnosed.
Dr. Calabrese: Even in the most recent rituximab-associated cases of PML, several patients were empirically given additional immunosuppressive therapy because it was presumed that they had a comorbid neuropsychiatric rheumatic complication. The presence of neuropsychiatric complications ascribed to an autoinflammatory disease generally warrants escalation of immunosuppressive therapy. It has always been standard practice for us to rule out opportunistic infection, but JCV infection has not been on the radar screen until very recently.
Dr. Molloy: I’d like to emphasize that, in our literature review, 50% of the rheumatic disease patients diagnosed with PML had been treated with more intensive immunosuppressive therapy. It was only after they continued to deteriorate that JCV infection was suspected and PML ultimately diagnosed.
Dr. Berger: Is it fair to say that the incidence of PML in SLE is about 10 times that in rheumatoid arthritis?
Dr. Molloy: In the hospital discharge database, it was 10-fold higher in SLE than in rheumatoid arthritis, but we can’t draw a conclusion from the AERS database because we don’t have a denominator. The database consists of voluntary submission of cases.
Dr. Calabrese: The information that we can expect to glean from the database is profoundly limited, for all the reasons that you enumerated. Despite the flaws, we’re obligated to continuously examine it because sometimes a case or two may provide some special insight.
Dr. Simpson: As neurologists, we often lag behind rheumatologists in the use of new treatments, including intravenous immune globulin (IVIG) and now rituximab. Rituximab is becoming the go-to drug for a number of neurologic diseases. I’m using it quite a bit and have observed some dramatic responses in patients with chronic inflammatory demyelinating polyneuropathy, for example, in whom IVIG or plasmapheresis was failing. Anecdotally, some of the turnarounds in polymyositis and even myasthenia gravis are remarkable as well. I’m not sure to what extent neurologists—particularly peripheral neurologists—who use rituximab are recognizing PML.
Dr. Fox: The index of suspicion is probably vastly different among multiple sclerosis (MS) specialists and general neurologists. Neurologists who treat MS will be acutely aware of PML because of its association with natalizumab.
Dr. Berger: Yes, but you’re talking about possibly two orders of magnitude difference between natalizumab and rituximab. In fact, PML is rarely reported in the setting of neurologic disease. It’s mostly reported in the setting of rheumatologic disease.
Dr. Rudick: I don’t necessarily agree with you. Ascertaining the true incidence of PML with agents other than natalizumab is difficult. One is unlikely to miss a case of PML in an MS patient treated with natalizumab, but most cases stemming from the use of these other disease-modifying drugs are probably being missed.
Dr. Calabrese: I get two messages out of this body of work. Number one is that while PML is rare, it is seen across the spectrum of immunosuppressive agents, including biologic and nonbiologic drugs. Number two is that PML is seriously underreported and underrecognized, which is probably leading to suboptimal patient care. Rituximab was recently approved for treatment of Wegener granulomatosis, and this disease is heavily pretreated with cyclophosphamide. You would expect that PML is on the radar among clinicians caring for patients whose diseases warrant the use of increasingly complex, potent, and novel immunosuppressives.
Dr. Berger: There is one other biologic agent you left out—alemtuzumab. It wipes out all of the B cells and T cells; the B cells repopulate but the T cells remain suppressed for a long period. If ever there was a drug whose action mirrors what happens in HIV, alemtuzumab is that drug. Yet, PML is rarely seen with alemtuzumab. Alemtuzumab-associated PML has not been reported in the MS population, and it has only been seen in two transplantations that I’m aware of. I’m not saying that it doesn’t occur, but we’re not seeing it with the same frequency that one would predict given its profile.
