The appearance of progressive multifocal leukoencephalopathy (PML) as a complication of human immunodeficiency virus (HIV) infection dates to shortly after the first description of acquired immunodeficiency syndrome (AIDS). The advent of highly active antiretroviral therapy (HAART) dramatically altered the nature of HIV infection, resulting in a substantial decline in mortality and, in essence, turning AIDS into a chronic disease. As patients lived longer with HIV infection, one consequence was an increased incidence of neurologic complications. By the early 1980s, AIDS was well recognized as an underlying disorder that predisposed to PML.

As many as 70% of HIV patients will eventually have involvement of either the peripheral or central nervous system (CNS). Most patients with HIV are managed by primary care clinicians, including those in the fields of family practice, internal medicine, or infectious disease, and the complexity of the neurologic disorders associated with HIV often results in either delayed diagnosis or misdiagnosis. For example, the evolution of HIV in the plasma, where most clinicians measure it, may differ from its evolution in the spinal fluid and brain. An emerging issue is that of hepatitis C coinfection, which may itself be associated with central and peripheral neurologic complications.

Treatment of HIV with antiretroviral agents has numerous neurologic implications. These include the potential ability of these agents to penetrate the blood-brain barrier, their efficacy in both treating and preventing cognitive impairment and other CNS disorders, and their toxic effects in the CNS and peripheral nervous system.

NEUROLOGIC COMPLICATIONS OF AIDS

Neurologic disease in AIDS patients can be classified in several ways. One of the most logical, particularly for primary care clinicians, is the separation of primary from secondary neurologic disorders:

• Primary neurologic disorders are enigmatic and difficult to characterize; they include HIV-associated neurocognitive disorders in adults, encephalopathy in children, myelopathy or spinal cord disease, and peripheral neuropathy.
• Secondary complications are related to progressive immunosuppression. These include opportunistic infections such as cytomegalovirus, toxoplasmosis, or cryptococcal meningitis; and neoplasms such as primary CNS lymphoma. Opportunistic infections and neoplasms have declined in incidence in the HAART era.

AT-RISK POOLS FOR PML

The AIDS epidemic significantly changed the epidemiology of PML, turning a formerly rare disease into a much more common one. In South Florida, the incidence of PML in patients with AIDS increased by 12 times from the 5-year period 1981 to 1984 compared with 1991 to 1994. Only two non-AIDS cases of PML were reported in South Florida during this 15-year period.¹

At present, nonimmunosuppressed, healthy individuals account for fewer than 1% of all cases of PML. Non-HIV–related PML represents 10% to 20% of all PML cases. Cancer survivors and patients with rheumatoid arthritis who are treated with immunotherapy constitute the largest at-risk pools among this group. PML related to HIV represents 80% to 90% of PML cases, drawing from a pool of 1.2 million HIV-infected individuals in the United States.

UNIQUE PRESENTATION OF HIV-ASSOCIATED PML

The brain lesion in PML is classically a nonenhancing focal lesion, preferentially in white matter, but lesion characteristics often depart from this characteristic picture. For example, relatively faint contrast enhancement of lesions on magnetic resonance imaging has been observed, as well as involvement of white matter and gray matter. The distribution and character of brain lesions in PML may also differ from the classic picture. For example, the lesion may not be focal, particularly when PML is combined with the symmetric white matter abnormalities that are seen in HIV encephalopathy; this nonclassic presentation can cause difficulty in radiologic differentiation of PML and HIV encephalopathy.

Cerebellar degeneration

A unique presentation of PML is possible in HIV-infected patients. In 1998, Tagliati et al² described a syndrome of degeneration of the cerebellum in 10 HIV-infected patients. One patient had JC virus (JCV) detected by polymerase chain reaction (PCR) in cerebellar biopsy tissue. The authors proposed the possibility of latent JCV infection of cerebellar granular cells in HIV-infected patients with cerebellar atrophy, lacking further evidence of other features of PML.

Optimize HAART

A suppressed plasma HIV viral load is the strongest prognostic factor for an improved course in PML.⁴ In the pre-HAART era, the mean survival of HIV-associated PML was 3 to 6 months, with long-term survival estimated at 10%.⁵ The use of HAART has achieved a dramatic improvement in long-term survival, to upwards of 50%.⁶ Neurologic deficits are often irreversible even with HAART, but most HAART recipients show stability in neurologic status for years.

Other key characteristics associated with improved survival in HIV-associated PML appear to be younger age, PML as the heralding manifestation of AIDS, initiation of HAART upon diagnosis of PML, higher CD4 count, and absence of severe neurologic impairment.^5–7

Investigational therapies

Specific antiviral drug regimens targeting JCV have been tested empirically in case studies and in clinical trials in patients with AIDS- and non–AIDS-related PML.

Cytosine arabinoside (Ara-C). Ara-C is a nucleoside analog used as an antineoplastic agent; it terminates chain elongation and inhibits DNA polymerase to confer antiviral activity. Ara-C decreased JCV replication in vitro.⁸ Based on anecdotal reports of efficacy in cancer-related cases of PML,⁹ Ara-C was tested in a multicenter trial of 57 patients with HIV and biopsy-confirmed PML.¹⁰ Neither intravenous nor intrathecal Ara-C combined with established antiviral therapy for AIDS improved the prognosis of these patients, and Ara-C has since been abandoned as a strategy to treat HIV-related PML.

Cidofovir. The noncyclic nucleoside phosphonate cidofovir garnered attention as a potential treatment for PML based on case reports of efficacy in HIV as well as non-HIV patients. Subsequently, a large multicenter study failed to detect any significant added benefit with cidofovir beyond that of HAART.¹¹ Retrospective European studies confirmed the lack of clinical benefit with cidofovir.^6,7,12

Interferon alfa. Case reports with interferon alfa-2a and -2b for the treatment of PML show conflicting results with respect to clinical response, symptomatic improvement, and survival, but toxicity has been substantial. In a series of 97 patients with AIDS-related PML, Geschwind et al determined that interferon alfa had no effect on survival beyond that of HAART.¹³

Mirtazapine. Serotonin receptor antagonists such as mirtazapine can block JCV entry into glial cells via serotonin 5-hydroxytryptamine receptors, providing a rationale for their use as a potential treatment for PML. Verma et al describe a case of clinical improvement (stable neurologic deficit) and PML lesion regression in a 63-year-old bedbound woman with polycythemia vera with biopsy-proven non–HIV-related PML that had progressed to quadriparesis.¹⁴

Mefloquine. The antimalarial drug mefloquine inhibits viral replication in cultured human glial cells and astrocytes, inhibits JC viral DNA replication, and showed efficacy against two JCV strains in cell culture.¹⁵ A randomized study to assess the effectiveness of mefloquine for treatment of PML has been completed and its results await publication.

SUMMARY

The incidence of PML has remained unchanged from the pre-HAART to the HAART era, but the prognosis is greatly improved. The clinical presentation of PML in AIDS patients may deviate from the classic triad of progressive, multifocal, white matter disease. It may be static and unifocal, and it may involve gray matter and neurons as well as white matter. The number of neurologic manifestations is vast and can include the cerebellar syndrome. Lumbar puncture with a PCR negative for JCV does not confirm the absence of PML.

The standard of care for HIV-associated PML is HAART, with the goal of achieving immunologic recovery and optimal virologic control. Whether therapeutic results obtained in patients with HIV-associated PML can be translated to the setting of non–HIV-associated PML is unclear.

DISCUSSION

Dr. Simpson: As a followup to the Ara-C trial that was published,¹⁰ PML confirmed by brain biopsy was one of the enrolling criteria, and the planned study population was 65 patients. Longitudinal examination of viral load in cerebrospinal fluid (CSF) was a part of the study, and we found that the lower the viral load, the better the prognosis. Fifty-two patients were enrolled before the trial was stopped because it was clear that Ara-C was not producing a benefit. The patients had multifocal disease but, because Ara-C does not effectively cross the blood-brain barrier, penetration in the brain was minimal even with the use of an intrathecal shunt in this study.

Dr. Major: Do you think viral load in CSF is a predictor of disease severity and outcome in PML?

Dr. Rudick: Generally speaking, that’s probably true. We have found, as have many of our colleagues who run a lot of CSF samples, that high viral loads are not a good thing.

Dr. Bennett: How is it that the incidence of PML has not changed from the pre-HAART to the post-HAART era? How do you account for this in terms of the change in patients’ T-cell function from pre- to post-HAART?

Dr. Simpson: I don’t know. Intuitively, why do patients treated with HAART, who are relatively immune reconstituted, develop PML? The problem is that not everyone is immune reconstituted. HAART fails in some patients. Further, PML remains a disease that is more common in late-stage HIV among patients with low CD4 counts and high viral loads, meaning that a large population of patients is available to develop this disease. With that said, it is perplexing that the incidence has not gone down more than it has.

Dr. Major: There’s a phenomenon called “unmasking PML with HAART,” in which individuals have no signs of PML upon initiation of HAART, but then very shortly after, PML is diagnosed.

Dr. Berger: You’re talking about PML immune reconstitution inflammatory syndrome (IRIS).

Dr. Major: IRIS can occur before PML, or PML and IRIS can be concurrent. In some patients, once the infection starts, it persists; this suggests that the virus is carried to the brain through the infected lymphocyte populations and may explain why the incidence of PML has not changed from the pre-HAART to the HAART era.

Dr. Calabrese: In patients with HIV who develop PML within the first 6 months of HAART, are we seeing the IRIS phenomenon or is it a presenting sign of advanced HIV?

Dr. Simpson: It’s well known that a number of opportunistic infections can develop in the setting of HAART. In fact, whether one should delay HAART when initiating therapy for opportunistic infections has been debated for just this reason. Most people presume IRIS to be a massive immunologic hit to all organ systems, as CD4 counts rise dramatically to produce hyperimmune-mediated phenomena such as Guillain-Barré syndrome. To what extent immunologic recovery is or is not linked to PML and why it happens are fascinating questions.

Dr. Berger: Opportunistic infections, PML among them, that occur following the initiation of HAART and recovery of the immune system are almost always an IRIS-mediated phenomenon in which the disease has been smoldering and then surfaces because of the release of an inflammatory response.

Dr. Calabrese: In patients with cerebellar degeneration, do you typically detect JCV in PCR in the spinal fluid?

Dr. Simpson: Not in the early stages, but in some patients with later-stage disease,³ the answer is yes. Certainly, PCR of CSF samples to look for JCV is the diagnostic test of choice. But in the early days, when we had no idea what caused this cerebellar syndrome, we were doing cerebellar biopsies.

The appearance of progressive multifocal leukoencephalopathy (PML) as a complication of human immunodeficiency virus (HIV) infection dates to shortly after the first description of acquired immunodeficiency syndrome (AIDS). The advent of highly active antiretroviral therapy (HAART) dramatically altered the nature of HIV infection, resulting in a substantial decline in mortality and, in essence, turning AIDS into a chronic disease. As patients lived longer with HIV infection, one consequence was an increased incidence of neurologic complications. By the early 1980s, AIDS was well recognized as an underlying disorder that predisposed to PML.

As many as 70% of HIV patients will eventually have involvement of either the peripheral or central nervous system (CNS). Most patients with HIV are managed by primary care clinicians, including those in the fields of family practice, internal medicine, or infectious disease, and the complexity of the neurologic disorders associated with HIV often results in either delayed diagnosis or misdiagnosis. For example, the evolution of HIV in the plasma, where most clinicians measure it, may differ from its evolution in the spinal fluid and brain. An emerging issue is that of hepatitis C coinfection, which may itself be associated with central and peripheral neurologic complications.

Treatment of HIV with antiretroviral agents has numerous neurologic implications. These include the potential ability of these agents to penetrate the blood-brain barrier, their efficacy in both treating and preventing cognitive impairment and other CNS disorders, and their toxic effects in the CNS and peripheral nervous system.

NEUROLOGIC COMPLICATIONS OF AIDS

Neurologic disease in AIDS patients can be classified in several ways. One of the most logical, particularly for primary care clinicians, is the separation of primary from secondary neurologic disorders:

• Primary neurologic disorders are enigmatic and difficult to characterize; they include HIV-associated neurocognitive disorders in adults, encephalopathy in children, myelopathy or spinal cord disease, and peripheral neuropathy.
• Secondary complications are related to progressive immunosuppression. These include opportunistic infections such as cytomegalovirus, toxoplasmosis, or cryptococcal meningitis; and neoplasms such as primary CNS lymphoma. Opportunistic infections and neoplasms have declined in incidence in the HAART era.

AT-RISK POOLS FOR PML

The AIDS epidemic significantly changed the epidemiology of PML, turning a formerly rare disease into a much more common one. In South Florida, the incidence of PML in patients with AIDS increased by 12 times from the 5-year period 1981 to 1984 compared with 1991 to 1994. Only two non-AIDS cases of PML were reported in South Florida during this 15-year period.¹

At present, nonimmunosuppressed, healthy individuals account for fewer than 1% of all cases of PML. Non-HIV–related PML represents 10% to 20% of all PML cases. Cancer survivors and patients with rheumatoid arthritis who are treated with immunotherapy constitute the largest at-risk pools among this group. PML related to HIV represents 80% to 90% of PML cases, drawing from a pool of 1.2 million HIV-infected individuals in the United States.

UNIQUE PRESENTATION OF HIV-ASSOCIATED PML

The brain lesion in PML is classically a nonenhancing focal lesion, preferentially in white matter, but lesion characteristics often depart from this characteristic picture. For example, relatively faint contrast enhancement of lesions on magnetic resonance imaging has been observed, as well as involvement of white matter and gray matter. The distribution and character of brain lesions in PML may also differ from the classic picture. For example, the lesion may not be focal, particularly when PML is combined with the symmetric white matter abnormalities that are seen in HIV encephalopathy; this nonclassic presentation can cause difficulty in radiologic differentiation of PML and HIV encephalopathy.

Cerebellar degeneration

A unique presentation of PML is possible in HIV-infected patients. In 1998, Tagliati et al² described a syndrome of degeneration of the cerebellum in 10 HIV-infected patients. One patient had JC virus (JCV) detected by polymerase chain reaction (PCR) in cerebellar biopsy tissue. The authors proposed the possibility of latent JCV infection of cerebellar granular cells in HIV-infected patients with cerebellar atrophy, lacking further evidence of other features of PML.

Optimize HAART

A suppressed plasma HIV viral load is the strongest prognostic factor for an improved course in PML.⁴ In the pre-HAART era, the mean survival of HIV-associated PML was 3 to 6 months, with long-term survival estimated at 10%.⁵ The use of HAART has achieved a dramatic improvement in long-term survival, to upwards of 50%.⁶ Neurologic deficits are often irreversible even with HAART, but most HAART recipients show stability in neurologic status for years.

Other key characteristics associated with improved survival in HIV-associated PML appear to be younger age, PML as the heralding manifestation of AIDS, initiation of HAART upon diagnosis of PML, higher CD4 count, and absence of severe neurologic impairment.^5–7

Investigational therapies

Specific antiviral drug regimens targeting JCV have been tested empirically in case studies and in clinical trials in patients with AIDS- and non–AIDS-related PML.

Cytosine arabinoside (Ara-C). Ara-C is a nucleoside analog used as an antineoplastic agent; it terminates chain elongation and inhibits DNA polymerase to confer antiviral activity. Ara-C decreased JCV replication in vitro.⁸ Based on anecdotal reports of efficacy in cancer-related cases of PML,⁹ Ara-C was tested in a multicenter trial of 57 patients with HIV and biopsy-confirmed PML.¹⁰ Neither intravenous nor intrathecal Ara-C combined with established antiviral therapy for AIDS improved the prognosis of these patients, and Ara-C has since been abandoned as a strategy to treat HIV-related PML.

Cidofovir. The noncyclic nucleoside phosphonate cidofovir garnered attention as a potential treatment for PML based on case reports of efficacy in HIV as well as non-HIV patients. Subsequently, a large multicenter study failed to detect any significant added benefit with cidofovir beyond that of HAART.¹¹ Retrospective European studies confirmed the lack of clinical benefit with cidofovir.^6,7,12

Interferon alfa. Case reports with interferon alfa-2a and -2b for the treatment of PML show conflicting results with respect to clinical response, symptomatic improvement, and survival, but toxicity has been substantial. In a series of 97 patients with AIDS-related PML, Geschwind et al determined that interferon alfa had no effect on survival beyond that of HAART.¹³

Mirtazapine. Serotonin receptor antagonists such as mirtazapine can block JCV entry into glial cells via serotonin 5-hydroxytryptamine receptors, providing a rationale for their use as a potential treatment for PML. Verma et al describe a case of clinical improvement (stable neurologic deficit) and PML lesion regression in a 63-year-old bedbound woman with polycythemia vera with biopsy-proven non–HIV-related PML that had progressed to quadriparesis.¹⁴

Mefloquine. The antimalarial drug mefloquine inhibits viral replication in cultured human glial cells and astrocytes, inhibits JC viral DNA replication, and showed efficacy against two JCV strains in cell culture.¹⁵ A randomized study to assess the effectiveness of mefloquine for treatment of PML has been completed and its results await publication.

SUMMARY

The incidence of PML has remained unchanged from the pre-HAART to the HAART era, but the prognosis is greatly improved. The clinical presentation of PML in AIDS patients may deviate from the classic triad of progressive, multifocal, white matter disease. It may be static and unifocal, and it may involve gray matter and neurons as well as white matter. The number of neurologic manifestations is vast and can include the cerebellar syndrome. Lumbar puncture with a PCR negative for JCV does not confirm the absence of PML.

The standard of care for HIV-associated PML is HAART, with the goal of achieving immunologic recovery and optimal virologic control. Whether therapeutic results obtained in patients with HIV-associated PML can be translated to the setting of non–HIV-associated PML is unclear.

DISCUSSION

Dr. Simpson: As a followup to the Ara-C trial that was published,¹⁰ PML confirmed by brain biopsy was one of the enrolling criteria, and the planned study population was 65 patients. Longitudinal examination of viral load in cerebrospinal fluid (CSF) was a part of the study, and we found that the lower the viral load, the better the prognosis. Fifty-two patients were enrolled before the trial was stopped because it was clear that Ara-C was not producing a benefit. The patients had multifocal disease but, because Ara-C does not effectively cross the blood-brain barrier, penetration in the brain was minimal even with the use of an intrathecal shunt in this study.

Dr. Major: Do you think viral load in CSF is a predictor of disease severity and outcome in PML?

Dr. Rudick: Generally speaking, that’s probably true. We have found, as have many of our colleagues who run a lot of CSF samples, that high viral loads are not a good thing.

Dr. Bennett: How is it that the incidence of PML has not changed from the pre-HAART to the post-HAART era? How do you account for this in terms of the change in patients’ T-cell function from pre- to post-HAART?

Dr. Simpson: I don’t know. Intuitively, why do patients treated with HAART, who are relatively immune reconstituted, develop PML? The problem is that not everyone is immune reconstituted. HAART fails in some patients. Further, PML remains a disease that is more common in late-stage HIV among patients with low CD4 counts and high viral loads, meaning that a large population of patients is available to develop this disease. With that said, it is perplexing that the incidence has not gone down more than it has.

Dr. Major: There’s a phenomenon called “unmasking PML with HAART,” in which individuals have no signs of PML upon initiation of HAART, but then very shortly after, PML is diagnosed.

Dr. Berger: You’re talking about PML immune reconstitution inflammatory syndrome (IRIS).

Dr. Major: IRIS can occur before PML, or PML and IRIS can be concurrent. In some patients, once the infection starts, it persists; this suggests that the virus is carried to the brain through the infected lymphocyte populations and may explain why the incidence of PML has not changed from the pre-HAART to the HAART era.

Dr. Calabrese: In patients with HIV who develop PML within the first 6 months of HAART, are we seeing the IRIS phenomenon or is it a presenting sign of advanced HIV?

Dr. Simpson: It’s well known that a number of opportunistic infections can develop in the setting of HAART. In fact, whether one should delay HAART when initiating therapy for opportunistic infections has been debated for just this reason. Most people presume IRIS to be a massive immunologic hit to all organ systems, as CD4 counts rise dramatically to produce hyperimmune-mediated phenomena such as Guillain-Barré syndrome. To what extent immunologic recovery is or is not linked to PML and why it happens are fascinating questions.

Dr. Berger: Opportunistic infections, PML among them, that occur following the initiation of HAART and recovery of the immune system are almost always an IRIS-mediated phenomenon in which the disease has been smoldering and then surfaces because of the release of an inflammatory response.

Dr. Calabrese: In patients with cerebellar degeneration, do you typically detect JCV in PCR in the spinal fluid?

Dr. Simpson: Not in the early stages, but in some patients with later-stage disease,³ the answer is yes. Certainly, PCR of CSF samples to look for JCV is the diagnostic test of choice. But in the early days, when we had no idea what caused this cerebellar syndrome, we were doing cerebellar biopsies.

The appearance of progressive multifocal leukoencephalopathy (PML) as a complication of human immunodeficiency virus (HIV) infection dates to shortly after the first description of acquired immunodeficiency syndrome (AIDS). The advent of highly active antiretroviral therapy (HAART) dramatically altered the nature of HIV infection, resulting in a substantial decline in mortality and, in essence, turning AIDS into a chronic disease. As patients lived longer with HIV infection, one consequence was an increased incidence of neurologic complications. By the early 1980s, AIDS was well recognized as an underlying disorder that predisposed to PML.

As many as 70% of HIV patients will eventually have involvement of either the peripheral or central nervous system (CNS). Most patients with HIV are managed by primary care clinicians, including those in the fields of family practice, internal medicine, or infectious disease, and the complexity of the neurologic disorders associated with HIV often results in either delayed diagnosis or misdiagnosis. For example, the evolution of HIV in the plasma, where most clinicians measure it, may differ from its evolution in the spinal fluid and brain. An emerging issue is that of hepatitis C coinfection, which may itself be associated with central and peripheral neurologic complications.

Treatment of HIV with antiretroviral agents has numerous neurologic implications. These include the potential ability of these agents to penetrate the blood-brain barrier, their efficacy in both treating and preventing cognitive impairment and other CNS disorders, and their toxic effects in the CNS and peripheral nervous system.

NEUROLOGIC COMPLICATIONS OF AIDS

Neurologic disease in AIDS patients can be classified in several ways. One of the most logical, particularly for primary care clinicians, is the separation of primary from secondary neurologic disorders:

• Primary neurologic disorders are enigmatic and difficult to characterize; they include HIV-associated neurocognitive disorders in adults, encephalopathy in children, myelopathy or spinal cord disease, and peripheral neuropathy.
• Secondary complications are related to progressive immunosuppression. These include opportunistic infections such as cytomegalovirus, toxoplasmosis, or cryptococcal meningitis; and neoplasms such as primary CNS lymphoma. Opportunistic infections and neoplasms have declined in incidence in the HAART era.

AT-RISK POOLS FOR PML

The AIDS epidemic significantly changed the epidemiology of PML, turning a formerly rare disease into a much more common one. In South Florida, the incidence of PML in patients with AIDS increased by 12 times from the 5-year period 1981 to 1984 compared with 1991 to 1994. Only two non-AIDS cases of PML were reported in South Florida during this 15-year period.¹

At present, nonimmunosuppressed, healthy individuals account for fewer than 1% of all cases of PML. Non-HIV–related PML represents 10% to 20% of all PML cases. Cancer survivors and patients with rheumatoid arthritis who are treated with immunotherapy constitute the largest at-risk pools among this group. PML related to HIV represents 80% to 90% of PML cases, drawing from a pool of 1.2 million HIV-infected individuals in the United States.

UNIQUE PRESENTATION OF HIV-ASSOCIATED PML

The brain lesion in PML is classically a nonenhancing focal lesion, preferentially in white matter, but lesion characteristics often depart from this characteristic picture. For example, relatively faint contrast enhancement of lesions on magnetic resonance imaging has been observed, as well as involvement of white matter and gray matter. The distribution and character of brain lesions in PML may also differ from the classic picture. For example, the lesion may not be focal, particularly when PML is combined with the symmetric white matter abnormalities that are seen in HIV encephalopathy; this nonclassic presentation can cause difficulty in radiologic differentiation of PML and HIV encephalopathy.

Cerebellar degeneration

A unique presentation of PML is possible in HIV-infected patients. In 1998, Tagliati et al² described a syndrome of degeneration of the cerebellum in 10 HIV-infected patients. One patient had JC virus (JCV) detected by polymerase chain reaction (PCR) in cerebellar biopsy tissue. The authors proposed the possibility of latent JCV infection of cerebellar granular cells in HIV-infected patients with cerebellar atrophy, lacking further evidence of other features of PML.

Optimize HAART

A suppressed plasma HIV viral load is the strongest prognostic factor for an improved course in PML.⁴ In the pre-HAART era, the mean survival of HIV-associated PML was 3 to 6 months, with long-term survival estimated at 10%.⁵ The use of HAART has achieved a dramatic improvement in long-term survival, to upwards of 50%.⁶ Neurologic deficits are often irreversible even with HAART, but most HAART recipients show stability in neurologic status for years.

Other key characteristics associated with improved survival in HIV-associated PML appear to be younger age, PML as the heralding manifestation of AIDS, initiation of HAART upon diagnosis of PML, higher CD4 count, and absence of severe neurologic impairment.^5–7

Investigational therapies

Specific antiviral drug regimens targeting JCV have been tested empirically in case studies and in clinical trials in patients with AIDS- and non–AIDS-related PML.

Cytosine arabinoside (Ara-C). Ara-C is a nucleoside analog used as an antineoplastic agent; it terminates chain elongation and inhibits DNA polymerase to confer antiviral activity. Ara-C decreased JCV replication in vitro.⁸ Based on anecdotal reports of efficacy in cancer-related cases of PML,⁹ Ara-C was tested in a multicenter trial of 57 patients with HIV and biopsy-confirmed PML.¹⁰ Neither intravenous nor intrathecal Ara-C combined with established antiviral therapy for AIDS improved the prognosis of these patients, and Ara-C has since been abandoned as a strategy to treat HIV-related PML.

Cidofovir. The noncyclic nucleoside phosphonate cidofovir garnered attention as a potential treatment for PML based on case reports of efficacy in HIV as well as non-HIV patients. Subsequently, a large multicenter study failed to detect any significant added benefit with cidofovir beyond that of HAART.¹¹ Retrospective European studies confirmed the lack of clinical benefit with cidofovir.^6,7,12

Interferon alfa. Case reports with interferon alfa-2a and -2b for the treatment of PML show conflicting results with respect to clinical response, symptomatic improvement, and survival, but toxicity has been substantial. In a series of 97 patients with AIDS-related PML, Geschwind et al determined that interferon alfa had no effect on survival beyond that of HAART.¹³

Mirtazapine. Serotonin receptor antagonists such as mirtazapine can block JCV entry into glial cells via serotonin 5-hydroxytryptamine receptors, providing a rationale for their use as a potential treatment for PML. Verma et al describe a case of clinical improvement (stable neurologic deficit) and PML lesion regression in a 63-year-old bedbound woman with polycythemia vera with biopsy-proven non–HIV-related PML that had progressed to quadriparesis.¹⁴

Mefloquine. The antimalarial drug mefloquine inhibits viral replication in cultured human glial cells and astrocytes, inhibits JC viral DNA replication, and showed efficacy against two JCV strains in cell culture.¹⁵ A randomized study to assess the effectiveness of mefloquine for treatment of PML has been completed and its results await publication.

SUMMARY

The incidence of PML has remained unchanged from the pre-HAART to the HAART era, but the prognosis is greatly improved. The clinical presentation of PML in AIDS patients may deviate from the classic triad of progressive, multifocal, white matter disease. It may be static and unifocal, and it may involve gray matter and neurons as well as white matter. The number of neurologic manifestations is vast and can include the cerebellar syndrome. Lumbar puncture with a PCR negative for JCV does not confirm the absence of PML.

The standard of care for HIV-associated PML is HAART, with the goal of achieving immunologic recovery and optimal virologic control. Whether therapeutic results obtained in patients with HIV-associated PML can be translated to the setting of non–HIV-associated PML is unclear.

DISCUSSION

Dr. Simpson: As a followup to the Ara-C trial that was published,¹⁰ PML confirmed by brain biopsy was one of the enrolling criteria, and the planned study population was 65 patients. Longitudinal examination of viral load in cerebrospinal fluid (CSF) was a part of the study, and we found that the lower the viral load, the better the prognosis. Fifty-two patients were enrolled before the trial was stopped because it was clear that Ara-C was not producing a benefit. The patients had multifocal disease but, because Ara-C does not effectively cross the blood-brain barrier, penetration in the brain was minimal even with the use of an intrathecal shunt in this study.

Dr. Major: Do you think viral load in CSF is a predictor of disease severity and outcome in PML?

Dr. Rudick: Generally speaking, that’s probably true. We have found, as have many of our colleagues who run a lot of CSF samples, that high viral loads are not a good thing.

Dr. Bennett: How is it that the incidence of PML has not changed from the pre-HAART to the post-HAART era? How do you account for this in terms of the change in patients’ T-cell function from pre- to post-HAART?

Dr. Simpson: I don’t know. Intuitively, why do patients treated with HAART, who are relatively immune reconstituted, develop PML? The problem is that not everyone is immune reconstituted. HAART fails in some patients. Further, PML remains a disease that is more common in late-stage HIV among patients with low CD4 counts and high viral loads, meaning that a large population of patients is available to develop this disease. With that said, it is perplexing that the incidence has not gone down more than it has.

Dr. Major: There’s a phenomenon called “unmasking PML with HAART,” in which individuals have no signs of PML upon initiation of HAART, but then very shortly after, PML is diagnosed.

Dr. Berger: You’re talking about PML immune reconstitution inflammatory syndrome (IRIS).

Dr. Major: IRIS can occur before PML, or PML and IRIS can be concurrent. In some patients, once the infection starts, it persists; this suggests that the virus is carried to the brain through the infected lymphocyte populations and may explain why the incidence of PML has not changed from the pre-HAART to the HAART era.

Dr. Calabrese: In patients with HIV who develop PML within the first 6 months of HAART, are we seeing the IRIS phenomenon or is it a presenting sign of advanced HIV?

Dr. Simpson: It’s well known that a number of opportunistic infections can develop in the setting of HAART. In fact, whether one should delay HAART when initiating therapy for opportunistic infections has been debated for just this reason. Most people presume IRIS to be a massive immunologic hit to all organ systems, as CD4 counts rise dramatically to produce hyperimmune-mediated phenomena such as Guillain-Barré syndrome. To what extent immunologic recovery is or is not linked to PML and why it happens are fascinating questions.

Dr. Berger: Opportunistic infections, PML among them, that occur following the initiation of HAART and recovery of the immune system are almost always an IRIS-mediated phenomenon in which the disease has been smoldering and then surfaces because of the release of an inflammatory response.

Dr. Calabrese: In patients with cerebellar degeneration, do you typically detect JCV in PCR in the spinal fluid?

Dr. Simpson: Not in the early stages, but in some patients with later-stage disease,³ the answer is yes. Certainly, PCR of CSF samples to look for JCV is the diagnostic test of choice. But in the early days, when we had no idea what caused this cerebellar syndrome, we were doing cerebellar biopsies.

Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, opportunistic infection caused by the JC virus (JCV). Formerly an example of neurologic arcana, PML became an important clinical concern when it developed in patients with human immunodeficiency virus (HIV) infection. More recently, PML has attracted the attention of rheumatologists following reports of its being associated with the use of targeted therapies such as natalizumab and rituximab.¹

A recent survey of rheumatologists’ knowledge of and attitudes towards PML revealed that concerns over PML affect decisions on the use of biologic agents. Further, rheumatologists have important real and perceived learning gaps regarding PML; for example, 41% of those surveyed could not identify the diagnostic test of choice for PML.²

PML IN RHEUMATIC DISEASES

Examination of the immunosuppressive therapies prescribed to these patients within 6 months of the onset of neurologic symptoms attributed to PML revealed that low-dose (≤ 15 mg/d) prednisone, with or without an antimalarial agent, was the only immunosuppressive therapy in 31% of patients with SLE and in 11% of patients with rheumatic diseases other than SLE. Three patients had no documented immunosuppressive therapy in the 6 months prior to the onset of PML. Two patients with SLE were prescribed rituximab; no cases were reported in association with biologic therapies other than rituximab.⁴

In order to circumvent reporting bias, a nationwide hospital discharge database representing nearly 300 million patient discharges was used to determine the relative frequency of PML in patients with rheumatic diseases.⁵ Because of the reliance on diagnostic coding, rheumatic diseases were likely underreported in this sample; information on therapies was unavailable. After excluding patients who had HIV or cancer or were organ transplant recipients, four cases of PML were identified per 100,000 SLE discharges. This rate was 10-fold higher than the rate associated with rheumatoid arthritis and 20-fold higher than that of the background population.

These data show that PML is a rare occurrence in patients with rheumatic diseases, and SLE appears to be associated with a predisposition to PML. This predisposition in patients with SLE does not appear to be proportional to the degree of iatrogenic immunosuppression, emphasizing the role of host factors.

DISEASE-MODIFYING DRUGS AND PML RISK

In addition to certain disease states, disease-modifying biologic drugs have recently been associated with rare instances of PML.

Rituximab

The first case of rituximab-associated PML in the setting of rheumatoid arthritis was recorded in September 2008.⁶ The patient had longstanding rheumatoid arthritis and Sjögren syndrome. She received four courses of rituximab and was diagnosed with PML 18 months after the last dose; she died 1 month later. Her therapy for rheumatoid arthritis included a tumor necrosis factor (TNF) antagonist prior to rituximab initiation and treatment with methotrexate and steroids before, during, and after rituximab therapy. Oropharyngeal cancer developed in this patient 9 months prior to the onset of PML and was treated with chemotherapy and radiation therapy.

Another case of PML in a patient with rheumatic disease who had been treated with rituximab was notable because it was the first in which the patient had not previously been treated with an anti-TNF agent.⁷

Ascertaining cause of PML in patients treated with rituximab is difficult because the potential pathogenic mechanism remains unknown. Humoral immunity is not protective against PML, leading to speculation that the loss of other B-cell functions, such as those of antigen-presenting cells or cytokine production, may lead to a defect in cell-mediated immunity. Another theory posits that reconstitution of naïve B cells with latent JCV infection following B-cell depletion from rituximab therapy may somehow facilitate the development of PML.

Efalizumab is a monoclonal antibody that targets CD11a, the alpha subunit of lymphocyte function–associated antigen 1. Efalizumab blocks binding to intercellular adhesion molecule 1, and thereby blocks T-cell adhesion and migration. CD11a is also expressed on a variety of other leukocytes and lymphocytes such as B cells, monocytes, and natural killer cells.

Efalizumab was approved in 2003 by the FDA for the treatment of moderate to severe plaque psoriasis. It is estimated that 46,000 patients have been treated with efalizumab worldwide since its approval. In 2008, a black box warning was added to the efalizumab prescribing information following the occurrence of serious infections, including pulmonary tuberculosis, necrotizing fasciitis, and invasive fungal infections.⁸ Subsequently, four cases of PML, three of which were fatal, were reported in psoriasis patients treated with efalizumab. Of note, these were the first cases of PML reported in patients with psoriasis. Of more concern, the affected patients were among a group of approximately 1,100 patients who had been treated with efalizumab for more than 3 years. In February 2009, a public health advisory was issued by the FDA,⁹ and efalizumab was voluntarily withdrawn by its manufacturer 2 months later.

Belatacept

Belatacept is a recombinant soluble fusion protein of the extracellular domain of human cytotoxic T-lymphocyte antigen-4 with a fragment of a modified Fc domain of immunoglobulin G1. Recently approved by the FDA for prophylaxis of renal transplant rejection, it is a second-generation, higher-avidity version of abatacept. Abatacept is licensed for the treatment of rheumatoid arthritis and is under investigation for the treatment of vasculitis and SLE. Belatacept differs from abatacept by only two amino acids.

Two cases of PML have been reported in association with belatacept, one in a patient following renal transplantation and the other in a patient following liver transplantation. Both patients had been treated with other standard immunosuppressive therapies for prophylaxis of organ transplant rejection, including mycophenolate mofetil.

Mycophenolate mofetil

Mycophenolate mofetil is the prodrug of mycophenolic acid. Both have been the subjects of FDA alerts regarding PML, based on a January 2008 report of 10 definite and 7 possible cases of PML occurring with mycophenolate mofetil. The patients affected included four with SLE, none of whom underwent a renal transplant.¹⁰

In a retrospective cohort study of 32,757 renal transplant patients, Neff et al¹¹ found 14 cases of PML per 100,000 person-years among patients treated with mycophenolate mofetil following kidney transplant compared with none in patients who did not receive mycophenolate mofetil. It is difficult to ascertain risk with mycophenolate mofetil because it is standard therapy among renal transplant patients, leaving few patients in these groups unexposed.

Given the FDA alert with respect to mycophenolate mofetil and PML,¹⁰ the frequent use of mycophenolate mofetil in the setting of SLE, and the concerns about possible predisposition to PML among patients with SLE, it will be important to clarify the level of risk in patients with SLE who are treated with mycophenolate mofetil.

AGGREGATE EXPERIENCE: REVIEW OF FEDERAL DATABASE

Ten cases of PML were confirmed with cyclophosphamide treatment, and cyclophosphamide was the most recent DMARD prescribed in two of these cases. Five cases were confirmed with mycophenolate mofetil (in four of which it was the most recently prescribed DMARD) and six with azathioprine (in three of which it was the most recently prescribed DMARD).

Risk of PML with DMARD therapy

Rituximab. The confirmation of six cases of PML among rituximab-treated rheumatoid arthritis patients is a source of concern. Nevertheless, PML is a rare adverse event. It occurs in fewer than 1 in 10,000 rituximab-treated patients who have rheumatoid arthritis, among a total of approximately 130,000 such patients. A better understanding of the potential mechanism responsible for the increased risk of developing PML may help in risk prediction and to guide patient selection for this agent.

Anti-TNF therapy. A paucity of confirmed cases in patients treated with anti-TNF therapy argues against a significant risk of PML associated with this therapy, especially considering the estimated 2 to 3 million rheumatoid arthritis patients who are receiving treatment with anti-TNF agents. A note of caution is sounded by a recent case report of PML in a rheumatoid arthritis patient. The patient had been treated with infliximab, with the only background therapy being methotrexate.¹³ Ongoing vigilance is therefore necessary.

Mycophenolate mofetil. All five confirmed cases of PML in mycophenolate mofetil-treated patients had earlier received treatment with cyclophosphamide. These data indicate no clear signal of excess risk with mycophenolate mofetil above that seen with other nonbiologic immunosuppressive agents, such as cyclophosphamide or azathioprine.

CONCLUSION AND RECOMMENDATIONS

PML has been reported in association with a variety of disease states, although a predisposition in patients with SLE has become apparent. Synthetic and biologic immunosuppressive therapies have also been implicated, but PML may also occur in the setting of minimal iatrogenic immunosuppression.

Until greater clarity can be achieved, all patients with systemic rheumatic diseases should be considered at risk for PML, regardless of the nature or intensity of their immunosuppressive therapy. In this context, differentiating PML from neurologic syndromes related to the underlying rheumatic disease (eg, neuropsychiatric SLE, cerebral vasculitis) is critical, particularly given the markedly different approaches to management.

PML should be considered in patients with unexplained subacute progressive focal and diffuse neurologic deficits, especially if their clinical or radiologic status worsens in the face of increased intensity of immunosuppressive therapy. Spinal cord or optic nerve involvement argues against PML. A normal magnetic resonance image (MRI) has a high negative predictive value, and frank infarction is not a feature of PML. In classic PML, contrast enhancement is typically absent and routine cerebrospinal fluid (CSF) analysis is typically normal. However, contrast enhancement and edema on MRI, lymphocytic CSF pleocytosis, and elevated CSF protein may be seen in the more recently described “inflammatory PML,” in which case the distinction from cerebral vasculitis or neuropsychiatric SLE may be more difficult. Angiography appears normal in patients with PML.

The diagnostic test of choice is a polymerase chain reaction (PCR) assay for JCV in CSF. If the PCR is repeatedly negative, then a brain biopsy should be considered, especially in the setting of progressive neurologic decline in patients receiving immunosuppressive therapy.

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.

Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, opportunistic infection caused by the JC virus (JCV). Formerly an example of neurologic arcana, PML became an important clinical concern when it developed in patients with human immunodeficiency virus (HIV) infection. More recently, PML has attracted the attention of rheumatologists following reports of its being associated with the use of targeted therapies such as natalizumab and rituximab.¹

A recent survey of rheumatologists’ knowledge of and attitudes towards PML revealed that concerns over PML affect decisions on the use of biologic agents. Further, rheumatologists have important real and perceived learning gaps regarding PML; for example, 41% of those surveyed could not identify the diagnostic test of choice for PML.²

PML IN RHEUMATIC DISEASES

Examination of the immunosuppressive therapies prescribed to these patients within 6 months of the onset of neurologic symptoms attributed to PML revealed that low-dose (≤ 15 mg/d) prednisone, with or without an antimalarial agent, was the only immunosuppressive therapy in 31% of patients with SLE and in 11% of patients with rheumatic diseases other than SLE. Three patients had no documented immunosuppressive therapy in the 6 months prior to the onset of PML. Two patients with SLE were prescribed rituximab; no cases were reported in association with biologic therapies other than rituximab.⁴

In order to circumvent reporting bias, a nationwide hospital discharge database representing nearly 300 million patient discharges was used to determine the relative frequency of PML in patients with rheumatic diseases.⁵ Because of the reliance on diagnostic coding, rheumatic diseases were likely underreported in this sample; information on therapies was unavailable. After excluding patients who had HIV or cancer or were organ transplant recipients, four cases of PML were identified per 100,000 SLE discharges. This rate was 10-fold higher than the rate associated with rheumatoid arthritis and 20-fold higher than that of the background population.

These data show that PML is a rare occurrence in patients with rheumatic diseases, and SLE appears to be associated with a predisposition to PML. This predisposition in patients with SLE does not appear to be proportional to the degree of iatrogenic immunosuppression, emphasizing the role of host factors.

DISEASE-MODIFYING DRUGS AND PML RISK

In addition to certain disease states, disease-modifying biologic drugs have recently been associated with rare instances of PML.

Rituximab

The first case of rituximab-associated PML in the setting of rheumatoid arthritis was recorded in September 2008.⁶ The patient had longstanding rheumatoid arthritis and Sjögren syndrome. She received four courses of rituximab and was diagnosed with PML 18 months after the last dose; she died 1 month later. Her therapy for rheumatoid arthritis included a tumor necrosis factor (TNF) antagonist prior to rituximab initiation and treatment with methotrexate and steroids before, during, and after rituximab therapy. Oropharyngeal cancer developed in this patient 9 months prior to the onset of PML and was treated with chemotherapy and radiation therapy.

Another case of PML in a patient with rheumatic disease who had been treated with rituximab was notable because it was the first in which the patient had not previously been treated with an anti-TNF agent.⁷

Ascertaining cause of PML in patients treated with rituximab is difficult because the potential pathogenic mechanism remains unknown. Humoral immunity is not protective against PML, leading to speculation that the loss of other B-cell functions, such as those of antigen-presenting cells or cytokine production, may lead to a defect in cell-mediated immunity. Another theory posits that reconstitution of naïve B cells with latent JCV infection following B-cell depletion from rituximab therapy may somehow facilitate the development of PML.

Efalizumab is a monoclonal antibody that targets CD11a, the alpha subunit of lymphocyte function–associated antigen 1. Efalizumab blocks binding to intercellular adhesion molecule 1, and thereby blocks T-cell adhesion and migration. CD11a is also expressed on a variety of other leukocytes and lymphocytes such as B cells, monocytes, and natural killer cells.

Efalizumab was approved in 2003 by the FDA for the treatment of moderate to severe plaque psoriasis. It is estimated that 46,000 patients have been treated with efalizumab worldwide since its approval. In 2008, a black box warning was added to the efalizumab prescribing information following the occurrence of serious infections, including pulmonary tuberculosis, necrotizing fasciitis, and invasive fungal infections.⁸ Subsequently, four cases of PML, three of which were fatal, were reported in psoriasis patients treated with efalizumab. Of note, these were the first cases of PML reported in patients with psoriasis. Of more concern, the affected patients were among a group of approximately 1,100 patients who had been treated with efalizumab for more than 3 years. In February 2009, a public health advisory was issued by the FDA,⁹ and efalizumab was voluntarily withdrawn by its manufacturer 2 months later.

Belatacept

Belatacept is a recombinant soluble fusion protein of the extracellular domain of human cytotoxic T-lymphocyte antigen-4 with a fragment of a modified Fc domain of immunoglobulin G1. Recently approved by the FDA for prophylaxis of renal transplant rejection, it is a second-generation, higher-avidity version of abatacept. Abatacept is licensed for the treatment of rheumatoid arthritis and is under investigation for the treatment of vasculitis and SLE. Belatacept differs from abatacept by only two amino acids.

Two cases of PML have been reported in association with belatacept, one in a patient following renal transplantation and the other in a patient following liver transplantation. Both patients had been treated with other standard immunosuppressive therapies for prophylaxis of organ transplant rejection, including mycophenolate mofetil.

Mycophenolate mofetil

Mycophenolate mofetil is the prodrug of mycophenolic acid. Both have been the subjects of FDA alerts regarding PML, based on a January 2008 report of 10 definite and 7 possible cases of PML occurring with mycophenolate mofetil. The patients affected included four with SLE, none of whom underwent a renal transplant.¹⁰

In a retrospective cohort study of 32,757 renal transplant patients, Neff et al¹¹ found 14 cases of PML per 100,000 person-years among patients treated with mycophenolate mofetil following kidney transplant compared with none in patients who did not receive mycophenolate mofetil. It is difficult to ascertain risk with mycophenolate mofetil because it is standard therapy among renal transplant patients, leaving few patients in these groups unexposed.

Given the FDA alert with respect to mycophenolate mofetil and PML,¹⁰ the frequent use of mycophenolate mofetil in the setting of SLE, and the concerns about possible predisposition to PML among patients with SLE, it will be important to clarify the level of risk in patients with SLE who are treated with mycophenolate mofetil.

AGGREGATE EXPERIENCE: REVIEW OF FEDERAL DATABASE

Ten cases of PML were confirmed with cyclophosphamide treatment, and cyclophosphamide was the most recent DMARD prescribed in two of these cases. Five cases were confirmed with mycophenolate mofetil (in four of which it was the most recently prescribed DMARD) and six with azathioprine (in three of which it was the most recently prescribed DMARD).

Risk of PML with DMARD therapy

Rituximab. The confirmation of six cases of PML among rituximab-treated rheumatoid arthritis patients is a source of concern. Nevertheless, PML is a rare adverse event. It occurs in fewer than 1 in 10,000 rituximab-treated patients who have rheumatoid arthritis, among a total of approximately 130,000 such patients. A better understanding of the potential mechanism responsible for the increased risk of developing PML may help in risk prediction and to guide patient selection for this agent.

Anti-TNF therapy. A paucity of confirmed cases in patients treated with anti-TNF therapy argues against a significant risk of PML associated with this therapy, especially considering the estimated 2 to 3 million rheumatoid arthritis patients who are receiving treatment with anti-TNF agents. A note of caution is sounded by a recent case report of PML in a rheumatoid arthritis patient. The patient had been treated with infliximab, with the only background therapy being methotrexate.¹³ Ongoing vigilance is therefore necessary.

Mycophenolate mofetil. All five confirmed cases of PML in mycophenolate mofetil-treated patients had earlier received treatment with cyclophosphamide. These data indicate no clear signal of excess risk with mycophenolate mofetil above that seen with other nonbiologic immunosuppressive agents, such as cyclophosphamide or azathioprine.

CONCLUSION AND RECOMMENDATIONS

PML has been reported in association with a variety of disease states, although a predisposition in patients with SLE has become apparent. Synthetic and biologic immunosuppressive therapies have also been implicated, but PML may also occur in the setting of minimal iatrogenic immunosuppression.

Until greater clarity can be achieved, all patients with systemic rheumatic diseases should be considered at risk for PML, regardless of the nature or intensity of their immunosuppressive therapy. In this context, differentiating PML from neurologic syndromes related to the underlying rheumatic disease (eg, neuropsychiatric SLE, cerebral vasculitis) is critical, particularly given the markedly different approaches to management.

PML should be considered in patients with unexplained subacute progressive focal and diffuse neurologic deficits, especially if their clinical or radiologic status worsens in the face of increased intensity of immunosuppressive therapy. Spinal cord or optic nerve involvement argues against PML. A normal magnetic resonance image (MRI) has a high negative predictive value, and frank infarction is not a feature of PML. In classic PML, contrast enhancement is typically absent and routine cerebrospinal fluid (CSF) analysis is typically normal. However, contrast enhancement and edema on MRI, lymphocytic CSF pleocytosis, and elevated CSF protein may be seen in the more recently described “inflammatory PML,” in which case the distinction from cerebral vasculitis or neuropsychiatric SLE may be more difficult. Angiography appears normal in patients with PML.

The diagnostic test of choice is a polymerase chain reaction (PCR) assay for JCV in CSF. If the PCR is repeatedly negative, then a brain biopsy should be considered, especially in the setting of progressive neurologic decline in patients receiving immunosuppressive therapy.

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.

Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, opportunistic infection caused by the JC virus (JCV). Formerly an example of neurologic arcana, PML became an important clinical concern when it developed in patients with human immunodeficiency virus (HIV) infection. More recently, PML has attracted the attention of rheumatologists following reports of its being associated with the use of targeted therapies such as natalizumab and rituximab.¹

A recent survey of rheumatologists’ knowledge of and attitudes towards PML revealed that concerns over PML affect decisions on the use of biologic agents. Further, rheumatologists have important real and perceived learning gaps regarding PML; for example, 41% of those surveyed could not identify the diagnostic test of choice for PML.²

PML IN RHEUMATIC DISEASES

Examination of the immunosuppressive therapies prescribed to these patients within 6 months of the onset of neurologic symptoms attributed to PML revealed that low-dose (≤ 15 mg/d) prednisone, with or without an antimalarial agent, was the only immunosuppressive therapy in 31% of patients with SLE and in 11% of patients with rheumatic diseases other than SLE. Three patients had no documented immunosuppressive therapy in the 6 months prior to the onset of PML. Two patients with SLE were prescribed rituximab; no cases were reported in association with biologic therapies other than rituximab.⁴

In order to circumvent reporting bias, a nationwide hospital discharge database representing nearly 300 million patient discharges was used to determine the relative frequency of PML in patients with rheumatic diseases.⁵ Because of the reliance on diagnostic coding, rheumatic diseases were likely underreported in this sample; information on therapies was unavailable. After excluding patients who had HIV or cancer or were organ transplant recipients, four cases of PML were identified per 100,000 SLE discharges. This rate was 10-fold higher than the rate associated with rheumatoid arthritis and 20-fold higher than that of the background population.

These data show that PML is a rare occurrence in patients with rheumatic diseases, and SLE appears to be associated with a predisposition to PML. This predisposition in patients with SLE does not appear to be proportional to the degree of iatrogenic immunosuppression, emphasizing the role of host factors.

DISEASE-MODIFYING DRUGS AND PML RISK

In addition to certain disease states, disease-modifying biologic drugs have recently been associated with rare instances of PML.

Rituximab

The first case of rituximab-associated PML in the setting of rheumatoid arthritis was recorded in September 2008.⁶ The patient had longstanding rheumatoid arthritis and Sjögren syndrome. She received four courses of rituximab and was diagnosed with PML 18 months after the last dose; she died 1 month later. Her therapy for rheumatoid arthritis included a tumor necrosis factor (TNF) antagonist prior to rituximab initiation and treatment with methotrexate and steroids before, during, and after rituximab therapy. Oropharyngeal cancer developed in this patient 9 months prior to the onset of PML and was treated with chemotherapy and radiation therapy.

Another case of PML in a patient with rheumatic disease who had been treated with rituximab was notable because it was the first in which the patient had not previously been treated with an anti-TNF agent.⁷

Ascertaining cause of PML in patients treated with rituximab is difficult because the potential pathogenic mechanism remains unknown. Humoral immunity is not protective against PML, leading to speculation that the loss of other B-cell functions, such as those of antigen-presenting cells or cytokine production, may lead to a defect in cell-mediated immunity. Another theory posits that reconstitution of naïve B cells with latent JCV infection following B-cell depletion from rituximab therapy may somehow facilitate the development of PML.

Efalizumab is a monoclonal antibody that targets CD11a, the alpha subunit of lymphocyte function–associated antigen 1. Efalizumab blocks binding to intercellular adhesion molecule 1, and thereby blocks T-cell adhesion and migration. CD11a is also expressed on a variety of other leukocytes and lymphocytes such as B cells, monocytes, and natural killer cells.

Efalizumab was approved in 2003 by the FDA for the treatment of moderate to severe plaque psoriasis. It is estimated that 46,000 patients have been treated with efalizumab worldwide since its approval. In 2008, a black box warning was added to the efalizumab prescribing information following the occurrence of serious infections, including pulmonary tuberculosis, necrotizing fasciitis, and invasive fungal infections.⁸ Subsequently, four cases of PML, three of which were fatal, were reported in psoriasis patients treated with efalizumab. Of note, these were the first cases of PML reported in patients with psoriasis. Of more concern, the affected patients were among a group of approximately 1,100 patients who had been treated with efalizumab for more than 3 years. In February 2009, a public health advisory was issued by the FDA,⁹ and efalizumab was voluntarily withdrawn by its manufacturer 2 months later.

Belatacept

Belatacept is a recombinant soluble fusion protein of the extracellular domain of human cytotoxic T-lymphocyte antigen-4 with a fragment of a modified Fc domain of immunoglobulin G1. Recently approved by the FDA for prophylaxis of renal transplant rejection, it is a second-generation, higher-avidity version of abatacept. Abatacept is licensed for the treatment of rheumatoid arthritis and is under investigation for the treatment of vasculitis and SLE. Belatacept differs from abatacept by only two amino acids.

Two cases of PML have been reported in association with belatacept, one in a patient following renal transplantation and the other in a patient following liver transplantation. Both patients had been treated with other standard immunosuppressive therapies for prophylaxis of organ transplant rejection, including mycophenolate mofetil.

Mycophenolate mofetil

Mycophenolate mofetil is the prodrug of mycophenolic acid. Both have been the subjects of FDA alerts regarding PML, based on a January 2008 report of 10 definite and 7 possible cases of PML occurring with mycophenolate mofetil. The patients affected included four with SLE, none of whom underwent a renal transplant.¹⁰

In a retrospective cohort study of 32,757 renal transplant patients, Neff et al¹¹ found 14 cases of PML per 100,000 person-years among patients treated with mycophenolate mofetil following kidney transplant compared with none in patients who did not receive mycophenolate mofetil. It is difficult to ascertain risk with mycophenolate mofetil because it is standard therapy among renal transplant patients, leaving few patients in these groups unexposed.

Given the FDA alert with respect to mycophenolate mofetil and PML,¹⁰ the frequent use of mycophenolate mofetil in the setting of SLE, and the concerns about possible predisposition to PML among patients with SLE, it will be important to clarify the level of risk in patients with SLE who are treated with mycophenolate mofetil.

AGGREGATE EXPERIENCE: REVIEW OF FEDERAL DATABASE

Ten cases of PML were confirmed with cyclophosphamide treatment, and cyclophosphamide was the most recent DMARD prescribed in two of these cases. Five cases were confirmed with mycophenolate mofetil (in four of which it was the most recently prescribed DMARD) and six with azathioprine (in three of which it was the most recently prescribed DMARD).

Risk of PML with DMARD therapy

Rituximab. The confirmation of six cases of PML among rituximab-treated rheumatoid arthritis patients is a source of concern. Nevertheless, PML is a rare adverse event. It occurs in fewer than 1 in 10,000 rituximab-treated patients who have rheumatoid arthritis, among a total of approximately 130,000 such patients. A better understanding of the potential mechanism responsible for the increased risk of developing PML may help in risk prediction and to guide patient selection for this agent.

Anti-TNF therapy. A paucity of confirmed cases in patients treated with anti-TNF therapy argues against a significant risk of PML associated with this therapy, especially considering the estimated 2 to 3 million rheumatoid arthritis patients who are receiving treatment with anti-TNF agents. A note of caution is sounded by a recent case report of PML in a rheumatoid arthritis patient. The patient had been treated with infliximab, with the only background therapy being methotrexate.¹³ Ongoing vigilance is therefore necessary.

Mycophenolate mofetil. All five confirmed cases of PML in mycophenolate mofetil-treated patients had earlier received treatment with cyclophosphamide. These data indicate no clear signal of excess risk with mycophenolate mofetil above that seen with other nonbiologic immunosuppressive agents, such as cyclophosphamide or azathioprine.

CONCLUSION AND RECOMMENDATIONS

PML has been reported in association with a variety of disease states, although a predisposition in patients with SLE has become apparent. Synthetic and biologic immunosuppressive therapies have also been implicated, but PML may also occur in the setting of minimal iatrogenic immunosuppression.

Until greater clarity can be achieved, all patients with systemic rheumatic diseases should be considered at risk for PML, regardless of the nature or intensity of their immunosuppressive therapy. In this context, differentiating PML from neurologic syndromes related to the underlying rheumatic disease (eg, neuropsychiatric SLE, cerebral vasculitis) is critical, particularly given the markedly different approaches to management.

PML should be considered in patients with unexplained subacute progressive focal and diffuse neurologic deficits, especially if their clinical or radiologic status worsens in the face of increased intensity of immunosuppressive therapy. Spinal cord or optic nerve involvement argues against PML. A normal magnetic resonance image (MRI) has a high negative predictive value, and frank infarction is not a feature of PML. In classic PML, contrast enhancement is typically absent and routine cerebrospinal fluid (CSF) analysis is typically normal. However, contrast enhancement and edema on MRI, lymphocytic CSF pleocytosis, and elevated CSF protein may be seen in the more recently described “inflammatory PML,” in which case the distinction from cerebral vasculitis or neuropsychiatric SLE may be more difficult. Angiography appears normal in patients with PML.

The diagnostic test of choice is a polymerase chain reaction (PCR) assay for JCV in CSF. If the PCR is repeatedly negative, then a brain biopsy should be considered, especially in the setting of progressive neurologic decline in patients receiving immunosuppressive therapy.

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.

Our remarkable progress in understanding progressive multifocal leukoencephalopathy (PML) since its discovery more than 50 years ago has evolved in three stages, concurrent with the changing epidemiology of PML: the pre–human immunodeficiency virus (HIV) era; the HIV era, with highly active antiretroviral therapy (HAART) bringing further change; and the biologic therapy era.

Before the appearance of HIV, PML developed mostly in patients who had lymphoma, other malignancies, and rare forms of immunosuppression. The development of HIV changed the nature of PML, with more than 75% of cases now reported in HIV-infected patients. Within the HIV population, the epidemiology and prognosis of PML have undergone additional changes since the late 1990s. The introduction of HAART transformed PML from an almost uniformly fatal and inexorably progressive disease to one in which long-term survival is expected, particularly in the setting of robust immune reconstitution.¹

The third and most recent stage in the evolution of PML and our understanding of it has coincided with the introduction and use of increasingly potent immunosuppressive regimens and novel biologic immunologic therapies that target various aspects of the integrated immune response. These agents are being applied not only in the field of autoimmune and autoinflammatory disease but also in transplantation and oncology.

Collectively, vulnerable populations (ie, patients with lymphoreticular malignancies and autoinflammatory diseases) are now being subjected to therapies that singly or in combination have unknown effects on the immune system. As a byproduct, practitioners who were only vaguely aware of PML in the past now must consider PML in their differential diagnosis, develop a rational plan for evaluating such patients, and recognize when referral to a specialist is indicated. Recent descriptions of atypical forms of PML^2,3 add to the challenge for clinicians, as do reports of cases of PML in patients with minimal immunosuppression, in the absence of immunosuppressive therapy, and in patients who appear to have “normal” immune systems but in fact have diseases such as sarcoidosis.⁴ Rare cases are also being reported in patients with advanced liver disease.⁴

This article offers recommendations for enhanced awareness of PML, suggestions for improved evaluation of predisposed patients, and a summary of currently accepted treatment strategies.

WHEN TO SUSPECT PML

Patients being treated with immunosuppressive biologic agents represent a significant group that is predisposed to PML. At one time, focal neurologic deficits were required to consider the possibility of PML, but cognitive/behavioral abnormalities rather than focal neurologic findings are often the presenting sign in individuals treated with immune-modulating biologic agents. This phenomenon is most strikingly observed in recipients of natalizumab. Any central nervous system (CNS) dysfunction in a patient taking an immunosuppressive biologic agent should arouse suspicion for PML.

Peripheral neuropathy is not caused by PML but can coexist with it. Accordingly, in patients with rheumatologic disease who are receiving immune modifiers, neuromuscular symptoms in the absence of brain abnormalities on magnetic resonance imaging (MRI) argue against consideration of PML but do not rule it out—especially in patients with connective tissue diseases.

Systemic lupus erythematosus (SLE) represents a special challenge for several reasons. First, SLE appears to be a predisposing factor among other connective tissue diseases.⁵ In addition, SLE is associated with a variety of CNS complications, including a spectrum of focal and diffuse signs and symptoms that can mimic PML and lead to underdiagnosis.

Underrecognition is a risk in the HIV population as well, where cognitive impairment is common. Irrespective of immune or virologic status, 57% of HIV patients demonstrate impairment on neuropsychiatric testing. Often, mild to moderate cognitive impairment in HIV is attributed to HIV encephalopathy with no further workup, resulting in a missed or late diagnosis of PML.

IMAGING CONSIDERATIONS

In the rheumatologic disease population, especially those with SLE, and the HIV population, neuroimaging is indicated in any patient who presents with cognitive impairment. Typical radiographic characteristics of PML on MRI are subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery. T1-weighted images will reveal hypointense lesions that usually do not enhance, but may do so in fewer than 10% of patients with PML. Typically, no mass effect is seen.

In addition to rare faint gadolinium enhancement of lesions, other lesion characteristics may depart from the classic picture—for example, white matter and gray matter involvement, and monofocal instead of multifocal lesions. In HIV-positive patients, MRI can demonstrate diffuse cerebellar atrophy and subtle white matter abnormalities within the cerebellum.

Unfortunately, nonspecific white matter lesions occur in HIV infection as well as connective tissue diseases, compromising diagnostic specificity of a single imaging study. Nevertheless, progression of clinical signs and symptoms and progressive MRI changes should prompt a more vigorous diagnostic evaluation for PML. Alternatively, a normal MRI in a patient in whom PML is suspected has strong negative predictive value. In either situation, baseline neuroimaging is not recommended.

A neurology consult is advised when a patient has a predisposing condition for PML or suspicious neurologic signs or symptoms, whether focal or diffuse, and in whom an MRI demonstrates white matter changes.

Evaluation for JC virus DNA

When the neurology consult has been scheduled, and before the actual visit to the neurologist, a cerebrospinal fluid (CSF) sample should be obtained and evaluated for JC virus (JCV) DNA using a highly sensitive polymerase chain reaction (PCR) assay. Lumbar puncture in the setting of possible PML is critical to exclude the presence of other opportunistic infections.

The importance of using ultrasensitive PCR assays for diagnosing PML cannot be overstated, as falsely negative CSF PCR has been observed for JCV DNA despite high levels of JCV DNA in spinal fluid when utilizing less sensitive assays. The most sensitive commercial assays can detect as few as 50 copies of JCV DNA per mL of CSF fluid.

The risk of PML imparted by biologic agents other than natalizumab and nonbiologic immunosuppressive agents has been difficult to quantify, but no immune-modifying drug or combination of drugs appears entirely free of risk. Any patient who has had significant or prolonged immunosuppression should be considered vulnerable, and any patient with suspicion of PML based on unexplained neurologic symptoms warrants CSF examination for JCV DNA.

Brain biopsy

In patients with progressive clinical and MRI findings that suggest PML, but whose CSF PCR for JCV DNA is repeatedly negative, a brain biopsy is appropriate regardless of background immunosuppression. In the patient with rheumatologic disease, for example, suspicion of PML should be heightened if there is neurologic deterioration in the face of escalating antiinflammatory or immunosuppressive therapy for immune-driven inflammatory disease. Diagnostic urgency is particularly warranted in those disorders where the possibility for immune reconstitution is highest (ie, those receiving immunosuppressive regimens).

PML MANAGEMENT DEPENDS ON CLINICAL SETTING

Management of PML starts with risk stratification to identify those patients most prone to developing PML based on their immune status; the presence of autoimmune disease; the subtype of disease (in the case of SLE); and the nature, intensity, and duration of their immunosuppression. If a high-risk patient develops signs and symptoms of PML, the diagnosis should be anticipated and serious consideration given to withholding immunosuppressive therapies while the patient is being worked up.

Accelerating immune reconstitution

Once a diagnosis of PML is confirmed, immune reconstitution should be accelerated whenever possible. This can include temporary or permanent withdrawal of immunosuppressive therapy and initiation of plasmapheresis. Evidence supports continuing plasma exchange until natalizumab serum drug levels decline to less than 1 μg/mL to achieve desaturation of the alpha-4 integrin receptor.⁶ Typically, desaturation of the targeted integrin receptor occurs after five plasmapheresis sessions.

Immune reconstitution may also precipitate a syndrome known as the immune reconstitution inflammatory syndrome (IRIS), characterized by enlargement and contrast enhancement of PML lesions, appearance of new brain lesions, and worsening of neurologic deficits. The infiltration of the brain with inflammatory multinucleated cells and lymphocytes following abrupt immune reconstitution requires treatment. Opinion suggests that judicious use of corticosteroids may control the immune response in the brain in patients with PML-IRIS,^7,8 although further studies are needed.

Involving the patient in treatment decisions

Because risk tolerance varies considerably among individuals, patients should be informed of the risks of PML on the basis of their disease and the agents used to treat it. They should also be given information about the effects of individual treatments on the course of their disease, and they should be encouraged to participate in the selection of therapy.

SUMMARY

The approach to PML in the biologic era starts with an increased awareness of the disease followed by recognition of vulnerable populations and factors that contribute to the development of PML, such as biologic and nonbiologic immunosuppressive therapy. Optimal management includes a low threshold for investigating neurologic signs and symptoms and new-onset signs and symptoms in vulnerable populations, the use of MRI to detect typical PML brain lesions and other atypical brain features (ie, cerebellar atrophy), lumbar puncture and spinal CSF analysis to detect JCV DNA, and timely neurologic consultation for further evaluation. Much still needs to be learned about PML and the risks imparted by background diseases and individual drugs used in rheumatologic, neurologic, and oncologic disease.

Our remarkable progress in understanding progressive multifocal leukoencephalopathy (PML) since its discovery more than 50 years ago has evolved in three stages, concurrent with the changing epidemiology of PML: the pre–human immunodeficiency virus (HIV) era; the HIV era, with highly active antiretroviral therapy (HAART) bringing further change; and the biologic therapy era.

Before the appearance of HIV, PML developed mostly in patients who had lymphoma, other malignancies, and rare forms of immunosuppression. The development of HIV changed the nature of PML, with more than 75% of cases now reported in HIV-infected patients. Within the HIV population, the epidemiology and prognosis of PML have undergone additional changes since the late 1990s. The introduction of HAART transformed PML from an almost uniformly fatal and inexorably progressive disease to one in which long-term survival is expected, particularly in the setting of robust immune reconstitution.¹

The third and most recent stage in the evolution of PML and our understanding of it has coincided with the introduction and use of increasingly potent immunosuppressive regimens and novel biologic immunologic therapies that target various aspects of the integrated immune response. These agents are being applied not only in the field of autoimmune and autoinflammatory disease but also in transplantation and oncology.

Collectively, vulnerable populations (ie, patients with lymphoreticular malignancies and autoinflammatory diseases) are now being subjected to therapies that singly or in combination have unknown effects on the immune system. As a byproduct, practitioners who were only vaguely aware of PML in the past now must consider PML in their differential diagnosis, develop a rational plan for evaluating such patients, and recognize when referral to a specialist is indicated. Recent descriptions of atypical forms of PML^2,3 add to the challenge for clinicians, as do reports of cases of PML in patients with minimal immunosuppression, in the absence of immunosuppressive therapy, and in patients who appear to have “normal” immune systems but in fact have diseases such as sarcoidosis.⁴ Rare cases are also being reported in patients with advanced liver disease.⁴

This article offers recommendations for enhanced awareness of PML, suggestions for improved evaluation of predisposed patients, and a summary of currently accepted treatment strategies.

WHEN TO SUSPECT PML

Patients being treated with immunosuppressive biologic agents represent a significant group that is predisposed to PML. At one time, focal neurologic deficits were required to consider the possibility of PML, but cognitive/behavioral abnormalities rather than focal neurologic findings are often the presenting sign in individuals treated with immune-modulating biologic agents. This phenomenon is most strikingly observed in recipients of natalizumab. Any central nervous system (CNS) dysfunction in a patient taking an immunosuppressive biologic agent should arouse suspicion for PML.

Peripheral neuropathy is not caused by PML but can coexist with it. Accordingly, in patients with rheumatologic disease who are receiving immune modifiers, neuromuscular symptoms in the absence of brain abnormalities on magnetic resonance imaging (MRI) argue against consideration of PML but do not rule it out—especially in patients with connective tissue diseases.

Systemic lupus erythematosus (SLE) represents a special challenge for several reasons. First, SLE appears to be a predisposing factor among other connective tissue diseases.⁵ In addition, SLE is associated with a variety of CNS complications, including a spectrum of focal and diffuse signs and symptoms that can mimic PML and lead to underdiagnosis.

Underrecognition is a risk in the HIV population as well, where cognitive impairment is common. Irrespective of immune or virologic status, 57% of HIV patients demonstrate impairment on neuropsychiatric testing. Often, mild to moderate cognitive impairment in HIV is attributed to HIV encephalopathy with no further workup, resulting in a missed or late diagnosis of PML.

IMAGING CONSIDERATIONS

In the rheumatologic disease population, especially those with SLE, and the HIV population, neuroimaging is indicated in any patient who presents with cognitive impairment. Typical radiographic characteristics of PML on MRI are subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery. T1-weighted images will reveal hypointense lesions that usually do not enhance, but may do so in fewer than 10% of patients with PML. Typically, no mass effect is seen.

In addition to rare faint gadolinium enhancement of lesions, other lesion characteristics may depart from the classic picture—for example, white matter and gray matter involvement, and monofocal instead of multifocal lesions. In HIV-positive patients, MRI can demonstrate diffuse cerebellar atrophy and subtle white matter abnormalities within the cerebellum.

Unfortunately, nonspecific white matter lesions occur in HIV infection as well as connective tissue diseases, compromising diagnostic specificity of a single imaging study. Nevertheless, progression of clinical signs and symptoms and progressive MRI changes should prompt a more vigorous diagnostic evaluation for PML. Alternatively, a normal MRI in a patient in whom PML is suspected has strong negative predictive value. In either situation, baseline neuroimaging is not recommended.

A neurology consult is advised when a patient has a predisposing condition for PML or suspicious neurologic signs or symptoms, whether focal or diffuse, and in whom an MRI demonstrates white matter changes.

Evaluation for JC virus DNA

When the neurology consult has been scheduled, and before the actual visit to the neurologist, a cerebrospinal fluid (CSF) sample should be obtained and evaluated for JC virus (JCV) DNA using a highly sensitive polymerase chain reaction (PCR) assay. Lumbar puncture in the setting of possible PML is critical to exclude the presence of other opportunistic infections.

The importance of using ultrasensitive PCR assays for diagnosing PML cannot be overstated, as falsely negative CSF PCR has been observed for JCV DNA despite high levels of JCV DNA in spinal fluid when utilizing less sensitive assays. The most sensitive commercial assays can detect as few as 50 copies of JCV DNA per mL of CSF fluid.

The risk of PML imparted by biologic agents other than natalizumab and nonbiologic immunosuppressive agents has been difficult to quantify, but no immune-modifying drug or combination of drugs appears entirely free of risk. Any patient who has had significant or prolonged immunosuppression should be considered vulnerable, and any patient with suspicion of PML based on unexplained neurologic symptoms warrants CSF examination for JCV DNA.

Brain biopsy

In patients with progressive clinical and MRI findings that suggest PML, but whose CSF PCR for JCV DNA is repeatedly negative, a brain biopsy is appropriate regardless of background immunosuppression. In the patient with rheumatologic disease, for example, suspicion of PML should be heightened if there is neurologic deterioration in the face of escalating antiinflammatory or immunosuppressive therapy for immune-driven inflammatory disease. Diagnostic urgency is particularly warranted in those disorders where the possibility for immune reconstitution is highest (ie, those receiving immunosuppressive regimens).

PML MANAGEMENT DEPENDS ON CLINICAL SETTING

Management of PML starts with risk stratification to identify those patients most prone to developing PML based on their immune status; the presence of autoimmune disease; the subtype of disease (in the case of SLE); and the nature, intensity, and duration of their immunosuppression. If a high-risk patient develops signs and symptoms of PML, the diagnosis should be anticipated and serious consideration given to withholding immunosuppressive therapies while the patient is being worked up.

Accelerating immune reconstitution

Once a diagnosis of PML is confirmed, immune reconstitution should be accelerated whenever possible. This can include temporary or permanent withdrawal of immunosuppressive therapy and initiation of plasmapheresis. Evidence supports continuing plasma exchange until natalizumab serum drug levels decline to less than 1 μg/mL to achieve desaturation of the alpha-4 integrin receptor.⁶ Typically, desaturation of the targeted integrin receptor occurs after five plasmapheresis sessions.

Immune reconstitution may also precipitate a syndrome known as the immune reconstitution inflammatory syndrome (IRIS), characterized by enlargement and contrast enhancement of PML lesions, appearance of new brain lesions, and worsening of neurologic deficits. The infiltration of the brain with inflammatory multinucleated cells and lymphocytes following abrupt immune reconstitution requires treatment. Opinion suggests that judicious use of corticosteroids may control the immune response in the brain in patients with PML-IRIS,^7,8 although further studies are needed.

Involving the patient in treatment decisions

Because risk tolerance varies considerably among individuals, patients should be informed of the risks of PML on the basis of their disease and the agents used to treat it. They should also be given information about the effects of individual treatments on the course of their disease, and they should be encouraged to participate in the selection of therapy.

SUMMARY

The approach to PML in the biologic era starts with an increased awareness of the disease followed by recognition of vulnerable populations and factors that contribute to the development of PML, such as biologic and nonbiologic immunosuppressive therapy. Optimal management includes a low threshold for investigating neurologic signs and symptoms and new-onset signs and symptoms in vulnerable populations, the use of MRI to detect typical PML brain lesions and other atypical brain features (ie, cerebellar atrophy), lumbar puncture and spinal CSF analysis to detect JCV DNA, and timely neurologic consultation for further evaluation. Much still needs to be learned about PML and the risks imparted by background diseases and individual drugs used in rheumatologic, neurologic, and oncologic disease.

Our remarkable progress in understanding progressive multifocal leukoencephalopathy (PML) since its discovery more than 50 years ago has evolved in three stages, concurrent with the changing epidemiology of PML: the pre–human immunodeficiency virus (HIV) era; the HIV era, with highly active antiretroviral therapy (HAART) bringing further change; and the biologic therapy era.

Before the appearance of HIV, PML developed mostly in patients who had lymphoma, other malignancies, and rare forms of immunosuppression. The development of HIV changed the nature of PML, with more than 75% of cases now reported in HIV-infected patients. Within the HIV population, the epidemiology and prognosis of PML have undergone additional changes since the late 1990s. The introduction of HAART transformed PML from an almost uniformly fatal and inexorably progressive disease to one in which long-term survival is expected, particularly in the setting of robust immune reconstitution.¹

The third and most recent stage in the evolution of PML and our understanding of it has coincided with the introduction and use of increasingly potent immunosuppressive regimens and novel biologic immunologic therapies that target various aspects of the integrated immune response. These agents are being applied not only in the field of autoimmune and autoinflammatory disease but also in transplantation and oncology.

Collectively, vulnerable populations (ie, patients with lymphoreticular malignancies and autoinflammatory diseases) are now being subjected to therapies that singly or in combination have unknown effects on the immune system. As a byproduct, practitioners who were only vaguely aware of PML in the past now must consider PML in their differential diagnosis, develop a rational plan for evaluating such patients, and recognize when referral to a specialist is indicated. Recent descriptions of atypical forms of PML^2,3 add to the challenge for clinicians, as do reports of cases of PML in patients with minimal immunosuppression, in the absence of immunosuppressive therapy, and in patients who appear to have “normal” immune systems but in fact have diseases such as sarcoidosis.⁴ Rare cases are also being reported in patients with advanced liver disease.⁴

This article offers recommendations for enhanced awareness of PML, suggestions for improved evaluation of predisposed patients, and a summary of currently accepted treatment strategies.

WHEN TO SUSPECT PML

Patients being treated with immunosuppressive biologic agents represent a significant group that is predisposed to PML. At one time, focal neurologic deficits were required to consider the possibility of PML, but cognitive/behavioral abnormalities rather than focal neurologic findings are often the presenting sign in individuals treated with immune-modulating biologic agents. This phenomenon is most strikingly observed in recipients of natalizumab. Any central nervous system (CNS) dysfunction in a patient taking an immunosuppressive biologic agent should arouse suspicion for PML.

Peripheral neuropathy is not caused by PML but can coexist with it. Accordingly, in patients with rheumatologic disease who are receiving immune modifiers, neuromuscular symptoms in the absence of brain abnormalities on magnetic resonance imaging (MRI) argue against consideration of PML but do not rule it out—especially in patients with connective tissue diseases.

Systemic lupus erythematosus (SLE) represents a special challenge for several reasons. First, SLE appears to be a predisposing factor among other connective tissue diseases.⁵ In addition, SLE is associated with a variety of CNS complications, including a spectrum of focal and diffuse signs and symptoms that can mimic PML and lead to underdiagnosis.

Underrecognition is a risk in the HIV population as well, where cognitive impairment is common. Irrespective of immune or virologic status, 57% of HIV patients demonstrate impairment on neuropsychiatric testing. Often, mild to moderate cognitive impairment in HIV is attributed to HIV encephalopathy with no further workup, resulting in a missed or late diagnosis of PML.

IMAGING CONSIDERATIONS

In the rheumatologic disease population, especially those with SLE, and the HIV population, neuroimaging is indicated in any patient who presents with cognitive impairment. Typical radiographic characteristics of PML on MRI are subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery. T1-weighted images will reveal hypointense lesions that usually do not enhance, but may do so in fewer than 10% of patients with PML. Typically, no mass effect is seen.

In addition to rare faint gadolinium enhancement of lesions, other lesion characteristics may depart from the classic picture—for example, white matter and gray matter involvement, and monofocal instead of multifocal lesions. In HIV-positive patients, MRI can demonstrate diffuse cerebellar atrophy and subtle white matter abnormalities within the cerebellum.

Unfortunately, nonspecific white matter lesions occur in HIV infection as well as connective tissue diseases, compromising diagnostic specificity of a single imaging study. Nevertheless, progression of clinical signs and symptoms and progressive MRI changes should prompt a more vigorous diagnostic evaluation for PML. Alternatively, a normal MRI in a patient in whom PML is suspected has strong negative predictive value. In either situation, baseline neuroimaging is not recommended.

A neurology consult is advised when a patient has a predisposing condition for PML or suspicious neurologic signs or symptoms, whether focal or diffuse, and in whom an MRI demonstrates white matter changes.

Evaluation for JC virus DNA

When the neurology consult has been scheduled, and before the actual visit to the neurologist, a cerebrospinal fluid (CSF) sample should be obtained and evaluated for JC virus (JCV) DNA using a highly sensitive polymerase chain reaction (PCR) assay. Lumbar puncture in the setting of possible PML is critical to exclude the presence of other opportunistic infections.

The importance of using ultrasensitive PCR assays for diagnosing PML cannot be overstated, as falsely negative CSF PCR has been observed for JCV DNA despite high levels of JCV DNA in spinal fluid when utilizing less sensitive assays. The most sensitive commercial assays can detect as few as 50 copies of JCV DNA per mL of CSF fluid.

The risk of PML imparted by biologic agents other than natalizumab and nonbiologic immunosuppressive agents has been difficult to quantify, but no immune-modifying drug or combination of drugs appears entirely free of risk. Any patient who has had significant or prolonged immunosuppression should be considered vulnerable, and any patient with suspicion of PML based on unexplained neurologic symptoms warrants CSF examination for JCV DNA.

Brain biopsy

In patients with progressive clinical and MRI findings that suggest PML, but whose CSF PCR for JCV DNA is repeatedly negative, a brain biopsy is appropriate regardless of background immunosuppression. In the patient with rheumatologic disease, for example, suspicion of PML should be heightened if there is neurologic deterioration in the face of escalating antiinflammatory or immunosuppressive therapy for immune-driven inflammatory disease. Diagnostic urgency is particularly warranted in those disorders where the possibility for immune reconstitution is highest (ie, those receiving immunosuppressive regimens).

PML MANAGEMENT DEPENDS ON CLINICAL SETTING

Management of PML starts with risk stratification to identify those patients most prone to developing PML based on their immune status; the presence of autoimmune disease; the subtype of disease (in the case of SLE); and the nature, intensity, and duration of their immunosuppression. If a high-risk patient develops signs and symptoms of PML, the diagnosis should be anticipated and serious consideration given to withholding immunosuppressive therapies while the patient is being worked up.

Accelerating immune reconstitution

Once a diagnosis of PML is confirmed, immune reconstitution should be accelerated whenever possible. This can include temporary or permanent withdrawal of immunosuppressive therapy and initiation of plasmapheresis. Evidence supports continuing plasma exchange until natalizumab serum drug levels decline to less than 1 μg/mL to achieve desaturation of the alpha-4 integrin receptor.⁶ Typically, desaturation of the targeted integrin receptor occurs after five plasmapheresis sessions.

Immune reconstitution may also precipitate a syndrome known as the immune reconstitution inflammatory syndrome (IRIS), characterized by enlargement and contrast enhancement of PML lesions, appearance of new brain lesions, and worsening of neurologic deficits. The infiltration of the brain with inflammatory multinucleated cells and lymphocytes following abrupt immune reconstitution requires treatment. Opinion suggests that judicious use of corticosteroids may control the immune response in the brain in patients with PML-IRIS,^7,8 although further studies are needed.

Involving the patient in treatment decisions

Because risk tolerance varies considerably among individuals, patients should be informed of the risks of PML on the basis of their disease and the agents used to treat it. They should also be given information about the effects of individual treatments on the course of their disease, and they should be encouraged to participate in the selection of therapy.

SUMMARY

The approach to PML in the biologic era starts with an increased awareness of the disease followed by recognition of vulnerable populations and factors that contribute to the development of PML, such as biologic and nonbiologic immunosuppressive therapy. Optimal management includes a low threshold for investigating neurologic signs and symptoms and new-onset signs and symptoms in vulnerable populations, the use of MRI to detect typical PML brain lesions and other atypical brain features (ie, cerebellar atrophy), lumbar puncture and spinal CSF analysis to detect JCV DNA, and timely neurologic consultation for further evaluation. Much still needs to be learned about PML and the risks imparted by background diseases and individual drugs used in rheumatologic, neurologic, and oncologic disease.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS). Although originally associated with broad-based immunosuppression (human immunodeficiency virus infection, lymphoproliferative disorders, and immunosuppressive medications), recognition of PML in patients with selective immunosuppression is growing. This restricted immunodeviation can arise from autoimmune disorders such as systemic lupus erythematosus, selective immunosuppressive therapies (eg, rituximab, leflunomide, and efalizumab), or immunosuppression limited to the CNS (eg, treatment with natalizumab).

This article reviews approaches to the management of PML, with specific recommendations regarding PML associated with natalizumab therapy.

APPROACH TO PML TREATMENT

The ideal approach to PML treatment is generally two-pronged: antiviral therapies to directly reduce viral replication and immune reconstitution that empowers the immune system to attack the JC virus (JCV). Challenges to treatment are the difficulty in culturing JCV for in vitro studies, lack of an animal model of PML, and infrequency of PML cases.

Antiviral therapies

At present, no antiviral agent has confirmed efficacy in PML. Nucleoside analogues, serotonin 5-hydroxytryptamine receptor antagonists (to block the JCV receptor), and several cytokines provided exciting prospects in preclinical studies for treatment of PML in humans. Unfortunately, subsequent clinical studies of cytarabine, cidofovir, and interferon alfa all yielded disappointing results. A derivative of cidofovir, CMX001, is also being evaluated for efficacy in PML. Mefloquine was identified through a broad pharmaceutical screening study to have strong antiviral effects in vitro, but a clinical trial to assess its effects was stopped. It remains unclear whether the failure of clinical studies after successful in vitro studies is secondary to low drug penetration into the CNS, treatment initiation too late in the course of PML, or other differences not yet fully understood.

Immune reconstitution

Given the widespread failure of antiviral regimens, the mainstay of PML treatment is immune reconstitution. When immunosuppression is secondary to a medical disorder, efforts are pursued to reverse the primary disorder. For example, highly active antiretroviral therapy significantly prolongs survival in antiretroviral-naïve acquired immunodeficiency syndrome patients.^1,2 Decreasing the intensity of immunosuppressive therapy in solid organ transplant may improve survival with PML. When PML is associated with biologic therapies for autoimmune diseases, early diagnosis and immediate suspension of therapy is thought to improve outcomes.

EXPERIENCE WITH NATALIZUMAB

PML in the setting of natalizumab therapy is related to cumulative exposure to natalizumab. As of August 4, 2011, there had been 150 cases of natalizumab-related PML documented in more than 88,000 patients exposed to natalizumab worldwide³ (see page S18, “Multiple sclerosis, natalizumab, and PML: Helping patients decide”). The incidence of PML in natalizumab-treated patients varies according to the number of infusions received, but the incidence of PML by each epoch of treatment exposure (1 to 24 infusions, 25 to 36 infusions, 37 to 48 infusions) appears to have remained stable over time.³

The mortality associated with natalizumab-related PML was 19% (29 deaths among the 150 confirmed cases) as of August 4, 2011.³ In cases with at least 6 months of follow-up, mortality has remained at about 20%. Many who survived were left with serious morbidity and permanent disability, although interpretation of disability is difficult because functional impairment is a hallmark of multiple sclerosis (MS) irrespective of PML. Survival in patients with natalizumab-associated PML appears to be better than with PML associated with other conditions, possibly because of early diagnosis achieved through clinical vigilance and swift immune reconstitution through natalizumab discontinuation and either plasmapheresis or immunoabsorption. Predictors of survival include younger age at diagnosis, less disability prior to onset of PML, more localized disease on magnetic resonance imaging (MRI) of the brain, and shorter time from symptom onset to PML diagnosis.

Clinical characteristics of natalizumab-associated PML

Several clinical observations should increase suspicion of natalizumab-associated PML.^3–5 For example, the most common presenting symptoms are cognitive, motor, language, and visual impairment. Gadolinium-enhancing lesions are observed at presentation in about one-half of patients. Seizures and paroxysmal events can occur at presentation, which helps to differentiate PML from an MS relapse.

Approximately one-half of patients with natalizumab-associated PML have an initial viral load of less than 500 copies/mL, underscoring the need for ultrasensitive polymerase chain reaction (PCR) testing. An ultrasensitive JCV assay (Focus Diagnostics, Cypress, California) is available that can detect less than 50 copies/mL of JCV DNA. Because the viral copy numbers in the cerebrospinal fluid (CSF) may be low in patients treated with natalizumab, the CSF PCR may be falsely negative. In several cases of PML, JCV was undetectable in the CSF by PCR, identified only later by repeat PCR or brain biopsy.⁴ Serum JCV PCR is not useful in the screening or diagnosis of PML.

Natalizumab-associated PML has not been observed with therapy of 6 months’ or less duration. After 6 months of natalizumab therapy, new MRI lesions are rare in patients who are negative for neutralizing antibodies. A new MRI lesion in such a patient should be considered suspicious for PML. Our standard protocol is to check for neutralizing antibodies at 6 months in all patients treated with natalizumab. Symptoms of PML develop in affected patients whose duration of therapy ranges from 6 to 81 infusions. Symptoms often develop well before PML is diagnosed.^4,5

Forty-six percent of patients treated with natalizumab who develop PML have received previous autologous bone marrow transplantation or chemo therapy, including mitoxantrone, azathioprine, methotrexate, and mycophenolate mofetil. In comparison, up to 25% of MS patients who were treated with natalizumab (13% in the United States, 24% in Europe) have had prior chemotherapy treatment. Prior immunosuppressive therapy increases the risk of PML by two- to fourfold, which may explain the higher rate of PML in Europe compared with that of the United States.^4,5

Testing for immune response to JCV

A JCV enzyme-linked immunosorbent assay (ELISA) test has been developed that identifies patients with an immune response to JCV. Among MS patients, 55% test positive for JCV through this assay.⁶ The false-negative rate of the test is 5%, and the overall annual seroconversion rate is estimated to be about 2%, necessitating repeat testing.

Based on results of this assay, the estimated risk of PML in seropositive patients is about 1 in 500.⁶ The test was positive in 28 of 28 patients who developed PML. The probability of this relationship occurring by chance is 0.5528, which suggests that this assay is useful to stratify risk for development of PML. Although the rate of false negatives makes the test an imperfect predictor, it is still useful in clinical practice. The test became available clinically in late summer 2011. Further longitudinal observation studies (STRATIFY-1 and STRATIFY-2) on the use of the JCV ELISA to detect anti-JCV antibodies in the blood of natalizumab-treated patients with MS are under way.

Stratifying risk for natalizumab-related PML

The possibility of reducing the risk of PML in natalizumab-treated patients through natalizumab holidays is attractive. When exploring this option, one must consider whether the risk of recurrent disease activity with treatment interruption outweighs the potentially decreased risk of PML.⁸ A randomized controlled multicenter clinical trial of natalizumab interruption is ongoing, with the recruitment phase complete after enrollment of 175 patients. Patients taking natalizumab at study entry have been randomized to one of three arms: continuation of monthly natalizumab for 6 months, placebo for 6 months, or an alternate treatment (interferon beta-1a, glatiramer acetate, or monthly intravenous steroids) for 6 months administered open-label by clinician and patient choice.

The primary outcome measures are markers of immune function and overall disease activity during treatment interruption and after resumption. Patients are monitored monthly using MRI to measure disease activity. Those who experience relapse will have the option of returning to natalizumab therapy or switching to an alternate treatment. The results of this prospective, randomized, controlled trial will provide a greater understanding of the safety issues surrounding natalizumab holidays.

Management of natalizumab-related PML

Management of patients taking natalizumab starts with risk stratification in an attempt to prevent the development of PML. If suspicion for PML is raised based on symptoms, early diagnosis can be accomplished through the use of a sensitive JCV PCR assay, with a repeat PCR if negative. Natalizumab treatment should be withheld during the workup for PML.

Reprinted, with permission, from Neurology (Khatri BO, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72:402–409).

When immunosuppression is rapidly reversed in cases of natalizumab-associated PML, an overly exuberant immune response targeting JCV in the CNS is observed 2 to 6 weeks later. The response, termed immune reconstitution inflammatory syndrome (IRIS), is not always easy to differentiate from progression of PML. Nonetheless, most clinicians recommend high-dose corticosteroids if a clinical and imaging syndrome resembling IRIS develops several weeks after immune restoration.¹⁰ The objective is to achieve the immune reconstitution needed to control JCV infection while limiting the collateral damage of inflammation on the remaining brain tissue.

SUMMARY

Risk factors for natalizumab-associated PML include duration of treatment with natalizumab, previous chemotherapy, and JCV antibody serology. Early diagnosis requires the use of an ultrasensitive JCV PCR assay. Treatment is focused on early diagnosis, immediate cessation of pharmacologic causes of immunosuppression, and active efforts to accelerate immune restoration.

DISCUSSION

Dr. Calabrese: What are your thoughts about plasmapheresis for rituximab-related cases of PML?

Dr. Fox: It’s probably not going to be as helpful as with natalizumab. Rituximab has pharmacokinetics that are similar to those of other monoclonal antibodies, with a half-life in the range of 14 to 20 days. So it’s pretty much absent from the body within 1 to 2 months of infusion. The enduring benefit from rituximab comes not from the persistent presence of the monoclonal antibody, but the persistent absence of CD19 B cells. Plasmapheresis is unlikely to be effective because it won’t accelerate return of CD19 B cells to the peripheral circulation. In rituximab-related PML, stimulating the bone marrow to produce more B cells in order to restore the immune system is more likely to be effective. In contrast, I did recommend plasma pheresis in a case of efalizumab-related PML. Because efalizumab is a binding antibody to the CD11a receptor, we wanted to accelerate its removal.

Dr. Molloy: In an MS patient who responds well to natalizumab, do you ever explore a strategy of dose reduction or extending the dosing interval of natalizumab?

Dr. Fox: Let me put that into a clinical context. A 35-year old man has had relapsing-remitting MS for 3 years. Two years ago, after disease activity occurred while he was using an injectable therapy, he started natalizumab and has been clinically and radiologically stable on natalizumab. Then, he gets the JCV assay, it’s positive, and he asks if it’s time to get off natalizumab “because of the risk of that brain virus.”

What do I tell him? Should I change the dosing interval? At this point, we are not doing either. One reason is the unpredictable pharmacokinetics of the drug. The dose and dosing regimen were chosen to have 85% or greater receptor saturation in 95% or more of patients over the course of the recommended 4-week dosing interval. If you increase the interval to 6 weeks or 8 weeks, you can’t predict in individual patients whether or not meaningful desaturation occurs and thus allows some immune cells to enter the brain to protect against PML (but not too many, or MS disease activity will return).

Dr. Simpson: Do you have an algorithm for working up patients?

Dr. Fox: It depends on the level of suspicion given the patient’s symptoms. It’s difficult to find a single MS patient who does not have some fluctuation of symptoms over time and some worsening of symptoms such as stiffness, fatigue, and cognitive difficulties. They all have changes in mood, so if one took any symptom change—any change in their report of mood and cognition— as the cutoff for a workup, we wouldn’t be giving natalizumab at all. But if a patient or family says, “I am worried,” then we need to work it up. Also, if there are clearcut new or worsening neurologic symptoms, we pursue a workup. Often, the change in symptoms is revealed when the patient comes in for his or her monthly infusion and the nurse asks the four questions from the preinfusion checklist (as part of the mandatory Tysabri Outreach: Unified Commitment to Health [TOUCH] prescribing program for natalizumab).¹¹

If there are new symptoms, we hold infusions and do a two-stage evaluation. The first stage is a brain MRI to evaluate for change from baseline (the US Food and Drug Administration requires a brain MRI at baseline before starting natalizumab therapy). Most patients undergo a brain MRI every 6 to 12 months while on natalizumab therapy, with instructions to the neuroradiologist to evaluate carefully for new lesions. In our institution, the PML MRI evaluation is a fine-toothcomb assessment of lesions from the most recent MRI compared with the current MRI. Depending on the results of the current MRI and on our level of suspicion, we may proceed to a spinal tap, even if the MRI findings are stable. We have done 8 to 10 spinal taps in patients taking natalizumab when we were suspicious enough to evaluate for PML. Occasional patients continue to have active disease, relapses, and new lesions even without developing antibodies while taking natalizumab.

Dr. Rudick: We need a quick, quantitative analysis method to compare one MRI with another. It is easy to say, “Consider PML if there are new lesions.” It’s not so easy to know if the lesions are new. We are participating in a National Institutes of Health study regarding identification of biomarkers of interferon’s effects, and the study requires obtaining MRI scans at baseline and 6 months. We have state-of-the-art subtraction MRI to quantify new lesions on the followup MRI. However, there is significant disagreement on the number of new lesions determined by clinical raters, and disagreement between the clinical raters and the numbers generated by the computer program.

Dr. Major: Is the incidence of natalizumab-related PML based on the number of months or on the number of infusions?

Dr. Fox: It is based on the number of infusions. You bring up a good point because these patients may interrupt treatment when they go on vacation, for example, or have a lapse in insurance coverage. Most patients follow the every-4-weeks protocol and receive 13 infusions in a year. Perhaps 10% to 15% do not follow it precisely.

Dr. Molloy: Is everyone who takes natalizumab being followed for PML even if they discontinue natalizumab? Have any differences emerged in the factors that predispose to PML among those who continue therapy compared with those who discontinue? I ask because I’m wondering why the incidence appears to stabilize, or even go down, after 36 infusions.

Dr. Fox: PML has not been reported beyond several months after stopping natalizumab; concern about PML can decrease fairly quickly after stopping the drug. Many of us expected the risk of PML to continue rising with cumulative treatment, so were pleasantly surprised to see a plateau in the risk of PML after about 36 months. We don’t understand what leads to this plateau.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS). Although originally associated with broad-based immunosuppression (human immunodeficiency virus infection, lymphoproliferative disorders, and immunosuppressive medications), recognition of PML in patients with selective immunosuppression is growing. This restricted immunodeviation can arise from autoimmune disorders such as systemic lupus erythematosus, selective immunosuppressive therapies (eg, rituximab, leflunomide, and efalizumab), or immunosuppression limited to the CNS (eg, treatment with natalizumab).

This article reviews approaches to the management of PML, with specific recommendations regarding PML associated with natalizumab therapy.

APPROACH TO PML TREATMENT

The ideal approach to PML treatment is generally two-pronged: antiviral therapies to directly reduce viral replication and immune reconstitution that empowers the immune system to attack the JC virus (JCV). Challenges to treatment are the difficulty in culturing JCV for in vitro studies, lack of an animal model of PML, and infrequency of PML cases.

Antiviral therapies

At present, no antiviral agent has confirmed efficacy in PML. Nucleoside analogues, serotonin 5-hydroxytryptamine receptor antagonists (to block the JCV receptor), and several cytokines provided exciting prospects in preclinical studies for treatment of PML in humans. Unfortunately, subsequent clinical studies of cytarabine, cidofovir, and interferon alfa all yielded disappointing results. A derivative of cidofovir, CMX001, is also being evaluated for efficacy in PML. Mefloquine was identified through a broad pharmaceutical screening study to have strong antiviral effects in vitro, but a clinical trial to assess its effects was stopped. It remains unclear whether the failure of clinical studies after successful in vitro studies is secondary to low drug penetration into the CNS, treatment initiation too late in the course of PML, or other differences not yet fully understood.

Immune reconstitution

Given the widespread failure of antiviral regimens, the mainstay of PML treatment is immune reconstitution. When immunosuppression is secondary to a medical disorder, efforts are pursued to reverse the primary disorder. For example, highly active antiretroviral therapy significantly prolongs survival in antiretroviral-naïve acquired immunodeficiency syndrome patients.^1,2 Decreasing the intensity of immunosuppressive therapy in solid organ transplant may improve survival with PML. When PML is associated with biologic therapies for autoimmune diseases, early diagnosis and immediate suspension of therapy is thought to improve outcomes.

EXPERIENCE WITH NATALIZUMAB

PML in the setting of natalizumab therapy is related to cumulative exposure to natalizumab. As of August 4, 2011, there had been 150 cases of natalizumab-related PML documented in more than 88,000 patients exposed to natalizumab worldwide³ (see page S18, “Multiple sclerosis, natalizumab, and PML: Helping patients decide”). The incidence of PML in natalizumab-treated patients varies according to the number of infusions received, but the incidence of PML by each epoch of treatment exposure (1 to 24 infusions, 25 to 36 infusions, 37 to 48 infusions) appears to have remained stable over time.³

The mortality associated with natalizumab-related PML was 19% (29 deaths among the 150 confirmed cases) as of August 4, 2011.³ In cases with at least 6 months of follow-up, mortality has remained at about 20%. Many who survived were left with serious morbidity and permanent disability, although interpretation of disability is difficult because functional impairment is a hallmark of multiple sclerosis (MS) irrespective of PML. Survival in patients with natalizumab-associated PML appears to be better than with PML associated with other conditions, possibly because of early diagnosis achieved through clinical vigilance and swift immune reconstitution through natalizumab discontinuation and either plasmapheresis or immunoabsorption. Predictors of survival include younger age at diagnosis, less disability prior to onset of PML, more localized disease on magnetic resonance imaging (MRI) of the brain, and shorter time from symptom onset to PML diagnosis.

Clinical characteristics of natalizumab-associated PML

Several clinical observations should increase suspicion of natalizumab-associated PML.^3–5 For example, the most common presenting symptoms are cognitive, motor, language, and visual impairment. Gadolinium-enhancing lesions are observed at presentation in about one-half of patients. Seizures and paroxysmal events can occur at presentation, which helps to differentiate PML from an MS relapse.

Approximately one-half of patients with natalizumab-associated PML have an initial viral load of less than 500 copies/mL, underscoring the need for ultrasensitive polymerase chain reaction (PCR) testing. An ultrasensitive JCV assay (Focus Diagnostics, Cypress, California) is available that can detect less than 50 copies/mL of JCV DNA. Because the viral copy numbers in the cerebrospinal fluid (CSF) may be low in patients treated with natalizumab, the CSF PCR may be falsely negative. In several cases of PML, JCV was undetectable in the CSF by PCR, identified only later by repeat PCR or brain biopsy.⁴ Serum JCV PCR is not useful in the screening or diagnosis of PML.

Natalizumab-associated PML has not been observed with therapy of 6 months’ or less duration. After 6 months of natalizumab therapy, new MRI lesions are rare in patients who are negative for neutralizing antibodies. A new MRI lesion in such a patient should be considered suspicious for PML. Our standard protocol is to check for neutralizing antibodies at 6 months in all patients treated with natalizumab. Symptoms of PML develop in affected patients whose duration of therapy ranges from 6 to 81 infusions. Symptoms often develop well before PML is diagnosed.^4,5

Forty-six percent of patients treated with natalizumab who develop PML have received previous autologous bone marrow transplantation or chemo therapy, including mitoxantrone, azathioprine, methotrexate, and mycophenolate mofetil. In comparison, up to 25% of MS patients who were treated with natalizumab (13% in the United States, 24% in Europe) have had prior chemotherapy treatment. Prior immunosuppressive therapy increases the risk of PML by two- to fourfold, which may explain the higher rate of PML in Europe compared with that of the United States.^4,5

Testing for immune response to JCV

A JCV enzyme-linked immunosorbent assay (ELISA) test has been developed that identifies patients with an immune response to JCV. Among MS patients, 55% test positive for JCV through this assay.⁶ The false-negative rate of the test is 5%, and the overall annual seroconversion rate is estimated to be about 2%, necessitating repeat testing.

Based on results of this assay, the estimated risk of PML in seropositive patients is about 1 in 500.⁶ The test was positive in 28 of 28 patients who developed PML. The probability of this relationship occurring by chance is 0.5528, which suggests that this assay is useful to stratify risk for development of PML. Although the rate of false negatives makes the test an imperfect predictor, it is still useful in clinical practice. The test became available clinically in late summer 2011. Further longitudinal observation studies (STRATIFY-1 and STRATIFY-2) on the use of the JCV ELISA to detect anti-JCV antibodies in the blood of natalizumab-treated patients with MS are under way.

Stratifying risk for natalizumab-related PML

The possibility of reducing the risk of PML in natalizumab-treated patients through natalizumab holidays is attractive. When exploring this option, one must consider whether the risk of recurrent disease activity with treatment interruption outweighs the potentially decreased risk of PML.⁸ A randomized controlled multicenter clinical trial of natalizumab interruption is ongoing, with the recruitment phase complete after enrollment of 175 patients. Patients taking natalizumab at study entry have been randomized to one of three arms: continuation of monthly natalizumab for 6 months, placebo for 6 months, or an alternate treatment (interferon beta-1a, glatiramer acetate, or monthly intravenous steroids) for 6 months administered open-label by clinician and patient choice.

The primary outcome measures are markers of immune function and overall disease activity during treatment interruption and after resumption. Patients are monitored monthly using MRI to measure disease activity. Those who experience relapse will have the option of returning to natalizumab therapy or switching to an alternate treatment. The results of this prospective, randomized, controlled trial will provide a greater understanding of the safety issues surrounding natalizumab holidays.

Management of natalizumab-related PML

Management of patients taking natalizumab starts with risk stratification in an attempt to prevent the development of PML. If suspicion for PML is raised based on symptoms, early diagnosis can be accomplished through the use of a sensitive JCV PCR assay, with a repeat PCR if negative. Natalizumab treatment should be withheld during the workup for PML.

Reprinted, with permission, from Neurology (Khatri BO, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72:402–409).

When immunosuppression is rapidly reversed in cases of natalizumab-associated PML, an overly exuberant immune response targeting JCV in the CNS is observed 2 to 6 weeks later. The response, termed immune reconstitution inflammatory syndrome (IRIS), is not always easy to differentiate from progression of PML. Nonetheless, most clinicians recommend high-dose corticosteroids if a clinical and imaging syndrome resembling IRIS develops several weeks after immune restoration.¹⁰ The objective is to achieve the immune reconstitution needed to control JCV infection while limiting the collateral damage of inflammation on the remaining brain tissue.

SUMMARY

Risk factors for natalizumab-associated PML include duration of treatment with natalizumab, previous chemotherapy, and JCV antibody serology. Early diagnosis requires the use of an ultrasensitive JCV PCR assay. Treatment is focused on early diagnosis, immediate cessation of pharmacologic causes of immunosuppression, and active efforts to accelerate immune restoration.

DISCUSSION

Dr. Calabrese: What are your thoughts about plasmapheresis for rituximab-related cases of PML?

Dr. Fox: It’s probably not going to be as helpful as with natalizumab. Rituximab has pharmacokinetics that are similar to those of other monoclonal antibodies, with a half-life in the range of 14 to 20 days. So it’s pretty much absent from the body within 1 to 2 months of infusion. The enduring benefit from rituximab comes not from the persistent presence of the monoclonal antibody, but the persistent absence of CD19 B cells. Plasmapheresis is unlikely to be effective because it won’t accelerate return of CD19 B cells to the peripheral circulation. In rituximab-related PML, stimulating the bone marrow to produce more B cells in order to restore the immune system is more likely to be effective. In contrast, I did recommend plasma pheresis in a case of efalizumab-related PML. Because efalizumab is a binding antibody to the CD11a receptor, we wanted to accelerate its removal.

Dr. Molloy: In an MS patient who responds well to natalizumab, do you ever explore a strategy of dose reduction or extending the dosing interval of natalizumab?

Dr. Fox: Let me put that into a clinical context. A 35-year old man has had relapsing-remitting MS for 3 years. Two years ago, after disease activity occurred while he was using an injectable therapy, he started natalizumab and has been clinically and radiologically stable on natalizumab. Then, he gets the JCV assay, it’s positive, and he asks if it’s time to get off natalizumab “because of the risk of that brain virus.”

What do I tell him? Should I change the dosing interval? At this point, we are not doing either. One reason is the unpredictable pharmacokinetics of the drug. The dose and dosing regimen were chosen to have 85% or greater receptor saturation in 95% or more of patients over the course of the recommended 4-week dosing interval. If you increase the interval to 6 weeks or 8 weeks, you can’t predict in individual patients whether or not meaningful desaturation occurs and thus allows some immune cells to enter the brain to protect against PML (but not too many, or MS disease activity will return).

Dr. Simpson: Do you have an algorithm for working up patients?

Dr. Fox: It depends on the level of suspicion given the patient’s symptoms. It’s difficult to find a single MS patient who does not have some fluctuation of symptoms over time and some worsening of symptoms such as stiffness, fatigue, and cognitive difficulties. They all have changes in mood, so if one took any symptom change—any change in their report of mood and cognition— as the cutoff for a workup, we wouldn’t be giving natalizumab at all. But if a patient or family says, “I am worried,” then we need to work it up. Also, if there are clearcut new or worsening neurologic symptoms, we pursue a workup. Often, the change in symptoms is revealed when the patient comes in for his or her monthly infusion and the nurse asks the four questions from the preinfusion checklist (as part of the mandatory Tysabri Outreach: Unified Commitment to Health [TOUCH] prescribing program for natalizumab).¹¹

If there are new symptoms, we hold infusions and do a two-stage evaluation. The first stage is a brain MRI to evaluate for change from baseline (the US Food and Drug Administration requires a brain MRI at baseline before starting natalizumab therapy). Most patients undergo a brain MRI every 6 to 12 months while on natalizumab therapy, with instructions to the neuroradiologist to evaluate carefully for new lesions. In our institution, the PML MRI evaluation is a fine-toothcomb assessment of lesions from the most recent MRI compared with the current MRI. Depending on the results of the current MRI and on our level of suspicion, we may proceed to a spinal tap, even if the MRI findings are stable. We have done 8 to 10 spinal taps in patients taking natalizumab when we were suspicious enough to evaluate for PML. Occasional patients continue to have active disease, relapses, and new lesions even without developing antibodies while taking natalizumab.

Dr. Rudick: We need a quick, quantitative analysis method to compare one MRI with another. It is easy to say, “Consider PML if there are new lesions.” It’s not so easy to know if the lesions are new. We are participating in a National Institutes of Health study regarding identification of biomarkers of interferon’s effects, and the study requires obtaining MRI scans at baseline and 6 months. We have state-of-the-art subtraction MRI to quantify new lesions on the followup MRI. However, there is significant disagreement on the number of new lesions determined by clinical raters, and disagreement between the clinical raters and the numbers generated by the computer program.

Dr. Major: Is the incidence of natalizumab-related PML based on the number of months or on the number of infusions?

Dr. Fox: It is based on the number of infusions. You bring up a good point because these patients may interrupt treatment when they go on vacation, for example, or have a lapse in insurance coverage. Most patients follow the every-4-weeks protocol and receive 13 infusions in a year. Perhaps 10% to 15% do not follow it precisely.

Dr. Molloy: Is everyone who takes natalizumab being followed for PML even if they discontinue natalizumab? Have any differences emerged in the factors that predispose to PML among those who continue therapy compared with those who discontinue? I ask because I’m wondering why the incidence appears to stabilize, or even go down, after 36 infusions.

Dr. Fox: PML has not been reported beyond several months after stopping natalizumab; concern about PML can decrease fairly quickly after stopping the drug. Many of us expected the risk of PML to continue rising with cumulative treatment, so were pleasantly surprised to see a plateau in the risk of PML after about 36 months. We don’t understand what leads to this plateau.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection of the central nervous system (CNS). Although originally associated with broad-based immunosuppression (human immunodeficiency virus infection, lymphoproliferative disorders, and immunosuppressive medications), recognition of PML in patients with selective immunosuppression is growing. This restricted immunodeviation can arise from autoimmune disorders such as systemic lupus erythematosus, selective immunosuppressive therapies (eg, rituximab, leflunomide, and efalizumab), or immunosuppression limited to the CNS (eg, treatment with natalizumab).

This article reviews approaches to the management of PML, with specific recommendations regarding PML associated with natalizumab therapy.

APPROACH TO PML TREATMENT

The ideal approach to PML treatment is generally two-pronged: antiviral therapies to directly reduce viral replication and immune reconstitution that empowers the immune system to attack the JC virus (JCV). Challenges to treatment are the difficulty in culturing JCV for in vitro studies, lack of an animal model of PML, and infrequency of PML cases.

Antiviral therapies

At present, no antiviral agent has confirmed efficacy in PML. Nucleoside analogues, serotonin 5-hydroxytryptamine receptor antagonists (to block the JCV receptor), and several cytokines provided exciting prospects in preclinical studies for treatment of PML in humans. Unfortunately, subsequent clinical studies of cytarabine, cidofovir, and interferon alfa all yielded disappointing results. A derivative of cidofovir, CMX001, is also being evaluated for efficacy in PML. Mefloquine was identified through a broad pharmaceutical screening study to have strong antiviral effects in vitro, but a clinical trial to assess its effects was stopped. It remains unclear whether the failure of clinical studies after successful in vitro studies is secondary to low drug penetration into the CNS, treatment initiation too late in the course of PML, or other differences not yet fully understood.

Immune reconstitution

Given the widespread failure of antiviral regimens, the mainstay of PML treatment is immune reconstitution. When immunosuppression is secondary to a medical disorder, efforts are pursued to reverse the primary disorder. For example, highly active antiretroviral therapy significantly prolongs survival in antiretroviral-naïve acquired immunodeficiency syndrome patients.^1,2 Decreasing the intensity of immunosuppressive therapy in solid organ transplant may improve survival with PML. When PML is associated with biologic therapies for autoimmune diseases, early diagnosis and immediate suspension of therapy is thought to improve outcomes.

EXPERIENCE WITH NATALIZUMAB

PML in the setting of natalizumab therapy is related to cumulative exposure to natalizumab. As of August 4, 2011, there had been 150 cases of natalizumab-related PML documented in more than 88,000 patients exposed to natalizumab worldwide³ (see page S18, “Multiple sclerosis, natalizumab, and PML: Helping patients decide”). The incidence of PML in natalizumab-treated patients varies according to the number of infusions received, but the incidence of PML by each epoch of treatment exposure (1 to 24 infusions, 25 to 36 infusions, 37 to 48 infusions) appears to have remained stable over time.³

The mortality associated with natalizumab-related PML was 19% (29 deaths among the 150 confirmed cases) as of August 4, 2011.³ In cases with at least 6 months of follow-up, mortality has remained at about 20%. Many who survived were left with serious morbidity and permanent disability, although interpretation of disability is difficult because functional impairment is a hallmark of multiple sclerosis (MS) irrespective of PML. Survival in patients with natalizumab-associated PML appears to be better than with PML associated with other conditions, possibly because of early diagnosis achieved through clinical vigilance and swift immune reconstitution through natalizumab discontinuation and either plasmapheresis or immunoabsorption. Predictors of survival include younger age at diagnosis, less disability prior to onset of PML, more localized disease on magnetic resonance imaging (MRI) of the brain, and shorter time from symptom onset to PML diagnosis.

Clinical characteristics of natalizumab-associated PML

Several clinical observations should increase suspicion of natalizumab-associated PML.^3–5 For example, the most common presenting symptoms are cognitive, motor, language, and visual impairment. Gadolinium-enhancing lesions are observed at presentation in about one-half of patients. Seizures and paroxysmal events can occur at presentation, which helps to differentiate PML from an MS relapse.

Approximately one-half of patients with natalizumab-associated PML have an initial viral load of less than 500 copies/mL, underscoring the need for ultrasensitive polymerase chain reaction (PCR) testing. An ultrasensitive JCV assay (Focus Diagnostics, Cypress, California) is available that can detect less than 50 copies/mL of JCV DNA. Because the viral copy numbers in the cerebrospinal fluid (CSF) may be low in patients treated with natalizumab, the CSF PCR may be falsely negative. In several cases of PML, JCV was undetectable in the CSF by PCR, identified only later by repeat PCR or brain biopsy.⁴ Serum JCV PCR is not useful in the screening or diagnosis of PML.

Natalizumab-associated PML has not been observed with therapy of 6 months’ or less duration. After 6 months of natalizumab therapy, new MRI lesions are rare in patients who are negative for neutralizing antibodies. A new MRI lesion in such a patient should be considered suspicious for PML. Our standard protocol is to check for neutralizing antibodies at 6 months in all patients treated with natalizumab. Symptoms of PML develop in affected patients whose duration of therapy ranges from 6 to 81 infusions. Symptoms often develop well before PML is diagnosed.^4,5

Forty-six percent of patients treated with natalizumab who develop PML have received previous autologous bone marrow transplantation or chemo therapy, including mitoxantrone, azathioprine, methotrexate, and mycophenolate mofetil. In comparison, up to 25% of MS patients who were treated with natalizumab (13% in the United States, 24% in Europe) have had prior chemotherapy treatment. Prior immunosuppressive therapy increases the risk of PML by two- to fourfold, which may explain the higher rate of PML in Europe compared with that of the United States.^4,5

Testing for immune response to JCV

A JCV enzyme-linked immunosorbent assay (ELISA) test has been developed that identifies patients with an immune response to JCV. Among MS patients, 55% test positive for JCV through this assay.⁶ The false-negative rate of the test is 5%, and the overall annual seroconversion rate is estimated to be about 2%, necessitating repeat testing.

Based on results of this assay, the estimated risk of PML in seropositive patients is about 1 in 500.⁶ The test was positive in 28 of 28 patients who developed PML. The probability of this relationship occurring by chance is 0.5528, which suggests that this assay is useful to stratify risk for development of PML. Although the rate of false negatives makes the test an imperfect predictor, it is still useful in clinical practice. The test became available clinically in late summer 2011. Further longitudinal observation studies (STRATIFY-1 and STRATIFY-2) on the use of the JCV ELISA to detect anti-JCV antibodies in the blood of natalizumab-treated patients with MS are under way.

Stratifying risk for natalizumab-related PML

The possibility of reducing the risk of PML in natalizumab-treated patients through natalizumab holidays is attractive. When exploring this option, one must consider whether the risk of recurrent disease activity with treatment interruption outweighs the potentially decreased risk of PML.⁸ A randomized controlled multicenter clinical trial of natalizumab interruption is ongoing, with the recruitment phase complete after enrollment of 175 patients. Patients taking natalizumab at study entry have been randomized to one of three arms: continuation of monthly natalizumab for 6 months, placebo for 6 months, or an alternate treatment (interferon beta-1a, glatiramer acetate, or monthly intravenous steroids) for 6 months administered open-label by clinician and patient choice.

The primary outcome measures are markers of immune function and overall disease activity during treatment interruption and after resumption. Patients are monitored monthly using MRI to measure disease activity. Those who experience relapse will have the option of returning to natalizumab therapy or switching to an alternate treatment. The results of this prospective, randomized, controlled trial will provide a greater understanding of the safety issues surrounding natalizumab holidays.

Management of natalizumab-related PML

Management of patients taking natalizumab starts with risk stratification in an attempt to prevent the development of PML. If suspicion for PML is raised based on symptoms, early diagnosis can be accomplished through the use of a sensitive JCV PCR assay, with a repeat PCR if negative. Natalizumab treatment should be withheld during the workup for PML.

Reprinted, with permission, from Neurology (Khatri BO, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009; 72:402–409).

When immunosuppression is rapidly reversed in cases of natalizumab-associated PML, an overly exuberant immune response targeting JCV in the CNS is observed 2 to 6 weeks later. The response, termed immune reconstitution inflammatory syndrome (IRIS), is not always easy to differentiate from progression of PML. Nonetheless, most clinicians recommend high-dose corticosteroids if a clinical and imaging syndrome resembling IRIS develops several weeks after immune restoration.¹⁰ The objective is to achieve the immune reconstitution needed to control JCV infection while limiting the collateral damage of inflammation on the remaining brain tissue.

SUMMARY

Risk factors for natalizumab-associated PML include duration of treatment with natalizumab, previous chemotherapy, and JCV antibody serology. Early diagnosis requires the use of an ultrasensitive JCV PCR assay. Treatment is focused on early diagnosis, immediate cessation of pharmacologic causes of immunosuppression, and active efforts to accelerate immune restoration.

DISCUSSION

Dr. Calabrese: What are your thoughts about plasmapheresis for rituximab-related cases of PML?

Dr. Fox: It’s probably not going to be as helpful as with natalizumab. Rituximab has pharmacokinetics that are similar to those of other monoclonal antibodies, with a half-life in the range of 14 to 20 days. So it’s pretty much absent from the body within 1 to 2 months of infusion. The enduring benefit from rituximab comes not from the persistent presence of the monoclonal antibody, but the persistent absence of CD19 B cells. Plasmapheresis is unlikely to be effective because it won’t accelerate return of CD19 B cells to the peripheral circulation. In rituximab-related PML, stimulating the bone marrow to produce more B cells in order to restore the immune system is more likely to be effective. In contrast, I did recommend plasma pheresis in a case of efalizumab-related PML. Because efalizumab is a binding antibody to the CD11a receptor, we wanted to accelerate its removal.

Dr. Molloy: In an MS patient who responds well to natalizumab, do you ever explore a strategy of dose reduction or extending the dosing interval of natalizumab?

Dr. Fox: Let me put that into a clinical context. A 35-year old man has had relapsing-remitting MS for 3 years. Two years ago, after disease activity occurred while he was using an injectable therapy, he started natalizumab and has been clinically and radiologically stable on natalizumab. Then, he gets the JCV assay, it’s positive, and he asks if it’s time to get off natalizumab “because of the risk of that brain virus.”

What do I tell him? Should I change the dosing interval? At this point, we are not doing either. One reason is the unpredictable pharmacokinetics of the drug. The dose and dosing regimen were chosen to have 85% or greater receptor saturation in 95% or more of patients over the course of the recommended 4-week dosing interval. If you increase the interval to 6 weeks or 8 weeks, you can’t predict in individual patients whether or not meaningful desaturation occurs and thus allows some immune cells to enter the brain to protect against PML (but not too many, or MS disease activity will return).

Dr. Simpson: Do you have an algorithm for working up patients?

Dr. Fox: It depends on the level of suspicion given the patient’s symptoms. It’s difficult to find a single MS patient who does not have some fluctuation of symptoms over time and some worsening of symptoms such as stiffness, fatigue, and cognitive difficulties. They all have changes in mood, so if one took any symptom change—any change in their report of mood and cognition— as the cutoff for a workup, we wouldn’t be giving natalizumab at all. But if a patient or family says, “I am worried,” then we need to work it up. Also, if there are clearcut new or worsening neurologic symptoms, we pursue a workup. Often, the change in symptoms is revealed when the patient comes in for his or her monthly infusion and the nurse asks the four questions from the preinfusion checklist (as part of the mandatory Tysabri Outreach: Unified Commitment to Health [TOUCH] prescribing program for natalizumab).¹¹

If there are new symptoms, we hold infusions and do a two-stage evaluation. The first stage is a brain MRI to evaluate for change from baseline (the US Food and Drug Administration requires a brain MRI at baseline before starting natalizumab therapy). Most patients undergo a brain MRI every 6 to 12 months while on natalizumab therapy, with instructions to the neuroradiologist to evaluate carefully for new lesions. In our institution, the PML MRI evaluation is a fine-toothcomb assessment of lesions from the most recent MRI compared with the current MRI. Depending on the results of the current MRI and on our level of suspicion, we may proceed to a spinal tap, even if the MRI findings are stable. We have done 8 to 10 spinal taps in patients taking natalizumab when we were suspicious enough to evaluate for PML. Occasional patients continue to have active disease, relapses, and new lesions even without developing antibodies while taking natalizumab.

Dr. Rudick: We need a quick, quantitative analysis method to compare one MRI with another. It is easy to say, “Consider PML if there are new lesions.” It’s not so easy to know if the lesions are new. We are participating in a National Institutes of Health study regarding identification of biomarkers of interferon’s effects, and the study requires obtaining MRI scans at baseline and 6 months. We have state-of-the-art subtraction MRI to quantify new lesions on the followup MRI. However, there is significant disagreement on the number of new lesions determined by clinical raters, and disagreement between the clinical raters and the numbers generated by the computer program.

Dr. Major: Is the incidence of natalizumab-related PML based on the number of months or on the number of infusions?

Dr. Fox: It is based on the number of infusions. You bring up a good point because these patients may interrupt treatment when they go on vacation, for example, or have a lapse in insurance coverage. Most patients follow the every-4-weeks protocol and receive 13 infusions in a year. Perhaps 10% to 15% do not follow it precisely.

Dr. Molloy: Is everyone who takes natalizumab being followed for PML even if they discontinue natalizumab? Have any differences emerged in the factors that predispose to PML among those who continue therapy compared with those who discontinue? I ask because I’m wondering why the incidence appears to stabilize, or even go down, after 36 infusions.

Dr. Fox: PML has not been reported beyond several months after stopping natalizumab; concern about PML can decrease fairly quickly after stopping the drug. Many of us expected the risk of PML to continue rising with cumulative treatment, so were pleasantly surprised to see a plateau in the risk of PML after about 36 months. We don’t understand what leads to this plateau.

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. In the United States alone, it is believed that approximately 27 million people are affected by this degenerative condition. Many factors are known to increase the risk of developing OA, including heredity, obesity, joint or nerve injury, repeated overuse of certain joints, lack of physical activity, and aging. Treatment for OA needs to be individualized according to the stage of the disease, patient tolerability, comorbidities involved, and response to therapies to meet the goals of reducing pain, improving joint mobility and quality of life, and limiting functional impairment while avoiding drug toxicity. This supplement will review the latest advances in the pathogenesis, underlying phenotypes, and current therapeutic options of OA.
Click here to read Supplement.

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. In the United States alone, it is believed that approximately 27 million people are affected by this degenerative condition. Many factors are known to increase the risk of developing OA, including heredity, obesity, joint or nerve injury, repeated overuse of certain joints, lack of physical activity, and aging. Treatment for OA needs to be individualized according to the stage of the disease, patient tolerability, comorbidities involved, and response to therapies to meet the goals of reducing pain, improving joint mobility and quality of life, and limiting functional impairment while avoiding drug toxicity. This supplement will review the latest advances in the pathogenesis, underlying phenotypes, and current therapeutic options of OA.
Click here to read Supplement.

Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide. In the United States alone, it is believed that approximately 27 million people are affected by this degenerative condition. Many factors are known to increase the risk of developing OA, including heredity, obesity, joint or nerve injury, repeated overuse of certain joints, lack of physical activity, and aging. Treatment for OA needs to be individualized according to the stage of the disease, patient tolerability, comorbidities involved, and response to therapies to meet the goals of reducing pain, improving joint mobility and quality of life, and limiting functional impairment while avoiding drug toxicity. This supplement will review the latest advances in the pathogenesis, underlying phenotypes, and current therapeutic options of OA.
Click here to read Supplement.

Researchers have developed a new process for manufacturing ultra-low molecular weight heparin, and they believe it’s superior to current methods.

In addition to reducing the potential for contamination, this process produced 2 structurally homogeneous ultra-low molecular weight heparins that were identical in performance and safety to fondaparinux. But these heparins were purer, faster, and less expensive to produce.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in New York, and his colleagues reported their discovery in the October 28 edition of Science.

“With this discovery, we have successfully demonstrated that replacing the current model of drug production with a chemoenzymatic approach can greatly reduce the cost of drug development and manufacturing, while also increasing drug performance and safety . . . ,” Dr Linhardt said.

These heparins—like fondaparinux—were chemically synthesized from non-animal materials. So the risk of contamination is reduced, when compared to the risk with traditional heparin production.

In addition, the new production process is superior to that used with fondaparinux, the researchers said. The new process requires 10 to 12 steps, whereas fondaparinux production requires roughly 50.

The investigators were also able to increase the heparin yield 500-fold with the new process. They said it could decrease the cost of manufacture by a similar amount.

And the ultra-low molecular weight heparins proved to be as effective as fondaparinux in rabbit models.

“[W]e were able to quickly build multiple doses in a simple laboratory setting and feel that this is something than can be quickly and easy commercialized to reduce the cost of this drug and help to shift how pharmaceutical companies approach the synthesis of carbohydrate-containing drugs,” Dr Linhardt said.

These findings are part of a larger body of work in the Linhardt lab to completely replace all types of heparin-based or other glycoprotein-based drugs with safer, low-cost, synthetic versions that do not rely on foreign, potentially contaminated animal sources.

Researchers have developed a new process for manufacturing ultra-low molecular weight heparin, and they believe it’s superior to current methods.

In addition to reducing the potential for contamination, this process produced 2 structurally homogeneous ultra-low molecular weight heparins that were identical in performance and safety to fondaparinux. But these heparins were purer, faster, and less expensive to produce.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in New York, and his colleagues reported their discovery in the October 28 edition of Science.

“With this discovery, we have successfully demonstrated that replacing the current model of drug production with a chemoenzymatic approach can greatly reduce the cost of drug development and manufacturing, while also increasing drug performance and safety . . . ,” Dr Linhardt said.

These heparins—like fondaparinux—were chemically synthesized from non-animal materials. So the risk of contamination is reduced, when compared to the risk with traditional heparin production.

In addition, the new production process is superior to that used with fondaparinux, the researchers said. The new process requires 10 to 12 steps, whereas fondaparinux production requires roughly 50.

The investigators were also able to increase the heparin yield 500-fold with the new process. They said it could decrease the cost of manufacture by a similar amount.

And the ultra-low molecular weight heparins proved to be as effective as fondaparinux in rabbit models.

“[W]e were able to quickly build multiple doses in a simple laboratory setting and feel that this is something than can be quickly and easy commercialized to reduce the cost of this drug and help to shift how pharmaceutical companies approach the synthesis of carbohydrate-containing drugs,” Dr Linhardt said.

These findings are part of a larger body of work in the Linhardt lab to completely replace all types of heparin-based or other glycoprotein-based drugs with safer, low-cost, synthetic versions that do not rely on foreign, potentially contaminated animal sources.

Researchers have developed a new process for manufacturing ultra-low molecular weight heparin, and they believe it’s superior to current methods.

In addition to reducing the potential for contamination, this process produced 2 structurally homogeneous ultra-low molecular weight heparins that were identical in performance and safety to fondaparinux. But these heparins were purer, faster, and less expensive to produce.

Robert Linhardt, PhD, of Rensselaer Polytechnic Institute in New York, and his colleagues reported their discovery in the October 28 edition of Science.

“With this discovery, we have successfully demonstrated that replacing the current model of drug production with a chemoenzymatic approach can greatly reduce the cost of drug development and manufacturing, while also increasing drug performance and safety . . . ,” Dr Linhardt said.

These heparins—like fondaparinux—were chemically synthesized from non-animal materials. So the risk of contamination is reduced, when compared to the risk with traditional heparin production.

In addition, the new production process is superior to that used with fondaparinux, the researchers said. The new process requires 10 to 12 steps, whereas fondaparinux production requires roughly 50.

The investigators were also able to increase the heparin yield 500-fold with the new process. They said it could decrease the cost of manufacture by a similar amount.

And the ultra-low molecular weight heparins proved to be as effective as fondaparinux in rabbit models.

“[W]e were able to quickly build multiple doses in a simple laboratory setting and feel that this is something than can be quickly and easy commercialized to reduce the cost of this drug and help to shift how pharmaceutical companies approach the synthesis of carbohydrate-containing drugs,” Dr Linhardt said.

These findings are part of a larger body of work in the Linhardt lab to completely replace all types of heparin-based or other glycoprotein-based drugs with safer, low-cost, synthetic versions that do not rely on foreign, potentially contaminated animal sources.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

To the Editor: I read with interest the article by Drs. Callahan and Baranowski¹ in your April 2011 issue about managing newly diagnosed atrial fibrillation. I believe several issues merit further discussion.

First of all, as mentioned in the article, pulmonary vein isolation, or radiofrequency catheter ablation of the left atrium, can cure paroxysmal atrial fibrillation. Callahan and Baranowski described the optimal indication for this procedure, but they failed to mention the potential adverse effects, that is, esophageal ulcer and atrio-esophageal fistula.² Owing to the proximity of the esophagus and the accompanying vagus nerve to the posterior wall of the left atrium, it is estimated that 47% of patients develop thermal mucosal injury and 18% develop esophageal ulcer after ablation, while 0.5% develop atrio-esophageal fistula.³ Gastric hypomotility and pyloric spasm are reported as well. It would therefore be prudent to inform patients of such risks if a persistently symptomatic young patient demands this procedure, since the damage might be long-lasting.

In addition, in deciding on long-term anticoagulation for patients with atrial fibrillation, the CHADS₂ score is often utilized (1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack). Although it is validated and widely applicable, the CHADS₂ score carries the disadvantages of oversimplification and of overclassifying atrial fibrillation patients into the intermediate-risk category.⁴ Lip et al,⁵ in a seminal article surveying a large group of patients who had nonvalvular atrial fibrillation, proposed using a new and also simple risk stratification scheme, the 2009 Birmingham scheme. This scheme uses the acronym CHA₂DS₂-VASc and differs from the CHADS₂ score in that patients age 75 or older get 2 points, those age 65 to 74 get 1 point, those with vascular disease get 1 point, and women get 1 point. They show that this new scheme fares marginally better than the original CHADS₂ score, with fewer patients wrongly assigned to the intermediate-risk category. That means a lower percentage of patients will receive unnecessary anticoagulation and suffer from unneeded anguish. Subsequent studies also prove that this newer scoring index possesses higher sensitivity and predicts thromboembolic events more accurately than the CHADS₂ score. Thus, I believe this should also be factored into the decision process when initiating warfarin in atrial fibrillation patients, especially in light of the fact that scanty evidence exists for the use of newer anticoagulants based on the CHADS₂ score.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

In Reply: Dr. Chao raises several important points regarding our manuscript on the management of newly diagnosed atrial fibrillation.¹

Dr. Chao mentions some of the complications of pulmonary vein antrum isolation. A review of catheter ablation for atrial fibrillation was outside the scope of our manuscript, so the details of the procedure and potential complications were not covered. Dr. Chao does mention some of the important potential complications. However, the complication rates he cites are not generally supported by the available medical literature. Thermal mucosal injury of the esophagus was reported at rates as low as 4% in the same studies cited by Dr. Chao in patients undergoing pulmonary vein antrum isolation with conscious sedation. The rate of 47% was seen in patients undergoing the procedure with general anesthesia. The rate of atrio-esophageal fistula is not well known. As of 2010, about 49 cases were reported in the literature.² Rates have been described ranging from 0.01% to 0.2%,^3–9 far lower than the rate mentioned by Dr. Chao. A careful review with the patient of the risks, benefits, and alternatives is standard practice before any elective, invasive procedure.

Multiple anticoagulation schemes have been proposed, including the Birmingham 2009 scheme.¹⁰ We included the CHADS₂ score in our paper because it is widely accepted and well validated. The Birmingham 2009 scheme acknowledges other potential risk factors such as female sex, history of vascular disease, and age between 65 and 75 years. It will be interesting to see if it will ever supplant the CHADS₂ score. However, no risk stratification scheme should replace sound clinical judgment. Individual patient factors must be considered when deciding whether anticoagulation is appropriate for an individual patient.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.

To the Editor: The interesting report by Korniyenko and colleagues of the delayed diagnosis of visceral angioedema due to angiotensin-converting enzyme (ACE) inhibitor therapy¹ should alert readers that a long duration of use of ACE inhibitors should not rule out the diagnosis of ACE inhibitor-induced angioedema, as symptoms can be delayed for up to a decade.

Risk factors for angioedema for patients on ACE inhibitor therapy that have been identified so far include black race, the XPNPEP2 C-2399A polymorphism in men (which leads to decreased aminopeptidase P activity),² and concomitant use of the mTOR inhibitors sirolimus (Rapamune) or everolimus (Afinitor) in renal transplant recipients.³ All of these factors further decrease metabolism of the vasoactive peptide bradykinin. However, the effect of cofactors such as use of nonsteroidal anti-inflammatory drugs, aspirin, simvastatin, estrogen, or a tendency for angioedema (such as in patients with recurrent or episodic idiopathic angioedema) on lowering the threshold for angioedema or increasing the severity of the angioedema episode or episodes after starting ACE inhibitor therapy remains unknown.

Physicians should also be aware of angioedema as a significant side effect of the new renin inhibitor aliskiren (marketed by Novartis Pharmaceuticals as Rasilez in the United Kingdom and as Tekturna in the United States) for treatment of essential hypertension.⁴ A pooled analysis of 31 studies in 12,188 patients showed the incidence of angioedema associated with aliskiren monotherapy to be 0.4%, similar to that with ACE inhibitors: relative risk 0.31, 95% confidence interval 0.07–1.47 for 150 mg; relative risk 0.57, 95% confidence interval 0.17–1.89 for 300 mg).⁵ However, no patients were hospitalized with a serious angioedema event.

Although the mechanism of action of aliskiren via renin inhibition would suggest that bradykinin may not be the causative agent of angioedema, physicians should ensure that patients who report significant angioedema episodes or those who present with angioedema have their medication history thoroughly reviewed to prevent a serious untoward event.

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4

In Reply: We agree with Dr. Khan that the duration of ACE inhibitor therapy should never be used to rule out ACE inhibitor-associated angioedema. In an Italian study of 85 cases of angioedema with ACE inhibitor therapy, the mean ACE inhibitor exposure was a full 12 months before angioedema was diagnosed.¹ More disturbing was the fact that another 12 months elapsed before the ACE inhibitor actually was discontinued. This would indicate that neither the patient nor the physician related the angioedema to ACE inhibitor therapy. In patients with visceral angioedema, since the diagnosis is unusually challenging, even a further delay can be expected.

Angioedema has been reported with aliskiren, but the 0.04% incidence reported by White et al² may reflect very simply that physicians are more alert and on the lookout now more than they ever were when ACE inhibitors were first available. Obviously, greater awareness will lead to more frequent diagnosis. As Dr. Khan points out, there is no known mechanism by which aliskiren should cause angioedema, whereas there is fairly solid evidence that ACE inhibitor-associated angioedema is mediated by bradykinin.^3,4