Risk Factors For Progressive Multifocal Leukoencephalopathy Research Articles

Progressive Multifocal Leukoencephalopathy Associated with Sphingosine-1-Phosphate Receptor Modulators: A Large Case Series

Risk factors for progressive multifocal leukoencephalopathy (PML) associated with sphingosine-1-phosphate receptor (S1PR) modulators are not as well-characterized as for natalizumab. We characterized S1PR modulator-associated PML cases and risk factors for PML using spontaneous adverse event reports. We reviewed case reports from the FDA Adverse Event Reporting System database and the medical literature. We identified 57 PML cases encompassing all marketed S1PR modulators approved for multiple sclerosis, the majority (n = 53) associated with fingolimod. Ten cases reported a fatal outcome. Length of S1PR modulator exposure (≥18 months) appears to be a robust risk factor for PML. Patient age ≥50 years was identified as a potential risk factor, although this may be the result of several biases. We propose that prior immunosuppressant exposure should be considered as a potential risk factor for further validation. No conclusions could be drawn regarding JC virus serology and lymphopenia severity. Spontaneous adverse event reports support the observation that extended S1PR modulator exposure appears to be a robust PML risk factor. As a result, the U.S. Prescribing Information for each product in the S1PR modulator class was updated. Validation of other potential risk factors would support efforts to stratify and mitigate the risk of S1PR modulator-associated PML.

Progressive multifocal leukoencephalopathy in patients with immunovirological control and at least 6 months of combination antiretroviral therapy.

: Progressive multifocal leukoencephalopathy (PML) has rarely been reported in people with HIV (PWH) with long-term HIV immune-virological control. We describe the clinical and biological characteristics of patients with confirmed PML among PWH with a CD4+ cell count more than 200 cells/μl and an undetectable HIV RNA viral load after at least 6 months of combined antiretroviral therapy (cART) at the time of PML diagnosis, in the large French multicenter Dat'AIDS cohort. : Among 571 diagnoses of PML reported in the Dat'AIDS cohort between 2000 and 2019, 10 cases (1.75%) occurred in PWH with a CD4+ cell count greater than 200 cells/μl and an undetectable HIV RNA viral load after at least 6 months of cART. Median CD4+ cell count at PML diagnosis was 395 cells/μl (IQR 310-477). The median duration between the last detectable HIV viral load and the PML diagnosis was 41.1 months (IQR 8.2-67.4). Only one patient treated with rituximab-based chemotherapy for a large B-cell lymphoma had an established risk factor for PML. Among the nine other patients with no apparent severe immunodeficiency, multiple factors of impaired immunity could have led to the development of PML: hepatitis C virus (HCV) co-infection (n = 6), cirrhosis (n = 4), HHV-8 co-infection (n = 3) with Kaposi's sarcoma (n = 2) in association with Castleman's disease (n = 1) and indolent IgA multiple myeloma (n = 1). : This study highlights that factors other than low CD4+ cell count and high HIV viral load may be associated with the occurrence of PML. Further studies are warranted to investigate in greater detail the immunologic characteristics of PWH with immune-virological control who develop PML.

T cell insufficiency enables emergence of polyomavirus antibody escape variants

Abstract Deficient adaptive immunity underlies CNS diseases caused by JC polyomavirus (JCPyV), a ubiquitous member of the human virome. The best characterized of these is progressive multifocal leukoencephalopathy (PML), a frequently fatal brain demyelinating disease. Risk factors for PML are poorly defined but mainly involve conditions of T cell insufficiency or dysfunction, including AIDS and particular immunomodulatory therapies (natalizumab, rituximab). JCPyV isolates from PML patients’ brains frequently contain point mutations in the major capsid protein, VP1. However, these variants are not present in the patients’ kidneys, the major site of JCPyV persistence. How/if these mutations confer neurovirulence is actively debated. Mapping a common JCPyV-PML VP1 mutation into mouse polyomavirus (MuPyV), we found that this variant virus was resistant to a neutralizing monoclonal antibody (mAb) and poorly replicated in the kidney. Cryo EM analysis unambiguously defined the antibody epitope and identified the mechanism of antibody escape. Passaging MuPyV in the presence of VP1 mAb allowed emergence of antibody escape variants in vitro. To investigate the connection between T cell impairment and antibody escape in vivo, we infected antibody-deficient μMT mice with MuPyV, treated them with VP1 mAb, then subjected them to CD4 and CD8 antibody-mediated T cell depletion during persistent infection. In contrast to non-T cell depleted mice, which maintained long term control over MuPyV infection, T cell depletion led to lethal MuPyV disease resulting from the outgrowth of antibody-escape variants. These data show that a narrow PyV antibody response compounded by T cell insufficiency promotes emergence of nAb escape neurotropic variants.

The Progressive Multifocal Leukoencephalopathy Consortium as a Model for Advancing Research and Dialogue on Rare Severe Adverse Drug Reactions.

Progressive multifocal leukoencephalopathy (PML) is a rare but serious disease. Caused by the JC virus (JCV), it occurs in individuals with weakened immune systems and is a potential adverse reaction for certain immunomodulatory drugs. The PML Consortium was created to find better methods to predict, prevent, and treat PML. The Consortium brought together the pharmaceutical industry with academic, regulatory, and patient communities to advance research and dialogue on PML through a not-for-profit, collaborative approach involving a grant program, scientific workshops and conferences, and disease awareness efforts. Over nearly a decade, the Consortium contributed to the PML and JCV fields by advancing research, scientific exchange, and awareness of PML. In addition to advancing knowledge and helping to build cross-sector consensus on research priorities, the Consortium’s grant program filled a funding gap and brought new investigators into PML and JCV research. Additionally, the Consortium’s workshops and conferences created platforms for exchange that drove dialogue on knowledge gaps and future research directions. The Consortium also contributed to the scientific knowledge base with two literature reviews, one on PML treatment studies and a second on T cell deficiencies as a risk factor for PML and the brain as a site for conversion of harmless JCV into a pathogenic virus. Finally, the Consortium addressed a significant information gap with its disease awareness website for healthcare professionals, patients, and caregivers. Beyond its impact on the PML and JCV fields, the PML Consortium is important because it provides a precedent for how the pharmaceutical industry, academic researchers, patient organizations, and government can work together to address rare diseases, in particular rare adverse events. This kind of collaboration could be replicated to speed progress in addressing other rare diseases and adverse events, with significant potential benefits for the scientific, medical, and patient communities.FundingPML Consortium (PML Consortium, Washington, DC).

Diagnosis and Treatment of Progressive Multifocal Leukoencephalopathy Associated with Multiple Sclerosis Therapies.

Progressive multifocal leukoencephalopathy (PML) is a rare, but serious, complication encountered in patients treated with a select number of disease-modifying therapies (DMTs) utilized in treating multiple sclerosis (MS). PML results from a viral infection in the brain for which the only demonstrated effective therapy is restoring the perturbed immune system-typically achieved in the patient with MS by removing the offending therapeutic agent or, in the case of HIV-associated PML, treatment with highly active antiretroviral therapies. Other therapies for PML remain either ineffective or experimental. Significant work to understand the virus and host interaction has been undertaken, but lack of an animal model for the disorder has significantly hindered progress, especially with respect to development of treatments. Strategies to limit risk of PML with natalizumab, a drug that carries a uniquely high risk for the development of the disorder, have been developed. Identifying factors such as positive JC virus antibody status that increase PML risk, at least in theory, should decrease the incidence rate of the disease. Whether other risk factors for PML can be identified and validated or unique strategies should be employed in association with other DMTs that predispose to PML and whether this has a salutary effect on outcome remains to be demonstrated. Identifying PML early, then promptly eliminating drug in the case of natalizumab-associated PML has demonstrated better outcomes, but the complication of PML continues to carry significant morbidity and mortality. While the scientific community has yet to identify targeted therapy with proven efficacy against JCV or PML there are several candidates being studied.

The role of natalizumab in the treatment of multiple sclerosis: benefits and risks.

Natalizumab, a monoclonal antibody that blocks lymphocyte infiltration in the central nervous system, is a valuable tool in the treatment of relapsing forms of multiple sclerosis (MS). In a phase III clinical trial comparing natalizumab with placebo over 2 years, natalizumab reduced annualized relapse rate by 68%, 12-week confirmed disability progression by 42%, and reduced contrast-enhancing lesions by 92%. In post hoc analyses, natalizumab treatment was associated with 37% of patients achieving no evidence of disease activity (versus 7% on placebo) and 30% achieving sustained disability improvement (versus 19% on placebo). Natalizumab did not achieve a statistically significant primary composite disability outcome in a trial of 887 patients with secondary progressive MS, but it did demonstrate a benefit on a prespecified component of the 9-Hole Peg Test. The greatest risk of natalizumab treatment is progressive multifocal leukoencephalopathy (PML), with a 23% mortality rate. Risk stratification on the basis of immunosuppressant exposure, natalizumab treatment duration and anti-John Cunningham virus (JCV) antibody status and index has greatly improved clinical decision making. Other potential serious natalizumab-associated risks reported in clinical trials and postmarketing settings include infusion reactions, hepatotoxicity and rare, serious opportunistic infections. With more than a decade of continuous postmarketing experience, natalizumab remains a very effective option for patients with relapsing forms of MS. To optimize appropriate selection of natalizumab for patients with relapsing MS, however, a thorough understanding of individual patient risk factors for PML or other adverse events is also required.

The use of natalizumab for multiple sclerosis.

Natalizumab is a monoclonal antibody that acts as an α4 integrin antagonist to prevent leukocyte trafficking into the central nervous system. It is US Food and Drug Administration (FDA) approved for the treatment of relapsing–remitting multiple sclerosis (RRMS). Natalizumab demonstrated high efficacy in Phase III trials by reducing the annualized relapse rate, preventing multiple sclerosis (MS) lesion accumulation on magnetic resonance imaging, and decreasing the probability of sustained progression of disability. The leading safety concern with natalizumab is its association with progressive multifocal leukoencephalopathy (PML), a rare brain infection typically seen only in severely immunocompromised patients caused by reactivation of the John Cunningham virus (JCV). Careful analysis of risk factors for PML in natalizumab-treated MS patients, specifi-cally the presence of anti-JCV antibodies, has led to risk mitigation strategies to improve safety. Additional biomarkers are under investigation to further aid risk stratification. Natalizumab’s high efficacy and favorable tolerability profile have led to a broad use by MS physicians, as both first-and second-line treatments. This review discusses the natalizumab efficacy, safety, and tolerability and finishes with pragmatic considerations regarding its use in clinical practice.

A link between long-term natalizumab dosing in MS and PML: Putting the puzzle together.

When an infectious serious adverse event is linked with a therapy for an underlying disease, it usually is seen in a few weeks or months, not years. This is not the case with the effective monoclonal antibody therapy for patients with multiple sclerosis (MS) natalizumab (Tysabri), the α4 integrin inhibitor preventing inflammatory T cells entering the brain. The infectious adverse event in patients with MS is another demyelinating disease, progressive multifocal leukoencephalopathy (PML), caused by lytic infection of oligodendrocytes with JC virus (JCV), a ubiquitous agent in the population. Although cases of PML are seen in patients with MS after receiving as few as 7 monthly doses, the highest incidence of PML, 1/75 or higher,1 occurs after 24 monthly doses. Other risk factors for PML in these patients implicate prior exposure to JCV infection evidenced by presence of antiviral antibody as well as previous immunosuppressive treatments.2

First Estimates of Incidence of Progressive Multifocal Leukoencephalopathy Developing Among 10,459 Non-HIV Lymphoma VA Patients Who Receive Rituximab: Results From the Veterans Administration Database (1999–2012).

AbstractAbstract 2752 Introduction:Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease that is the result of activation of a highly prevalent dormant JC virus during immunosuppressed states such as advanced HIV, malignancy or immune-modulating medications. Rituximab, an immunomodulator, has been approved for both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). We previously reported 57-non-HIV patients developed PML after rituximab (1). This report identified the need for epidemiological cohort studies to further evaluate incidence rates and risk factors for PML by comparing Rituximab treated patients with suitable non-treated patients. Of note, natilzumab-associated PML is now well-characterized, with a reported incidence of 21 PML cases per 10,000 natilizumab-treated persons (2). Methods:In this first such epidemiological study we identified from the national data of the Department of Veteran's Affairs (VA), 61,132 patients with a primary International Classification of Diseases version 9 (ICD-9) code for either HL or NHL between 1999 to 2011 and reported the use of Rituximab among patients with and without PML. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure (VINCI) after obtaining approvals from the VA Institutional Review Board and other oversight groups. Results:We identified 62,642 with a primary diagnosis of HL or NHL and excluded 1,510 (2.4%) patients with VA lab confirmed HIV. Our final cohort had 61,132 patients, 10,459 (17.1%) received Rituximab. A total of 12 (0.020%) patients had developed PML, 5 (0.008%) belonged to the Rituximab group and 7 (0.011%) to non-rituximab group; which results in a statistically significant unadjusted relative risk of 3.46 (95% confidence interval 1.1, 10.9).Univariate analyses of outcomes other than rate-estimates are not statistically significant between PML patients who received rituximab and those that did not receive rituximab, primarily due to extremely small sample sizes (5 and 7 patients, respectively) (Table 1). Overall, compared to non-rituximab PML patients, rituximab PML patients were younger at PML diagnosis and age of death by more than 6-years; although they did appear to live slightly longer post PML diagnosis by about 4-months.Table 1:Descriptive and outcome characteristics of 12 PML patients with either NHL or HL in the VA medical systemPML Patients without Rituximab (n=7)PML Patients with Rituximab (n=5)Male (%)6 (85.7)5 (100)Died (%)7 (100)4 (80)Mean age at death (sd)68.3 years (6.6)62.0 years (4.3)Mean age at PML diagnosis (sd)67.9 years (6.2)63.2 years (5.4)Mean time to death from lymphoma diagnosis (sd)26.7 months (26.6)31.2 months (15.9)Mean time to death from PML diagnosis (sd)4.9 months (8.8)8.4 months (9.7)Mean time to PML diagnosis from lymphoma diagnosis (sd)21.8 months (28.6)37.6 months (31.3)Mean time to PML diagnosis from first rituximab dose (sd)N/A29.1 months (30.2)•sd – standard deviation Conclusions:These results show that among lymphoma patients, the use of Rituximab is associated with a statistically significant relative risk for documented PML of 3.46. We now report a baseline rate among Veterans of 4.78 PML cases per 10,000 rituximab treated Veterans with lymphoma (25% of the rate reported among natilizumab-treated multiple sclerosis patients). As with hepatitis B, measurement of JC virus might be considered prior to initiation of rituximab therapy. Acknowledgment:This project was supported through the resources of the Wiliam JB Dorn Veterans Affairs Medical Center.Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Disclosures:No relevant conflicts of interest to declare.

Spanish consensus on the use of natalizumab (Tysabri®) – 2011

IntroductionNatalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients. DevelopmentAt an initial meeting of experts on multiple sclerosis (MS) (the authors of this consensus), the relevant topics of the consensus were decided and assigned for development. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefit/risk, monitoring treatment, and treatment withdrawal and follow-up. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review rounds and meetings, the final draft was produced. ConclusionsAlthough natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory test and magnetic resonance imaging (MRI) should be available for comparison purposes in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to antibodies against JC virus status, prior immunosuppressive therapy, and treatment duration. The follow-up, in particular, the frequency of MRI scans, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to treat and follow individual patients.

Incidence and risk factors for Progressive Multifocal Leukoencephalopathy among patients with selected rheumatic diseases

To ascertain the incidence of progressive multifocal leukoencephalopathy (PML) in patients with selected rheumatic diseases, to describe the characteristics of PML cases occurring in this setting, and to evaluate the extent to which such cases occurred in the context of biologic therapies such as rituximab or tumor necrosis factor antagonists. We conducted a large population-based study to describe the incidence and risk factors for PML among patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, inflammatory bowel disease, and ankylosing spondylitis using national inpatient and outpatient administrative data from the entire Center for Medicare and Medicaid Services from 2000-2009. Suspected PML cases were identified using hospital discharge diagnosis codes. Risk factors for PML were evaluated using outpatient data ≥6 months prior to PML diagnosis. Among 2,030,578 patients with autoimmune diseases of interest, a total of 53 PML cases were identified (2.6 per 100,000 patients). Most PML cases had human immunodeficiency virus (HIV) and/or cancer. Nine PML cases had evidence for biologic use prior to PML hospitalization, of which 3 had neither HIV nor malignancy and were exposed to biologics within 12 (rituximab) or 6 months (all other biologics) prior to PML diagnosis. PML occurred at an estimated incidence of 0.2 per 100,000 patients with autoimmune diseases who did not have HIV or malignancy. PML occurs at a very low incidence among patients with rheumatic diseases but can occur even in the absence of HIV or malignancy.

Consenso español sobre la utilización de natalizumab (Tysabri®) - 2011

IntroductionNatalizumab is very effective at reducing relapses and delaying disease progression in patients with relapsing-remitting multiple sclerosis (RRMS). However, treatment has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The aim of this article is to provide a consensus view on the assessment and stratification of these risks, and to improve the management of natalizumab-treated patients. DevelopmentAt an initial meeting of experts on multiple sclerosis (the authors of this consensus), the relevant topics of the consensus were determined and assigned for further elaboration. Topics included how to establish benefit and risk in general, stratification for risk of PML, informing patients of benefits/risks, and how to monitor patients during treatment and after discontinuing treatment. During the drafting phase, all available information published or presented at international meetings was reviewed. After a series of review sessions and meetings, the final draft was produced. ConclusionsAlthough natalizumab is a very effective drug, its use needs to be considered carefully in view of possible adverse effects and the risk of PML in particular. The neurologist should carefully explain the risks and benefits of treatment in terms the patient can best understand. Before starting treatment, baseline laboratory tests and magnetic resonance imaging (MRI) should be available for future comparisons in the event of suspected PML. The risk of PML should be stratified into high, medium and low risk groups according to presence or absence of anti-JC virus antibodies, prior immunosuppressive therapy, and treatment duration. The follow-up, and frequency of MRI scans in particular, should depend on the risk group to which patient belongs. As our understanding of the risk factors for PML develops, it should be possible to offer patients increasingly individualised therapy. This is a consensus that establishes general recommendations, but neurologists must use their clinical expertise to monitor patients individually.

Pharmacovigilance and PML in the oncology setting

Methods developed by the Southern Network on Adverse Reactions project, the only state-funded pharmacovigilance program in the nation, are invaluable in identifying rare and serious drug events and in disseminating related safety reports quickly throughout the medical community. An important discovery was identification and reporting of an association of rituximab and progressive multifocal leukoencephalopathy (PML) in patients without human immunodeficiency virus (HIV). A recent investigation identified 57 patients with rituximab-associated PML, including bone marrow samples, brain biopsies, and autopsy materials from patients with lymphoma and PML who tested positive for JC virus. The investigation identified an association of rituximab-chemotherapy administration and PML, although a causal relationship remains an area of active investigation. Additional investigations evaluated the epidemiology of PML in the oncology setting before and after the introduction of rituximab for lymphoma treatment. Focused analyses investigated risk factors for development of this rare complication. Further studies are needed to investigate the pathophysiology, epidemiology, and risk factors for PML developing among HIV-negative cancer patients who receive rituximab and chemotherapy.

Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients

Progressive multifocal leukoencephalopathy (PML), a rare, potentially fatal demyelinating disease, affects primarily immunocompromised individuals. The Food and Drug Administration (FDA) received reports of PML associated with efalizumab (Raptiva), a biologic agent approved for psoriasis. In July 2009, efalizumab was voluntarily withdrawn from the US market because of the risk of PML. To describe 3 cases of PML in psoriasis patients treated with efalizumab. The FDA's Adverse Event Reporting System (AERS) database was searched for post-marketing reports of PML associated with biologic agents that are FDA approved for psoriasis (adalimumab, alefacept, efalizumab, etanercept, infliximab) from market approval to January 30, 2009. Twelve cases suggestive of PML were identified: adalimumab (1), efalizumab (4), etanercept (3), and infliximab (4). Efalizumab was the only drug with cases reporting PML in the setting of psoriasis. All cases of PML in efalizumab-treated patients presented 3 years or more after treatment initiation and resulted in death. Cases of PML in patients treated with adalimumab, etanercept, or infliximab occurred in patients treated for conditions other than psoriasis and were confounded by the use of other immunosuppressive therapies or were not confirmed PML cases. AERS data are limited because of an underreporting of spontaneous post-marketing adverse events and variable quality and quantity of information provided. These cases suggest that prolonged efalizumab therapy is a risk factor for PML. Although the cases reported treatment for longer than 3 years, a specific treatment duration that does not place patients at risk for PML has not been defined.

Demyelination as a complication of new immunomodulatory treatments

This review discusses demyelinating events of the nervous system that have been associated with new immunomodulatory treatments, in particular monoclonal antibodies (mAbs). Natalizumab, a mAb targeting the alpha-4 integrins, which is efficient in relapsing-remitting multiple sclerosis, has been associated with progressive multifocal leukoencephalopathy (PML). We will review the putative mechanisms linking natalizumab with JC virus, the agent of PML. Efalizumab, a mAb targeting a member of the integrin family, CD11a, was approved for the treatment of psoriasis, but had to be withdrawn in 2009 because of the occurrence of three cases of PML. Rituximab, an anti-CD20 mAb, is used in different neoplastic and autoimmune diseases and may soon enter the pharmacopeia of multiple sclerosis. It has been suggested that rituximab is a risk factor for PML; however, evidence of such a link is unclear. Antitumor necrosis factor-alpha agents are used in several autoimmune diseases. Several cases of demyelinating events of the nervous system have been reported, prompting a heightened surveillance of treated patients. Recent data are reassuring, suggesting that the incidence of such events is relatively low. Neurologists must become familiar with neurological complications of new immunomodulatory treatments, a field situated at the interface of neurology, immunology and infection.

Progressive multifocal leukoencephalopathy: A national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases

Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, central nervous system demyelinating disease that results from reactivation of the JC virus, which generally occurs in immunosuppressed hosts. The aim of this study was to generate a national estimate of the frequency of PML among patients with rheumatic diseases. Data were obtained from the Nationwide Inpatient Sample database. This is a 20% sample of all hospital discharges, weighted to represent the entire US inpatient population. Data were analyzed for the years 1998-2005 inclusive, representing 297,797,180 hospital discharges. Cases of PML, systemic lupus erythematosus (SLE), and other rheumatic diseases were identified by diagnostic codes from the International Classification of Diseases, Ninth Revision, Clinical Modification. A total of 9,675 cases of PML were identified. The majority were associated with human immunodeficiency virus (HIV; 7,934 patients [82.00%]), hematologic cancers (813 patients [8.40%]), and solid cancers (274 patients [2.83%]). Among the rheumatic diseases, 43 cases of PML (0.44%) were associated with SLE, 24 (0.25%) with rheumatoid arthritis (RA), and 25 (0.26%) with other connective tissue diseases (CTDs). When patients with other potential risk factors for PML (HIV, malignancy, bone marrow or other organ transplantation) were excluded, the rates of PML per 100,000 discharges coded for SLE, RA, and other CTDs were 4, 0.4 and 2, respectively, compared with a rate of PML in the background population of 0.2/100,000 discharges. This study was confined to hospitalized patients with rheumatic diseases, and it was also limited by the lack of information regarding immunosuppressive therapy. Nevertheless, the findings suggest that, although rare overall, PML occurs more commonly in SLE than in other rheumatic diseases.

Natalizumab in the treatment of multiple sclerosis

Natalizumab is a monoclonal antibody, representing a new class of medication for treating relapsing multiple sclerosis (MS). Conventional treatments include interferons, glatiramer acetate and chemotherapies such as mitoxantrone and cyclophosphamide. These therapies offer only modest clinical benefits and are commonly not tolerated due to side effects. Natalizumab has been proven in large-scale, blinded, randomized, controlled trials to have an exceptional effect on preventing relapses, decreasing the risk of sustained progression of disability, and increasing the rate of disease-free patients over a 24-month period compared to placebo. These trials led to the speedy approval of natalizumab for treating relapsing MS, but its use was halted a few months after its induction after several cases of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease affecting the central nervous system. After a long deliberation by an FDA advisory panel and strong support from the MS community, natalizumab was reapproved with stringent restrictions including patient, provider and site registration. Natalizumab is now considered second-line therapy for patients who have failed first-line agents such as interferon or glatiramer acetate. As little is known about additional risk factors for PML and other potential infections, patients and providers must work together to carefully decide if potential benefits outweigh these rare but potentially devastating complications.

Investigation of pre-diagnostic virological markers for progressive multifocal leukoencephalopathy in human immunodeficiency virus-infected patients.

Progressive multifocal leukoencephalopathy (PML) is a severe neurological disorder due to JC virus (JCV) infection. Pre-diagnostic biological markers and risk factors for PML are not well understood. We conducted a case-control study nested within the Multicenter AIDS Cohort Study to examine the association between JCV viruria and viremia and serum antibody to JCV capsids, in relation to subsequent PML diagnoses, 5 months to 12 years later. Other demographic and immunologic factors were also examined. The study population included 28 incident cases of PML, 26 matched HIV-positive controls, and 50 HIV-negative controls. Prevalence of JCV viruria was 37% in cases, 42% in HIV-positive controls, and 28% in HIV-negative controls (P = 0.43). Among persons with JCV viruria, persistent viruria was more common in cases (89%) than in HIV-positive controls (33%) (P = 0.02). Presence of JCV viruria was not related to the time to PML diagnosis (OR: 1.03, 95% CI: 0.8-1.4); however, the urinary concentration of JCV DNA increased with proximity to the date of PML diagnosis in cases. JCV seropositivity did not differ between cases or controls (P = 0.42). Four cases tested JCV seronegative, including one case only 5 months prior to diagnosis with PML. JCV DNA was detected in the serum of one HIV-positive control. Smoking was the only demographic variable analyzed associated with an increased risk for PML (MOR: 9.0, 95% CI: 1.2-394.5). The results suggest that persistent JCV viruria and increasing urinary concentration of JCV DNA may be predictive of PML for some patients.

Human demyelinating disease and the polyomavirus JCV

Many human neurological diseases involve demyelination of the central and/or peripheral nervous systems. These include the hereditary leukodystrophies -which have a genetic basis; multiple sclerosis (MS) -where the underlying cause of demyelination remains unknown; and progressive multifocal leukoencephalopathy (PML) -where the etiology is well-established as being viral. The human neurotropic polyomavirus -JC virus (JCV) -is the etiologic agent of PML, a fatal demyelinating disease of the central nervous system that occurs mainly in immunosuppressed patients, especially those with HIV/AIDS. JCV belongs to the polyomavirus family of tumor viruses that are characterized by non-enveloped icosahedral capsids containing small, circular, double-stranded DNA genomes. Serological studies have shown that JCV is widespread throughout the human population, but infections are usually restricted by the immune system, particularly cell-mediated immunity, causing the virus to enter a latent phase. An important corollary of this is that situations of severe immunosuppression may permit JCV to replicate and are thus a risk factor for PML.

Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: Impact of novel therapies

The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts <or=0.2 x 10(9)/L as risk factors for PML in patients treated with purine analogues. Mortality rates were 95.4% (group A patients), 90% (purine analogues), and 62.5% (HDT/HSCT recipients). At univariate analysis, the only factor that significantly correlated with recovery from infection was female sex. Our findings indicate (1) the possible reduction in reported cases associated with Hodgkin disease and the increasing number of published cases associated with the new antineoplastic therapies (purine analogues and HDT/HSCT); (2) among patients treated with purine analogues, PML is more common in male patients with CD4 cell counts <or=0.2 x 10(9)/L; (3) the use of rituximab after HDT/HSCT seems to delay the onset of PML; and (4) the prognosis is slightly better in transplant recipients.