Progressive multifocal leukoencephalopathy in autoimmune diseases

doi:10.1016/j.jbspin.2011.11.002

Joint Bone Spine

Volume 79, Issue 4, July 2012, Pages 351-355

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Abstract

Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection due to reactivation of the JC virus. Most reported cases occurred in HIV-infected patients (80% of cases), patients with lymphoid malignancies (13%) and transplant recipients taking immunosuppressants (5%). Less often, PML has been described in patients with chronic inflammatory joint diseases associated with autoimmune disorders (lupus, rheumatoid arthritis [RA] and vasculitis) (2%). Magnetic resonance imaging of the brain shows suggestive changes and confirmation of the diagnosis is obtained by performing PCR tests to identify the JC virus in the cerebrospinal fluid or, when necessary, a brain biopsy. No treatments have been proven effective. Most patients experience progressive disease that is fatal within a few months or induces incapacitating neurological impairments. The risk of PML is 0.4/100 000 in patients with RA. In the few case-reports of PML in RA patients, the treatments used included methotrexate (five cases) combined with a biological agent such as infliximab (one case), rituximab (four cases), or leflunomide (two cases including one with concomitant rituximab). PML is an extremely rare but devastating complication. Rituximab therapy is associated with an increased prevalence of PML in RA patients (4/100 000), who should be informed of this risk. In patients with lupus, the risk of PML is higher than in RA (4/100 000) and 40% of cases of PML occur during low-dose glucocorticoid therapy without immunosuppressive therapy.

Introduction

Progressive multifocal leukoencephalopathy (PML) is a subacute infection of the central nervous system (CNS) due to reactivation of the JC virus (JCV). In most cases, immunosuppression is required for PML to develop. PML has been reported chiefly in patients with HIV infection (80% of cases) or lymphoid malignancies (13%) and in transplant recipients taking immunosuppressant agents (5%). However, PML has also been described in association with chronic inflammatory joint diseases and autoimmune diseases (systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], or vasculitis) (2%) [1].

Section snippets

Progressive multifocal leukoencephalopathy

PML was first described by Alstrom in 1958. The causative agent was named the JCV for John Cunningham, the first patient in whom the virus was identified, by Padgett et al. in 1971 [2].

Multiple sclerosis (MS)

The prevalence of PML is not increased in patients with MS. Reported cases were related to the use of natalizumab [4], [14]. As of April 2010, 42 cases had been reported worldwide [4], [15], [16], [17]. Most of the patients had a history of treatment with immunosuppressants (mitoxanthrone, azathioprine, or methotrexate). Of the first three cases, two occurred in patients with MS treated with interferon-beta and 1 in a patient with Crohn's disease and a history of infliximab and azathioprine

Recommendations

At present, no tools are available for preventing or evaluating the risk of PML in patients with chronic inflammatory joint diseases associated with autoimmune disorders. Serological screening for the JCV provides only limited information. A positive test does not distinguish between patients with the prototype variant and those with the archetype variant. However, a negative test may constitute reassuring information that should be provided to the patient at rituximab initiation.

Early

Conclusions

The prevalence of PML is increased in the main autoimmune disorders seen by rheumatologists, most notably SLE, vasculitides, and RA. Spondylarthropathies are not associated with an increased risk of PML. The main drugs incriminated to date are immunosuppressants and rituximab combined with methotrexate or leflunomide. Although PML is very rare, patients should be informed of the risk. To date, no cases have been reported with etanercept, adamimumab, certolizumab, abatacept, or tocilizumab.

When

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

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Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system due to reactivation of the JC virus (JCV). PML is extremely uncommon despite the high prevalence of the virus in the general population. No specific treatment is available, and the prognosis is bleak. The diagnosis is based on brain imaging findings, detection of the JCV genome in cerebrospinal fluid samples and, in some cases, histological studies of the brain lesions. The pathophysiological mechanisms that drive the development of PML are incompletely understood. However, a consistent feature is the presence of a predisposing factor, most notably immunosuppression. The risk of developing PML varies with the underlying disease (e.g., HIV infection or autoimmune disease) and with the drugs used to treat them. Biologics have been ranked according to the risk of PML during their use. Natalizumab, a monoclonal antibody given to treat multiple sclerosis, is among the drugs associated with a high risk of PML. Patients given natalizumab are now closely monitored based on anti-JCV antibody titers and index values. In rheumatology, the expanding use of biologics has led to an increase in cases of PML, with rituximab being associated with the highest risk. Given the absence of specific recommendations, exhaustive registries and postmarketing observational studies are urgently needed to gauge the risk of PML according to the underlying disease and drug treatments, with the goal of defining optimal monitoring protocols.
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La leucoencéphalopathie multifocale progressive (LEMP) est une maladie démyélinisante du système nerveux central, causée par une réactivation du virus JC. Le développement de la LEMP est très rare malgré la prévalence élevée de l’infection par le virus dans la population générale. Il n’existe pas de traitement spécifique et le pronostic est sombre. Le diagnostic repose sur l’imagerie cérébrale, la présence du génome viral dans le liquide cérébrospinal et parfois sur l’analyse histologique des lésions cérébrales. Si les mécanismes physiopathologiques permettant le développement de la LEMP ne sont pas parfaitement connus, son apparition se fait toujours dans un contexte favorisant, en particulier une immunosuppression. Le risque de développer une LEMP apparaît différent en fonction des situations cliniques (infection par le VIH, maladies auto-immunes) et des traitements employés. Ceci a conduit à stratifier les biomédicaments en fonction de la fréquence de survenue de la LEMP. Le natalizumab, anticorps monoclonal utilisé dans le traitement de la sclérose en plaques, fait partie des traitements associés à un risque élevé de LEMP. Actuellement, sa prescription est étroitement surveillée et repose sur une surveillance de la sérologie du virus JC et du taux d’anticorps ou index value au minimum. En rhumatologie, l’utilisation croissante des biothérapies est responsable d’une augmentation des cas de LEMP, le rituximab étant le traitement le plus associé à ce risque. En l’absence de recommandations spécifiques, la mise en place de registres et d’études observationnelles post-marketing exhaustives est une priorité pour différencier le risque de LEMP selon les traitements et le contexte clinique, afin de définir les modalités de surveillance adaptées.
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ReviewProgressive multifocal leukoencephalopathy in autoimmune diseases

Abstract

Introduction

Section snippets

Progressive multifocal leukoencephalopathy

Multiple sclerosis (MS)

Recommendations

Conclusions

Disclosure of interest

Lancet

Blood

Clin Radiol

Lancet Neurol

Rev Med Interne

Lancet Neurol

J Autoimmun

Autoimmun Rev

J Neurol Sci

Joint Bone Spine

J Infect

J Neurol Sci

Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive neurologic deficits

N Engl J Med

Pathogenesis of progressive multifocal leukoencephalopathy–revisited

J Infect Dis

Progressive multifocal leukoencephalopathy and newer biological agents

Drug Saf

Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease

Arthritis Rheum

PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids

Neurology

Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis

Arch Neurol

Determinants of survival in progressive multifocal leukoencephalopathy

Neurology

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

Arthritis Rheum

Review
Progressive multifocal leukoencephalopathy in autoimmune diseases