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    You are here : Home » About MS » Multiple Sclerosis Treatments » Drug Treatments » Disease Modifying Drugs » Tysabri » Progressive Multifocal Leukoencephalopathy

    Progressive Multifocal Leukoencephalopathy

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    PMLProgressive Multifocal Leukoencephalopathy (PML) is a rare infectious disease caused by the John Cunningham virus (JC Virus) [1].

    The JC virus is a polyomavirus that only affects human beings [3]. Therefore, research on JC virus pathogenesis is limited by the lack of an animal model [3].

    Approximately 35–80% of healthy adults have JC virus antibodies because at some point in their life they were infected with the JC virus; however, in such patients it normally remains latent [3].

    In most cases only those with compromised immune systems go on to develop an infection [3].

    PML has emerged as a major complication in patients with severe immunodeficiency such as HIV. It is estimated that approximately 2-5% of patients with AIDS develop PML [1].

    More recently cases of PML have emerged in organ and stem cell transplant recipients as well as those undergoing treatment with combination immuno-modulatory drug therapies [2].

    The JC virus results in damage to the myelin protecting the nerves specifically in the white matter of the brain [1]. Since the white matter of the brain is targeted, symptoms consist of a variety of cognitive deficits [1].

    To this day there is no treatment for PML; however, several potential therapies and treatments are currently being investigated.

    Patients with PML will usually experience the following symptoms:

    Headaches
    Clumsiness and loss of coordination
    Aphasia (loss of language ability)
    Memory loss
    Problems with seeing
    Progressive weakness of the arms and legs

    Symptoms depend upon which area of the brain is affected. They progress over a period of days to weeks, and sometimes months, but eventually lead to death unless the immune system can be reconstituted.


    Tysabri and PML

    Taking Tysabri can increase the chance of someone developing PML. The JC virus is commonly found in the general population however it only leads to PML if the immune system is weakened, either naturally by a disease such as AIDS or because it has been suppressed by a drug treatment. The immune system contains cells which protect the brain from the JC virus. When PML occurs in those taking Tysabri, it is believed that these cells are stopped from crossing the blood brain barrier by the adhesion molecules.

    The chances of developing PML are quite small. To date 212 people have contracted PML and 46 people have died from the condition. (Figures correct as of 1st March 2012).

    Due to the risk of PML, patients taking Tysabri are monitored very closely throughout the process. A test designed to determine the risk of patients contracting PML is currently in trial in the US. It is thought that if the JC virus is present in the system prior to being prescribed Tysabri, then the risk of PML is considerably higher than in those who do not have the JC virus in their system. It will not be able to tell a person whether or not they will contract PML; especially given that a person can become infected with the JC virus at anytime. However, it aims to be able to give the patient a more accurate idea of their chances of contracting PML.

    References

    1. Berger, J.R., & Major, E.O. (1999). Progressive multifocal leukoencephalopathy. Seminars in Neurology, 19(1): 193–200.
    2. Mateen, F. J., Muralidharan, R., Carone, M., van de Beek, D., Harrison, D. M., Aksamit, A. J., Gould, M. S., Clifford, D. B. and Nath, A. (2011). Progressive multifocal leukoencephalopathy in transplant recipients. Annals of Neurology, 70(2): 305–322.
    3. Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J., Stebler C., Gosert R., Hirsch, H. (2009)/ Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. The Journal of Infectious Diseases, 199: 837–846.

    © Multiple Sclerosis Resource Centre (MSRC)

    Further Information

    Tysabri

    MSRC Tysabri User Diaries

    Tysabri Research & News

    The Deferno Trust

    Impairment of JCV-specific T-cell response by corticotherapy: Effect on PML-IRIS management?

    PMLSummary: This study from Switzerland examined the net effects of corticosteroids (CS) on the virus-specific T-cell responses, especially JC virus, to determine the optimal timing of corticosteroid administration in patients with MS with natalizumab-caused progressive multifocal leucoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS).

    The results showed that CS led T cells, either CD4+ or Cd8+, towards a less differentiated phenotype. There was a significant decrease in the proliferation of EBV-, influenza- and JCV-specific T–cell proliferation response upon CS treatment. CS significantly decreased the proliferation of all three virus-specific CD4+ T cells. CS also caused a significant decrease in cytokine production of CD8+ T cells only when these cells were stimulated by JCV, but not EBV or influenza.

    Therefore, CS have a significant effect on the virus-specific T-cell response, in particular on JCV, and it is suggested that giving CS before there are signs of immune reconstitution, may be deleterious as such treatment may blunt the JCV-specific T-cell response, leading to the unopposed progression of PML with grim consequences.

    When CS are considered, there is conclusive rational to give CS only when the patient shows the first clinical or MRI signs of IRIS. Studies directly addressing patients with MS with natalizumab-caused PML are warranted.

    Abstract
    OBJECTIVE:
    To investigate the impact of corticosteroids (CS) on the viral-specific T-cell response, in particular the JC virus (JCV)-specific one, in an attempt to determine the optimal timing of CS in the management of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS).

    METHODS:
    A blood draw was performed before and 7 days after the administration of IV CS to 24 patients with relapsing multiple sclerosis (MS). The phenotypic pattern of T cells was determined by CCR7 and CD45RA. To assess the impact of CS treatment on proliferative response of JCV-, influenza-, and Epstein-Barr virus (EBV)-specific T cells, a thymidine incorporation proliferation assay was performed. An intracellular cytokine staining assay was performed to determine the effect of CS treatment on the production of cytokine by virus-specific T cells. JCV T-cell assays were performed only in JCV-infected patients with MS as detected by serologies (Stratify) or detection of JCV DNA in the urine by PCR.

    RESULTS:
    CS led T cells, CD4+ and CD8+, toward a less differentiated phenotype. There was a significant decrease of EBV-, influenza-, and JCV-specific T-cell proliferative response upon CS treatment. There was a significant decrease in the frequency of interferon (IFN) γ- and tumor necrosis factor (TNF) α-producing JCV-specific CD8+ T cells, but not EBV- or influenza-specific CD4+ or CD8+ T cells.

    CONCLUSIONS:
    CS have a profound impact on the virus-specific T-cell response, especially on JCV, suggesting that when CS are considered, they should not be given before the onset of clinical or radiologic signs of IRIS. Studies addressing directly patients with MS with natalizumab-caused PML are warranted.

    CLASSIFICATION OF EVIDENCE:
    This study provides Class III evidence that methylprednisolone treatment decreases the frequency of JCV-specific CD8+ T cells producing IFN-γ and TNFα, impairing control of JCV, suggesting this should be used to treat but not to prevent PML-IRIS. No clinical outcomes were measured.

    Antoniol C, Jilek S, Schluep M, Mercier N, Canales M, Le Goff G, Campiche C, Pantaleo G, Du Pasquier RA.

    Source: Pubmed PMID: 23175722 & Neurology. 2012 Nov 21 (05/12/12)

    CYT107 gets orphan drug status in Europe for treatment of PML

    PMLCytheris SA, a privately held clinical-stage biopharmaceutical company focused on treating lymphopenia driven diseases, announced that the European Commission has granted an orphan designation for Cytheris' CYT017, glycosylated recombinant human interleukin-7 (glycosylated r-h-IL7), for the treatment of Progressive Multifocal Leukoencephalopathy (PML).

    Additionally, Cytheris obtained scientific advice for a phase IIb study protocol with CYT107 in HIV-related PML. Cytheris has reached an agreement with the EMA on the key study endpoints. Cytheris will start this phase IIb study, intended to be pivotal, in early 2013.

    PML is a severe demyelinating disease of the central nervous system caused by the JC virus. It occurs in many conditions leading to severe lymphopenia such as HIV infection, some cancers and organ transplantation treated with immunosuppressive therapies. PML is a very rare disease, affecting around four out of a million individuals. There is currently no marketed drug for the treatment of this devastating condition.

    "This orphan designation strongly supports the development of CYT107 as the treatment for PML. The disease has a mortality rate of around 40 to 50 per cent at one year whilst survivors often present severe neurological complications and disabilities," said Therese Croughs, chief medical officer at Cytheris. "We already gathered clinical data supporting the efficacy and safety of CYT107 in PML through several compassionate use treatments. We are committed to conduct our pivotal clinical study as rapidly as possible."

    "PML is an extremely serious disease driven by severe lymphopenia for which CYT107 is ideally placed to bring clear benefits through its targeted activity on immune T cell recovery and enhancement," said Damian Marron, CEO at Cytheris. "PML affects around 4,000 people in the US and EU alone. Bringing a treatment to this population would not only save and change patients' lives but would also respond to the pharmaceutical industry's desire to develop breakthrough drugs for targeted indications."

    CYT107 is also in development in HIV Immune Non-Responders (HIV-INR) virologically controlled by anti-retroviral treatment. Fifteen to twenty five per cent of HIV patients are lymphopenic despite optimal treatment (HAART) leading to a significant increase in risk of death and serious complications. CYT107 also holds great promise in other lymphopenic conditions such as idiopathic lymphopenia or cancer associated lymphopenia.

    Source: Pharmabiz.com Copyright © 2012 Saffron Media Pvt. Ltd (07/08/12)



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