Immunological and clinical consequences of treating a patient with natalizumab.

BACKGROUND: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). OBJECTIVES: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). METHODS: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. RESULTS: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. CONCLUSION: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study.

BACKGROUND: Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy (PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. METHODS: We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. FINDINGS: We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. INTERPRETATION: Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. FUNDING: Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.

Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 α-chain (CD11a) in MS patients.

OBJECTIVE: To determine the long-term effect of natalizumab (NTZ) treatment on the expression of integrins and chemokine receptors involved in the migration of T cells towards the central nervous system (CNS). METHODS: We drew the blood of 23 patients just before starting NTZ therapy and every 12 months thereafter, for up to 48 months of treatment. We assessed the ex-vivo expression of phenotype markers (CCR7 and CD45RA), CNS-addressing integrins (CD11a, CD49d and CD29) and chemokine receptors (CXCR3 and CCR6) in CD4+ or CD8+ T-cell subsets by flow cytometry. RESULTS: As compared to the pre-NTZ values, there was a marked increase in central memory (CCR7+/CD45RA-) CD4+ T cells and in effector memory (CCR7-/CD45RA-) CD8+ T cells at 12 and 24 months. In addition to an expected downregulation of both VLA-4 subunits (CD49d/CD29), we also found decreased T-cell expression of CXCR3 at 12 months, and of CD11a (LFA-1 αL subunit) at 12 months, but mostly at 24 months of NTZ treatment. CONCLUSION: Our data show a nadir of CD11a expression at 2 years of NTZ treatment, at the peak of incidence of progressive multifocal leukoencephalopathy (PML), indirectly suggesting that a lack of these molecules may play a role in the onset of PML in NTZ-treated patients.

Viral- and myelin-specific cellular immune response in patients treated with natalizumab: a cross-sectional and a longitudinal prospective study

Introduction: Natalizumab, a monoclonal antibody binding to the alpha4 integrins, is efficient in preventing relapses and progression of disability in multiple sclerosis (MS) patients. However, a total of seven MS patients treated with natalizumab suffered from progressive multifocal leukoencephalopathy (PML), on a total of 53?000 patients (data of March 6, 2009) treated with this drug. PML is a disease affecting immunosuppressed people, which is caused by the polyomavirus JC (JCV). This virus produces a lytic infection of the oligodendrocytes. Yet, natalizumab cannot be considered as a classical immunosuppressant, such as suggested by the fact that no increased incidence of other opportunistic infections was reported with this drug. It has been postulated that, by closing the blood-brain, natalizumab might prevent JCV-specific CD8_ T cells to reach the CNS and perform immune surveillance. Alternatively, it has been suggested that this drug acts by releasing JCV from the bone marrow, one of its site of latency. In this study, we address the question whether there is an increased activity of JCV in the blood of natalizumab-treated MS patients. Material and Methods: In this prospective longitudinal study, we are following a cohort of 24 MS patients receiving monthly injections of natalizumab. Blood and urine are drawn every one to three months, up to 12 months. As a control group, we follow 16 MS patients treated with IFN-beta. For this control group, there are two time-points: before and 1094 months after treatment onset. We are analysing the viral (JCV-, EBV- and CMV-) as well as the myelin- (MOG-, MOBP-) specific cellular immune responses using proliferation and ELISPOT (IFNgamma) assays. For JCV, we study the response against VP1, the major capsid protein. For JCV VP1, MOG and MOBP, we use 15-mer peptides overlapping by 10 amino acids, thus eliciting CD4_ as well as CD8_ T cell response. These peptides encompasse the whole sequence of the proteins. For EBV and CMV, we use pools of immunodominant 8- to 10-mer peptides eliciting CD8_ T cells. At the same time-points, using RTPCR, we determine the presence of JCV DNA coding for the VP1 protein in the PBMC, plasma, and urine. Results: At the time of writing this abstract, 16 patients have reached the 9-month (T9), and 11 the T12 time-point. We expect that by the ISNV meeting in June 2009, 18 and 14 patients will be at T9 and T12, respectively. Virological and immunological results will be presented. 9th International Symposium on NeuroVirology 2_6 June 2009 39 J Neurovirol Downloaded from informahealthcare.com by Cantonale et Universitaire on 06/25/10 For personal use only. Conclusions: This ongoing longitudinal prospective study should tell us whether there is an enhanced JCV activity in the peripheral blood of patients on natalizumab. This work is supported by the FNS (PP00B-106716), the Swiss MS Society and a research grant from Biogen Dompe.

Demyelination as a complication of new immunomodulatory treatments.

Purpose of review: This review discusses demyelinating events of the nervous system that have been associated with new immunomodulatory treatments, in particular monoclonal antibodies (mAbs). Recent findings: 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. Summary: Neurologists must become familiar with neurological complications of new immunomodulatory treatments, a field situated at the interface of neurology, immunology and infection.

Pharmacovigilance update [Pharmacovigilance update]

Main pharmacovigilance signals and alerts issued in 2009 are reviewed. Efalizumab was withdrawn from the market due to increased risks, including progressive multifocal leukoencephalopathy (PML) and questionable efficacy. New cases of PML are still being reported with rituximab and natalizumab. Rare cases of pure red cell aplasia have been observed with mycophenate. Gastrointestinal perforation, severe skin rashes and various ocular disorders have been reported during erlotinib use. Severe skin rashes have been related to etravirine. Acute renal failure and pancreatitis can occur with exenatide. A link between sitagliptin and pancreatitis is suspected. Raised concerns of causality between insuline glargine and malignant tumors are not supported by strong evidence. Proton pump inhibitors seem to blunt clopidogrel benefit. Aliskiren can cause angioedema.

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

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.

Pharmacovigilance et teratovigilance 2008 [Pharmacovigilance and teratovigilance 2008]

Various signals and alerts of pharmacovigilance were issued in 2008. Frequent neuropsychiatric adverse events are reported with varenicline and rimonabant and the marketing authorization of the latter has been suspended. Ezetimibe/simvastatin combination is suspected of causing cancer while it's clinical utility remains to be proved. Neuroleptics, typical and atypical, are associated with an increased risk of death in elderly with dementia. Safety is a concern with various biological drugs. Rituximab, natalizumab and efalizumab are involved in rare cases of progressive multifocal leukoencephalopathy with fatal issue. Screening of HLA-B*5701, a good predictor of hypersensitivity reaction to abacavir, is recommended prior to starting therapy. Mycophenolate turns out to be a human teratogen.

Management of Fulminant Multiple Sclerosis With Rituximab: A Case Report.

INTRODUCTION: Malignant variant is a rare subtype of multiple sclerosis (MS) that is rapidly progressive and may lead to significant disability or even death. No consensus exists on best management of this disorder, although corticosteroids and plasmapheresis are commonly used in the acute phase, followed either by MS-specific disease-modifying therapy or an immunosuppressant. CASE REPORT: The patient is a 30-year-old man with relapsing-remitting MS previously well controlled with natalizumab, who has developed fulminant disease activity upon natalizumab cessation. In the acute phase, patient had a suboptimal response to multiple corticosteroid treatments but responded very well to plasmapheresis. Patient continued to have worsening disease activity despite fingolimod treatment. Disease control has been eventually achieved by switching to rituximab. CONCLUSION: Rituximab treatment should be considered for a patient with fulminant MS who responded well to plasmapheresis.

The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients.

OBJECTIVE: To assess longitudinally the antiviral immune response of T cells from patients with multiple sclerosis (MS) treated with fingolimod (FTY) vs other disease-modifying treatments (DMTs). METHODS: We assessed cellular immune responses specific to influenza virus (FLU), JC virus (JCV), and varicella-zoster virus (VZV) using quantification of interferon-γ secretion by enzyme-linked immunospot in patients with MS on FTY (n = 31), including 2 with herpes zoster (HZ), natalizumab (n = 11), and other DMTs (n = 11). We used viral lysates for FLU and VZV and a pool of peptides for FLU, JCV (VP-1), and VZV (IE63). RESULTS: Besides an expected drop of T cells, we found that, proportionally to the number of CD3(+) T cells, only FTY-treated patients with MS exhibited an increased VZV/IE63-specific T cell response peaking 6 months into treatment, a response that returned to baseline after 12 and 24 months. Two FTY-treated patients developed an HZ 6 months into treatment, coinciding with an absent VZV/IE63-specific T cell response. However, cellular immune responses specific to VZV lysate, JCV, and FLU (lysate and pool of peptide epitopes) were similar between all 3 categories (FTY, natalizumab, and other DMTs) of study patients. CONCLUSIONS: FTY-treated patients with MS exhibit an increased VZV/IE63-specific cellular immune response after 6 months of treatment. FTY-treated patients who develop an HZ are not able to mount such a response, suggesting that a T cell response directed against this viral protein may be key in preventing the occurrence of HZ.