Nearly one-half of Brazilian patients with multiple sclerosis using natalizumab are DNA-JC virus positive

Fragoso, Yára Dadalti; Mendes, Maria Fernanda; Arruda, Walter Oleschko; Becker, Jéfferson; Brooks, Joseph Bruno Bidin; Carvalho, Margarida; Comini-Frota, Elizabeth Regina; Domingues, Renan Barros; Ferreira, Maria Lúcia Brito; Finkelsztejn, Alessandro; Gama, Paulo Diniz da; Gomes, Sidney; Gonçalves, Marcus Vinícius Magno; Kaimen-Maciel, Damacio Ramón; Morales, Rogério de Rizo; Muniz, André Luiz; Ruocco, Heloisa Helena; Salgado, Pedro Rippel; Albuquerque, Livia Brito Bezerra de; Gama, Rodrigo Assad Diniz da; Georgeto, Sérgio Murilo; Lopes, Josiane; Oliveira, Celso Luis Silva; Oliveira, Fabiana Sodré de; Safanelli, Juliana; Saldanha, Patricia Correia de Oliveira; Satomi, Massaco

doi:10.1590/0004-282x20130121

Cited by 8 publications

(9 citation statements)

References 10 publications

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“…Subclinical JCV reactivation may also occur in blood of natalizumab-treated MS patients, as we and others have previously reported 6–8, 13, 28 . We found JCV in blood of 9 of 32 (28.1%) natalizumab-treated patients, a result comparable to viremia of 35% in a different cohort, recently reported by Major et al 29 .…”

Section: Discussionsupporting

confidence: 64%

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Chalkias

Dang

Bord

et al. 2014

Annals of Neurology

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Objective To determine the prevalence of JC virus (JCV) reactivation and JCV-specific cellular immune response during prolonged natalizumab treatment for multiple sclerosis (MS). Methods We enrolled 43 JCV-seropositive MS patients, including 32 on natalizumab monotherapy>18 months, 6 on interferon β-1a monotherapy>36 months and 5 untreated controls. We performed QPCR in cerebrospinal fluid (CSF), blood and urine for JCV DNA and we determined JCV-specific T cell responses using enzyme-linked immunosorbent spot (ELISpot) and intracellular cytokine staining (ICS) assays, ex vivo and after in vitro stimulation with JCV peptides. Results JCV DNA was detected in the CSF of 2/27 (7.4%) natalizumab-treated MS patients who had no symptoms or MRI lesions consistent with progressive multifocal leukoencephalopathy. JCV DNA was detected in blood of 12/43 (27.9%) and in urine of 11/43 (25.6%) subjects without difference between natalizumab-treated patients and controls. JC viral load was higher in CD34+ cells and in monocytes compared to other subpopulations. ICS was more sensitive than ELISpot, and JCV-specific T cell responses, mediated by both CD4+ and CD8+ T-lymphocytes, were detected more frequently after in vitro stimulation. JCV-specific CD4+ T-cells were detected ex vivo more frequently in MS patients with JCV DNA in CD34+ (p=0.05) and B cells (p=0.03). Interpretation Asymptomatic JCV reactivation may occur in CSF of natalizumab-treated MS patients. JCV DNA load is higher in circulating CD34+ cells and monocytes compared to other mononuclear cells, and JCV in blood might trigger a JCV-specific CD4+ T-cell response. JCV-specific cellular immune response is highly prevalent in all JCV-seropositive MS patients, regardless of treatment.

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Section: Discussionsupporting

confidence: 64%

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Chalkias

Dang

Bord

et al. 2014

Annals of Neurology

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“…In fact, although secondgeneration STRATIFY JCV Ⓡ showed an increased sensitivity, some patients present a negativity to anti-JCPyV antibodies and a detectable JCPyV DNA in urine or blood. Our data confirm that anti-JCPyV antibodies assay, alone, is not sufficient for JCPyV diagnosis and should be associated with JCPyV-DNA detection in different body compartments, in order to accurately identify JCPyV infected patients (Fragoso et al, 2013;Major et al, 2013;Delbue et al, 2015). Consequently, different approaches to detect JCPyV infection are required for a more accurate Table 3 Contextual analysis of the anti-JCPyV antibodies versus JCPyV-DNA detection.…”

Section: Discussionmentioning

confidence: 52%

Which is the best PML risk stratification strategy in natalizumab-treated patients affected by multiple sclerosis?

Prezioso

Zingaropoli

Iannetta

et al. 2020

Multiple Sclerosis and Related Disorders

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Background: The risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCPyV), is the main limitation to the use of natalizumab, highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Establishing the PML risk against expected benefits represents an obligatory requirement of MS treatment algorithm. In order to achieve this goal, the aims of this study were to establish if JCPyV-DNA detection and non-coding control region (NCCR) arrangements could play a role of biomarkers, supporting anti-JCPyV antibodies measurement, actually the only parameter for PML risk stratification. Methods: Thirty RRMS patients in treatment with natalizumab were enrolled. Urine and blood samples were collected according to this calendar: baseline (T0), 4 (T1), 8 (T2), 12 (T3), 16 (T4), 20 months (T5) after beginning of natalizumab therapy. After JCPyV DNA extraction, a specific quantitative-PCR (Q-PCR) and arrangements' analysis of NCCR and Viral Capsid Protein 1 (VP1) were carried out. Results: Q-PCR detected JCPyV DNA in urine and blood from baseline (T0) to 20 natalizumab infusions (T5), although JC viral load in urine was significantly higher compared to viremia, at all selected time points. A contextual analysis of the anti-JCPyV-antibodies versus JCPyV-DNA detection revealed that viral DNA preceded the antibodies' presence in the serum. During the first year of natalizumab treatment, sequences isolated from blood displayed an archetype JCPyV NCCR structure with the occurrence of point mutations, whereas after one year NCCR reorganizations were observed in plasma and PBMC with duplication of NF-1 binding site in box F, duplication of box C and partial or total deletion of box D. VP1 analysis showed the amino acid change mutation S269F in plasma and S267L in PBMC, involving the receptor-binding region of VP1. Phylogenetic analysis suggested a stability and a similarity across different isolates of the JCPyV VP1. Conclusions: We highly recommend considering JCPyV-DNA detection and NCCR reorganizations as viral biomarkers in order to accurately identify JCPyV-infected patients with a specific humoral response not yet detectable and to identify NCCR arrangements correlated with the onset of neurovirulent variants. Specifically, to date, 13 disease-modifying therapies (DMTs) for treatment of relapsing-remitting multiple sclerosis (RRMS), the most prevalent MS phenotype, have been approved by the Food and Drug Administration (FDA) and have changed the scenery for care of RRMS patients (Tintore et al., 2019). Although these newer drugs allowed long periods of disease activity-free remission (Giovannoni et al., 2018),

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“…The risk of seropositivity rises with increasing age and male gender . But several reports show that the annualized seroconversion rate in natalizumab‐treated patients with MS seems to be higher than expected, possibly due to a higher sensitivity caused by natalizumab usage …”

Section: Introductionmentioning

confidence: 96%

“…Patients with anti‐JCV antibodies in serum or plasma are at risk for developing PML. Although 33‐91% of the general population is positive for this virus, epidemiologic data in patients with MS show that about half of the patients seem to be positive for JCV antibodies …”

Section: Introductionmentioning

confidence: 99%

JCV serology in time: 3 years of follow-up

et al. 2016

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Nearly one-half of Brazilian patients with multiple sclerosis using natalizumab are DNA-JC virus positive

Cited by 8 publications

References 10 publications

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

JC virus reactivation during prolonged natalizumab monotherapy for multiple sclerosis

Which is the best PML risk stratification strategy in natalizumab-treated patients affected by multiple sclerosis?

JCV serology in time: 3 years of follow-up

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