John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients

Kempen, Zoé L E van; Leurs, Cyra E.; Vries, Annick de; Vennegoor, Anke; Rispens, Theo; Wattjes, Mike P.; Killestein, Joep

doi:10.1111/ene.13355

Cited by 10 publications

(7 citation statements)

References 15 publications

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“…According to our results, during NTZ treatment, patients showed a statistically significant increase in their JCV index (1.20 vs 1.90, p =0.0009) and NTZ treatment was associated with a significant percentage of patients (16.5%) seroconverted to a positive status. Similar results have been reported from other study in literature in which the annualized seroconversion rate has been described as 6-7% in the first year of NTZ therapy, progressing to 10-25% after 4 years of continuous treatment with this drug [15][16][17][18][19].…”

Section: Discussionsupporting

confidence: 91%

Changes in Anti-JCV Antibody Status in a Large Population of Multiple Sclerosis Patients Treated with Natalizumab

et al. 2020

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Introduction Natalizumab (NTZ) can be associated with an opportunistic infection, progressive multifocal leukoencephalopathy (PML), caused by John Cunningham virus (JCV). High titer of anti-JCV antibody (JCV index) in patients treated with NTZ for over 2 years limit it use, leading to treatment discontinuation. Objective Aim of the study was to investigate the JCV index changes pre, during and post NTZ treatment and describe the trend after a long period of NTZ discontinuation. Methods Patients with relapsing-remitting multiple sclerosis (RR-MS) treated with NTZ between 2010 and 2018 were enrolled in this retrospective-prospective observational study. Inclusion criteria were: (1) diagnosis of RR-MS according to the McDonald criteria 2010, (2) at least six NTZ administrations, (3) at least two determinations of JCV Index during the follow-up period, (4) NTZ discontinuation period for more than 6 months. JCV index was determined by STRATIFY II. There were three different timepoints: NTZ initiation (T0), NTZ discontinuation (T1) and time after NTZ suspension (T2). Seroconversion was defined as changing status of serum JCV antibody. Main outcomes were the JCV index changes and the rate of seroconversion. Results At baseline we enrolled 285 patients (208 JCV negative, 67 JCV positive, and 10 not available). There was a statistically significant increase of JCV index during NTZ treatment period (T0 vs T1, p =0.0009) and during NTZ discontinuation period (T1 vs T2, p =0.04). Patients seroconverted to a positive status more frequently during NTZ treatment than after discontinuation (p =0.008). Moreover, patients who shifted to fingolimod (FTY) as exit strategy after NTZ discontinuation, showed a statistically significant increase of JCV index. Conclusion Our data confirmed that a high percentage of patients shift to or remain in a positive JCV status during NTZ treatment and after discontinuation. NTZ suspension seems not to be able to interfere on JCV status modification over an extended period. The choice of alternative treatment as exit strategy after NTZ discontinuation should be carefully considered because it could negatively influence the PML risk stratification of patients. Eleonora Sgarlata and Clara Grazia Chisari equally contributed.

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Section: Discussionsupporting

confidence: 91%

Changes in Anti-JCV Antibody Status in a Large Population of Multiple Sclerosis Patients Treated with Natalizumab

et al. 2020

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“…Seropositivity for JCV may be subject to a variety of influences and the values reported by different authors may therefore be somewhat skewed. For example, some large studies did not find any association between JCV positivity and the previous use of natalizumab or other immunosuppressive drugs [ 15 , 32 ]. Other authors reported the contrary, finding that seroconversion rates increased by more than 8.0% per year of use of natalizumab [ 21 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica

Paz¹,

Branco²,

Pereira³

et al. 2018

Epidemiol Health

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OBJECTIVESJohn Cunningham virus (JCV) is a polyoma virus that infects humans, mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies in human serum has been reported to be between 50.0 and 90.0%. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish the rates of JCV seropositivity in these individuals.METHODSThe present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used the following search terms: “JCV” OR “JC virus” AND “multiple sclerosis” OR “MS” OR “NMO” OR “neuromyelitis optica” AND “prevalence.” These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, MEDLINE, SciELO, LILACS, Google Scholar, and Embase.RESULTSAfter the initial selection, 18 papers were included in the review. These articles reported the prevalence of JCV antibodies in the serum of patients with MS or NMO living in 26 countries. The systematic review identified data on 29,319 patients with MS/NMO and found that 57.1% of them (16,730 individuals) were seropositive for the anti-JCV antibody (range, 40.0 to 69.0%).CONCLUSIONSThe median worldwide prevalence of JCV among adults with MS or NMO was found to be 57.1%.

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“…The variable median results of NAT free circulating levels observed among studies (from 18 to 51 μg/ml) may be assay dependent, but a common characteristics noted within each study was the high variability among patients (less than 4 μg and up to 100 or 200 μg) ( 71 , 74 , 75 ). No clear relationship has been evidenced to identify factors involved in this heterogeneity although body weight might contribute ( 76 , 77 ). Nevertheless, for a given patient, trough levels soon reach a plateau and remain stable whatever the number of infusions ( 9 ) and for more than 90% of them were over 10 μg/ml ( 78 ).…”

Section: Drug Monitoringmentioning

confidence: 99%

“…No specific biologic risk linked to NAT properties has been definitively identified in this susceptibility, which is also observed in other immunosuppression states either related to HIV or monoclonal antibody treatments or other DMT. In the context of NAT, no drug overdose was noticed at the time of infection ( 77 ) and risk evaluation remained to be assessed on treatment duration and anti JC antibody status. In order to limit the risk of PML, EID protocols seem to maintain a sufficient efficacy, although the real benefit on large cohorts has not yet been reported, and the ongoing NOVA study might contribute to this evaluation ( 91 ).…”

Section: Drug Monitoringmentioning

confidence: 99%

Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring

et al. 2020

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Multiple sclerosis is a chronic demyelinating disease of the central nervous system (CNS) with an autoimmune component. Among the recent disease-modifying treatments available, Natalizumab, a monoclonal antibody directed against the alpha chain of the VLA-4 integrin (CD49d), is a potent inhibitor of cell migration toward the tissues including CNS. It potently reduces relapses and active brain lesions in the relapsing remitting form of the disease. However, it has also been associated with a severe infectious complication, the progressive multifocal leukoencephalitis (PML). Using the standard protocol with an injection every 4 weeks it has been shown by a close monitoring of the drug that trough levels soon reach a plateau with an almost saturation of the target cell receptor as well as a down modulation of this receptor. In this review, mechanisms of action involved in therapeutic efficacy as well as in PML risk will be discussed. Furthermore the interest of a biological monitoring that may be helpful to rapidly adapt treatment is presented. Indeed, development of anti-NAT antibodies, although sometimes unapparent, can be detected indirectly by normalization of CD49d expression on circulating mononuclear cells and might require to switch to another drug. On the other hand a stable modulation of CD49d expression might be useful to follow the circulating NAT levels and apply an extended interval dose scheme that could contribute to limiting the risk of PML.

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John Cunningham virus conversion in relation to natalizumab concentration in multiple sclerosis patients

Abstract: Higher natalizumab concentrations do not explain the increased JCV seroconversion rate in natalizumab treated patients.

Cited by 10 publications

References 15 publications

Changes in Anti-JCV Antibody Status in a Large Population of Multiple Sclerosis Patients Treated with Natalizumab

Changes in Anti-JCV Antibody Status in a Large Population of Multiple Sclerosis Patients Treated with Natalizumab

Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica

Natalizumab in Multiple Sclerosis Treatment: From Biological Effects to Immune Monitoring

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