{
  "abstract": "Background Natalizumab is a highly effective drug for patients with relapsing-remitting multiple sclerosis (MS). A disadvantage of this treatment is the risk of progressive multifocal leukoencephalopathy in patients who are seropositive for the John Cunningham virus (JCV). JCV seroconversion rates increase under natalizumab treatment compared with non-natalizumab using controls. The aim of this study was to assess whether lower natalizumab trough concentrations are associated with reduced JCV seroconversion compared with higher natalizumab trough concentrations.Methods Two overlapping cohorts of patients treated with intravenous natalizumab in the Netherlands were combined for this study. JCV seroconversion was assessed during periods of high (≥15 µg/mL) and low (<15 µg/mL) natalizumab trough concentrations. Low trough concentrations were mainly the result of trough concentration guided personalised extended interval dosing (EID). The seroconversion rates during high and low trough concentrations were compared using a generalised linear mixed model with a Poisson link function.Results A total of 357 patients from 21 hospitals in the Netherlands were included. The annual seroconversion rate of 8.4% observed in patients during periods of high trough concentrations (n=226) was 2.32 times higher than the seroconversion rate of 4.8% in patients during periods of low trough concentrations (n=252) (95% CI=1.32 to 4.08, p=0.0035).Conclusions The seroconversion rate observed in patients with MS with low trough concentrations was substantially lower compared with those with high trough concentrations during natalizumab treatment. This emphasises the importance of personalised EID, where intervals between infusions are prolonged to achieve lower natalizumab trough concentrations, to increase drug safety.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Liza M Y Gelissen"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Alyssa A Toorop"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Pien M Schipper"
    },
    {
      "affiliations": [
        "Department of Neurology, Alrijne Ziekenhuis, Leiden, Netherlands"
      ],
      "name": "Elske Hoitsma"
    },
    {
      "affiliations": [
        "Department of Neurology, Isala Diaconessenhuis Meppel, Meppel, Netherlands"
      ],
      "name": "Esther M P E Zeinstra"
    },
    {
      "affiliations": [
        "Department of Neurology, Maasstad Hospital, Rotterdam, Netherlands"
      ],
      "name": "Luuk C van Rooij"
    },
    {
      "affiliations": [
        "Department of Neurology, Amphia Hospital, Breda, Netherlands"
      ],
      "name": "Caspar E P van Munster"
    },
    {
      "affiliations": [
        "Department of Neurology, Flevoziekenhuis, Almere, Netherlands"
      ],
      "name": "Anke Vennegoor"
    },
    {
      "affiliations": [
        "Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands"
      ],
      "name": "Jop Mostert"
    },
    {
      "affiliations": [
        "Department of Neurology, Erasmus MC, Rotterdam, Netherlands"
      ],
      "name": "Beatrijs Wokke"
    },
    {
      "affiliations": [
        "Department of Neurology, OLVG, Amsterdam, Netherlands"
      ],
      "name": "Nynke F Kalkers"
    },
    {
      "affiliations": [
        "Department of Neurology, St Antonius Hospital, Nieuwegein, Netherlands"
      ],
      "name": "Erwin L J Hoogervorst"
    },
    {
      "affiliations": [
        "Department of Neurology, Jeroen Bosch Hospital, ’s Hertogenbosch, Netherlands"
      ],
      "name": "Jeroen van Eijk"
    },
    {
      "affiliations": [
        "Department of Neurology, Slingeland Hospital, Doetinchem, Netherlands"
      ],
      "name": "Christiaan M Roosendaal"
    },
    {
      "affiliations": [
        "Department of Neurology, Reinier de Graaf Gasthuis, Delft, Netherlands"
      ],
      "name": "Jolijn J Kragt"
    },
    {
      "affiliations": [
        "Department of Neurology, Spaarne Gasthuis, Haarlem, Netherlands"
      ],
      "name": "Marijke Eurelings"
    },
    {
      "affiliations": [
        "Department of Neurology, Ziekenhuisgroep Twente, Almelo, Netherlands"
      ],
      "name": "Jessie van Genugten"
    },
    {
      "affiliations": [
        "Department of Neurology, Ommelander Hospital Groningen, Scheemda, Netherlands"
      ],
      "name": "Jessica Nielsen"
    },
    {
      "affiliations": [
        "Department of Neurology, Medical Centre Leeuwarden, Leeuwarden, Netherlands"
      ],
      "name": "L G F Sinnige"
    },
    {
      "affiliations": [
        "Department of Neurology, Wilhelmina Ziekenhuis Assen, Assen, Netherlands"
      ],
      "name": "Mark E Kloosterziel"
    },
    {
      "affiliations": [
        "Department of Neurology, Elisabeth-TweeSteden Ziekenhuis, Tilburg, Netherlands"
      ],
      "name": "Edo P J Arnoldus"
    },
    {
      "affiliations": [
        "Department of Neurology, Diakonessenhuis Utrecht Zeist Doorn Locatie Utrecht, Utrecht, Netherlands"
      ],
      "name": "Willem H Bouvy"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Eva M Strijbis"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Bob van Oosten"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands",
        "Quality of Care, Amsterdam Public Health Research Institute, Amsterdam, Netherlands"
      ],
      "name": "Brigit A De Jong"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Bernard M J Uitdehaag"
    },
    {
      "affiliations": [
        "Department of Epidemiology and Data Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands"
      ],
      "name": "Birgit I Lissenberg-Witte"
    },
    {
      "affiliations": [
        "Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands"
      ],
      "name": "Floris C Loeff"
    },
    {
      "affiliations": [
        "Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands",
        "Diagnostic Services, Sanquin Research, Amsterdam, Netherlands"
      ],
      "name": "Theo Rispens"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Joep Killestein"
    },
    {
      "affiliations": [
        "Department of Neurology, MS Center, Amsterdam UMC De Boelelaan Site, Amsterdam, Netherlands"
      ],
      "name": "Zoé L E van Kempen"
    }
  ],
  "title": "Low natalizumab trough concentrations are associated with reduced seroconversion of the John Cunningham virus in natalizumab-treated patients with multiple sclerosis",
  "uid": "7bbc46d1-2f98-58c1-a8c7-47902f3176c9"
}