title: Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.
abstract: OBJECTIVE
  Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML.
  
  
  METHODS
  We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain.
  
  
  RESULTS
  IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2).
  
  
  CONCLUSIONS
  The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.
authors.affiliation: Department of Immunology, Ramón y Cajal University Hospital, Institute Ramon y Cajal for Biomedical Research, Madrid, Spain; Spanish Network for the Research in Multiple Sclerosis, Spain.
authors.forename: Luisa M
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authors.forename: Lucienne
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authors.lastname: Costa-Frossard
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authors.lastname: Masterman
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authors.lastname: Prada
authors.forename: Agustín
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authors.forename: Clara
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authors.lastname: de Andrés
authors.forename: Mar
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authors.lastname: Tintoré
authors.forename: Lluis
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authors.lastname: Ramió-Torrentà
authors.forename: Eulalia
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authors.lastname: Rodríguez-Martín
authors.forename: Carmen
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authors.lastname: Picón
authors.forename: Manuel
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authors.lastname: Comabella
authors.forename: Ester
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authors.lastname: Quintana
authors.forename: Eduardo
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authors.lastname: Agüera
authors.forename: Santiago
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authors.lastname: Díaz
authors.forename: Ricardo
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authors.lastname: Fernandez-Bolaños
authors.forename: Juan A
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authors.lastname: García-Merino
authors.forename: Lamberto
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authors.lastname: Landete
authors.forename: Manuel
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authors.lastname: Menéndez-González
authors.forename: Laura
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authors.lastname: Navarro
authors.forename: Domingo
authors.initials: D
authors.lastname: Pérez
authors.forename: Fernando
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authors.lastname: Sánchez-López
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: Serrano-Castro
authors.forename: Alberto
authors.initials: A
authors.lastname: Tuñón
authors.forename: Mercedes
authors.initials: M
authors.lastname: Espiño
authors.forename: Alfonso
authors.initials: A
authors.lastname: Muriel
authors.forename: Amit
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authors.lastname: Bar-Or
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authors.initials: JC
authors.lastname: Álvarez-Cermeño
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D007577:JC Virus / Q000276:immunology; D007968:Leukoencephalopathy, Progressive Multifocal / Q000134:cerebrospinal fluid* / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000188:drug therapy; D000069442:Natalizumab; D043025:Oligoclonal Bands / Q000134:cerebrospinal fluid*; D012306:Risk
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D000069442:Natalizumab; D043025:Oligoclonal Bands