Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab.
Villar, Luisa M. PhD 1,2; Costa-Frossard, Lucienne MD 2,3; Masterman, Thomas MD 4; Fernandez, Oscar MD 2,5; Montalban, Xavier MD 2,6; Casanova, Bonaventura MD 2,7; Izquierdo, Guillermo MD 2,8; Coret, Francisco MD 2,9; Tumani, Hayrettin MD 10; Saiz, Albert MD 2,11; Arroyo, Rafael MD 2,12; Fink, Katharina MD 4; Leyva, Laura PhD 2,5; Espejo, Carmen PhD 2,6; Simo-Castello, Maria PhD 2,7; Garcia-Sanchez, Maria I. PhD 2,8; Lauda, Florian MD 10; Llufriu, Sara MD 2,11; Alvarez-Lafuente, Roberto PhD 2,12; Olascoaga, Javier MD 2,13; Prada, Alvaro MD 2,14; Oterino, Agustin MD 15; de Andres, Clara MD 2,16; Tintore, Mar MD 2,6; Ramio-Torrenta, Lluis MD 2,17; Rodriguez-Martin, Eulalia PhD 1,2; Picon, Carmen BSci 1,2; Comabella, Manuel MD 2,6; Quintana, Ester PhD 17; Aguera, Eduardo MD 18; Diaz, Santiago MD 19; Fernandez-Bolanos, Ricardo MD 20; Garcia-Merino, Juan A. MD 2,21; Landete, Lamberto MD 22; Menendez-Gonzalez, Manuel MD 23; Navarro, Laura MD 24; Perez, Domingo MD 25; Sanchez-Lopez, Fernando MD 18; Serrano-Castro, Pedro J. MD 26; Tunon, Alberto MD 27; Espino, Mercedes PhD 1,2; Muriel, Alfonso BSci 28; Bar-Or, Amit MD 29; Alvarez-Cermeno, Jose C. MD 2,3
[Article]
Annals of Neurology.
77(3):447-457, March 2015.
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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).
Interpretation: 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. Ann Neurol 2015;77:447-457
(C) 2015 John Wiley & Sons, Ltd