New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab
Authors: Toboso Inmaculada , Tejeda-Velarde Amalia , Alvarez-Lafuente Roberto , Arroyo Rafael , Hegen Harald , Deisenhammer Florian , Sainz de la Maza Susana , Alvarez-Cermeño José C. , Izquierdo Guillermo , Paramo Dolores , Oliva Pedro , Casanova Bonaventura , Agüera-Morales Eduardo , Franciotta Diego , Gastaldi Matteo , Fernández Oscar , Urbaneja Patricia , Garcia-Dominguez José M. , Romero Fernando , Laroni Alicia , Uccelli Antonio , Perez-Sempere Angel , Saiz Albert , Blanco Yolanda , Galimberti Daniela , Scarpini Elio , Espejo Carmen , Montalban Xavier , Rasche Ludwig , Paul Friedemann , González Inés , Álvarez Elena , Ramo Cristina , Caminero Ana B. , Aladro Yolanda , Calles Carmen , Eguía Pablo , Belenguer-Benavides Antonio , Ramió-Torrentà Lluis , Quintana Ester , Martínez-Rodríguez José E. , Oterino Agustín , López de Silanes Carlos , Casanova Luis I. , Landete Lamberto , Frederiksen Jette , Bsteh Gabriel , Mulero Patricia , Comabella Manuel , Hernández Miguel A. , Espiño Mercedes , Prieto José M. , Pérez Domingo , Otano María , Padilla Francisco , García-Merino Juan A. , Navarro Laura , Muriel Alfonso , Frossard Lucienne Costa , Villar Luisa M. 
Published: December 2020

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression.

Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from &lt;1/3,300 in patients with anti-John Cunninghan virus antibody indices &lt;0.9 and relapse rate &gt;0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from &lt;1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices &lt;0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case.

Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.