Inmaculada Toboso1, Amalia Tejeda-Velarde1, Roberto Alvarez-Lafuente2, Rafael Arroyo3, Harald Hegen4, Florian Deisenhammer4, Susana Sainz de la Maza5, José C Alvarez-Cermeño5, Guillermo Izquierdo6, Dolores Paramo6, Pedro Oliva7, Bonaventura Casanova8, Eduardo Agüera-Morales9, Diego Franciotta10, Matteo Gastaldi10, Oscar Fernández11, Patricia Urbaneja11, José M Garcia-Dominguez12, Fernando Romero12, Alicia Laroni13, Antonio Uccelli13, Angel Perez-Sempere14, Albert Saiz15, Yolanda Blanco15, Daniela Galimberti16, Elio Scarpini16, Carmen Espejo17, Xavier Montalban17, Ludwig Rasche18, Friedemann Paul18,19, Inés González20, Elena Álvarez20, Cristina Ramo21, Ana B Caminero22, Yolanda Aladro23, Carmen Calles24, Pablo Eguía25, Antonio Belenguer-Benavides26, Lluis Ramió-Torrentà27, Ester Quintana27, José E Martínez-Rodríguez28, Agustín Oterino29, Carlos López de Silanes30, Luis I Casanova30, Lamberto Landete31, Jette Frederiksen32, Gabriel Bsteh4, Patricia Mulero17, Manuel Comabella17, Miguel A Hernández33, Mercedes Espiño1, José M Prieto34, Domingo Pérez35, María Otano36, Francisco Padilla37, Juan A García-Merino38, Laura Navarro39, Alfonso Muriel40, Lucienne Costa Frossard5, Luisa M Villar1. 1. Immunology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain. 2. Instituto de Investigación Sanitaria San Carlos (IDISSC), Hospital Clinico San Carlos, Madrid, Spain. 3. Department of Neurology, Hospital Universitario Quiron Salud, Madrid, Spain. 4. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria. 5. Neurology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain. 6. Neurology Department, Hospital Universitario Virgen Macarena, Sevilla, Spain. 7. Neurology Department, Hospital Universitario Central de Asturias, Oviedo, Spain. 8. Neurology Department, Hospital Universitario la Fe, Valencia, Spain. 9. Neurology Department, Hospital Universitario Reina Sofia, Cordoba, Spain. 10. Istituti di Recovero e Cura a Carattere Scientifico (IRCCS) Mondino Foundation, Pavia, Italy. 11. Neurology Department, Hospital Regional Universitario, Malaga, Spain. 12. Neurology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain. 13. University of Genoa, Ospedale Policlinico San Martino, Genoa, Italy. 14. Neurology Department, Hospital General Universitario de Alicante, Alicante, Spain. 15. Neurology Service, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain. 16. Centro Dino Ferrari, Fondazione Ca' Granda, Istituti di Recovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico, University of Milan, Milan, Italy. 17. Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya, Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain. 18. Department of Neurology, NeuroCure Clinical Research Center, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany. 19. Experimental and Clinical Research Center, Charité-Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine, Berlin, Germany. 20. Neurology Department, Hospital Alvaro Cunqueiro, Vigo, Spain. 21. Neurology Department, Hospital Germans Trias i Pujol, Badalona, Spain. 22. Neurology Department, Hospital Nuestra Señora de Sonsoles, Avila, Spain. 23. Neurology Department, Hospital Universitario Getafe, Getafe, Spain. 24. Neurology Department, Hospital Universitario Son Espases, Palma de Mallorca, Spain. 25. Neurology Department, Hospital Doctor Jose Molina Orosa, Arrecife, Spain. 26. Neurology Department, Hospital General Universitario de Castellón, Castellón, Spain. 27. Neurology Department, Hospital Universitario Doctor Josep Trueta, Girona, Spain. 28. Neurology Department, Hospital del Mar, Barcelona, Spain. 29. Neurology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain. 30. Neurology Department, Hospital Universitario de Torrejón, Torrejón de Ardoz, Spain. 31. Neurology Department, Hospital Universitario Dr. Peset, Valencia, Spain. 32. Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark. 33. Neurology Department, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain. 34. Neurology Department, Hospital Clínico de Santiago, Santiago de Compostela, Spain. 35. Neurology Department, Hospital del Bierzo, Ponferrada, Spain. 36. Neurology Department, Complejo Hospitalario de Navarra, Pamplona, Spain. 37. Neurology Department, Hospital Clinico de Malaga, Malaga, Spain. 38. Neurology Department, Hospital Puerta de Hierro, Majadahonda, Madrid, Spain. 39. Neurology Department, Hospital General de Elche, Elche, Spain. 40. Biostatistics Unit, Hospital Univesitario Ramon y Cajal, Instituto Ramon y Cajal para la Investigación Sanitaria (IRYCIS), Madrid, Spain.
Abstract
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 <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >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 <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <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.
Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosispatients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosispatients (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 <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >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 <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <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 sclerosispatients, as predictors of progressive multifocal leucoencephalopathy.
Authors: Carmen Picón; Amalia Tejeda-Velarde; José Ignacio Fernández-Velasco; Manuel Comabella; Roberto Álvarez-Lafuente; Ester Quintana; Susana Sainz de la Maza; Enric Monreal; Noelia Villarrubia; José Carlos Álvarez-Cermeño; María Inmaculada Domínguez-Mozo; Lluís Ramió-Torrentà; Eulalia Rodríguez-Martín; Ernesto Roldán; Yolanda Aladro; Silvia Medina; Mercedes Espiño; Jaime Masjuan; Clara Matute-Blanch; Marta Muñoz-San Martín; Carmen Espejo; Carmen Guaza; Alfonso Muriel; Lucienne Costa-Frossard; Luisa María Villar Journal: Front Immunol Date: 2021-07-12 Impact factor: 7.561
Authors: Bethany A O'Hara; Gretchen V Gee; Sheila A Haley; Jenna Morris-Love; Charlotte Nyblade; Chris Nieves; Barbara A Hanson; Xin Dang; Timothy J Turner; Jeffrey M Chavin; Alex Lublin; Igor J Koralnik; Walter J Atwood Journal: Int J Mol Sci Date: 2021-09-10 Impact factor: 5.923