Virus-specific effects of disease-modifying therapies on herpesvirus antibody titers in multiple sclerosis

Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6) have both been implicated in multiple sclerosis (MS), yet it remains unclear whether disease-modifying therapies (DMTs) shape antiviral humoral responses. We analyzed antiviral IgG titers in MS patients stratified by current DMT (N = 498 for HHV-6A/B, 410 for EBNA-1, 361 for cytomegalovirus (CMV)). Multivariable regression models were built separately for each virus, adjusting for age, sex, HLA-DRB1*15:01 carriage, EDSS, treatment duration, and prior treatment efficacy, using interferon-beta (IFN-beta) as the reference category.

The HHV-6A/B model showed a significant global fit (p = 1.16 × 10^-6), with fingolimod independently associated with reduced titers relative to IFN-beta (p = 0.006), alongside negative effects of age (p = 0.001) and higher titers among HLA-DRB1*15:01 carriers (p = 0.028). Neither the EBNA-1 nor the CMV model reached global significance, although age remained a strong predictor of CMV IgG (p = 0.002). These findings indicate that DMTs do not exert a uniform effect on herpesvirus serology in MS: fingolimod is specifically associated with attenuated HHV-6A/B seroreactivity, whereas EBNA-1 and CMV titers appear to be governed mainly by host factors.

Interpreting antiviral serology in MS from a treatment-stratified perspective may therefore be necessary to identify biologically significant signals specific to each drug. MAGM has a technician contract from “REI: Red de Enfermedades Inflamatorias” (RD24/0007/0017). This work was financially supported by Ministerio de Ciencia e Innovación (Proyectos de generación de conocimiento)-Fondo Europeo de Desarrollo Regional (Feder) (PID2021-126041OB-I00), “Esclerosis Múltiple España” and “Fundación LAIR”.

Environmental Factors in Degenerative Diseases Research Group, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain Stefano Ruberto, María I. Domínguez-Mozo, Isabel Ortega-Madueño, Guadalupe Pérez de Villar, Andrea Alonso-Garrido, Iván Pérez-Gutiérrez, María A. García-Martínez & Roberto Álvarez-Lafuente Red de Enfermedades Inflamatorias (REI), Red Española de Esclerosis Múltiple, Madrid, Spain María I.

Domínguez-Mozo & Roberto Álvarez-Lafuente Servicio de Inmunología, Red de Enfermedades Inflamatorias (REI), Hospital Universitario Ramón y Cajal, ISCIII, Red Española de Esclerosis Múltiple, IRYCIS, Madrid, Spain Servicio de Neurología, Red de Enfermedades Inflamatorias (REI), Hospital Universitario Ramón y Cajal, ISCIII, Red Española de Esclerosis Múltiple, IRYCIS, Madrid, Spain Servicio de Neurología, Hospital Universitario de Getafe. / Instituto de Investigación IdiPAZ, Universidad Europea Madrid, Madrid, Spain Department of Neurology, University Hospital Torrejón, Torrejón de Ardoz, Spain School of Medicine, Francisco de Vitoria University, Madrid, Spain Servicio de Neurología, Hospital General Universitario Gregorio Marañón / Red de Enfermedades Inflamatorias (REI), Madrid, Spain María Luisa Martínez-Ginés & José Manuel García-Domínguez Departamento de Neurología, Hospital Universitario Quirónsalud Madrid, Madrid, Spain Stefano Ruberto, María Inmaculada Domínguez-Mozo, Noelia Villarrubia, Isabel Ortega Madueño, Guadalupe Pérez de Villar, Andrea Alonso Garrido, Iván Pérez-Gutiérrez and María Ángel García-Martínez: nothing to disclose. Luisa María Villar: has served at scientific advisory boards, participated in meetings sponsored by, received speaking honoraria or travel funding or research grants from Roche, Sanofi, Merck, Biogen, Bristol Myers, and Novartis. Lucienne Costa-Frossard: reports compensation for consulting services and speaker honoraria from Biogen, Bristol Myers Squibb, Janssen, Merck-Serono, Novartis, Sanofi, Roche, and Teva.

Yolanda Aladro: has received research grants, travel support and lecturing and consulting fees from: Teva, Biogen, Roche, Merck, Novartis, Almirall, Sanofi-Genzime, Janssen and Bristol Myers Squibb. Ignacio Casanova-Peño: has received payments for consulting services from Novartis and Merck, speaking honoraria from Merck, Novartis, Sanofi, and Neuraxpharm, support for attending meetings from Merck, and research grants from TEVA and Sanofi. María Luisa Martínez-Ginés: has received compensation for consulting services and speaking fees from Merck, Biogen, Novartis, Sanofi-Genzyme, Almirall, ROCHE, BMS, Juvisé and TEVA.