PT  - JOURNAL ARTICLE
AU  - Manuel Comabella
AU  - Mar Tintore
AU  - Augusto Sao Avilés
AU  - Pere Carbonell-Mirabent
AU  - Sunny Malhotra
AU  - Alex Rovira
AU  - Nicolás Fissolo
AU  - Jan D Lünemann
AU  - Xavier Montalban
TI  - Increased cytomegalovirus immune responses at disease onset are protective in the long-term prognosis of patients with multiple sclerosis
AID  - 10.1136/jnnp-2022-330205
DP  - 2023 Mar 01
TA  - Journal of Neurology, Neurosurgery & Psychiatry
PG  - 173--180
VI  - 94
IP  - 3
4099  - http://jnnp.bmj.com/content/94/3/173.short
4100  - http://jnnp.bmj.com/content/94/3/173.full
SO  - J Neurol Neurosurg Psychiatry2023 Mar 01; 94
AB  - Objective It remains unclear whether viral infections interfere with multiple sclerosis (MS) disease progression. We evaluated the prognostic role of antibody responses toward viruses determined at disease onset on long-term disease outcomes.Methods Humoral immune responses against Epstein-Barr virus (EBV)-encoded nuclear antigen EBNA1, viral capsid antigen (VCA) and early antigen, and toward cytomegalovirus (HCMV), human herpesvirus 6 and measles were investigated in a cohort of 143 patients with MS for their association with long-term disability and inflammation disease outcomes.Results Median (IQR) follow-up was 20 (17.2–22.8) years. In univariable analysis, increased HCMV levels were associated with a lower risk to Expanded Disability Status Scale 4.0 (HR 0.95; 95% CI 0.91 to 0.99; p=0.03), to develop a secondary progressive MS (HR 0.94; 95% CI 0.90 to 0.99; p=0.02) and to first-line treatment (HR 0.98; 95% CI 0.96 to 0.99; p=0.04). High HCMV IgG levels were associated with a longer time to first-line treatment (p=0.01). Increased immune responses against EBV-VCA were associated with higher risk for first-line (HR 1.45; 95% CI 1.12 to 1.88; p=0.005) and second-line treatments (HR 2.03; 95% CI 1.18 to 3.49; p=0.01), and high VCA IgG levels were associated with shorter time to first-line (p=0.004) and second-line (p=0.02) therapies. EBNA1-specific IgG levels correlated with disease severity (0.17; p=0.04) and with an increased relapse rate during follow-up (relapse rate 1.26; 95% CI 1.03 to 1.56; p=0.02) that remained stable in multivariable analysis.Conclusions These results indicate that elevated immune responses against HCMV at disease onset have protective effects on long-term disability and inflammation disease outcomes. Our data also indicate that increased immune responses against EBV in early phases may influence long-term disease prognosis.Data are available on reasonable request.