Epstein-Barr Virus Antibodies to Differentiate Multiple Sclerosis From Other Neuroinflammatory Diseases

Year: 2026

Type: article

Abstract: Importance: Differentiating multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), especially in seronegative cases, remains challenging due to overlapping clinical and imaging features. High-level Epstein-Barr virus (EBV)-derived Epstein-Barr nuclear antigen 1 (EBNA-1) peptide antibody titers may be an MS-specific biomarker that could the improve differential diagnosis. Objective: To determine whether longitudinal EBNA-1 peptide antibodies can distinguish MS from MOGAD and NMOSD. Design, Setting, and Participants: This was a retrospective, multicenter, longitudinal, case-control study with patients from Austria, Germany, and the US. This study assessed samples from 2 independent retrospective cohorts. A test cohort and a validation cohort assessed longitudinal plasma samples from patients with MS, MOGAD, or NMOSD. Patients were recruited between 2001 and 2023 and followed up for 2 years. A combined analysis of both cohorts was conducted in January 2025. Exposures: Plasma EBNA-1 peptide immunoglobulin G (IgG) titers measured by enzyme-linked immunosorbent assay after diagnosis and in 3 follow-up samples. Main Outcomes and Measures: Diagnostic utility of persistent EBNA-1 peptide antibody levels across 4 time points in patients with MS compared with patients with MOGAD and NMOSD. Results: This study included the plasma samples of 2091 patients (mean [SD] age, 31.0 [16.9] years; 1137 female [54.4%]) with neuroinflammatory disease and 1976 healthy controls (mean [SD] age, 39.8 [16.2] years; 1120 male [56.7%]) recruited between 2001 and 2023. The test cohort (310 patients; 54.8% female) included 184 patients with MS, 65 with MOGAD, and 61 with NMOSD (including 12 who were seronegative for aquaporin 4 [AQP4] IgG). The validation cohort (183 patients; 126 female [68.8%]) included 142 patients with MS, 24 with MOGAD, and 17 with NMOSD. In the test cohort, 177 patients with MS (96.2%) had high-level titers in 2 or more of 4 follow-up samples compared with 5 patients (7.7%) with MOGAD (odds ratio [OR], 303.4; 95% CI, 94.4-908.6) and 11 patients (18.0%) with NMOSD (OR, 114.9; 95% CI, 43.0-280.0). Among patients with NMOSD who were seronegative for AQP4-IgG, only 1 (11.1%) had persistent high-level EBNA-1 peptide antibody titers compared with 61 matched patients (96.7%) with MS (OR, 236.0; 95% CI, 18.6-2588.0). In the validation cohort, 135 patients (95.1%) with MS had high-level titers in 2 or more of 4 follow-up samples compared with 4 patients (16.7%) with MOGAD (OR, 96.4; 95% CI, 26.6-293.0) and 3 patients (17.6%) with NMOSD (OR, 90.0; 95% CI, 19.7-319.7). Conclusions and Relevance: Results of this case-control study reveal that persistent high-level EBNA-1 peptide antibody titers may serve as a reliable biomarker for differentiating MS from MOGAD, and NMOSD.

Source: JAMA Neurology

Institutions: Medical University of Vienna, Witten/Herdecke University, Olgahospital, Klinikum Stuttgart, University of California, San Francisco, University of Utah, Boston Children's Hospital, Harvard University, Massachusetts General Hospital, Loma Linda University, Washington University in St. Louis, University at Buffalo, State University of New York, Baylor College of Medicine, Texas Children's Hospital, New York University, Paracelsus Medical University, Innsbruck Medical University, Universität Innsbruck

Language: English

Topic: Multiple Sclerosis Research Studies

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: green

OpenAlex ID: W7134268431