Targeting progressive multiple sclerosis: Toward mechanism-informed precision medicine

Area of Science:

• Neuroimmunology
• Neurology
• Clinical Therapeutics

Background:

• Modern disease-modifying therapies (DMTs) significantly reduce relapses and MRI-detected inflammation in multiple sclerosis (MS).
• Disability progression in MS increasingly occurs independently of relapses, indicating a critical unmet need in understanding progression biology.
• Epstein-Barr virus (EBV) is implicated in MS initiation, while later stages involve intrinsic brain mechanisms like inflammation, demyelination, and aging.

Purpose of the Study:

• To review the therapeutic revolution in multiple sclerosis over the past three decades.
• To highlight the unmet need in addressing disability progression independent of relapse activity.
• To discuss emerging biomarkers and novel therapeutic strategies for progressive MS.

Main Methods:

• Review of randomized clinical trials and real-world data on MS therapies.
• Analysis of epidemiological and molecular evidence linking Epstein-Barr virus (EBV) to MS.
• Evaluation of emerging biomarkers (e.g., NfL, GFAP, MRI metrics) for monitoring MS progression.
• Assessment of novel therapeutic approaches targeting inflammation and disease biology.

Main Results:

• DMTs substantially reduce relapse rates and MRI-detected inflammation in MS.
• Disability progression in MS is increasingly independent of relapses, especially after midlife.
• Emerging biomarkers enable more precise monitoring of progressive pathology.
• New therapies targeting inflammation and intrinsic brain mechanisms show promise.

Conclusions:

• Future MS management must shift towards mechanism-informed algorithms for personalized treatment.
• Addressing disability progression requires targeting compartmentalized inflammation, remyelination failure, and accelerated aging.
• Integration of biomarkers, genetics, and machine learning will enhance benefit-risk stratification for MS patients.