Latest developments in MS research:
1. Do signs of MS show up in healthcare data decades before diagnosis?
2. Do blood biomarkers hold the key to predicting disability worsening in progressive MS?
3. How reliable are JCV antibody tests in assessing PML risk for MS patients on biosimilar natalizumab?
These noteworthy MS news highlights and more are included in our recently published ECTRIMS Research Updates – a 30-day snapshot of global news and publications on MS research, treatment, and care.
ECTRIMS Research Updates can be sent to you every month, delivered straight to your inbox, via our free subscription service. Simply select all “topics” that are of interest to you, and when one of those appears in our news and publication cycle, you’ll be sure to hear from us.
Pathogenesis
The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis
Interferon-induced immunoproteasome drastically decreases proteasomal activity in neurons, leading to a switch in neuronal metabolism with increased oxidative injury and ferroptosis.
A collaborative work between the INIMS and the Meyer-Schwesinger lab shows that interferon-induced PSMB8, an immunoproteasome subunit, occurs in inflamed neurons. Its integration into the proteasome reduces overall proteasome activity, leading to the accumulation of PFKFB3, a key metabolic regulator.
This triggers a metabolic shift toward glycolysis, oxidative stress, and ferroptosis – a form of programmed cell death. Importantly, both genetic deletion and pharmacological inhibition of PSMB8 or its downstream target PFKFB3 offered neuroprotection in vitro and in a mouse model of MS, highlighting a promising pathway for therapy.
PIRA
Standardized Definition of Progression Independent of Relapse Activity (PIRA) in Relapsing-Remitting Multiple Sclerosis
Incidence and persistence of PIRA may depend on the specific definition used.
In a comprehensive analysis of 360 definitions, the authors demonstrate that how PIRA is defined significantly impacts its reported incidence and persistence. To address this, they propose a harmonised definition that incorporates re-baselining after PIRA events, relapses, and EDSS improvements; requires disability worsening in the absence of relapses since the previous EDSS; confirmation that the worsening persists above threshold for at least 12-month; and considers only EDSS scores recorded more than 30 days after preceding relapses.
Their approach, designed to balance sensitivity and specificity to persisting disability worsening, is available through the MSoutcomes R package to support consistent application across a broad spectrum of MS study designs.
Imaging and Non-Imaging Biomarkers
Blood biomarkers for predicting disability worsening in progressive multiple sclerosis: a multinational, individual participant-level analysis
JNNP | June 2025
International collaboration identifies a prognostic value of serum GFAP and NfL in people with progressive MS.
This large international study, using individual participant data from over 1,000 people with progressive MS (pwPMS), investigated the prognostic value of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) for confirmed disability worsening (CDW).
The authors found that higher GFAP levels were associated with increased risk of future CDW – particularly in individuals with secondary progressive MS. In contrast, elevated NfL predicted CDW only in participants with primary progressive MS.
These findings suggest a distinct prognostic role for each biomarker, depending on MS subtype, and highlight their potential for personalised risk stratification in progressive MS.
Broad rim lesions are a new pathological and imaging biomarker for rapid disease progression in multiple sclerosis
Broad rim lesions identified as a biomarker of rapid MS progression.
While current MS therapies reduce relapse rates, they do little to slow disease progression.
Researchers analysed brain tissue from 186 individuals with MS from the Netherland Brain Bank and found a specific lesion type – marked by an extensive rim of activated myeloid cells – with signs of innate immune activation, inflammatory cytokine production, and apoptosis. These lesions were linked to faster disease progression.
An independent PET imaging study of 114 individuals confirmed the association between these lesions and disease progression.
The findings suggest broad rim lesions could serve as a biomarker for rapid MS progression, supporting better patient selection for future trials.
Therapeutics
A comparison of JC virus assay performance provided with originator and biosimilar natalizumab
Multiple Sclerosis Journal | June 2025
UK data demonstrate non concordance between different JCV tests.
JC virus (JCV) can cause progressive multifocal leukoencephalopathy (PML) – a rare but severe brain infection – in immunosuppressed individuals, including people treated with natalizumab. Risk can be stratified based on JCV antibody status, and current risk calculators rely on cohort data tested using different JCV assays.
UK data with 497 people with MS – who switched from natalizumab to biosimilar natalizumab – demonstrate non concordance between different JCV tests. Nearly 48% of patients who previously tested negative on one JCV antibody assay were reclassified as positive using another.
This discrepancy, particularly at low index values where treatment decisions are most sensitive, raises concerns about PML risk stratification, potentially leading to unnecessary monitoring, increased patient anxiety, and reduced access to highly effective therapy.
The findings highlight the need for coordinated efforts to ensure accurate and consistent testing.
High-Dose Vitamin D in Clinically Isolated Syndrome Typical of Multiple Sclerosis: The D-Lay MS Randomized Clinical Trial
French trial data support the role of high-dose vitamin D in early MS.
Vitamin D deficiency is a known risk factor for MS, but evidence for supplementation as a treatment remains conflicting. The D-Lay MS trial evaluated high-dose oral cholecalciferol (100,000 IU every two weeks) as monotherapy to reduce disease activity in 316 individuals with clinically isolated syndrome (CIS).
Over 24 months, disease activity occurred in 60.3% of the vitamin D group vs 74.1% in the placebo group, with a significant delay in time to disease activity.
These results suggest that pulse high-dose vitamin D may reduce disease activity in CIS and early relapsing-remitting MS, supporting its further investigation as an add-on therapy.
Clinical
Phenotyping Healthcare Use 2–3 Decades Before the First Multiple Sclerosis Demyelinating Event
Annals of Clinical and Translational Neurology | June 2025
People who develop MS show increased healthcare use up to 28 years before diagnosis.
In this study using population-based administrative data from Ontario, researchers compared healthcare use up to 28 years before MS onset between over 35,000 people with MS and matched controls. They found that physician visits related to mental health and ill-defined signs/symptoms were consistently elevated as early as 28 years pre-diagnosis. Visits for nervous system, musculoskeletal, injury-related, respiratory, and digestive conditions were also higher 22–24 years before MS onset.
These findings suggest that subtle, system-wide health differences emerge long before a first demyelinating event, offering insight into the prodromal phase of MS and the potential for earlier identification.