Visible Progress: How Biomarkers Are Re-shaping Multiple Sclerosis Care

Disease-modifying therapies have revolutionised relapsing–remitting MS, yet 30–40 % of patients gain little from first-line interferon-β or glatiramer acetate. Traditional metrics—annual relapse rate, EDSS changes and new MRI lesions—often register damage only after axonal loss is irreversible. Fluid biomarkers promise earlier warning, allowing faster treatment switches and shorter clinical trials by giving objective read-outs within months rather than years.

Qualities of an ideal biomarker
Harris & Sadiq highlight four practical tests. A candidate should: (1) map onto a known MS mechanism; (2) be measurable in easily obtained fluids (serum preferred, CSF acceptable); (3) change predictably when therapy works; and (4) deliver reproducible results across laboratories that use standardised pre-analytics.

Drug immunogenicity: neutralising antibodies
Persistent neutralising antibodies (NAbs) against interferon-β or natalizumab diminish drug efficacy and justify switching therapy. Up to 47 % of subcutaneous IFN-β-1b users and roughly 9 % of natalizumab users develop NAbs within six months. Routine screening is already standard practice.

Inflammatory activity: fetuin-A and osteopontin
Fetuin-A concentrations in CSF rise during active disease and fall steeply in natalizumab responders within a year, whereas non-responders show little change. Osteopontin, abundant in MS plaques, mirrors relapse severity and likewise declines on natalizumab—together providing a window on ongoing inflammation that MRI may miss.

Oxidative stress: 8-iso-prostaglandin-F₂α
About one-third of patients with secondary-progressive MS show CSF levels of 8-iso-PGF₂α that far exceed those seen in relapsing disease. This subgroup may benefit disproportionately from antioxidants such as dimethyl fumarate, underscoring the heterogeneity of pathophysiological drivers in MS.

B-cell chemo-attraction: CXCL13
High CXCL13 in CSF predicts rapid conversion from clinically isolated syndrome to MS and drops markedly after B-cell-depleting rituximab or natalizumab. Its dynamic range and mechanistic specificity make CXCL13 one of the most promising response biomarkers now nearing clinical adoption.

Axonal injury: neurofilament light and heavy chains
Neurofilament levels spike during acute relapses and correlate with future disability. Both natalizumab and rituximab reduce CSF NFL roughly three-fold within a year, signalling reduced axonal loss. Commercial serum assays, validated since the 2014 review, are poised to replace lumbar puncture for routine monitoring.

Progression risk: CHI3L1 (YKL-40)
Elevated CSF YKL-40 in clinically isolated syndrome heralds faster conversion to RRMS and greater MRI lesion dissemination. Levels also fall after one year of natalizumab, linking this glycoprotein to both prognosis and treatment response.

Multi-omic approaches on the horizon
Harris & Sadiq anticipated the current pivot from single analytes to molecular signatures. Transcriptomic profiling reveals interferon-stimulated gene over-expression and Th-17 skewing in non-responders, while microRNA panels (e.g., miR-29 family suppression by IFN-β) and extracellular vesicle cargo profiling are emerging as complementary layers. High-density antigen and lipid arrays, although technically demanding, may one day tailor therapy to individual antibody repertoires.

What is clinically ready today?
NAbs testing is entrenched. CSF—and increasingly serum—neurofilament has crossed into everyday practice, supported by commercial assays and reference ranges. CXCL13 and fetuin-A remain in the research domain but are edging closer to approval as assay standardisation improves.

Practical lessons for clinicians
A panel that combines inflammation (CXCL13), axonal damage (NFL) and oxidative stress (8-iso-PGF₂α) provides a richer picture than any single marker. Phenotype matters: fetuin-A is informative in relapsing and secondary-progressive MS but not primary-progressive disease. Interpret changes in the therapeutic context—declining NFL on natalizumab is reassuring, whereas the same drop during a purely remyelinating trial might be irrelevant. Above all, harmonised collection, storage and assay protocols are essential for reproducibility.

Looking forward
The authors concluded that no solitary biomarker will suffice for comprehensive disease monitoring, a prediction vindicated by the subsequent decade. Neurofilament has broken through; CXCL13 is not far behind; and multiplex signatures integrating proteomic, transcriptomic and lipidomic data are maturing rapidly. Together they promise to transform the aspirational goal of “no evidence of disease activity” into a measurable, actionable target for everyone living with MS.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Harris, V.K., Sadiq, S.A. Biomarkers of Therapeutic Response in Multiple Sclerosis: Current Status. Mol Diagn Ther 18, 605–617 (2014).