Review: Precision Medicine for Multiple Sclerosis

More than 20 disease-modifying drugs have been approved for multiple sclerosis (MS), but the disease is now known to be quite heterogeneous in treatment response and course.

Key decision points in MS management would therefore benefit from precision medicine—the use of information about an individual’s genomics, environment, and lifestyle, not just their signs and symptoms—to subtype their disease and make personalized decisions about their treatment.

In Multiple Sclerosis Journal, Tanuja Chitnis, MD, co-director of the Multiple Sclerosis Center at Brigham and Women’s Hospital, and Alexandre Prat, MD, of the University of Montreal, review the principles of precision medicine, emerging biological markers, and the evolving role of biomarkers in decision-making about MS management.

Disease Prevention Biomarkers

Over 200 genetic markers of MS susceptibility have been identified genome-wide. Environmental and lifestyle risk factors include hypovitaminosis D, Epstein–Barr virus seropositivity, obesity in adolescence, smoking, and sleep–wake cycle disturbance. Machine learning and other forms of artificial intelligence may allow the creation of composite genetic, clinical, and biomarker algorithms that predict MS risk for individuals.

Diagnostic Biomarkers

Clinical and MRI features that predict the development of MS after a first clinical attack or clinically isolated syndromes are critical to the early diagnosis of MS. These include age at onset, oligoclonal bands, the number of T2 lesions, serum neurofilament light chains (NFL), and astrocyte-derived chitinase-3–like protein 1 (CHI3L1) in cerebrospinal fluid.

Proteomic and metabolomic biomarkers are also under investigation. Finally, there’s growing evidence some patients have radiologically isolated syndromes, without clinical symptoms. In this subgroup, spinal cord MRI lesions suggest a high risk of a first clinical event.

Prognostic Biomarkers

Despite the many alleles associated with MS susceptibility, there’s been little progress in finding genetic links to disease course. The largest study of disease severity to date, published in Neurology Genetics, failed to find any genetic association, and no biochemical biomarker of MS disease course has been identified.

However, several biomarkers have shown consistent prognostic utility in multiple studies or large studies with validation cohorts:

  • NFL levels in cerebrospinal fluid (CSF) have been associated with conversion to MS, disability, and MRI correlates
  • Serum NFL levels correlate with CSF levels and inflammatory activity and, in part, with long-term brain atrophy
  • Glial fibrillary acidic protein levels in CSF have been associated with disability accrual
  • CHI3L1 levels in CSF have predicted conversion to MS and have been linked to disability accrual

Biomarkers of Treatment Response

An important objective of precision medicine is the ability to determine whether an individual patient will respond better to one class of drug than another. Several groups have identified pharmacogenomic/genetic markers associated with better response to beta-interferon or glatiramer acetate. Other research examines circulating microRNA, serum antibody profiles, and proteomic and metabolomic markers.

Ultimately a biomarker panel or composite biomarker may be required that reflects the different stages of the disease.

Biomarkers of Treatment Safety

Pharmacogenomics is also being applied to MS drug safety given the possibility of serious side effects, notably progressive multifocal leukoencephalopathy (PML) and secondary autoimmunity.

Various biomarkers of PML susceptibility are being tested, including JC virus antibodies, CD62L expression, and the combination of JC virus index thresholds and prior immunosuppressant use. Pharmacogenomic risk factors for other common adverse events need to be ascertained.

Disease Progression Biomarkers

Several mechanisms underlie MS progression independent of relapses, including diffuse microglial activation, astrocyte dysfunction, mitochondrial dysfunction, and axonal damage with Wallerian and retrograde degeneration. Measuring NFL in serum and CSF and measuring glutamate by spectroscopy might guide treatments that target these specific mechanisms.

The authors also discuss various approaches to outcomes measurement in MS, the potential to create precision management algorithms, and the future of MS therapeutics.

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