881558

research-article20202020
MSJ0010.1177/1352458519881558Multiple Sclerosis JournalT Chitnis and A Prat

MULTIPLE
SCLEROSIS MSJ
JOURNAL

Special Issue: ACTRIMS 2019

A roadmap to precision medicine Multiple Sclerosis Journal

1­–11

for multiple sclerosis DOI: 10.1177/

https://doi.org/10.1177/1352458519881558
1352458519881558
https://doi.org/10.1177/1352458519881558

© The Author(s), 2020.

Article reuse guidelines:
Tanuja Chitnis and Alexandre Prat sagepub.com/journals-
permissions

Abstract:  Multiple sclerosis (MS) affects approximately 1 million persons in the United States, and is the Correspondence to:
T Chitnis
leading cause of neurological disability in young adults. The concept of precision medicine is now being Partners Multiple Sclerosis
Center, Department of
applied to MS and has the promise of improved care. MS patients experience a variety of neurological Neurology, Brigham and
symptoms, and disease severity ranges from mild to severe, and the biological underpinnings of these Women’s Hospital, 60
Fenwood Road, 9002K,
phenotypes are now starting to be elucidated. Precision medicine involves the classification of disease Boston, MA 02115, USA.
subtypes based on the underlying biology, rather than clinical phenotypes alone, and may govern disease tchitnis@rics.bwh.harvard.
edu
course and treatment response. Over 18 disease-modifying drugs have been approved for the treatment Tanuja Chitnis
of MS, and several biomarkers of treatment response are emerging. This article provides an overview of Partners Multiple Sclerosis
Center, Department of
the concepts of precision medicine and emerging biological markers and their evolving role in decision- Neurology, Brigham and
Women’s Hospital, Boston,
making in MS management. MA, USA/Harvard Medical
School, Boston, MA, USA/
Ann Romney Center for
Keywords:  Multiple sclerosis, biomarkers, patient, disability, precision medicine Neurologic Diseases,
Brigham and Women’s
Hospital, Boston, MA, USA
Date received: 31 August 2019; revised: 15 September 2019; accepted: 17 September 2019. Alexandre Prat
Department of Neurology,
Université de Montréal,
Montréal, QC, Canada

Precision medicine Precision medicine has evolved from genomic analy-

Precision medicine is an evolving paradigm in
medicine predicated on principles described in a
consensus statement by the National Research
Council (US) Committee on A Framework for
Developing a New Taxonomy of Disease. Toward
Precision Medicine:1
•• Describe and define diseases based on their
intrinsic biology in addition to traditional phys-
ical “signs and symptoms.”
•• Go beyond description and be directly linked to
a deeper understanding of disease mechanisms,
pathogenesis, and treatments.
•• Be highly dynamic, at least when used as a
research tool, continuously incorporating
newly emerging disease information.
More recently, an increased emphasis is being placed
on “intrinsic biology” rather than physical signs and
symptoms, which deviates from traditional drug
development, which focused on signs and symptoms.
Now the onus will be on drug manufacturers to not
only demonstrate a measurable effect in patients but
also to develop molecularly targeting therapies with a
clear placement within a systems biology organiza-
tional model of specific diseases.
sis of individual patients to incorporate the following
components:2
•• Predictive.
•• Preventive.
•• Pharmacotherapeutic (incorporating pharma-
cogenetics and pharmacogenomics).
•• Participatory patient (portable and protective).
Multiple sclerosis: overview of treatment and
heterogeneity of disease course
Multiple sclerosis (MS) affects approximately 1 mil-
lion persons in the United States and is the number
one cause of non-traumatic medical disability in
young persons. There have been significant advances
in MS care over the past 15 years in terms of drug
development, as well as improved diagnostic tools
and guidelines.3 MS is the first of the neurodegenera-
tive diseases for which there are an array of Food
and Drug Administration (FDA)-approved disease-
modifying treatments to choose from. This is owed
largely to initiating mechanisms of MS in the periph-
eral immune system, which are the main targets of
most MS therapies. However, it is well recognized
that many of the innate and central nervous system

journals.sagepub.com/home/msj 1
Multiple Sclerosis Journal 00(0)
(CNS)-centric mechanisms of inflammation as well
as neurodegenerative mechanisms are not targeted by
available disease-modifying therapies (DMTs) in MS4
and are critical to the “progressive” mechanisms of
MS. The differing mechanism of action (MOA) of the
different MS drug classes raises the question of
whether different patients will respond better to a spe-
cific therapy. This question has not satisfactorily been
answered in part because of lack of comparative stud-
ies between drug classes and the absence of specific
drug biomarkers matched to patients’ immunobiol-
ogy. This topic has not only medical, but also finan-
cial repercussions since the total estimated all-cause
healthcare costs for MS as reported by studies that
included direct and indirect costs ranged from
US$8528 to US$54,244 per patient per year.5 The
average annual cost of MS disease-modifying drugs
in the United States ranges from US$50,000 to
US$60,000 per year.6
There is considerable variation in MS symptoms and
disease course between patients, which may be due
to lesion targeting and underlying factors such as
age and gender. In addition, there may be heteroge-
neity due to biological mechanisms driving inflam-
matory and neurodegenerative mechanisms, which
in turn affect relapse frequency/location as well as
irreversible disability, disease progression, and over-
all disease severity. A landmark pathological paper
described four different subtypes of MS by patho-
logical features.7 Although this study did not find a
correlation between pathological subtypes and dis-
ease course, a subsequent study examined serum
samples from patients from type I and II groups, and
found differing antibody–antigen profiles when
assayed on an antigen array. The presence of cortical
lesions8 activated microglia8 and meningeal folli-
cles9 have been associated with progressive forms of
MS. There also may be differing subtypes of MS as
measured by magnetic resonance imaging (MRI),
and a paradigm of high versus low atrophy and
lesion volume may identify patients at extremes of
the MRI severity scale.10
Gender and age play a critical role in the heterogene-
ity of MS disease course, and in part in treatment
response. Younger patients experience a more inflam-
matory phase of disease with frequent relapses,11
while patients with onset after the age of 50 often pre-
sent with a more progressive course.12 Moreover,
younger age at onset is associated with slower disabil-
ity accumulation on the Expanded Disability Status
Scale (EDSS), which relies on locomotor changes,13
however, cognition may be more profoundly affected
in younger onset patients.14
2 journals.sagepub.com/home/msj
Mild/severe MS
An emerging paradigm is that MS patients experi-
ence varied disease trajectories with a significant
proportion of patients experiencing mild disability
accrual even 10–15 years after diagnosis, to early and
severe disability accrual experienced by approxi-
mately 15%–20% of patients.15 These different dis-
ease courses have taken on a variety of terms over the
years including mild/benign16,17 on the low end of the
spectrum, and malignant/severe/aggressive MS15,18
on the higher end of the spectrum. The range of dis-
ability accrual, measured by the EDSS according to
disease duration is summarized in the MS Severity
Score table, published by Roxburgh et al.19 Population
or cohort studies have identified several prognostic
factors for more severe or earlier disease progression,
which include, male sex,20–24 older age at onset,20–26
symptom location at initial presentation,20,21,24,26
number and pattern of attacks24,26,20–23,25 incomplete
recovery from the first relapse,20–22,27 and progressive
as opposed to relapsing symptoms from disease
onset.20–26 However, there are relatively few studies
that have addressed the underlying mechanisms of
these clinical and demographic features.
Decision points in MS management
The heterogeneity in disease course and in treatment
response demonstrates that there are key decision
points in MS management that would benefit from a
precision medicine approach leveraging validated
predictors/biomarkers (Figure 1):
•• Disease prevention biomarkers: biomarkers to
identify individuals at risk, in whom known
risk factors for MS may be modified.
•• Diagnostic biomarkers: biomarkers distin-
guishing between MS and other diseases, used
at early disease symptoms or radiological
evidence.
•• Prognostic biomarkers: prognostic biomarkers
may be most useful at diagnosis when the first
treatment decision is being made, but also at
different points in the MS disease course.
Biomarkers useful for treatment decision-mak-
ing include endophenotypic biomarkers that
distinguish patients who will have frequent
relapses, more aggressive disease, or early dis-
ease progression. These may be evaluated at
diagnosis, and then re-assessed periodically.
•• Treatment selection: algorithmic processes to
decide the best treatment for each patient, tak-
ing into consideration clinical indices, MRI
and including biomarkers. Predictors of treat-
ment response at first treatment initiation, and

Figure 1.  Key decision points for biomarkers (clinical, neuroimaging, genetic, and biochemical) in MS management.
at treatment failure/switch points are necessary
for the management of this chronic disease.28
•• Disease progression biomarkers: biomarkers
that quantify the underlying mechanisms of
disease progression or irreversible disability
accumulation such as deep gray matter and cor-
tical pathology, diffuse activation of microglia
and lack of remyelination may help to inform
further disease management, especially where
these can be paired with newer therapeutics tar-
geting these specific mechanisms.29
Measuring outcomes in MS
MS disease course may be measured through a vari-
ety of metrics including traditional clinical measures,
neuroimaging, novel biosensor measures, and bio-
markers (Figure 2). Ultimately, the validity of these
measures either individually or in aggregate needs to
be linked to the most important measure of outcome,
the effect on disability, and the patient’s overall life
and well-being.
Clinical measures
Neurological examination.  The EDSS has been used
as the primary disability outcome measure in MS,30,31
however has limited utility as an ordinal scale, with
reliance on ambulatory measures, particularly at the
higher ends of the scale. Newer measures such as the
journals.sagepub.com/home/msj 3
T Chitnis and A Prat
multiple sclerosis functional composite (MSFC) mea-
sure operate on a linear scale and equally weight
walking speed, hand function, and cognition (includes
the timed 25-foot walk (T25FW), 9-hole peg test, and
paced auditory serial addition testing (PASAT)).32
Furthermore iterations of this test have been sug-
gested to incorporate the symbol digit modalities test-
ing (SDMT) as a measure of processing speed, and
the low contrast visual acuity (LCVA) as a sensitive
measure of vision.33–36 It will need to be proven
whether these newer tests fulfill all of the criteria dis-
cussed above. Additional disease features including
fatigue, depression/anxiety and bladder dysfunction,
which often affect MS patients, need to be incorpo-
rated into a comprehensive yet easy to administer
platform.
Patient-reported outcomes.  In order to meet the cri-
teria of the “participatory patient” in precision medi-
cine, the incorporation of patient feedback through
focus groups and/or patient-reported outcomes
(PROs) is needed. Currently the MSQOL-54, which
incorporates the SF-36 has been the most frequently
used PRO questionnaire.14 Other questionnaires such
as the NeuroQOL are more recently being studied.37
Additional important MS-related symptoms to col-
lect are fatigue, depression. Incorporation of ques-
tions related to risk-aversion,38 work performance,39
and treatment satisfaction questionnaires40 may help
in tailoring therapeutic choices to individual patients.
Multiple Sclerosis Journal 00(0)
Figure 2.  “MS patient profile” depicting treatments, clinical, MRI, biomarker, and biosensor measures.
Web-based and smart-phone applications are cur-
rently being tested and may be a powerful and seam-
less means of gathering patient symptom and
patient-reported outcomes data.41,42
Biosensors and technological advances. Newer
methods strive to incorporate recent technological
advances, using biosensors or accelerometers to track
patient movement, gait, and other physical move-
ments as well as sleep in MS patients.43 This may
allow for a more comprehensive understanding of the
individual patient’s functional status gathered on a
daily basis, rather than at periodic visits in the neu-
rologist’s office.
Neuroimaging measures
Neuroimaging measures are of tantamount impor-
tance in MS since they provide the closest in vivo
approximation to pathological changes in the CNS.
MRI lesion location and features are fundamental to
MS diagnosis,3 as well as disease staging. T2 lesion
volume and brain atrophy measures are now routinely
incorporated into clinical trials, as well as predictive
algorithms of overall disease outcomes.44,45 Gray mat-
ter, white matter, and regional atrophy measures also
provide important predictors of specific MS outcomes
4 journals.sagepub.com/home/msj
including cognition and disability progression.46,47
Newer techniques such as diffusion tensor imaging,
quantification of cortical pathology and positron-
emission tomography (PET) imaging may provide
more granular detail on the different types of pathol-
ogy at different stages of disease.
Genomic, epigenomic, proteomic biomarkers
The Institute of Medicine (IOM) recently convened
an expert committee to provide recommendations for
advancing appropriate use of biomarkers and molecu-
larly targeted therapies.48 Their recommendations
include the development of common evidentiary
standards for clinical utility, federal review and labe-
ling of biomarker tests, and reimbursement models
that support the ongoing collection of data within a
rapid learning system.
Biochemical biomarkers for MS which can include
genomic, epigenomic, proteomic, and others have
been derived from a variety of sources, most com-
monly whole blood, serum, plasma, and peripheral
blood mononuclear cells. Cerebrospinal fluid (CSF),
urine, tears are also studied, although CSF is more
challenging to obtain especially longitudinal samples.
More recently, the microbiome has been shown to be

differentially expressed in MS patients compared to
controls,49 and may play a role in modulating the
immune response.
Biochemical biomarkers in MS may provide addi-
tional granularity in predicting outcomes and for
selecting appropriate therapies. These can be divided
into the following categories.
Disease prevention biomarkers.  There has been sig-
nificant progress in the past 10 years in identifying
genetic markers of MS risk, with now over 200 risk
variants identified. Environmental factors including
hypovitaminosis D, Epstein–Barr virus (EBV) sero-
positivity, obesity in adolescence, smoking and sleep–
wake cycle disturbance have been associated with MS
risk. Given the advent of big data in healthcare,
including electronic medical records, composite
genetic, clinical and biomarker risk algorithms may
be calculated for individuals.
Diagnostic biomarkers. A review of diagnostic bio-
markers for MS is beyond the scope of this review,
and can be found in other works.50,51 However, a key
advance is the advent of consensus clinical and imag-
ing criteria for the diagnosis of MS.3,52
Biomarkers including clinical and MRI features that
predict the development of MS after a first clinical
attack or clinically isolated syndromes (CIS) are criti-
cal in early diagnosis.53 In a large multicenter study,53
predictors of conversion in multivariable analyses
were oligolonal bands, the number of T2 lesions, and
age at CIS. This was replicated in other studies.54
Biomarkers suggested to be predictive of development
of MS after CIS include serum neurofilament light
chains (NFL)55 and CSF chitinase 3 like-1 levels.56
There is an increasing awareness of patients with radi-
ologically isolated syndromes and no clinical symp-
toms, and in this subgroup, the presence of spinal cord
MRI lesions carries a high risk of a first clinical
event.57,58 Furthermore biomarkers for CIS and radio-
logically isolated syndrome (RIS), under investigation
including proteomic and metabolomic biomarkers.
Prognostic biomarkers of MS disease course
Genetic modifiers of disease course
Although there are over 200 risk alleles associated
with MS susceptibility at genome-wide level (p-value
< 5e−8), little progress has been made toward identi-
fying genetic links to disease course. To date, the larg-
est study of disease severity failed to find any genetic
association.59
journals.sagepub.com/home/msj 5
T Chitnis and A Prat
Despite extensive investigation, a single validated
biochemical biomarker of MS disease course has not
been identified. However, several have shown con-
sistent effects in multiple studies or in studies with
large numbers and validation cohorts. CSF NFL subu-
nit were found to be predictive of conversion to MS,60
as well as associated with disability and MRI corre-
lates61–63 and is being evaluated as a biomarker of
treatment response.64,65 Serum NFL levels were found
to correlate with CSF levels,66 and shows promise as
a biomarker of inflammatory disease activity,64,67 and
correlates in part with long-term brain atrophy.68–70
Glial fibrillary acidic protein (GFAP) CSF levels have
been associated with disability accrual.71,72 Astrocyte-
derived chitinase 3-like 1 (CHI3L1) CSF levels pre-
dicted conversion to MS in two studies,60,73 and also
with disability accrual.74
Biomarkers of MS treatment response and
safety
Given now, the 18 DMTs that are available for relaps-
ing MS, the question arises whether an individual
patient will respond better to one class of drug than
another. There are limited studies identifying bio-
markers of treatment response, and the field of phar-
macogenetics/pharmacogenomics in MS is in its
infancy and limited by small numbers in cohort stud-
ies. Unfortunately, these facets have not traditionally
been incorporated into MS clinical trials. Moreover,
the area of MS drug safety is increasing in importance
given the severity of some DMT side effects includ-
ing progressive multifocal leukoencephalopathy
(PML) and secondary autoimmunity.
Beta-interferon
The most widely studied drug class in terms of bio-
markers and pharmacogenomics is beta-interferon
owing largely to its widespread and longitudinal use as
the first MS drug. Several groups identified a type I
interferon (IFN)-response gene expression signature
in MS patients,75,76 which has laid the groundwork for
furthermore work, some of which focused on mRNA
expression of MxA which is part of the type I IFN
gene response.77,78 More recently, a genetic allele asso-
ciated with IFN-response in three independent cohorts
of MS subjects has identified an intronic variant in
SLC9A9 associated with an increased IFN-gamma
response.79 Presence of an HLA-DRB1*1501 allele
has been associated with response to glatiramer ace-
tate.80 Additional biomarkers beyond pharmacog-
enomics/genetics that are being explored as markers of
disease course are circulating miRNA,81 serum anti-
body profiles, proteomic markers, and metabolomics.
Multiple Sclerosis Journal 00(0)
Ultimately a composite biomarker or biomarker panel
may be required to fully inform the different stages of
disease management.
Biomarkers of MS DMT safety
An area that is beginning to be explored in MS is
that of pharmacogenomics in DMT safety. There is a
strong focus, on elucidating risk factors and mecha-
nisms of progressive multifocal leukoencephalopa-
thy (PML), which can occur in MS patients treated
with natalizumab, fingolimod, and dimethyl fuma-
rate, and has been reported in systemic lupus erythe-
matosus (SLE) patients treated with rituximab, a
drug now commonly used in MS. A biomarker which
stratifies patients into high (ranging from 1/300 to
1/1000) or low risk (around 1/10,000) for PML
through testing for John Cunningham (JC) virus
antibodies,82 has at minimum, a 2.2% false negative
rate82 for detecting the virus in positive individu-
als.83 Furthermore iterations of this test have strati-
fied risk by JC virus index thresholds and prior
immunosuppressant use.84 Other studies have
attempted to identify additional biomarkers of PML
susceptibility including lymphocyte CD62L expres-
sion with variable results.85,86 CYP2C9 genetic poly-
morphisms are now used to determine siponimod
dose. Pharmacogenomic risk factors for common
adverse events for other MS drugs are needed in
order to identify appropriate patients for treatment.
Disease progression biomarkers
Several mechanisms underlie disease progression
independent of relapses, and include diffuse micro-
glial activation, astrocyte dysfunction, axonal damage
with Wallerian and retrograde degeneration and mito-
chondrial dysfunction. Biomarkers that measure these
mechanisms may include serum and CSF NFL,55,66
glutamate by spectroscopy,87 and may be utilized as
treatments that target these specific mechanisms are
developed.
Incorporating the patient perspective
It is critical to incorporate the patient perspective
into the identification of outcomes for treatment and
decision-making tools. Ultimately, the patient needs
to be a partner in the decision-making process with
physicians, and therapeutics developers, which
requires a level of health literacy88 which is critical
in moving forward patient participation. The con-
cept of patient preference outcomes89 which is well
suited to the heterogeneous symptomatology and
6 journals.sagepub.com/home/msj
disease course in MS, should be considered in clini-
cal trial planning.
Cost-effectiveness
The cost of MS medication influences both patient and
payor decision-making. In the case of payors in the
United States, medication tiering is often done not as a
result of scientific analysis, but because of marginal cost
differentials. Matching of the most appropriate medica-
tion to the right patient at the right time using precision-
medicine tools should lead to improved outcomes, lower
health utility costs, decreased loss of wages and most
importantly, improved patient satisfaction.
Integration of data
A variety of new measures or composites of existing
measures have been proposed, and may better reflect
the MS disease course. Ultimately, in order to inform
precision medicine approaches in MS, such metrics
should fulfill the following criteria.
1. Account for dysfunction across the entire
neuraxis.
2. Granularity to separate the components of the
neuraxis, as patients may experience dysfunc-
tion predominantly in one domain or another.
3. Ease of administration; passive monitoring if
possible.
4. Good correlation with patient reported out-
comes and patient-identified needs.
5. Platform for reporting to physician.
6. Link to neuroimaging outcomes.
7. Link to intrinsic biology.
Ultimately, the coalescence of patient data, neuroimag-
ing, biomarkers, biosensor data, technological devices,
as well as whole genome data, and companion diagnos-
tics may inform patient decision-making. Such a large
data set will need large-scale data storage and analysis
tools for data management and deployment of decision
support tools. This could be facilitated through integra-
tion with electronic health record systems, which are in
use in most major hospitals in the United States and
Canada today. Constant updating of such tools is neces-
sary for accurate use and application, and a model using
frequently updated machine-learning tools90 based on
newly validated prognostic features and longitudinal
patient data could potentially provide a powerful tool
for informed decision-making, as well as screening for
at risk subjects.90,91 Ultimately, development of such
modalities for MS sets the stage for similar tools in
other neurological diseases (Figure 3).

Figure 3.  Quantitative biologically based description of the individual MS patient state and precision management
algorithms.
Future of MS precision medicine and
therapeutics
The application of precision medicine, and in particu-
lar a more mechanistically based approach is a neces-
sary next step in MS.
Implementing these advances will require cooperation
between academic centers, pharmaceutical companies,
and bioinformatics groups, to identify validated bio-
markers in well-characterized longitudinal patient cohort
studies,50,92,93 and clinical trial data sets to develop inte-
grated data platforms. This process will greatly benefit
from involvement of patient societies and patient input.
Development and application of precision medicine
approaches to MS will also provide important insights
for other neurodegenerative and autoimmune diseases.
Acknowledgements
We would like to thank Adam Polgar for assistance
with creation of the figures.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
journals.sagepub.com/home/msj 7
T Chitnis and A Prat
Funding
The author(s) declared receipt of the following finan-
cial support for the research, authorship, and/or publi-
cation of this article: Dr Chitnis acknowledges funding
from the U.S. Department of Defense (MS170140).
ORCID iD
Tanuja Chitnis https://orcid.org/0000-0002-9897
-4422
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