PERSPECTIVES

originated in North America and Western

OPINION
Europe, and may not be generalizable to the
global MS population. Few well-designed
Comorbidity in multiple sclerosis: population-based studies have assessed
the incidence or prevalence of many
implications for patient care autoimmune diseases, cancers, ischaemic
heart disease and stroke among patients
with MS7.
Ruth Ann Marrie Clinically, the prevalence of comorbidity
at influential points in the disease course
Abstract | Most efforts aimed at understanding the notable heterogeneity of such as diagnosis or the transition from
outcomes in multiple sclerosis (MS) have focused on disease-specific factors, such as a relapsing to progressive course might
symptoms at initial presentation, initial relapse rate, and age at symptom onset. be more relevant than prevalence in a
These factors, however, explain relatively little of the heterogeneity of disease cross-section of the population. Prevalence of
outcomes. Owing to the high prevalence of comorbidity in MS and the potential for comorbidity has been evaluated at or before
MS diagnosis. One case-control study in
its prevention or treatment, comorbidity is of rising interest as a factor that could California used electronic medical records
explain the heterogeneity of outcomes. A rapidly growing body of evidence suggests to evaluate the prevalence of allergic and
that comorbidity adversely affects outcomes throughout the disease course in MS, autoimmune disease before MS diagnosis in
including diagnostic delays from symptom onset, disability at diagnosis and 5,296 patients with MS and 26,478 matched
subsequent progression, cognition, mortality, and health-related quality of life. controls. The prevalence of individual
comorbidities among patients with MS was
Therefore, clinicians need to incorporate the prevention and management of
low, with the most common conditions
comorbidity when treating patients with MS, but managing comorbidities in MS being atopic dermatitis (3.3%), asthma
successfully may require the adoption of new collaborative models of care. (2.8%), uveitis (1.3%) and inflammatory
bowel disease (0.8%)8. Uveitis occurred
Multiple sclerosis (MS) is a chronic occurs in MS and has been associated threefold more often and inflammatory
inflammatory and degenerative disease with microstructural changes in the brain bowel disease occurred 1.7fold more
of the CNS, with highly heterogeneous in specific locations5, but psychosocial often in patients with MS than in control
outcomes. Most efforts to understand factors unrelated to MS might also operate6, participants. In 2006, 8,983 participants in
this heterogeneity have focused on disease- and in some individuals depression can the North American Research Committee
specific characteristics, such as initial clinical precede MS onset by years. Therefore, on Multiple Sclerosis (NARCOMS) registry
presentation, with limited success1. Similarly, psychiatric disorders will be considered as self-reported their comorbidities, including
efforts aimed at modifying the disease comorbidities. the year of diagnosis9. At the time of MS
course have used immunological therapies, Increasing interest in comorbidity reflects symptom onset, 2,062 (24%) participants
such as dimethyl fumarate, with only its high prevalence, breadth of adverse reported a physical (medical) comorbidity,
modest success2. Increasingly, it is becoming impacts, and the potential for its prevention most often hypertension, chronic lung
recognized that MS outcomes are influenced or treatment using lifestyle modification disease or hyperlipidaemia9, and 698
by characteristics of the patient with MS, and readily available therapies. Herein, (8.4%) participants reported a psychiatric
such as genetics, socioeconomic factors, I review the prevalence of comorbidity in comorbidity. By the time of diagnosis, which
ethnicity and comorbidity 3. MS, discuss the effects of comorbidity on was an average of 7years after symptom
Comorbidity has been defined in clinically relevant outcomes in MS and onset, 3,141 (35%) participants reported
various ways. Herein, comorbidity refers consider the potential implications for a physical comorbidity and 1,537 (18%)
to the total burden of illness other than treatment and improving those outcomes. reported a psychiatric comorbidity. The
the disease of interest (MS)4, and focuses prevalence of uveitis at diagnosis (1.3%) and
on chronic conditions, such as diabetes Prevalence of comorbidities in MS of inflammatory bowel disease (1.6%) was
mellitus. Complications that arise from A recent systematic review highlighted the similar to those reported in the California
the underlying disease, such as neurogenic fact that comorbidity is common in MS7. In study. A 2016 study evaluated the prevalence
bladder, are excluded because the prevalent MS cohorts, the most common of comorbidity at the time of MS diagnosis
mechanisms by which they originate and comorbidities are depression (23.7%), in a population-based study of 16,803
their management are different from those anxiety (21.9%), hypertension (18.6%), Canadians with MS10. The most prevalent
of comorbidity. Sometimes, the distinction hyperlipidaemia (10.9%) and chronic lung comorbidities were depression (19.1%),
between comorbidity and complication disease (10.0%). However, much of the hypertension (15.2%), chronic lung
is challenging. For example, depression literature on which these figures are based disease (12.1%) and anxiety (11.1%) (FIG.1).

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20 than in patients with no comorbidities24.

18 5 years pre-diagnosis A Mexican cross-sectional study that
At diagnosis included 37 patients with MS evaluated the
16
presence of depression, anxiety, dysthymic
14 disorder and bipolar disorder using
structured interviews and questionnaires25.
Prevalence (%)

12
The severity of depression and anxiety was
10 not associated with the number of relapses,
but study power was limited and neither
8
the number of relapses nor the followup
6 period were specified, making it impossible
4 to determine relapse rates. In a different
study that included 141 patients with MS
2 from Tasmania who were monitored for
0 3years, time to relapse was not associated
Depression Anxiety Chronic Hypertension Hyperlipidemia Heart disease Diabetes with levels of lipids (total cholesterol,
lung disease
low-density lipoprotein, high-density
Comorbidity lipoprotein, triglycerides, apolipoprotein AI,
Figure 1 | Prevalence of comorbidity at MS diagnosis and 5years earlier10. Individuals with incident apolipoproteinE or apolipoproteinB) in the
Naturedata
multiple sclerosis (n=23,382) were identified using administrative (health claims) Reviews | Neurology
in four Canadian serum after accounting for age, baseline body
provinces (British Columbia, Manitoba, Quebec and Nova Scotia). Comorbidities were identified using mass index, 25(OH)D (vitaminD) level,
validated administrative case definitions, and their prevalence was described at the time of MS physical activity, smoking, statin use, season,
diagnosis and 5years before diagnosis. Depression was the most common comorbidity at diagnosis.
or use of immunomodulatory therapy 26. The
association between dyslipidaemia and time
All of the comorbidities evaluated, except burden on healthcare systems23, but this will to relapse was not specifically evaluated.
for hyperlipidaemia, were more common in not be discussed because reports in this area In 181 patients with clinically isolated
the MS population than in 116,638 control are limited. syndrome a first episode of neurological
participants without MS who were matched symptoms that lasts at least 24h and is caused
for age, sex and geographical location; these Diagnosis. Comorbidity is associated by inflammation or demyelination that
differences were also present as early as with diagnostic delays and the severity was treated with IFN1a, apolipoprotein
5years before diagnosis of MS. Similarly, of disability at diagnosis. Among 8,983 measurements were not associated with the
a Danish study that used prospectively participants in the NARCOMS registry, number of relapses over 2years18.
collected administrative data found that vascular, autoimmune, musculoskeletal,
depression and anxiety were more common gastrointestinal, visual and psychiatric MRI findings. Some comorbidities are
among patients with MS than among comorbidities, as well as smoking and associated with MRI findings; of these,
controls 2years before MS diagnosis11. obesity, were associated with longer migraine and dyslipidaemia are the most
The timing of onset of comorbidities diagnostic delays22, which varied in studied17,2532 (TABLE1). Studies that have
after MS diagnosis has not been evaluated magnitude depending on the comorbidity examined migraine and various MRI
systematically. However, the prevalence of and the age at MS symptom onset. Average measures (number and type of lesions,
physical comorbidities, including diabetes delays were greatest among people with lesion location, and brain atrophy) have
mellitus, hypertension, hyperlipidaemia12, symptom onset below the age of 25years, produced mixed findings, with some
ischaemic heart disease13, fibromyalgia14 and and ranged from 4.5years for gastroin- showing associations of migraine with
irritable bowel syndrome15, increases with testinal comorbidities to 10.3years for lesion number or location, and others
age (FIG.2). This increase with age is not seen visual comorbidities. After accounting not 2729. The inconsistent findings might
for psychiatric comorbidities16. for diagnostic delays, the odds of severe reflect differences in the characteristics
Collectively, these studies suggest that disability increased with the number of of the study populations, including the type
several comorbid conditions are often comorbidities present at diagnosis. Vascular, of migraine, and whether other
present by the time of MS diagnosis. The musculoskeletal and psychiatric comorbidity comorbidities were excluded. Dyslipidaemia
high burden of depression and anxiety at were independently associated with greater and elevated levels of total cholesterol,
diagnosis and throughout the disease course disability at diagnosis22. low-density lipoprotein and triglycerides
suggests that these comorbidities should be that do not meet criteria for dyslipidaemia,
a clinical priority from the time of the first Relapses. Acute exacerbations (relapses) have been associated with greater lesion
assessment of possibleMS. are defining features of MS2, but few studies burden, gadolinium-enhancing (active)
have evaluated the association between lesions and brain atrophy in cross-sectional
Effects of comorbidities in MS comorbidity and the risk of relapse, and only studies18,3032. Longitudinal studies are
The effects of comorbidities in MS are one has reported the presence of such an needed to fully understand the effects of
broad, including increased diagnostic association. In an online survey that included dyslipidaemia on MRI measures inMS.
delays, accelerated disability progression, 2,399 respondents, the odds of reporting a
increased changes visible on MRI, increased relapse that occured during the year prior Cognitive impairment. Cognitive
mortality and reduced quality of life1722. to the survey were 2.6fold higher in those impairment affects 4070% of patients
Comorbidity is also associated with greater patients with three or more comorbidities with MS33,34. Studies conducted in the

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 PERSPECTIVES

early 1990s failed to detect associations
between depression and cognition in
patients with MS, possibly owing to the
use of potentially confounded measures of
depression (such as the Beck Depression
Inventory), use of small samples35,36, and
failure to assess relevant domains, such as
processing speed and executive function.
Subsequently, studies suggested that
severe depression in MS is associated with
impaired working memory 37,38, executive
function37 and reduced information
processing speed39, similar to the pattern
observed in depressed individuals without
MS. However, these studies still evaluated
small numbers of depressed patients with
MS, did not use measures of depression
that were well-validated in MS, and did not
consider the effects of other comorbidities.
Studies published in 2014 and 2015
suggested that anxiety is associated with
reduced information processing speed in
MS40,41 as it is in people without MS42
and with reduced executive function41.
Further well-designed studies of the effects
of psychiatric comorbidity on cognitive
function are needed. The effect of physical
comorbidities on cognition has not been
evaluated. If future findings indicate that
comorbidity affects cognition, this would
suggest that efforts to improve cognitive
function or to prevent declines in cognitive
function would be best addressed by
preventing or treating comorbidity.
Disability. Several cross-sectional studies
suggest that comorbidity is associated
with disability in MS; the measures of
disability used have varied, but measures
of motor function and ambulation
have dominated43,44. In 110 patients
with relapsingremitting or secondary
Among patients without vascular
comorbidity at the time of MS diagnosis,
the median time before a cane was
required to walk was 18years, versus only
12years among patients with any vascular
comorbidity at diagnosis45. In an Australian
cohort, dyslipidaemia was associated with
greater disability progression, as measured
by the Expanded Disability Status Scale
score, over 3years46. A longitudinal study
of 146 patients with newly diagnosed MS
found that patients with musculoskeletal
comorbidities had a 5point decline in the
motor scale of the Functional Independence
Measure over 3years, whereas patients
without such comorbidities experienced
only a 2point decline (P=0.005)47.
Consistent with the adverse effects
of comorbidity on ambulatory disability
progression, a population-based cohort
study that included 4,519 patients with MS
and 4,972 controls without MS found that
psychiatric comorbidities in combination
with MS synergistically increased the risk of
being granted a disability pension, whereas
musculoskeletal disorders increased the risk
of disability pension non-synergistically 48.
Surprisingly, cardiovascular comorbidity did
not increase therisk48.
Quality of life. Depression and anxiety
are associated with reduced health-related
quality of life (HRQoL) in MS49, as are
physical comorbidities50,51. A 2016 study
evaluated the relationship between physical
comorbidities, psychiatric comorbidities
and HRQoL using a structural equation
60
50
Lifetime prevalence (%) in 2010
model17. Physical comorbidity had only
slight direct effects on HRQoL, but indirect
effects mediated by depression, anxiety
and fatigue were twice as strong.
Direct and indirect effects of depression
and anxiety were nearly as great as the
total effects of disability status. This study
highlights the complexity of the inter-
relationships between comorbidities and
their effects on outcomes.
Mortality. Although survival among
patients with MS has improved over time,
it remains 57years shorter than that of the
general population52. The most common
MSunrelated causes of death in patients
with MS are cancer, cardiovascular disease
and respiratory disease53,54. However,
several studies suggest that comorbidity is
associated with increased mortality in MS.
A study of 5,797 people with MS,
in which administrative health data were
analysed, diabetes (HR1.47, 95%CI
1.251.73), ischaemic heart disease
(HR1.50, 95%CI 1.281.75), depression
(HR1.62, 95%CI 1.391.88) and chronic
lung disease (HR1.21, 95%CI 1.031.42)
were associated with increased mortality in
MS, whereas anxiety was associated with a
reduced risk (HR0.61, 95%CI 0.480.76)21.
This study did not account for disability
status or comorbid health behaviours.
A Finnish study of 491 patients with MS
found that stroke was associated with
reduced survival55, but did not account for
disability status or health behaviours either.
Using survey data from 2,994 US veterans
Age group

20-44 years
progressive MS, insulin resistance was 45-59 years
associated with greater disability, whereas 40
60 years
lipid-related parameters were not 43. In
another cohort, a higher Framingham 30
General Cardiovascular Disease Risk
Score (which predicts the 10year risk of 20
cardiovascular disease) was associated with
a higher MS severity score (P<0.001)44. 10
However, the cross-sectional nature of
these studies limits causal inference and the 0
sample sizes weresmall. Depression Anxiety Hypertension Hyperlipidemia Heart disease Diabetes
Longitudinal studies also suggest
Comorbidity
that comorbidity accelerates disability
Figure 2 | Age-specific prevalence of common comorbidities in a prevalent multiple scle-
progression. Among NARCOMS
rosis cohort from Manitoba in 2010 (REFS12,16). Individuals with multiple
Nature sclerosis
Reviews were
| Neurology
participants, vascular comorbidity identified using population-based administrative (health claims) data. Comorbidities
(including diabetes, hypertension, were identified using validated administrative case definitions. In 2010, the prevalence of these
ischaemic heart disease and peripheral comorbidities was evaluated according to age group. The prevalence of physical comorbidities
vascular disease) was associated with an increased with age. The prevalence of psychiatric comorbidities did not differ substantially
increased risk of ambulatory disability 45. across age groups.

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with MS, comorbidity, as measured
using the Seattle Index of Comorbidity,
was associated with increased mortality
(HR1.09, 95%CI 1.0491.129) after
accounting for physical functioning, mental
health, smoking and physical activity 56.
Treatment of MS with comorbidity
Clinical trials of disease-modifying
therapy (DMT) and symptomatic therapies
(pharmacological and nonpharmacological)
in MS typically exclude individuals with
comorbidity 57, thereby limiting our
knowledge of the safety and effectiveness
of therapy in this subset of patients.
Nonetheless, observational studies suggest
that comorbidity affects treatment decisions.
A study of administrative data for 10,698
patients with incident MS in Canada

Table 1 | Association of comorbidity and MRI findings in MS

Design and Comorbidity MRI outcomes Relevant findings Refs
sample size studied
Longitudinal Apolipoprotein CE, T2 lesion High apolipoproteinB levels associated with increased number of new 18
181 patients with levels number and volume; T2 lesions (P<0.0001) and increased number of new or enlarging T2
CIS normalized measures lesions (P<0.0001)
of whole-brain, grey Higher LDLC (P=0.0002) and TCHOL (P=0.0001) associated with
matter and white matter increased number of new T2 lesions
volume Higher apolipoproteinE levels associated with greater deep grey matter
atrophy (P<0.0001)
Cross-sectional Headache Presence of lesions in 13 Patients with MS and midbrain plaques close to the periaqueductal grey 27
277 patients with distinct brain regions area had increased migraine-like headaches and tension-type headaches
MS
Longitudinal TCHOL, LDL, Monthly number of CE Mean TCHOL correlated with mean number of CE lesions (P=0.011), as did 32
18 patients with HDL, TAG, lesions for 6months LDL (P=0.02); on average, each CE lesion was associated with a 4.4mg/dl
CIS apolipoprotein higher TCHOL level
E
Cross-sectional Migraine CE, T1 and T2 lesion Patients with MS and migraine had increased number of CE lesions but not 29
509 patients with number and lesion CE lesion volume compared with patients without migraine
MS, 64 patients volume; brain atrophy
with CIS, 251 measures
matched controls
Cross-sectional Hypertension, T1, T2 lesion number Hypertension associated with decreased normalized grey matter volume 105
489 patients with heart disease, and lesion volume; brain (P=0.042) and normalized cortical volume (P=0.046)
MS, 61 patients smoking, atrophy measures Heart disease associated with decreased normalized grey matter volume
with CIS, 175 overweight/ (P=0.046) and normalized cortical volume (P=0.033)
matched controls obesity, type1 Obesity associated with increased T1 lesion volume (P=0.039)
diabetes Smoking associated with decreased normalized brain volume (P=0.049)
Cross-sectional Migraine, Number of CE, T1, T2 Migraine not associated with number or location of CE or T2 lesions but 106
204 patients with depression, lesions; number of associated with fewer T1 lesions (P<0.05)
MS anxiety T2 lesions in specific
locations
Cross-sectional Migraine Number of T2 lesions; Migraine associated with more frequent involvement of all three regions 28
37 patients with presence of lesions in evaluated (P=0.006)
MS and migraine, red nucleus, substantia No difference in number of supratentorial lesions (P=0.18)
42 patients with nigra, periaqueductal
MS without grey area
migraine
Cross-sectional Epilepsy Incidence of cortical All patients with epilepsy had cortical lesions on MRI; among those with 107
310 patients with lesions; brain volume epilepsy, poor control was associated lower brain volumes (P=0.01)
CIS or MS
Longitudinal Lipid profile CE lesion volume and Higher HDL levels associated with lower CE lesion volume (P<0.001) 31
178 patients with number; T2 lesion Higher TAGs associated with greater number (P=0.038) and volume of
MS volume; T1 lesion (P=0.023) CE lesions
volume; BPF Higher TCHOL associated with lower BPF (P=0.033)
Longitudinal Lipid profile Number of T2 and CE Higher LDLC associated with increased new or enlarging T2 lesions 30
135 patients with lesions; T2 and CE lesion (P=0.047)
CIS volume; % change in Higher TCHOL associated with greater number of T2 lesions over 2years
whole-brain volume, (P=0.001)
grey matter volume and Greater decrease in grey matter volume over 2years associated with
white matter volume higher LDLC (P=0.047) and TCHOL (P=0.05)
Cross-sectional Comorbidities None Presence of any comorbidity associated with decreased whole-brain 108
815 patients with identified by (P<0.001), cortical (P<0.001) and grey matter volumes (P<0.01), decreased
MS self-report and MTR in normal-appearing brain tissue (P<0.01) and normal appearing grey
confirmed by matter (P<0.05)
chart review
BPF,brain parenchymal fraction, CE,contrast enhancing; CIS,clinically isolated syndrome; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LDLC,
LDL cholesterol; MTR,magnetization transfer ratio; TAG,triglycerides; TCHOL,total cholesterol level.

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found that as the number of comorbidities
increased, the likelihood of initiating a DMT
decreased58. Comorbid anxiety delayed the
time to initiation of DMT (HR0.78, 95%CI
0.690.87), as did ischaemic heart disease
(HR0.72, 95%CI 0.590.87), whereas
depression shortened the time to treatment
initiation (HR1.13, 95%CI 1.001.27).
The choice of therapy was not affected by
comorbidity. These findings are consistent
with literature in other chronic diseases that
suggest that treatment differs in frequency or
intensity when comorbidity is present 5961.
The effects of DMT and symptomatic
therapies on the risks of comorbidity are
also relevant. Concerns about the effects of
DMT on the risk of comorbidity emerged
in the sentinel trial of IFN1b62, in which
withdrawals were reported owing to adverse
effects, such as emotional instability and
suicide attempts. However, a subsequent
study suggested that IFN does not increase
the risk of depression63.
The possibility of comorbid autoimmune
disease emerging secondary to DMT
has also been a concern. IFN might be
associated with an increased risk of thyroid
autoimmunity and dysfunction64, but reports
have been inconsistent65. A study of 1,792
participants in the New York State MS
Consortium registry evaluated whether DMT
influenced the risk of developing comorbid
autoimmune disease, including Crohn
disease, systemic lupus erythematosus,
myasthenia gravis, rheumatoid arthritis,
psoriasis, thyroid disease, type1 diabetes
mellitus and irritable/inflammatory
bowel syndrome66. The frequency of any
self-reported autoimmune disease did not
differ between patients who used DMT and
patients who were DMT-naive, however
the time from MS symptom onset to
diagnosis of another autoimmune disease
was shorter in patients who were treated
with DMT, suggesting possible surveillance
bias. This study did not evaluate the risk
of autoimmune disease by specific DMT.
In addition, irritable bowel syndrome was
misclassified with inflammatory bowel
disease. Treatment-emergent autoimmune
diseases are a well-recognized complication
of alemtuzumab, with up to one-fifth of
patients with MS treated with this drug
developing thyroid disease67, and one in
100 developing idiopathic thrombocytopenic
purpura68. The risk of treatment-emergent
autoimmune disease is reportedly higher
among patients with a family history of
autoimmune disease (OR9.42, 95%CI
3.5924.7) and a history of ever smoking
(OR3.91, 95%CI 1.768.67)69.
The emergence of vascular comorbidity
secondary to DMT is a more recent concern.
Treatment with fingolimod is associated
with increases in blood pressure over
time70. A retrospective cross-sectional study
of 188 patients with MS taking IFN1a undertreated78. Identification and treatment
(intramuscular or subcutaneous), glatiramer
acetate or natalizumab, and 100 patients who
were DMT-naive found that those patients
using DMT had higher diastolic blood
pressure and higher levels of plasma glucose
and high-density lipoprotein cholesterol71.
The cross-sectional design did not exclude
the possibility of greater comorbidity and
adverse health behaviours before treatment,
or that patients who received treatment
have more active or disabling disease that
might in turn lead to an increased risk of
comorbidity or physical inactivity.
Safety, tolerability and effectiveness of MS
treatment can be affected by comorbidity.
Comorbid migraine, for example, is
associated with lower tolerance of IFN
owing to worsening headache profiles72,73.
Comorbid diabetes mellitus is associated
with an increased risk of fingolimod-
associated macular oedema74. A secondary
analysis of a randomized controlled trial
assessing a fatigue management intervention
delivered by teleconference in patients with
MS found that comorbid diabetes mellitus
and arthritis altered the treatment
response; patients with diabetes improved
more slowly after intervention than
those without diabetes, whereas patients
with arthritis improved faster than those
without arthritis, although this improvement
was not sustained20. Therefore, rehabilitation
treatment goals probably need to be more
conservative (less aggressive) for people with
MS who have comorbidities.
Perspective on management of
comorbidity
The magnitude and breadth of the
effects of comorbidities on the different
aspects of MS mean that we must
incorporate the prevention and management
of comorbidity into the care of patients
with MS, which will require severalsteps.
First, patients with MS must be
empowered to adopt positive health
behaviours75. Smoking, obesity and physical
inactivity are associated with increased risks
of several of the comorbidities that are most
strongly associated with adverse outcomes,
such as diabetes mellitus, hypertension,
hyperlipidaemia and ischaemic heart disease.
Smoking and being overweight or obese have
also been independently associated with
more rapid disability progression in MS46,76.
Second, we need to better identify and
treat the most prevalent comorbidities:
depression and anxiety. Although effective
treatments exist 77, depression in patients
with MS remains underdiagnosed and
of anxiety have been the subject of even less
study than depression. Case identification,
or screening tools, such as the Hospital
Anxiety and Depression Scale, Patient
Health Questionnaire, or the Center for
Epidemiologic Studies Depression rating
scale, all have adequate sensitivity and
specificity to detect depression in MS79.
Less information is available regarding
anxiety screening tools80. Screening
tools rapidly determine whether further
mental health assessment is needed81, but
screening does not improve outcomes82
unless it constitutes part of an integrated
management plan83,84.
Third, management of vascular
comorbidities should be emphasized given
their rising incidence over time13, rising
prevalence with age12, widespread effects
on outcomes, and the existence of effective
treatments for them. A recent cohort study
of 50 people with MS who were obese and
had metabolic syndrome evaluated the
effects of treatment with metformin (n=20)
or pioglitozone (n=10) compared with no
treatment (n=20)85. Participants in either
treatment group had reduced leptin
levels, increased adiponectin levels,
and reduced numbers of myelin basic
protein peptide-specific cells secreting
proinflammatory cytokines compared
with patients who did not receive treatment.
The number of gadolinium-enhancing
lesions also decreased in both treatment
groups, suggesting that treatment of
metabolic syndrome could improve
outcomes. Blood pressure should be checked
at every clinic visit. The US Preventive
Task Force recommends screening for
abnormal blood glucose in adults aged
4070years who are overweight or obese,
and possibly rescreening every 3years for
those with initially normal values86. These
recommendations suggest that >50% of
patients with MS who are overweight or
obese87 should be screened at least every
3years. Lipid screening is recommended for
men aged 35years irrespective of cardiac
risk, and for men aged 2035years who are
at increased cardiac risk, whereas for women,
screening is only recommended if cardiac
risk is elevated88. In this context, increased
cardiac risk is defined as the presence of any
of diabetes, hypertension, obesity, tobacco
use, a history of atherosclerotic disease,

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Table 2 | Collaborative models of mental health care

Community model Setting Providers/type of care
Communication between Separate practices Primary care provider
practices Psychiatric consultant
Medical provided mental Separate practices Consultationliaison
health care Physician-provided care with specialized support
Colocation Shared space Space is shared but primary care and mental health services are separate; care is collaborative
Education and self-management training are provided
Treatment plans are independent
Shared care Shared space Services are provided at the primary care site; a care manager provides support and followup
regarding treatment response and adherence
Education and self-management training are provided
Mental health service provides outreach to the primary care provider
The treatment plan is a primary care plan of which mental health care is a component
Reverse shared care Shared space Services are provided at the mental health site
The primary care provider is in the mental health setting
The treatment plan is mental health oriented, of which primary care is a component
Unified care Shared space Full service primary care and mental health care in one place
All clinical services, medical records and treatment plans are integrated across the organization
Permission obtained from Province of British Columbia Ministry of Health. Integrated models of primary care and mental health & substance use care in the
community. 13 (British Columbia Ministry of Health, Vancouver, 2012)109.

or a family history of early cardiovascular
disease (before age 50years in men and age
60years in women). The optimal interval
for screening is uncertain, but every 5years
may be reasonable. It is unknown whether
treatment targets for diabetes, hypertension
and hyperlipidaemia should differ in people
with MS from those in people without
MS. Presently, I would aim for primary
prevention targets, but advocate clinical trials
to test whether aggressive treatment of these
conditions improves MS outcomes.
Fourth, we need to identify the best
models of care to achieve these goals.
Despite the lack of published work on
collaborative models in MS, several
collaborative models of care have been
proposed for improving mental health care
in general, which may provide guidance for
comorbidity management in MS (TABLE2).
These models involve a patient-centred
collaborative care team, a clearly identified
target population of interest, a structured
approach to mental health care using
measurement tools to ensure that treatment
meets the desired target, and rely on
evidence to support treatment decisions89.
They are underpinned by ongoing
communication between members of
the health care team to meet the goals of the
person seeking care. Core members
of collaborative teams may include primary
care providers, psychiatric specialists, and
a care manager or behavioural health
provider; the latter provider is responsible
for ongoing assessment of the patient.
A meta-analysis of primary care-based
collaborative models for managing
depression identified 37 randomized
controlled trials, and found that depression
outcomes were improved at 6months using
these models, with benefits persisting up
to 5years later 84. These models have been
successfully used to manage depression
in populations with chronic diseases such
as diabetes90, but principally focused on
the primary care setting, which may be
more difficult to translate to MS. Shared
care models in which mental health care
is embedded within the MS clinic may
be more feasible. In rheumatoid arthritis,
another immune-mediated disease
with a high burden of comorbidity, a
randomized controlled open-label trial
involving 970 patients evaluated the effect
of a nurse-led program for managing
comorbidity 91. Nurses asked patients about
key comorbidities. If a risk factor or poorly
managed comorbidity was identified, the
nurse reminded the patient about the
importance of managing the comorbidity,
encouraged followup with a primary
care provider or rheumatologist, and also
notified the primary care provider and
rheumatologist about the issue. Within
6months, the number of measures taken
to address comorbidities increased by 78%,
but long-term outcomes with respect to the
comorbidities were not evaluated. Such an
approach may be feasible in MS clinics and
should be evaluated, with assessment of
process measures, comorbidity outcomes,
and MSspecific outcomes.
Finally, we need to know how comorbidity
affects MS in order to mitigate those effects.
Direct biological effects might include
accelerated neurodegeneration, less effective
neural repair or increased peripheral immune
activation. Indirect effects might include
delays in diagnosis or altered treatment
responses. Mechanisms may differ across
comorbidities, and more than one mechanism
could operate for one particular comorbidity.
For example, several potential direct and
indirect mechanisms may underlie the
association between psychiatric comorbidity
and outcomes in MS. First, stress may play
a part in psychiatric comorbidity and poor
outcomes in chronic diseases9294. In MS,
stress increases the risk of depression and may
increase the risk of relapses95 and new brain
lesions96. Second, psychiatric comorbidity
may lead to changes in health behaviours
such as poorer diet, increased smoking and
lower adherence to treatment. One study
found that depression reduces adherence to
MS DMT97. Third, complex relationships
exist between psychiatric disorders and
immune function98, such that inflammation
may increase the risk of psychiatric disorders
and psychiatric disorders may alter immune
function. A meta-analysis of 24 studies
concluded that patients with depression
had higher levels of the proinflammatory
cytokines tumour necrosis factor and IL6
than individuals without depression99.
Individuals with generalized anxiety disorder
also have altered cytokine levels100, and
evidence of dysregulated Tcell function101.
When conducting mechanistic studies in
clinical samples, the confounding effects of
treatments that are used for comorbidities
should be considered, as treatments may
affect outcomes independently of their effects

6 | ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol

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on comorbidity. Statins, for example, have
been evaluated as a treatment for MS with
mixed reported effects: they have been shown
to have no effects on remission of relapses, but
to reduce brain atrophy in the treatment of
progressive MS102,103. Statins have pleiotropic
effects, including antioxidant effects, anti-
inflammatory and immunomodulatory
effects, which produce clinical benefits
independent of effects on cholesterol104.
Conclusions
Our understanding of the burden and
complexity of comorbidity in MS has
increased substantially over the past 5years,
and will continue to increase, as it is clear
now that we need to think about modifying
comorbidity to improve outcomes. It is time
to integrate comorbidity management into
MS care.
Ruth Ann Marrie is at the Departments of Internal
Medicine and Community Health Sciences, Max Rady
College of Medicine, Rady Faculty of Health Sciences,
University of Manitoba, 820 Sherbrook Street,
Winnipeg Manitoba R3A 1R9, Canada.
rmarrie@hsc.mb.ca
doi:10.1038/nrneurol.2017.33
Published online 17 Mar 2017
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Acknowledgements
This article was supported (in part) by a Don Paty Career
Development award from the MS Society of Canada, a
Manitoba Research Chair from Research Manitoba, and the
Waugh Family Chair in Multiple Sclerosis. R.A.M. receives
research funding from Canadian Institutes of Health
Research, Research Manitoba, MS Society of Canada, MS
Scientific Foundation, National MS Society, Rx & D Health
Research Foundation.
Competing interests statement
R.A.M has conducted clinical trials for Sanofi-Aventis (funds
awarded to institution with no personal compensation).

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