Comorbidity Disparities in Multiple Sclerosis
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IS MS UNDERSERVED?
ONLINE FIRST
Comorbidity Disparities in
Multiple Sclerosis
Comorbid diseases that are often more prevalent in underserved groups have
large effects on multiple sclerosis prognosis.
By Kathryn C. Fitzgerald, ScD; Daniela Pimentel Maldonado, MD; and
Ellen M. Mowry, MD, MCR
Comorbidity is emerging as a primarily).5 It is important to note that people with MS who
relevant component of clinical develop vascular comorbidities tend to have worse MS out-
care in people with multiple comes (eg, increased risk of ambulatory disability lower brain
sclerosis (MS). Comorbidities and gray matter volumes).6,7
are disorders coexisting with Studies of CVD in people with MS have largely focused
a given disease that are not on people living in Europe and Canada. Very little is known
downstream complications of the primary about CVD among traditionally underserved or underrep-
disease. Both MS risk and prognosis are het- resented groups of people with MS, although it is known
erogeneous, and recent research has high- that social determinants of health, including Black and
lighted the role of comorbidities as a potential Hispanic/Latinx identity and low socioeconomic status
contributor to the observed differences in (SES), are strong risk factors for CVD in the general popula-
outcomes. In addition, social determinants tion7; whether this confers additional comorbidity risk in
of health, including socioeconomic status, environmental people with MS or increases MS disease burden is unclear.
factors, racial and ethnic identity, and the interplay among A cross-sectional registry study of North American residents
these factors may also contribute to the link between MS with MS suggests indicators of low SES are associated with
and comorbid conditions, although data are limited.1 increased prevalence of vascular and related comorbidities
(eg, hypertension and hypercholesterolemia).8 It has been
Cardiovascular Comorbidities suggested that higher rates of CVD may be a contributing
Vascular and related comorbidities are overrepresented in cause to the earlier mortality seen in Black and Hispanic/
people with MS,2 including hypertension, ischemic heart dis- Latinx individuals with MS.9 Some data suggest that MS in
ease, and, possibly, heart failure, venous thromboembolism, individuals with low SES may have worse disease outcomes
and atrial fibrillation. These findings are largely derived from and higher risk of new-onset comorbidity7-10; however, large-
population-based registry studies conducted in Scandinavian scale, prospective studies are lacking.
countries and Canada. A study including all Danish-born cit-
izens with MS between 1980 and 2005 showed people with Metabolic Comorbidities
MS had nearly twice the risk for cerebrovascular disease and Similar to CVD comorbidity, closely related metabolic
cardiovascular disease (CVD) as people of the same sex, age, comorbidities including obesity, diabetes, insulin resistance,
and region of residence without MS.2 Similar population- and dyslipidemia are also overrepresented in people with
level registries in Canada, Sweden, and England also show a MS. Excess adiposity has been consistently identified as a
higher CVD risk in people with MS.3-5 In the Swedish registry, risk factor for MS. Some prospective studies show obesity as
people with MS also had increased risk of deep vein throm- a risk factor for faster rates of neurodegeneration in people
bosis (DVT), particularly among those with primary progres- with MS.10 Prevalence estimates of dyslipidemia in people
sive MS who had a 3 times higher risk of DVT. In the study with MS are also generally high (12%-30%).11 Early studies
from England, lower mortality rates were seen in people also suggest higher prevalence in people with vs without MS
with MS who were using lipid-lowering medications (statins for impaired fasting glucose (40% vs 21%) and insulin (17%
FEBRUARY 2021 PRACTICAL NEUROLOGY e1
IS MS UNDERSERVED?
vs 2%) levels.12,13 A variety of biologic mediators (eg, leptin, underlying biologic factors. The prevalence of various cancer
adiponectin) are involved in the regulation of immunity risk factors (eg, smoking and obesity) also differs widely with
and inflammation and influenced by immune activity. This social determinants of health, including education level as
potential link between metabolism and autoimmunity has well as racial and ethnic identity. As discussed, many of these
also motivated studies describing anti-inflammatory effects risk factors may also contribute to worse disease outcomes in
of several antidiabetic medications (eg, metformin, piogli- people with MS. Data on cancer incidence and survival rates
tazone) with respect to MS outcomes and biomarkers of in people with MS are very limited and needed, especially
inflammation.14 These observations also suggest the relative because underserved groups tend to have more severe MS
importance of optimal metabolic comorbidity management and so may also be exposed to stronger disease-modifying
as it relates to MS outcomes specifically. therapies (DMTs) that may confer higher risk of malignancy.
As with CVD comorbidity, social determinants of health
influence the prevalence of common metabolic disorders Comorbid Depression
amongst the general population, and rates of obesity are Depression is among the most common mental health
higher in Black and Hispanic/Latinx women compared with comorbidities in MS, with an estimated prevalence of
white women (>50% vs 38%).15 Diabetes prevalence is also approximately 50% compared with 16.2% in the general
higher in Hispanic/Latinx individuals, and health care dispari- population.25-27 Depression in MS is associated with lower
ties for glycemic control among diabetics also exist in relation quality of life, increased hospitalizations, and increased levels
to racial and ethnic identities.16 Data are limited regarding of fatigue, pain, and cognitive disturbances. Treating depres-
risk or prognosis of MS with respect to metabolic comorbidi- sion in MS may improve adherence to DMTs.25 Symptoms
ties or whether more optimal metabolic comorbidity man- of depression are also associated with worse walking speed,
agement would translate to improved MS outcomes. manual dexterity, and information processing speed in MS,
with varied associations amongst different age groups.26
Comorbid Cancer Interestingly, depression in MS seems to be more chronic
A comprehensive review suggests people with MS may than in the general population, regardless of psychiatric
have a higher risk of meningioma and urinary system can- treatment initiation or discontinuation, which may suggest
cers and a lower risk of pancreatic, ovarian, prostate, and a different pathophysiology.27 The Hospital Anxiety and
testicular cancers, although results of individual studies Depression Scale (HADS)-Depression and the Patient Health
yield inconsistent data.17 Nationwide cohort studies from Questionnaire-9 item (PHQ-9) are reliable scales for depres-
Denmark showed similar incidence of cancer from 1980 to sion screening in people withMS.28
2005 in those with MS and the general population.18 In con- In randomized placebo-controlled trials, paroxetine and
trast, cohort studies in Norway suggested that people with desipramine were studied for depression treatment in
MS had higher incidence of respiratory, urinary, and central people with MS with modest effects and limiting side effects
nervous system (CNS) cancers between 1930 and 1979.19 A seen.29 Racial and ethnic identities of the participants in
key consideration in studies of MS and cancer incidence is these studies was unreported or not representative of the
the dynamics of immunosuppressive or immunomodulatory general population. Cognitive behavioral therapy (CBT) is
medications, which may affect malignancy risk throughout more effective than supportive-expressive group therapy,
the time period studied. An Italian study found higher risk although optimal duration is unclear.30,31 Sertraline is also
of cancer among people with MS treated with the immuno- more effective in treating major depressive disorder in MS
suppressants azathioprine, methotrexate, or cyclophospha- compared with supportive-expressive group therapy.31 Some
mide compared with those treated with interferon-b or glat- evidence suggests a 16-week telephone-based psychotherapy
iramer acetate, and cancer incidence appeared dependent intervention improves symptoms of depression in persons
on length of treatment.20 A study from Sweden suggested with MS; however, participants in studies of that interven-
that cancer risk might be higher in individuals with MS tion were mostly white or did not have racial and ethnic
treated with fingolimod, but not natalizumab or rituximab.21 identity reported.32 A 2014 American Academy of Neurology
Disparities in cancer incidence and survival also exist for (AAN) guideline recommended the 16-week phone-based
underserved and underrepresented groups, with Black women psychotherapy intervention but found there was insuf-
having a higher risk for invasive breast cancer and worse over- ficient evidence to support or refute the use of sertraline,
all survival, and Black men having higher risk of prostate can- desipramine, paroxetine, individual in-person CBT, individual
cer.22,23 Among Hispanic/Latinx people, there is a higher likeli- in-person CBT plus relaxation training, or CBT-based group
hood of more advanced cancer at diagnosis and higher cancer therapy for the treatment of depressive symptoms in MS.32
mortality rates.24 Contributing causes are likely multifactorial Psychiatric comorbidities are also disproportionately
and possibly related to inequity in access to care, screening, or higher in Black and Hispanic/Latinx people with MS, with
e2 PRACTICAL NEUROLOGY FEBRUARY 2021IS MS UNDERSERVED?
higher depression scores and more self-reported depression and limited social support.43 Anxiety in MS is associated with
and anxiety in those age 18 to 29 years and increased sever- higher levels of disability, cognitive dysfunction, and lower
ity of depressive symptoms after age 60.26,33 Self-reported quality of life.44
levels of anxiety and depression are also worse in disabled A new diagnosis of MS triggers symptoms of anxiety in
or unemployed Black individuals with MS, whereas higher some, which might then decrease over time after diagnosis.42
education levels in this group correlate with lower levels MS might also increase anxiety at the workplace because of
of depression.34 In contrast, in the general population, few the constant effort by some to conceal their illness or a need
differences among groups identified by racial or ethnic iden- to decrease workload or overcompensate at work.45 The effect
tity are seen in the prevalence of depressive disorders after of the illness on close relationships with family and friends,
gender, income, and socioeconomic status are taken into with loss of independence being an important factor, is also
consideration.35,36 The prevalence of depression in individu- source of anxiety for people with MS. With better social sup-
als who self-identified as having Asian ethnicities has been port, people with MS feel less of a burden on others and are
estimated at 6.9% to 9.1%, which is lower than that of whites able to develop better coping skills.45 Symptoms of anxiety in
who are not Hispanic/Latinx. People with Asian identities, MS include avoidance and emotion-focused coping, smok-
however, receive treatment for depression less frequently ing, excessive drinking, depressed mood, low optimism, low
that is often of lower quality, and there are substantial varia- self-efficacy, high levels of stress, low perception of cognitive
tions between the many groups within the construct of ability, negative thoughts, high perception of risk, fatigue, and
Asian ethnicity (eg, Chinese, Japanese, or Pilipino) as well as pain. Providing information regarding MS to increase disease-
within those groups (eg, sex or age).37 Great diversity also related knowledge decreases anxiety levels in MS.42
exists within the construct of people identified as having Despite high prevalence, anxiety in MS frequently goes
Hispanic/Latinx identity,35 who are more likely to see prima- untreated. In order to address anxiety disorders in MS,
ry care providers for depression treatment compared with early recognition remains key. The HADS-Anxiety and the
white people, who are more likely to seek care from mental Generalized Anxiety Disorder 7-item (GAD-7) scales are
health specialists. In addition, limited English proficiency and reliable and valid measures that can be used to screen for
inadequate health literacy among many underserved groups anxiety disorders during clinical encounters with people
may limit access to and quality of care.38,39 with MS.28,45 An AAN guideline from 2014 determined
Successful depression treatment requires effective recogni- there is currently not enough evidence to support or refute
tion and treatment, which in turn depends on understanding efficacy of individual in-person CBT plus relaxation training,
of the cultural and socioeconomic realities of every patient.25 group relaxation and imagery, or CBT-based group therapy
People in underserved groups favor use of counseling to treat for anxiety in people with MS. Further rigorous and inclusive
depression and may be more likely to consider antidepres- research with randomized controlled trials on the efficacy of
sants to be addictive.26 Telecounseling has been shown to both psychologic and pharmacologic interventions to treat
have short-term medium-to-large effects in the treatment of anxiety in MS are needed.46
depression in underrepresented communities and is being Disparities in rates of anxiety in people with MS who have
studied as a potential tool to reduce mental health inequali- differing social determinants of health have been identi-
ties by eliminating the need for transportation; however, fied, although evidence is scant. Black individuals with MS
additional rigorous research of long-term effects is needed. have higher rates of anxiety compared with white individu-
Potential feelings of isolation and different views on appro- als, and self-reported anxiety is higher in those with either
priateness of style and content also need to be considered disabled or unemployed status.33,34 Hispanic/Latinx people
when recommending computerized therapies.25 In addition, with MS have higher rates of self-reported anxiety as well.34
culturally appropriate, guideline-driven treatment of depres- Paroxetine has been studied in underserved communities for
sion and anxiety has proven to be effective for people from the treatment of mood and anxiety disorders, and treatment
different cultural backgrounds in the US.40 response differed among groups, highlighting the impor-
tance of considering population heterogeneity when design-
Comorbid Anxiety ing clinical trials.46 Development of interventions that might
The prevalence of anxiety in persons with MS has been target comorbid depression and anxiety, such as broad-
estimated to be between 15.8% and 57%, which is higher spectrum transdiagnostic CBT, is also worthwhile to study
than the 0.8% to 6.4% observed in the general population.41,42 in diverse MS populations.34 Interventions focused on self-
Anxiety in MS has been linked to the unpredictable course efficacy by the use of social modeling and its effectiveness in
and effects of the disease on daily life. It is also linked with life reducing threats to identity, improving social functioning,
experiences and factors inherent to personality. Risk factors and reducing feelings of loneliness are other potential areas
for anxiety in MS include female sex, comorbid depression, of research in MS and anxiety.44
FEBRUARY 2021 PRACTICAL NEUROLOGY e3IS MS UNDERSERVED?
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Kathryn C. Fitzgerald, ScD
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26. Chan CK, Tian F, Pimentel Maldonado D, Mowry EM, Fitzgerald KC. Depression in multiple sclerosis across the adult KCF and DPM report no disclosures
lifespan [published online ahead of print, 2020 Dec 14]. Mult Scler. 2020;1352458520979304.
27. Koch MW, Patten S, Berzins S, Zhornitsky S, Greenfield J, Wall W, Metz LM. Depression in multiple sclerosis: a long- EMM has disclosures at www.practicalneurology.com
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