Comorbidity Disparities in Multiple Sclerosis

Comorbidity is emerging as a relevant component of clinical care in people with multiple sclerosis (MS). Comorbidities are disorders coexisting with a given disease that are not downstream complications of the primary disease. Both MS risk and prognosis are heterogeneous, and recent research has highlighted the role of comorbidities as a potential contributor to the observed differences in outcomes. Social determinants of health, including socioeconomic status (SES), environmental factors, racial and ethnic identity, and the interplay among these factors may also contribute to the link between MS and comorbid conditions, although data are limited.¹

Cardiovascular Comorbidities

Vascular and related comorbidities are overrepresented in people with MS,² including hypertension, ischemic heart disease, and, possibly, heart failure, venous thromboembolism, and atrial fibrillation. These findings are largely derived from population-based registry studies conducted in Scandinavian countries and Canada. A study including all Danish-born citizens with MS between 1980 and 2005 showed people with MS had nearly twice the risk for cerebrovascular disease and cardiovascular disease (CVD) as people of the same sex, age, and region of residence without MS.² Similar populationlevel registries in Canada, Sweden, and England also show a higher CVD risk in people with MS.^3-5 In the Swedish registry, people with MS also had increased risk of deep vein thrombosis (DVT), particularly among those with primary progressive MS who had 3 times higher risk of DVT. In the study from England, lower mortality rates were seen in people with MS who were using lipid-lowering medications (statins primarily).⁵ It is important to note that people with MS who develop vascular comorbidities tend to have worse MS outcomes (eg, increased risk of ambulatory disability or lower brain and gray matter volumes).^6,7

Studies of CVD in people with MS have largely focused on people living in Europe and Canada. Very little is known about CVD among traditionally underserved or underrepresented groups of people with MS, although it is known that social determinants of health, including Black and Hispanic/Latinx identity and low socioeconomic status (SES), are strong risk factors for CVD in the general population⁷; whether this confers additional comorbidity risk in people with MS or increases MS disease burden is unclear. A cross-sectional registry study of North American residents with MS suggests indicators of low SES are associated with increased prevalence of vascular and related comorbidities (eg, hypertension and hypercholesterolemia).⁸ It has been suggested that higher rates of CVD may be a contributing cause to the earlier mortality seen in Black and Hispanic/ Latinx individuals with MS.⁹ Some data suggest that MS in individuals with low SES may have worse disease outcomes and higher risk of new-onset comorbidity^7-10; however, largescale, prospective studies are lacking.

Metabolic Comorbidities

Similar to CVD comorbidity, closely related metabolic comorbidities including obesity, diabetes, insulin resistance, and dyslipidemia are also overrepresented in people with MS. Excess adiposity has been consistently identified as a risk factor for MS. Some prospective studies show obesity as a risk factor for faster rates of neurodegeneration in people with MS.¹⁰ Prevalence estimates of dyslipidemia in people with MS are also generally high (12%-30%).¹¹ Early studies also suggest higher prevalence in people with vs without MS for impaired fasting glucose (40% vs 21%) and insulin (17% vs 2%) levels.^12,13 A variety of biologic mediators (eg, leptin or adiponectin) are involved in the regulation of immunity and inflammation and influenced by immune activity. This potential link between metabolism and autoimmunity has also motivated studies describing anti-inflammatory effects of several antidiabetic medications (eg, metformin or pioglitazone) on MS outcomes and biomarkers of inflammation.¹⁴ These observations also suggest the relative importance of optimal metabolic comorbidity management as it relates to MS outcomes specifically.

As with CVD comorbidity, social determinants of health influence the prevalence of common metabolic disorders amongst the general population, and rates of obesity are higher in Black and Hispanic/Latinx women compared with white women (>50% vs 38%).¹⁵ Diabetes prevalence is also higher in Hispanic/Latinx individuals, and health care disparities for glycemic control among people with diabetes also exist for racial and ethnic identities.¹⁶ Data are limited regarding risk or prognosis of MS with respect to metabolic comorbidities or whether more optimal metabolic comorbidity management would translate to improved MS outcomes.

Comorbid Cancer

Comorbid Cancer A comprehensive review suggests people with MS may have a higher risk of meningioma and urinary system cancers and a lower risk of pancreatic, ovarian, prostate, and testicular cancers, although results of individual studies yield inconsistent data.¹⁷ Nationwide cohort studies from Denmark showed similar incidence of cancer from 1980 to 2005 in those with MS and the general population.¹⁸ In contrast, cohort studies in Norway suggested that people with MS had higher incidence of respiratory, urinary, and central nervous system (CNS) cancers between 1930 and 1979.¹⁹ A key consideration in studies of MS and cancer incidence is the dynamics of immunosuppressive or immunomodulatory medications, which may affect malignancy risk throughout the period studied. An Italian study found higher risk of cancer among people with MS treated with the immunosuppressants azathioprine, methotrexate, or cyclophosphamide compared with those treated with interferon-ß or glatiramer acetate, and cancer incidence appeared dependent on the length of treatment.²⁰ A study from Sweden suggested that cancer risk might be higher in individuals with MS treated with fingolimod, but not natalizumab or rituximab.²¹

Disparities in cancer incidence and survival also exist for underserved and underrepresented groups, with Black women having a higher risk for invasive breast cancer and worse overall survival, and Black men having higher risk of prostate cancer. ^22,23 Among Hispanic/Latinx people, there is a higher likelihood of more advanced cancer at diagnosis and higher cancer mortality rates.²⁴ Contributing causes are likely multifactorial and possibly related to inequity in access to care, screening, or underlying biologic factors. The prevalence of various cancer risk factors (eg, smoking and obesity) also differs widely with social determinants of health, including education level as well as racial and ethnic identity. As discussed, many of these risk factors may also contribute to worse disease outcomes in people with MS. Data on cancer incidence and survival rates in people with MS are very limited and needed, especially because underserved groups tend to have more severe MS and so may also be exposed to stronger disease-modifying therapies (DMTs) that may confer higher risk of malignancy.

Comorbid Depression

Depression is among the most common mental health comorbidities in MS, with an estimated prevalence of approximately 50% compared with 16.2% in the general population.^25-27 Depression in MS is associated with lower quality of life, increased hospitalizations, and increased levels of fatigue, pain, and cognitive disturbances. Treating depression in MS may improve adherence to DMTs.²⁵ Symptoms of depression are also associated with worse walking speed, manual dexterity, and information processing speed in MS, with varied associations amongst different age groups.²⁶ Interestingly, depression in MS seems to be more chronic than in the general population, regardless of psychiatric treatment initiation or discontinuation, which may suggest a different pathophysiology.²⁷ The Hospital Anxiety and Depression Scale (HADS)-Depression and the Patient Health Questionnaire-9 item (PHQ-9) are reliable scales for depression screening in people with MS.²⁸

In randomized placebo-controlled trials, paroxetine and desipramine were studied for depression treatment in people with MS with modest effects and limiting side effects seen.²⁹ Racial and ethnic identities of the participants in these studies were unreported or not representative of the general population. Cognitive behavioral therapy (CBT) is more effective than supportive-expressive group therapy, although the optimal duration is unclear.^30,31 Sertraline is also more effective in treating major depressive disorder in MS compared with supportive-expressive group therapy.³¹ Some evidence suggests a 16-week telephone-based psychotherapy intervention improves symptoms of depression in persons with MS; however, participants in studies of that intervention were mostly white or did not have racial and ethnic identity reported.³² A 2014 American Academy of Neurology (AAN) guideline recommended the 16-week phone-based psychotherapy intervention but found there was insufficient evidence to support or refute the use of sertraline, desipramine, paroxetine, individual in-person CBT, individual in-person CBT plus relaxation training, or CBT-based group therapy for the treatment of depressive symptoms in MS.³²

Psychiatric comorbidities are also disproportionately higher in Black and Hispanic/Latinx people with MS, with higher depression scores and more self-reported depression and anxiety in those age 18 to 29 years and increased severity of depressive symptoms after age 60.^26,33 Self-reported levels of anxiety and depression are also worse in disabled or unemployed Black individuals with MS, whereas higher education levels in this group correlate with lower levels of depression.³⁴ In contrast, in the general population, few differences among groups identified by racial or ethnic identity are seen in the prevalence of depressive disorders after gender, income, and SES are taken into consideration.^35,36 The prevalence of depression in individuals who self-identified as having Asian ethnicities has been estimated at 6.9% to 9.1%, which is lower than that of whites who are not Hispanic/Latinx. People with Asian identities, however, receive treatment for depression less frequently that is often of lower quality, and there are substantial variations between the many groups within the construct of Asian ethnicity (eg, Chinese, Japanese, or Pilipino) as well as within those groups (eg, sex or age).³⁷ Great diversity also exists within the construct of people identified as having Hispanic/Latinx identity,³⁵ who are more likely to see primary care providers for depression treatment compared with white people and who are more likely to seek care from mental health specialists. Limited English proficiency and inadequate health literacy among many underserved groups may also limit access to and quality of care.^38,39

Successful depression treatment requires effective recognition and treatment, which in turn depends on understanding the cultural and socioeconomic realities of every patient.²⁵ People in underserved groups favor the use of counseling to treat depression and may be more likely to consider antidepressants to be addictive.²⁶ Telecounseling has been shown to have short-term medium-to-large effects in the treatment of depression in underrepresented communities and is being studied as a potential tool to reduce mental health inequalities by eliminating the need for transportation; however, additional rigorous research of long-term effects is needed. Potential feelings of isolation and different views on the appropriateness of style and content also need to be considered when recommending computerized therapies.²⁵ In addition, culturally appropriate, guideline-driven treatment of depression and anxiety has proven to be effective for people from different cultural backgrounds in the US.⁴⁰

Comorbid Anxiety

The prevalence of anxiety in persons with MS has been estimated to be between 15.8% and 57%, which is higher than the 0.8% to 6.4% observed in the general population.^41,42 Anxiety in MS has been linked to the unpredictable course and effects of the disease on daily life. It is also linked with life experiences and factors inherent to personality. Risk factors for anxiety in MS include female sex, comorbid depression, and limited social support.⁴³ Anxiety in MS is associated with higher levels of disability, cognitive dysfunction, and lower quality of life.⁴⁴

A new diagnosis of MS triggers symptoms of anxiety in some, which might then decrease over time after diagnosis.⁴² MS might also increase anxiety at the workplace because of the constant effort by some to conceal their illness or a need to decrease workload or overcompensate at work.⁴⁵ The effect of the illness on close relationships with family and friends, with loss of independence being an important factor, is also a source of anxiety for people with MS. With better social support, people with MS feel less of a burden on others and can develop better coping skills.⁴⁵ Symptoms of anxiety in MS include avoidance and emotion-focused coping, smoking, excessive drinking, depressed mood, low optimism, low self-efficacy, high levels of stress, low perception of cognitive ability, negative thoughts, high perception of risk, fatigue, and pain. Providing information regarding MS to increase diseaserelated knowledge decreases anxiety levels in MS.⁴²

Despite high prevalence, anxiety in MS frequently goes untreated. In order to address anxiety disorders in MS, early recognition remains key. The HADS-Anxiety and the 7-item Generalized Anxiety Disorders Scale (GAD-7) are reliable and valid measures that can be used to screen for anxiety disorders during clinical encounters with people with MS.^28,45 An AAN guideline from 2014 determined there is currently not enough evidence to support or refute the efficacy of individual in-person CBT plus relaxation training, group relaxation and imagery, or CBT-based group therapy for anxiety in people with MS. Further rigorous and inclusive research with randomized controlled trials on the efficacy of both psychologic and pharmacologic interventions to treat anxiety in MS is needed.⁴⁶

Disparities in rates of anxiety in people with MS who have differing social determinants of health have been identified, although evidence is scant. Black individuals with MS have higher rates of anxiety compared with white individuals, and self-reported anxiety is higher in those with either disabled or unemployed status.^33,34 Hispanic/Latinx people with MS have higher rates of self-reported anxiety as well.³⁴ Paroxetine has been studied in underserved communities for the treatment of mood and anxiety disorders, and treatment response differed among groups, highlighting the importance of considering population heterogeneity when designing clinical trials.⁴⁶ Development of interventions that might target comorbid depression and anxiety, such as broadspectrum transdiagnostic CBT, is also worthwhile to study in diverse MS populations.³⁴ Interventions focused on selfefficacy by the use of social modeling and its effectiveness in reducing threats to identity, improving social functioning, and reducing feelings of loneliness are other potential areas of research in MS and anxiety.⁴⁴

Conclusion

Comorbidities are common in people with MS and may affect both the risk and the prognosis of the disease. Many of these comorbidities may be more common in Black and Hispanic/Latinx individuals with MS, as well as other underserved or underrepresented groups. In general, how such comorbidities relate to outcomes of MS in these groups has not been studied. Further, specific strategies to treat and minimize the effect of these comorbidities in underserved individuals with MS have not been investigated. Greater commitment is needed to ensure studies of comorbidities in MS include representative populations and to focus on successful treatment thereof in these populations.