Disproportionate Neurodegeneration in Black Patients With MS: The Need for Stratified Treatments

Darin T. Okuda, MD, FAAN, FANA

TAILORING TREATMENT AND SURVEILLANCE recommendations to the individual patient serves as an attractive goal in the effective management of any medical condition. Commonly, therapeutic approaches and preventive measures are recommended based on patient age with the hope that these interventions will help to improve long-term outcomes. Other key factors include disease severity, genetic markers from tumors that may inform on therapeutic response, and comorbid conditions. The incorporation of such data aims to improve our ability to more effectively deliver care that minimizes morbidity and mortality. Yet despite all the advances in modern medicine up to this point, very few treatment recommendations are stratified based on race and ethnicity. Ethnicity is a much deeper issue than it may seem, representing more than who people are, going beyond genetics and involving shared cultural, behavioral, or religious characteristics. Consequently, these factors can shape a variety of outcomes including treatment response, the time course of disease behavior, and clinical outcomes. Given this, having a goal of “ethnicity-based” medication labels may be less ideal and focusing on effectively identifying and treating individuals with higher risks within a group may serve as the better strategy. But is this concept more relevant in the management of disease affecting the brain and spinal cord than other conditions involving less eloquent structures within the human body? Many neuroimmunologists specializing in the care of autoimmune disorders of the central nervous system believe so.

Multiple sclerosis (MS) is an autoimmune condition leading to inflammatory injury within the central nervous system that may result in irreversible neurological disability. An increase in risk for acute inflammatory events within the brain and spinal cord is present in younger individuals. Preventing permanent neurological disability while preserving quality of life serves as important measure of success. An early understanding of who may be at risk for a more challenging disease course in the future remains elusive, and the search for clinical, imaging, blood, and spinal fluid biomarkers is a current focus of investigators in the field. At present, disease localization and severity and the temporal profile of clinical and MRI exacerbations serve as coarse measures on which opinions regarding disease severity are based.

The incidence of MS in women appears to be higher in African American individuals than in White, Hispanic, and Asian individuals.¹ In addition, the current scientific literature reveals that risk for the outcome of neurological disability may be influenced by race and ethnicity. Some Black or African American patients with relapsing MS may experience a more aggressive disease course² than others. However, collectively, these individuals experience a higher frequency of clinical relapses,³ a greater propensity for clinical attacks at the optic nerves and spinal cord,⁴ a lower probability for full recovery following a relapse, and a more accelerated accrual of neurological disability than White patients.⁵

In addition to clinical differences between groups, Black or African American patients with MS also appear to possess imaging indicators suggestive of more aggressive disease. Accelerated rates of brain atrophy along with retinal nerve fiber layer and ganglion cell inner plexiform layer atrophy were observed in African American patients when compared with White patients.⁶ An increase in the rate of cerebellar atrophy also appears to be present.⁷ Higher T2-lesion volumes⁸ and lower magnetization transfer ratio (MTR) values, suggestive of a decline in tissue integrity, in normal-appearing grey and white matter were also found to be lower in comparison with White patients with MS.⁹

Are there earlier and more subtle signs of early neurodegeneration in individuals, with no current neurological impairments, that enable the identification of Black or African American patients with MS who are at greater risk for future disability? Recently, investigators in the field have been focused on volumetric outcomes involving the whole brain, cortical grey matter, and deep brain structures such as the thalami to answer this question. The observation of a reduction in global or regional measures of volume within the brain suggests tissue compromise. More recently, the use of 3-dimensional (3D) conformational metrics—an approach centered on the study of shape, structure, and surface texture—has provided new information into how MS lesions¹⁰ and anatomical structures¹¹ may change over time. This approach also offers insights into the pattern of injury or neurodegenerative change that is not observed through conventional imaging techniques. In the study of the medulla-upper cervical spine using a conventional MRI sequence commonly acquired in clinical practice and in research trials, both the ventral and dorsal compartments of this region of interest exhibited greater rates of atrophy in African American patients with MS compared with those in White patients, despite both groups having Expanded Disability Status Scale scores of 0.0.¹¹ Interestingly, the rate of change at the dorsal surface, but not the ventral surface, was found to be more advanced in African American patients. The early reductions in tissue integrity affecting this region may have an early impact on the cuneate fasciculi and gracile or cuneate nuclei mediating sensation at the upper and lower body, respectively; the medial vestibular nuclei affecting head and eye movements; and the posterior longitudinal fasciculus controlling visceral motor and sensory signals, along with the area postrema that is vital in the control of autonomic functions. Why early involvement here is seen in African American patients with MS and not in White patients is not entirely clear but may be explained by the selective vulnerability of this posterior segment to autoimmune injury and early neurodegeneration. The resulting effect on clinical outcomes is not yet known, but these data are suggestive of early alterations in tissue integrity well before the onset of definitive neurological impairments.

One explanation for observed changes may involve secondary degeneration from nearby inflammatory lesions. Volume changes may also be the result of microanatomical inflammation and eventual scarring that remains below the resolution of our current MRI techniques. A global neurodegenerative process favoring specific structures such as the supratentorial white matter, cortex, deep grey matter, brainstem, or spinal cord may also be possible.

Identifying the most appropriate treatment strategy for Black or African American patients, given their risk as a group for a more challenging clinical course, is of great importance. It also represents a key unmet need in our field. The current FDA-approved disease-modifying therapies are known to be more similar in terms of having an effect during the inflammatory phase of MS, but are less similar in producing remarkable effects in reducing neurological disability and confirmed disability improvement. Understanding the reasons behind observed volume differences from different CNS structures is important, as it may inform clinicians on treatment decisions. Based on available scientific data, obvious inflammatory injuries, punctuated by the presence of contrast-enhancing and new T2-lesion formation on MRI, and neurodegenerative features defined by atrophy of tissue appear present. Whether whole brain atrophy or regional volume changes within the cortical grey matter, thalami, brainstem, and other structures represent a separate neuropathological process is not entirely clear. In some individuals with MS, a greater likelihood for early neurodegeneration may also exist in distinct tissue types over others (ie, brainstem over whole brain, etc).

That neurological disability could be reversed or the risk for future neurological impairments be prevented earlier is an ambitious yet achievable goal. Overall, Black or African American patients remain severely underrepresented in MS clinical trials. Post hoc analyses have been performed to evaluate the effect of treatment in non-White groups. Natalizumab was found to significantly reduce the annualized relapse rate by 60% as well as the mean number of gadolinium-enhancing and new or enlarging T2-weighted lesions.¹² In the review of data related to treatment response, when African American patients with MS were exposed to interferon beta-1a administered once per week intramuscularly, a significantly higher number developed MRI advancement compared with White patients.¹³ Investigators also observed an increase in relapses and lower rates of no evidence of disease activity. These data are meaningful, but it is important to highlight that the number of included participants for these poststudy analyses was small and genetic ancestry data were not uniformly captured. Based on these findings, we need to improve our inclusion of non-White groups within large clinical trials, as published data involving therapeutic efficacy and safety for our available treatments may not be entirely generalizable to all patients we care for.

Given the data presented here, should we consider not only the use of higher efficacy treatments but a deviation from our clinical surveillance recommendations when treating Black or African American people with MS? If such patients have a greater likelihood of more aggressive disease, why have we not been more vocal in formally modifying our surveillance recommendations for care? It would seem logical that a higher MRI frequency and shorter interval of time between clinical visits be recommended. An increase in the utilization of health care resources would also be expected if disability milestones were achieved earlier. Furthermore, less is known about how other concomitant medical conditions may be affecting disease severity in MS along with reported symptoms.

It should also be underscored here that the current diagnostic criteria for MS are deficient in providing guidance to patients who are non-White, yet these criteria are still being used as a means for diagnosis.¹⁴ Efforts specific to the focus of Black or African American patients may lead to opportunities for the earlier recognition of disease that would enable health care providers to intervene earlier so that neurological impairment risk could be reduced or prevented. To achieve this goal, effective access to treatment is critical. At present, all health care customers are faced with treatment algorithms created by pharmacy benefit managers and insurers, which frequently limit access to MS treatments prescribed by the health care team. Now may be the right time to consider using a new platform that allows for higher-risk groups to have easier access to higher-efficacy treatments for MS, regardless of the disease’s current clinical course.

Significant scientific opportunities exist for identifying the most effective treatments for patients with MS who are Black or African American. Many questions remain unanswered, and the scientific data are unclear as to whether long-term outcomes in MS are improved through the early use of high-efficacy MS treatments or whether conventional approaches are sound based on quantified risk-benefit ratios. The hope one day is to have more refined knowledge specific to race and ethnicity such that our suggested treatments could mirror the Joint National Committee recommendations for the management of hypertension in adults.¹⁵ The inclusion of not only other races and ethnicities but of those who are admixed would be equally valuable. Additionally, given recent world events, it is vital that health care providers realize that many other challenges exist beyond this science. After all, the best MS treatment may not be one that is most effective in suppressing inflammatory disease and neurodegeneration, but one that a person is willing to take––as prescribed.

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