Enhancing diversity of clinical trial populations in multiple sclerosis

BACKGROUND: Demographic characteristics, social determinants of health (SDoH), health inequities, and health disparities substantially influence the general and disease-specific health outcomes of people with multiple sclerosis (MS). Participants in clinical trials do not represent all people with MS treated in practice. Objective: To provide recommendations for enhancing diversity and inclusion in clinical trials in MS. METHODS: We held an international workshop under the Auspices of the International Advisory Committee on Clinical Trials in MS (the “Committee”) to develop recommendations regarding diversity and inclusivity of participants of clinical trials in MS. Workshop attendees included members of the Committee as well as external participants. External participants were selected based on expertise in trials, SDoH, health equity and regulatory science, and diversity with respect to gender, race, ethnicity, and geography. RESULTS: Recommendations include use of diversity plans, community engagement and education, cultural competency training, biologically justified rather than templated eligibility criteria, adaptive designs that allow broadening of eligibility criteria over the course of a trial, and logistical and practical adjustments to reduce study participant burden. Investigators should report demographic and SDoH characteristics of participants. CONCLUSION: These recommendations provide sponsors and investigators with methods of improving diversity and inclusivity of clinical trial populations in MS

Blood-Brain Barrier Breakdown in the Aging Human Hippocampus

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer’s disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Locus for severity implicates CNS resilience in progression of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults(1,2). Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility(3), these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS

Women’s Health: Contemporary Management of MS in Pregnancy and Post-Partum

Multiple sclerosis (MS) primarily affects women in childbearing age and is associated with an increased risk of adverse post-partum outcomes. Relapses and now fetal exposure to disease modifying treatments in the early phase of pregnancy and thereafter are of concern. Safe and effective contraception is required for women who wish to delay or avoid pregnancy while on disease-modifying treatments. Counseling and planning is essential to assess the risk of both fetal and maternal complications, particularly now in the era of highly efficient and riskier therapies. The purpose of this review is to provide a practical framework using the available data surrounding pregnancy in MS with the goal of optimizing outcomes during this phase in MS

Race and ethnicity on MS presentation and disease course

Multiple sclerosis (MS) has a strong racial and ethnic component and disproportionately affects whites of European background. Recent incidence reports suggest an increasing rate of MS among African Americans compared with whites. Despite this recent increase in MS in African Americans, Hispanics and Asians are significantly less likely to develop MS than whites of European ancestry. MS-specific mortality trends demonstrate distinctive disparities by race/ethnicity and age, suggesting that there is an unequal burden of disease. Inequalities in health along with differences in clinical characteristics that may be genetic, environmental, and social in origin may be contributing to disease variability and be suggestive of endophenotypes. The overarching goal of this review was to summarize the current understanding on the variability of disease that we observe in selected racial and ethnic populations: Hispanics and African Americans. Future challenges will be to unravel the genetic, environmental, and social determinants of the observed racial/ethnic disparities

MS in self-identified Hispanic/Latino individuals living in the US.

Self-identified Hispanic/Latino individuals living with multiple sclerosis (MS) in the continental United States (US) are a diverse group that represents different cultural and ancestral backgrounds. A marked variability in the way MS affects various subgroups of Hispanics in the US has been observed. We reviewed and synthesized available data about MS in Hispanics in the US. There are likely a host of multifactorial elements contributing to these observations that could be explained by genetic, environmental, and social underpinnings. Barriers to adequate MS care in Hispanics are likely to include delivery of culturally competent care and social and economic disadvantages. Considerable efforts, including the formation of a national consortium known as the Alliance for Research in Hispanic Multiple Sclerosis (ARHMS), are underway to help further explore these various factors

Gender Inequities in the Multiple Sclerosis Community: A Call for Action

We thank Moneim and colleagues for calling attention to theissue of gender inequality in MS clinical trial steering committeesand in authorship on publications emerging from phase 3 clinicaltrials.1Gender inequality is a long-standing problem in publica-tion practices in general,2as well as in neurology,3,4academicmedicine,5and science,6so it is not surprising to see it reflectedin thefield of multiple sclerosis (MS

Internuclear Ophthalmoplegia Characterizes Multiple Sclerosis Rather Than Neuromyelitis Optica Spectrum Disease

Neuromyelitis optica spectrum disease (NMOSD) and multiple sclerosis (MS) share clinical presentations including brainstem syndromes. Internuclear ophthalmoplegia (INO) is characterized by paresis of ipsilateral eye adduction in horizontal gaze. It usually corresponds to a lesion in the medial longitudinal fasciculus (MLF) and is commonly seen in MS. However, it is unclear if INO is as common in NMOSD