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.

Foot Melanoma Localized to Subungual Toe Location Portends Poorer Prognosis.

Our group previously reported that melanoma of the foot is associated with advanced disease on diagnosis and decreased survival. Lesions localized to the toe appeared to have the worst outcomes. In this study, we both expanded our study to include a 10-year population of patient with invasive melanoma of the foot and ankle and investigated additional factors associated with prognosis. Between January 2007 and December 2016, 211 patients underwent biopsy diagnosis and surgery for invasive melanoma in the BLANK health care system. Demographic, pathologic, staging, and localization characteristics were studied for overall survival. Lesions were localized to dorsal foot, plantar foot, toe (nonsubungual), and toe (subungual) locations. Multivariable analysis found Breslow depth, ulceration, lymph node involvement, and subungual toe location to be associated with poorer survival. Overall survival rate for foot melanoma was 70.6%. Overall survival for nonsubungual toe melanoma was 60.7%, compared to 53.1% for subungual toe melanoma. Of the subungual melanomas, 37.5% of presented as deep lesions with a Breslow depth >4.0 mm. Subungual melanoma was statistically significant for and found to be an independent prognostic factor associated with poorer survival and advanced disease. Based on the results of this study, there should be a low threshold to biopsy suspicious lesions of the toe and foot with particular attention to be dedicated to subungual lesions.

Ponseti Idiopathic and Nonidiopathic Clubfoot Correction With Secondary Surgeries.

The Ponseti method has revolutionized clubfoot treatment for not only idiopathic clubfoot but also non-idiopathic clubfoot. This study aimed to validate the existing literature with respect to the Ponseti method serving as first line treatment for clubfoot. The purpose of this study was to compare clubfoot type and recurrence with secondary surgical procedures following Ponseti method. Kaiser Permanente Northern California database was queried to identify clubfoot children under 3 years old with a consecutive 3-year membership. Associated comorbidities and operative procedure codes were identified. Chart review was performed on all surgical clubfoot patients who completed Ponseti method. Patients' average age at time of surgery, frequency of surgeries, and types of procedures performed were recorded. A logistic regression analysis assessed the adjusted association between surgery status and clubfoot type. Clubfoot incidence was about 1 in 1000 live births. Of the 375 clubfoot children, 334 (89%) were idiopathic and 41 (11%) were non-idiopathic. In the total study population, 82% (n = 309) patients maintained Ponseti correction without a secondary surgery; 66 patients (18%) underwent subsequent secondary surgeries. The non-idiopathic clubfoot underwent surgery more frequently compared to idiopathic clubfoot patients (41.5% vs 14.7%, respectively, p = .0001). Non-idiopathic clubfoot children underwent surgery at a younger age. This study validates the Ponseti method is the first line treatment for clubfoot correction despite etiology. However, patients with recurrent clubfoot may require secondary surgery following Ponseti method. Clubfoot recurrence surveillance is key for identifying early symptomatic recurrence in order to minimize foot rigidity and the need for osseous procedures.

Microorganisms Associated With Osteomyelitis of the Foot and Ankle.

Osteomyelitis of the foot and ankle is a challenge to treat and creates a significant demand on both the patient and the healthcare system. The purposes of this study were to determine the microorganisms associated with foot and ankle osteomyelitis, to evaluate the change in methicillin-resistant Staphylococcus aureus (MRSA) between 2005 and 2010, and to determine the relationship between these infecting organisms and patient comorbidities. The medical records for 302 patients diagnosed with osteomyelitis of the foot and ankle, 151 in 2005 and 151 in 2010, were randomly selected and evaluated. The authors reviewed the demographics, comorbidities, microorganism(s) confirmed with bone biopsy and culture, location, and use of antibiotics before bone biopsy. Gram-positive bacteria were the most prevalent, composing 81.9% of the isolates in 2005 and 59.6% in 2010. Methicillin-sensitive Staphylococcus aureus was the most common in both cohorts. Conversely, the incidence of MRSA statistically decreased from 28.3% to 10.6% from 2005 to 2010 (p < .0001). Gram-negative bacteria were found in 39.5% of the 2005 isolates and 31.8% of those from 2010. Pseudomonas sp. was the most common gram-negative bacteria. Patients with peripheral vascular disease had a significantly higher incidence of gram-negative bacteria (odds ratio 2.1, 95% confidence interval, 1.3 to 3.6, p = .003). The results of this study reveal that MSSA was the most common bacteria, incidence of MRSA decreased between the 2005 to 2010, and patients with peripheral vascular disease have a significantly higher incidence of gram-negative bacteria.

Melanoma of the Foot Is Associated With Advanced Disease and Poorer Survival.

The purpose of the present study was to review the outcomes and assess the prognostic factors associated with foot melanoma. We hypothesized that primary melanoma of the foot would be more likely to present at an advanced stage and be associated with poorer outcomes. Both univariate and multivariate analyses were conducted to examine the relationships between patients' demographic, clinical, and pathologic characteristics and deaths within 5 years. Categorical data were summarized as frequencies and percentages and continuous variables as mean ± standard deviation. The primary outcome measure was overall survival. On univariate analysis, the significant prognostic variables found included Breslow thickness, ulceration, sentinel node positivity, and localized presentation on the toe. Age, sex, and race were not prognostically significant in this model. Multivariate Cox proportional hazards analysis resulted in a model of foot melanoma with ulceration and location on the toe as independent prognostic variables. The 5-year survival rate for melanoma of the toe was 50%. The results of the present study have shown that physicians should have a low threshold to biopsy suspicious lesions of the foot and ankle. Advanced disease and poorer survival were noted with toe melanoma. An ulcerative lesion of the foot was also associated with poorer survival.

Improvement of driving skills in persons with relapsing-remitting multiple sclerosis: a pilot study.

OBJECTIVE: To determine the potential to improve driving-related skills using a simulator-based program in persons with relapsing-remitting multiple sclerosis (RRMS). DESIGN: Pre-post intervention. SETTING: A university driving simulator laboratory. PARTICIPANTS: Participants (N=50) with RRMS and Expanded Disability Status Scale (EDSS) scores between 1 and 7 were enrolled. Pre- and posttraining data from 36 participants (mean age ± SD, 46±11y; 30 women) who received training and 6 participants (mean age ± SD, 48±13y; 5 women) who did not receive training (control group) were compared. INTERVENTIONS: Five hours of driving training in a simulator. MAIN OUTCOME MEASURES: Performance on a road test at pre- and posttraining. Secondary outcome measures were performance on visual, physical, and cognitive tests. RESULTS: Overall, no significant differences were observed between the training and control groups before and after training. However, 4 of the 7 participants in the training group who failed the road test at pretraining passed posttraining, while the only participant in the control group who failed at pretraining still failed at posttraining. The training group also improved on perception of red and colored numbers, the Paced Auditory Serial Addition Test, and the dot cancellation test of the Stroke Driver Screening Assessment battery and reported less fatigue. These improvements were most pronounced among those with an EDSS score between 3 and 7. CONCLUSIONS: This pilot study demonstrates the potential of using a simulator to improve driving-related visual, cognitive, and on-road skills in individuals with RRMS, particularly those with an EDSS score >3. Future randomized controlled trials with adequate power are needed to expand this field of study.

Walking and physical performance in black and white adults with multiple sclerosis controlling for social determinants of health.

BACKGROUND: There is evidence for reduced walking and physical performance in persons with multiple sclerosis (MS) compared with healthy controls (HCs). There is further evidence suggesting increased overall mobility disability in Black persons with MS compared with White counterparts, yet little is known about the interplay of social determinants of health (SDOH) when considering differences in walking and physical performance. PURPOSE: This cross-sectional, comparative study examined differences in walking and physical performance in Black and White persons with MS and HCs (MS Status), statistically controlling for SDOH. METHODS: The study sample consisted of 208 persons with MS (141 White participants and 67 Black participants) and 95 HCs (59 White participants and 36 Black participants). Walking and physical function were measured using timed 25-foot walk (T25FW), six-minute walk (6MW), timed-up-and-go (TUG), and short physical performance battery (SPPB). We examined the differences in the walking and physical functions as a function of MS Status (MS vs. HCs) and Race (Black vs. White) using Multivariate Analysis of Covariance, controlling for age, sex, marital status and SDOH (i.e., education, employment, income). RESULTS: There were no significant interactions between MS Status and Race on the outcomes, and the main effects of MS Status and Race remained statistically significant, controlling for SDOH and covariates. The main effects indicated significant lower T25FW (F = 34.6, p < .001, È p2 = 0.11), 6MW (F = 58.5, p < .001, È p2 = 0.18), TUG (F = 22.1, p < .001, È p2 = 0.08), and SPPB (F = 25.2, p < .001, È p2 = 0.09) performance for MS than HCs, and lower T25FW (F = 15.5, p < .001, È p2 = 0.05), 6MW (F = 11.6, p < .001, È p2 = 0.04), and TUG (F = 4.1, p < .05, È p2 = 0.02) performance in Black than White samples. CONCLUSIONS: We conclude that MS Status and Race independently influence walking and physical performance even after accounting for SDOH, and Black persons with MS have compromised walking and physical performance, perhaps necessitating focal rehabilitation.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton's tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS.What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results.What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health.What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done.

Efficacy of Ofatumumab and Teriflunomide in Patients With Relapsing MS From Racial/Ethnic Minority Groups: ASCLEPIOS I/II Subgroup Analyses.

BACKGROUND AND OBJECTIVES: Race and ethnicity may influence the efficacy of disease-modifying therapies in patients with multiple sclerosis (MS). Incidence of MS in ethnically diverse groups may be higher; however, these populations are under-represented in MS trials. This post hoc analysis compared the proportion of patients achieving 3-parameter no evidence of disease activity (NEDA-3) with ofatumumab vs teriflunomide in participants with relapsing MS (RMS) enrolled in the ASCLEPIOS I/II trials by race/ethnicity subgroup. METHODS: ASCLEPIOS I/II were identical, double-blind, double-dummy, active-controlled, multicenter, phase 3 trials. Participants were randomized (1:1) to receive ofatumumab 20 mg every 4 weeks or teriflunomide 14 mg once daily for up to 30 months. Pooled data were used to determine the efficacy/safety of ofatumumab vs teriflunomide in participants who self-identified as non-Hispanic Black, non-Hispanic Asian, Hispanic/Latino, or non-Hispanic White. Participants who did not self-identify into one of these groups were classified as other/unknown. RESULTS: Of the 1,882 participants, 64 (3.4%) self-identified as non-Hispanic Black, 71 (3.8%) as non-Hispanic Asian, 145 (7.7%) as Hispanic/Latino, and 1,538 (81.7%) as non-Hispanic White. Baseline participant demographics/characteristics were largely balanced across subgroups, aside from minor variations in sex, disease duration, and MRI lesions. From months 0 to 24, the proportion of ofatumumab vs teriflunomide-treated patients achieving NEDA-3 (odds ratio [95% CI]) was as follows: non-Hispanic Black, 33.3% vs 3.4% (15.9 [1.67-151.71; p = 0.0162]); non-Hispanic Asian, 42.9% vs 21.9% (3.18 [0.95-10.59; p = 0.06]); Hispanic/Latino, 36.6% vs 18.6% (3.21 [1.32-7.79; p = 0.01]); and non-Hispanic White, 37.4% vs 16.6% (3.57 [2.73-4.67; p < 0.0001]). Rates of AEs were generally similar between treatment groups and across race/ethnicity subgroups; no new or unexpected safety signals were identified. DISCUSSION: Ofatumumab was associated with greater proportions of NEDA-3 achievement than teriflunomide across race/ethnicity subgroups in the ASCLEPIOS trials. Within each treatment group, the proportion of patients achieving NEDA-3 from months 0 to 24 was similar across the subgroups and overall pooled population. Both ofatumumab and teriflunomide were well tolerated. Future MS trials should include ethnically diverse groups to better inform treatment decisions and improve real-world patient outcomes. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT02792218 (clinicaltrials.gov/ct2/show/NCT02792218), NCT02792231 (clinicaltrials.gov/ct2/show/NCT02792231). Submission date: June 2, 2016. First enrollment: August 26, 2016. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients aged 18-55 years with RMS, the improvement in NEDA-3 with ofatumumab was comparably better than with teriflunomide among patients self-identified as non-Hispanic Black, non-Hispanic Asian, non-Hispanic White, Hispanic/Latino, and other/unknown.

Disparities by Race in Pregnancy Care and Clinical Outcomes in Women With Multiple Sclerosis: A Diverse Multicenter Cohort

BACKGROUND AND OBJECTIVES: Racial disparities exist in both neurologic and obstetric populations, underscoring the importance of evaluating pregnancy outcomes in diverse women with multiple sclerosis (MS). The objective of this multicenter retrospective study was to compare pregnancy care and outcomes between Black and Hispanic (underrepresented) and White women with MS. METHODS: Demographic and clinical data were extracted from medical records of 9 US MS centers for women with MS/clinically isolated syndrome who delivered live births between 2010 and 2021. Sites identified at last 15 consecutive Black/Hispanic women and a matching number of White women. Socioeconomic factors, pregnancy, and MS care/outcomes were compared between groups (underrepresented and White and then Black and Hispanic) using Wilcoxon rank sum (U statistic and effect size r reported), χ2, t tests and logistic regressions as appropriate to data type. Multiple imputation by chained equation was used to account for missing data. RESULTS: Overall, 294 pregnancies resulting in live births were analyzed ( 81 Black, 67 Hispanic, and 146 White mothers). Relative to underrepresented women, White women lived in areas of higher median (interquartile range [IQR]) Child Opportunity Index (79 [45.8] vs 22 [45.8], U = 3,824, r = 0.56, p < 0.0001) and were more often employed (84.9% vs 75%, odds ratio [OR] 2.57, CI 1.46-4.50, p = 0.0008) and privately insured (93.8% vs 56.8%, OR 11.6, CI 5.5-24.5, p < 0.0001) and more received a 14-week ultrasound (98.6% vs 93.9%, OR 4.66, CI 0.99-21.96, p = 0.027). Mode of delivery was significantly different between the three groups (X2(10,294) = 20.38, p = 0.03); notably, Black women had the highest rates of emergency cesarean deliveries, and Hispanic women highest rates of uncomplicated vaginal deliveries. Babies born to underrepresented women had lower median (IQR) birthweights than babies born to White women (3,198 g [435.3 g] vs 3,275 g [412.5 g], U = 9,255, r = 0.12, p = 0.04) and shorter median (IQR) breastfeeding duration (4.5 [3.3] vs 6.0 [4.2] months, U = 8,184, r = 0.21, p = 0.003). While underrepresented women were younger than White women (mean [SD] 30.9 [4.8] vs 33.8 [4.0], t = 1.97, CI 1.96-3.98, p < 0.0001), their median (Q1-Q3, IQR) Expanded Disability Status Scale was higher (1.5 [1-2.5, 1.5] vs 1 [0-1.5, 1.5], U = 7,260, r = 0.29, p < 0.0001) before pregnancy. Finally, medical records were missing more key data for Black women (19.7% missing vs 8.9% missing, OR 2.54, CI 1.25-5.06, p = 0.008). DISCUSSION: In this geographically diverse multicenter cohort, underrepresented women entered pregnancy with higher disability and fewer health care resources. Pregnancy represents a pivotal window where structural factors affect maternal and fetal health and neurologic trajectories; it is a critical period to optimize care and health outcomes.

Predictors of driving in individuals with relapsing-remitting multiple sclerosis.

BACKGROUND: We previously reported that performance on the Stroke Driver Screening Assessment (SDSA), a battery of four cognitive tests that takes less than 30 min to administer, predicted the driving performance of participants with multiple sclerosis (MS) on a road test with 86% accuracy, 80% sensitivity, and 88% specificity. OBJECTIVES: In this study, we further investigated if the addition of driving-related physical and visual tests and other previously identified cognitive predictors, including performance on the Useful Field of View test, will result in a better accuracy of predicting participants' on-road driving performance. METHODS: Forty-four individuals with relapsing-remitting MS (age = 46 ± 11 years, 37 females) and Expanded Disability Status Scale values between 1 and 7 were administered selected physical, visual and cognitive tests including the SDSA. The model that explained the highest variance of participants' performance on a standardized road test was identified using multiple regression analysis. A discriminant equation containing the tests included in the best model was used to predict pass or fail performance on the test. RESULTS: Performance on 12 cognitive and three visual tests were significantly associated with performance on the road test. Five of the tests together explained 59% of the variance and predicted the pass or fail outcome of the road test with 91% accuracy, 70% sensitivity, and 97% specificity. CONCLUSION: Participants' on-road performance was more accurately predicted by the model identified in this study than using only performance on the SDSA test battery. The five psychometric/off-road tests should be used as a screening battery, after which a follow-up road test should be conducted to finally decide the fitness to drive of individuals with relapsing-remitting MS. Future studies are needed to confirm and validate the findings in this study.

Impact of adherence to disease modifying therapies on long-term clinical and economic outcomes in multiple sclerosis: A claims analysis of real-world data.

BACKGROUND: Multiple sclerosis (MS) is a chronic neurodegenerative inflammatory disease that requires long-term commitment to treatment for optimal outcomes. A variety of disease-modifying therapies (DMTs) are now available that reduce relapses and delay disease progression in people with MS. However, adherence remains a significant issue, with a variety of mental, physical, and emotional factors contributing to non-adherence. In a large number of studies, non-adherence has been associated with worse clinical outcomes (relapses and disease severity), a higher economic burden, and loss of work productivity. However, many of these studies were short-term (1-2 years) or cross-sectional studies; thus, more data are needed on the long-term clinical and economic impacts of DMT non-adherence. The objective of this study was to determine the longer-term impact of adherence to DMTs on disease activity and healthcare resource utilization (HCRU) in people with MS. The study hypothesis was that non-adherence to DMTs would be associated long-term with worse clinical outcomes and a higher economic burden. METHODS: A retrospective administrative claims analysis of the US MarketScan® Commercial database (2011-2017) in individuals (18-65 years) with MS (based on International Classification of Disease coding) was conducted. Adherence was classified by proportion of days covered (PDC) ≥0.8 and non-adherence by PDC <0.8; sensitivity analyses helped further categorize as moderately (PDC ≥0.6-<0.8) or highly (PDC <0.6) non-adherent. Cohorts were matched using propensity score matching. Time to first relapse, annualized relapse rate (ARR), time to use of assistive devices (cane/walker or wheelchair), and annual HCRU (inpatient, emergency room [ER], outpatient, and MRI visits and costs) were compared between cohorts. RESULTS: 10,248 MS cases were identified; 58% met adherence criteria, and 42% met non-adherence criteria. Mean follow-up from diagnosis or first DMT claim was 5.3 years. Adherent individuals had a longer time to first relapse (hazard ratio [HR] 0.83; 95% confidence interval [CI]: 0.77-0.90; p<0.0001), a lower ARR (0.13 vs. 0.18, respectively; rate ratio [RR] 0.75 [95% CI: 0.71-0.79]; p<0.0001), and longer lag times to cane/walker use (HR 0.79 [95% CI: 0.66-0.94]; p=0.0067) and wheelchair use (HR 0.68 [95% CI: 0.55-0.83]; p=0.0002) than non-adherent individuals. Adherent individuals had fewer annual inpatient and ER visits and lower total costs than those who were non-adherent (p<0.0001). Sensitivity analyses showed that differences in disease activity and HCRU were generally more pronounced between matched adherent and highly non-adherent pairs than between matched adherent and moderately non-adherent pairs. CONCLUSION: Significant differences in MS disease activity and HCRU were observed based on adherence to DMTs. Our study underscores the negative impact of non-adherence to DMTs on long-term clinical and economic outcomes in MS.

Diversity, Equity, and Inclusion in the Multiple Sclerosis Community: A Call to Action.

Many medical organizations have begun to confront the longstanding problem of inequalities in health care delivery and the undeniable effect of disparities on health outcomes. The Consortium of Multiple Sclerosis Centers (CMSC) recognizes that disparities affect the lives of many people with multiple sclerosis (MS) and acknowledges the need to address this as an organization. The CMSC recently (1) appointed a task force, (2) conducted a survey of its membership, (3) commissioned this review article and call to action, and (4) formulated a mission statement on diversity, equity, and inclusion (DEI), which was adopted by the CMSC's Board of Governors in March 2023. This paper summarizes recent literature on health care disparities in MS, particularly those relating to race/ethnicity, sexual orientation, and gender identity. It presents findings from CMSC's survey of members' awareness of DEI issues, the need for education and resources for MS care providers, and existing institutional policies on DEI in the members' practice settings. It also presents the task force's recommendations for next steps, which includes the goal of greater diversity in the MS workforce of the future. The CMSC will continue to revisit DEI policies and practices over time with the goal of motivating greater awareness, momentum, and positive changes within the MS community.

Real-World Safety and Effectiveness After 5 Years of Dimethyl Fumarate Treatment in Black and Hispanic Patients with Multiple Sclerosis in ESTEEM.

INTRODUCTION: Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing-remitting MS. METHODS: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. RESULTS: Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min-max) months of follow-up was 32 (0-72) for Black, 29 (1-77) for Hispanic, and 41 (0-85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038-0.078) for Black, 0.077 (0.072-0.081) for non-Black, 0.069 (0.043-0.112) for Hispanic, and 0.076 (0.072-0.081) for non-Hispanic populations, representing reductions of 91-92% compared with ARR 12 months before study entry (all p < 0.0001). CONCLUSION: The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02047097.

The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial.

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555.

Social determinants of health in multiple sclerosis.

Social determinants of health are the conditions in which people are born, grow, live, work and age. These circumstances are the non-medical factors that influence health outcomes. Evidence indicates that health behaviours, comorbidities and disease-modifying therapies all contribute to multiple sclerosis (MS) outcomes; however, our knowledge of the effects of social determinants - that is, the 'risks of risks' - on health has not yet changed our approach to MS. Assessing and addressing social determinants of health could fundamentally improve health and health care in MS; this approach has already been successful in improving outcomes in other chronic diseases. In this narrative Review, we identify and discuss the body of evidence supporting an effect of many social determinants of health, including racial background, employment and social support, on MS outcomes. It must be noted that many of the published studies were subject to bias, and screening tools and/or practical interventions that address these social determinants are, for the most part, lacking. The existing work does not fully explore the potential bidirectional and complex relationships between social determinants of health and MS, and the interpretation of findings is complicated by the interactions and intersections among many of the identified determinants. On the basis of the reviewed literature, we consider that, if effective interventions targeting social determinants of health were available, they could have substantial effects on MS outcomes. Therefore, funding for and focused design of studies to evaluate and address social determinants of health are urgently needed.

Advancing Care and Outcomes for African American Patients With Multiple Sclerosis.

Multiple sclerosis (MS) has historically been underdiagnosed and undertreated among African Americans. Recent evidence suggests that African Americans with MS have a different clinical presentation, increased disease incidence and burden, and worse long-term outcomes vs their White counterparts. Due to limited data available for African Americans in MS clinical trials, it is difficult to make informed, generalizable conclusions about the natural history, prognosis, and therapeutic response in this population. In this narrative review, we highlight the nature and magnitude of the health disparities experienced by African Americans with MS and underscore the pressing need to increase knowledge about and understanding of MS disease manifestations in this group. In addition, we describe the mission and objectives of the recently established National African Americans with Multiple Sclerosis Registry, which is intended to be a platform to advance the care of African Americans with MS and address health disparities they may experience.

Generating real-world data from health records: design of a patient-centric study in multiple sclerosis using a commercial health records platform.

OBJECTIVE: The FlywheelMS study will explore the use of a real-world health record data set generated by PicnicHealth, a patient-centric health records platform, to improve understanding of disease course and patterns of care for patients with multiple sclerosis (MS). MATERIALS AND METHODS: The FlywheelMS study aims to enroll 5000 adults with MS in the United States to create a large, deidentified, longitudinal data set for clinical research. PicnicHealth obtains health records, including paper charts, electronic health records, and radiology imaging files from any healthcare site. Using a large-scale health record processing pipeline, PicnicHealth abstracts standard and condition-specific data elements from structured (eg, laboratory test results) and unstructured (eg, narrative) text and maps these to standardized medical vocabularies. Researchers can use the resulting data set to answer empirical questions and study participants can access and share their harmonized health records using PicnicHealth's web application. RESULTS: As of November 24, 2020, more than 4176 participants from 49 of 50 US states have enrolled in the FlywheelMS study. A median of 200 pages of records have been collected from 14 different doctors over 8 years per participant. Abstraction precision, established through inter-abstractor agreement, is as high as 97.8% when identifying and mapping data elements to a standard ontology. CONCLUSION: Using a commercial health records platform, the FlywheelMS study is generating a real-world, multimodal data set that could provide valuable insights about patients with MS. This approach to data collection and abstraction is disease-agnostic and could be used to address other clinical research questions in the future.

Advancing Inclusive Research: Establishing Collaborative Strategies to Improve Diversity in Clinical Trials.

Well-characterized disparities in clinical research have disproportionately affected patients of color, particularly in underserved communities. To tackle these barriers, Genentech formed the External Council for Advancing Inclusive Research, a 14-person committee dedicated to developing strategies to increase clinical research participation. To help improve the recruitment and retention of patients of color, this article chronicles our efforts to tangibly address the clinical research barriers at the system, study, and patient levels over the last four years. These efforts are one of the initial steps to fully realize the promise of personalized health care and provide increased patient benefit at less cost to society. Instead of simply acknowledging the problem, here we illuminate the collaborative and multilevel strategies that have been effective in delivering meaningful progress for patients.