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.

The impact of relapse definition and measures of durability on MS clinical trial outcomes.

BACKGROUND: Definitions of trial measures are consequential to accurately capturing outcomes and cross-trial comparability, particularly for derivative measures. OBJECTIVE: Using CombiRx, examine the impact of relapse definition on endpoints and evaluate the durability of progression measures in Relapsing Remitting Multiple Sclerosis (RRMS). METHODS: CombiRx relapse types were distinguished by the presence or timing of Expanded Disability Status Scale (EDSS) increase. Using the broadest definition of relapse, progression endpoints were assessed in patients without relapses on trial. Durability compared EDSS at study end and time of worsening. RESULTS: Broadening relapse definition to the most inclusive definition increased annualized relapse rate (ARR) threefold in all arms and decreased progression independent of relapse activity (PIRA), defined as 6-month confirmed disability worsening (6M CDW) without relapse, by 44%. Neither PIRA nor PIA (progression independent of any inflammatory activity) guaranteed durable worsening, with 43% and 40%, respectively, improving by end of study. Multivariate analysis showed two CDW events, not relapse, predicted durability among patients meeting 6M CDW. CONCLUSIONS: The stringency of relapse definition impacted absolute ARR and composite endpoints in RRMS. Despite the most generous relapse definition, 43% of patients meeting PIRA on trial did not have durable worsening suggesting that relapse definition and durability should be considered to avoid overestimating progression in RRMS trials.

Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy.

BACKGROUND: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. The objective of this study is to evaluate humoral and cellular immune responses to a third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. METHODS: This is an observational study evaluating immunological responses to third COVID-19 vaccine dose in participants treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Groups were compared by one-way ANOVA with Tukey multiple comparisons. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Pre-post comparisons were made by Wilcoxon paired t-tests, inter-cohort comparisons by Mann-Whitney t-test. RESULTS: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P < 0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p < 0.001) and were not significantly "boosted" by a third injection. CONCLUSIONS: Participants on anti-CD20 and S1PR modulator therapies had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.

Continuous EEG monitoring detects nonconvulsive seizure and Ictal-Interictal Continuum abnormalities in moderate to severe ICANS following systemic CAR-T therapy.

Background and Purpose: Immune Cell Effector Associated Neurotoxicity Syndrome (ICANS) is common amongst patients receiving CD19 targeted Chimeric Antigen Receptor T-cell (CAR-T) therapy. The purpose of this study is to characterize the incidence of seizures and ictal-interictal continuum (IIC) abnormalities in patients with ICANS. Methods: Retrospective review of consecutive patients treated with axicabtagene ciloleucel (axi-cel) for recurrent high-grade systemic lymphoma at Stanford Medical Center between 2/2016-6/2019. Electronic medical records (EMR) were reviewed for clinical features, treatment information, EEG data, CRS (cytokine release syndrome)/ICANS severity, and clinical outcomes. Results: Fifty-six patients met inclusion criteria. 85.7% of patients developed CRS, and 58.9% developed ICANS. Twenty-eight patients had EEG monitoring, of whom 26 had ICANS. Median duration of EEG monitoring was 30 hours (range .5-126 hours). Four patients (7.1%) had seizures (1 patient had a clinical generalized seizure, 2 patients had clinical and nonconvulsive seizures, and 1 patient had an isolated non-convulsive seizure). Ictal-interictal continuum abnormalities were common, of which generalized periodic discharges (GPDs) with triphasic morphology and GPDs with epileptiform morphology were most frequently seen. Generalized periodic discharges with triphasic wave morphology were found across Grade 2-3 peak ICANS severity, however the majority (86%) of patients with epileptiform GPDs had Grade 3 peak ICANS severity. Conclusions: Among patients receiving axi-cel, seizure occurred in 7.1% of the total cohort, representing 12% of patients with ICANS. Ictal-interictal continuum abnormalities are also seen in patients with ICANS, most commonly GPDs. 75% of patients with seizures had nonconvulsive seizures supporting the use of continuous video EEG monitoring in this population.

Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy.

Importance: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. Objective: Evaluate humoral and cellular immune responses to third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. Design: Observational study evaluating immunological response to third COVID-19 vaccine dose in volunteers treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Setting: Mount Sinai Hospital. Participants: People treated with anti-CD20 therapy or S1PR modulators and healthy volunteers. Exposure: Treatment with anti-CD20 therapy, S1PR modulator, or neither. Main outcomes and measures: Serum neutralizing antibodies and ex vivo T cell responses against SARS-CoV-2 antigens. Results: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P<0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p<0.001) and were not significantly "boosted" by a third injection. Conclusions and Relevance: Participants on immunomodulators had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.

Differential antibody response to COVID-19 vaccines across immunomodulatory therapies for multiple sclerosis.

BACKGROUND: Prior studies suggest reduced humoral response to COVID-19 vaccination in immunosuppressed populations. Disease modifying therapies (DMTs) for multiple sclerosis (MS) have variable immunomodulatory effects, and limited data are available for all DMTs. We aimed to determine the impact of DMTs on antibody response to COVID-19 vaccination among MS patients. METHODS: Patients with documented COVID-19 vaccination dates and anti-spike antibody results post-vaccination were identified between March-August 2021. Clinical data were retrospectively abstracted from chart review. Deidentified data were analyzed to evaluate antibody response, and multivariable logistic regression analyses were used to identify clinical and demographic predictors of antibody response. Data analysis was completed with SAS Studio, v3.8. RESULTS: A total of 353 individuals had documented COVID-19 vaccine and antibody test dates (58% Pfizer, 38% Moderna, and 4% Johnson & Johnson). Of these 353 patients, 72% developed antibodies, with a mean antibody test interval of 53 days (median 46) post final vaccine dose. 100% of those on no DMT (n = 34), injectables (n = 20), teriflunomide (n = 10), natalizumab (n = 71), and 97.8% of those on fumarates (n = 46/47) had a positive antibody result. One patient on cladribine (n = 1) had a negative antibody result. Of those on sphingosine-1 phosphate (S1P) modulators, 72.4% (n = 21/29) had a positive antibody result. Of those on anti-CD20 therapies, 37.6% (n = 53/141) had a positive antibody result. Multivariate modeling of the total cohort showed anti-CD20 therapy was significantly associated with lower odds of positive antibody response (OR = 0.024, 95% CI 0.01;0.05, p < 0.0001). Among S1P modulators, increased duration of therapy, and not lymphopenia, may be associated with lower odds of positive antibody response. Multivariate modeling of anti-CD20 therapies showed therapy duration < 1 year (OR 8.14, 95% CI 2.896;22.898 p < .0001) and prior COVID-19 infection (OR = 3.95, 95% CI 1.137;13.726, p = .03) were significantly associated with higher odds of a positive antibody response. In patients with recent B-cell data, mean B-cell count was higher in antibody-positive individuals compared to antibody-negative (32.9 vs. 3.9 cells, p = .0056). CONCLUSION: MS DMTs had variable impact on antibody response with mRNA and viral vector COVID-19 vaccines. All patients on no DMT, interferons, glatiramer acetate, teriflunomide, natalizumab, and nearly all on fumarates had positive antibody responses post-vaccine. S1P modulators and anti-CD20 therapies attenuated antibody response post-vaccine. For patients on anti-CD20 therapies, shorter duration of therapy and prior COVID-19 infection predicted positive antibody response. Further studies are needed to determine clinical significance of antibody testing, development of cellular mediated immunity, and benefits of booster vaccinations.

Immunological Aspects of Approved MS Therapeutics.

Multiple sclerosis (MS) is the most common neurological immune-mediated disease leading to disability in young adults. The outcome of the disease is unpredictable, and over time, neurological disabilities accumulate. Interferon beta-1b was the first drug to be approved in the 1990s for relapsing-remitting MS to modulate the course of the disease. Over the past two decades, the treatment landscape has changed tremendously. Currently, more than a dozen drugs representing 1 substances with different mechanisms of action have been approved (interferon beta preparations, glatiramer acetate, fingolimod, siponimod, mitoxantrone, teriflunomide, dimethyl fumarate, cladribine, alemtuzumab, ocrelizumab, and natalizumab). Ocrelizumab was the first medication to be approved for primary progressive MS. The objective of this review is to present the modes of action of these drugs and their effects on the immunopathogenesis of MS. Each agent's clinical development and potential side effects are discussed.

Women Connected to at Risk Indian Men Who Have Sex with Men: An Unexplored Network.

Little is known about the women connected to Indian MSM and their impact on HIV risk. We surveyed 240 Indian MSM, who identified their social networks (n = 7,092). Women (n = 1,321) comprised 16.7 % of the network, with 94.7 % representing non-sexual connections. MSM were classified as having low, moderate, or high female network proportion. MSM with moderate female network proportion (8-24 % total network) had significantly lowered odds of HIV seropositivity (AOR = 0.24, 95 % CI = 0.1-0.6). This suggests moderate proportions of female connections could mediate HIV risk. HIV prevention interventions in India could consider the greater involvement of women among their target audiences. Se sabe poco sobre las mujeres conectadas a HSH en India y su impacto en el riesgo de VIH. Se encuestó a 240 HSH indios, quienes identificaron sus redes sociales (n = 7,092). Las mujeres (n = 1,321) formaron al 16.7 % de la red, del cual el 94.7 % representa conexiones no sexuales. Los HSH se clasificaron como baja, moderada o alta proporción de red femenina. HSH con proporción moderada de red femenina (8-24 % del red total) tuvieron un riesgo significativamente reducido de seropositividad de VIH (AOR = 0,24; IC 95 % = 0,1-0,6). Esto sugiere que tener una proporción moderada de contactos femeninos podría atenuar el riesgo de VIH. Las intervenciones de prevención del VIH en India podrían considerar una mayor participación de las mujeres en su público objetivo.