Faculty Bibliography

BACKGROUND:The risk of SARS-CoV-2 infection and severity with disease modifying therapies (DMTs) in multiple sclerosis (MS) remains unclear, with some studies demonstrating increased risks of infection with B-cell-depleting (anti-CD20) therapies and severity, while others fail to observe an association. Most existing studies are limited by a reliance on 'numerator' data (i.e., COVID-19 cases) only. OBJECTIVE:To assess the risks of COVID-19 by DMT, this study aimed to assess both 'numerator' (patients with SARS-CoV-2 infection) and 'denominator' data (all patients treated with DMTs of interest) to determine if any DMTs impart an increased risk of SARS-CoV-2 infection or disease severity. METHODS:We systematically reviewed charts and queried patients during clinic encounters in the NYU MS Comprehensive Care Center (MSCCC) for evidence of COVID-19 in all patients who were on the most commonly used DMTs in our clinic (sphingosine-1-phosphate receptor (S1P) modulators (fingolimod/siponimod), rituximab, ocrelizumab, fumarates (dimethyl fumarate/diroximel fumarate), and natalizumab). COVID-19 status was determined by clinical symptoms (CDC case definition) and laboratory testing where available (SARS-CoV-2 PCR, SARS-CoV-2 IgG). Multivariable analyses were conducted to determine predictors of infection and severe disease (hospitalization or death) using SARS-CoV-2 infected individuals per DMT group and all individuals on a given DMT as denominator. RESULTS:We identified 1,439 MS patients on DMTs of interest, of which 230 had lab-confirmed (n = 173; 75.2%) or suspected (n = 57; 24.8%) COVID-19. Infection was most frequent in those on rituximab (35/138; 25.4%), followed by fumarates (39/217; 18.0%), S1P modulators (43/250; 17.2%), natalizumab (36/245; 14.7%), and ocrelizumab (77/589; 13.1%). There were 14 hospitalizations and 2 deaths. No DMT was found to be significantly associated with increased risk of SARS-CoV-2 infection. Rituximab was a predictor of severe SARS-CoV-2 infection among patients with SARS-CoV-2 infection (OR 6.7; 95% CI 1.1-41.7) but did not reach statistical significance when the entire patient population on DMT was used (OR 2.8; 95% CI 0.6-12.2). No other DMT was associated with an increased risk of severe COVID-19. CONCLUSIONS:Analysis of COVID-19 risk among all patients on the commonly used DMTs did not demonstrate increased risk of infection with any DMT. Rituximab was associated with increased risk for severe disease.

Myelin is a modified cell membrane that forms a multilayer sheath around the axon. It retains the main characteristics of biological membranes, such as lipid bilayer, but differs from them in several important respects. In this review, we focus on aspects of myelin composition that are peculiar to this structure and differentiate it from the more conventional cell membranes, with special attention to its constituent lipid components and several of the most common and important myelin proteins: myelin basic protein, proteolipid protein, and myelin protein zero. We also discuss the many-fold functions of myelin, which include reliable electrical insulation of axons to ensure rapid propagation of nerve impulses, provision of trophic support along the axon and organization of the unmyelinated nodes of Ranvier, as well as the relationship between myelin biology and neurologic disease such as multiple sclerosis. We conclude with a brief history of discovery in the field and outline questions for future research.

Background: Ocrelizumab (OCR), a humanized, anti-CD20 antibody therapy for multiple sclerosis (MS), is given at 6-month intervals. Some patients on OCR report worsening of MS-related symptoms in the weeks leading up to their infusion ('wearing-off' phenomena), but there are no published reports quantifying symptom variation in relation to the timing of OCR infusions.
Objective(s): We will measure symptom burden using SymptoMScreen, NeuroQol and WPAI:MS at 3 points in each infusion cycle over 2 infusion cycles and also obtain Ocrelizumab concentration (PK), neurofilament light chain (NfL), B-cell subsets, and routine clinical labs prior to each infusion.
Aim(s): To quantitate change in symptom burden throughout the infusion cycle in OCR-treated MS patients and to determine which clinical and paraclinical variables correlate with symptom worsening.
Method(s): Prospective, observational, two-center study enrolled patients with relapsing and progressive forms of MS that are initiating OCR or who have been on OCR for >= 1 year (ClinicalTrials. gov Identifier: NCT04855617). All patients receive MS care at NYU MS Care Center (NYU) in New York, NY, or the Elliot Lewis MS Center for MS (ELC) in Wellesley, MA. Patients aged 18-80 and with EDSS scores between 0-7 are eligible for enrollment.
Result(s): 110 participants were enrolled and are actively followed in the study (55 from NYU/55 from ELC). At baseline visit, the mean age was 46.0+/-12.7 years; 64.6% were female; 31.8% were non-White; 20.0% were Hispanic/ Latino; disease duration was 12.6+/-9.6 years; OCR treatment duration was 2.8+/-1.0 years; mean EDSS was 3.3+/-2.1 (EDSS<4, n=69 (62.7%), EDSS>=4, n=41 (37.3%)). Breakdown by disease subtypes was: relapsing-remitting, n=68 (61.8%), secondary progressive, n=24 (21.8%), primary progressive, n=18 (16.4%). Among 58 patients who completed at least 2 questionnaires to date, the symptom burden, as assessed with the SymptoMScreen, was unchanged from week 4 post-infusion to week 12 post-infusion (p-values ranged from 0.2-0.9 for each of the 11 individual domains by Wilcoxon nonparametric test).
Conclusion(s): SymBOLS, designed to assess for the wearing-off effect in OCR-treated patients, has successfully enrolled 110 patients across two US sites. Preliminary data suggest there are no changes to symptom burden during the first half of the infusion cycle. Additional data regarding changes during the second half of the cycle as well as NeuroQoL and work productivity (WPAI) data will be presented

Objective: To examine antibody and T-cell responses to mRNAplatform COVID-19 vaccines in Ocrelizumab-treated MS patients over a 12-month period. Introduction: B-cell depletion with Ocrelizumab attenuates humoral responses to vaccines. The kinetics of humoral and cellular immune responses to COVID-19 vaccines in B-cell depleted MS patients has not been reported.
Method(s): VIOLA (NCT04843774) is an open-label, observational study enrolling 60 MS patients on Ocrelizumab from NYU and Rocky Mountain at the University of Colorado MS Centers. First vaccine dose occurred >=2 weeks after ocrelizumab infusion; second-dose >=8 weeks before the next infusion. Antibody responses to SARS-COV-2 spike proteins were assessed with Elecsys Anti-SARS-CoV-2 (Roche Diagnostics) and multiplex bead-based immunoassays. T-cell responses to SARS-CoV-2 Spike protein were assessed with IFNgamma ELISpot (Invitrogen) and TruCulture (Myriad RBM) and high-dimensional immunophenotyping. Samples are collected pre-vaccination and at 4, 12, 24, and 48-weeks post-vaccination.
Result(s): As of 7/15/2021, 52 subjects have been enrolled (39.7+/-10.0 years; 73% female; 47% non-white), of whom 47 were fully vaccinated (85% Pfizer, 15% Moderna). Anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) were available for pre- and post-vaccine timepoints for 15 patients. Pre-vaccine, 1/15 (7%) patients had detectable titers, while at 4-weeks postvaccine, 10/15 (66%) patients had detectible titers (mean for positives: 1189 U/ml; 5 patients had positive titers <25 U/ml). T-cell activation based on induced IFNgamma secretion (TruCulture) at baseline and 4-week post-vaccine timepoints were available for 13 patients, of whom 12 (92%) were increased (mean pre-vaccine: 24 pg/ml; mean post-vaccine: 366 pg/ml, two-tailed t-test, p=0.0032).
Conclusion(s): This prospective study of humoral and cellular immune responses to COVID-19 vaccines in Ocrelizumab-treated patients will generate data to help guide management of MS patients on anti-CD20 therapies. Early results suggest that 4-weeks post-vaccination nearly all Ocrelizumab-treated MS patients develop T-cell immunity and two-thirds showed evidence of humoral response. Additional 4-week and 12-week post-vaccination data will be presented

Objective: To compare humoral and T-cell responses to COVID- 19 vaccines in 400 MS patients who were on Ocrelizumab ('OCR') v. other disease-modifying therapies ('non-OCR') at the time of vaccination. Introduction: Peripheral B-cell depletion with anti-CD20 therapies attenuates humoral responses to vaccines. Whether immune responses to COVID-19 vaccines differ between B-cell depleted and non-B cell depleted MS patients is not known.
Method(s): Consecutive MS patients from NYU MS Care Center were invited to participate if they completed COVID-19 vaccination >=6 weeks previously. Immune testing included anti-spike RBD antibody (Elecsys Anti-SARS-CoV-2) (Roche Diagnostics); multiplex bead-based immunoassays of antibody-responses to SARS-COV-2 spike proteins; T-cell responses to SARS-CoV-2 Spike protein using IFNgamma enzyme-linked immune-absorbent spot (Invitrogen) and TruCulture (Myriad RBM) assays; high dimensional immunophenotyping; and live virus immunofluorescencebased microneutralization assay.
Result(s): As of 7/15/2021, 105 MS subjects were enrolled (mean age: 40.5 years; 76% female; 41% non-white; 38% on OCR; 12% with prior COVID-19 infection). 95% were fully vaccinated with mRNA vaccines (Pfizer/Moderna); 5% - with adenovirus-based vaccine (Johnson&Johnson). Median time from sample collection to last vaccine was 79 days. Positive Elecsys Anti-SARS-CoV-2 Ab titers post-vaccine were detected in 11/37 (30%) in OCR (mean level: 702 U/mL among seropositives) and 54/54 (100%) patients in non-OCR (mean level: 2310 U/mL; p<0.0001). Positive response by multiplex assay (threshold of 'positive' defined as 2 SD below the mean for the non-OCR) were detected in 10/27 (37%) OCR and 29/31 (94%) non-OCR (p<0.00001). T-cell activation based on induced IFNgamma secretion (TruCulture) was detected in 20/25 (80%) OCR and 16/19 (84%) non-OCR patients (p=0.71).
Conclusion(s): Preliminary results suggest robust T-cell immune response to SARS-CoV2 vaccines in approximately 80% of both OCR and non-OCR MS patients. Antibody responses were markedly attenuated in OCR compared to non-OCR group. Updated results will be presented

BACKGROUND:Short-term outcomes of optic neuritis (ON) have been well characterized. Limited data exists on longer-term visual outcomes in patients who present with ON. The large MSBase registry allows for characterization of long-term visual outcomes after ON. METHODS:Via the MSBase Registry, data on patients from 41 centers was collected during routine clinical and research visits. Physical and visual disability were measured using the expanded disability status scale (EDSS) and the visual function score (VFS). Inclusion criteria for this analysis included age ≥ 18 years, clinically isolated syndrome (CIS), ON-onset, baseline visit within 6 months of onset, and at least one follow-up visit. Survival analysis was used to evaluate the association of disease-modifying treatment with time to conversion to clinically definite MS or sustained EDSS/VFS progression. RESULTS:Data from 60,933 patients were obtained from the MSBase registry in July 2019. Of these, 1317 patients met inclusion criteria; 935 were treated at some point in disease course, while 382 were never treated. At baseline, mean age was 32.3 ± 8.8 years, 74% were female, median EDSS was 2 (IQR 1-2), and median VFS was 1 (IQR 0-2). Median follow-up time was 5.2 years (IQR 2.4-9.3). Treatment was associated with reduced risk and delayed conversion to clinically definite MS (HR = 0.70, p < 0.001), sustained EDSS progression (HR = 0.46, p < 0.0001) and sustained VFS (HR = 0.41, p < 0.001) progression. CONCLUSIONS:In the MSBase cohort, treatment after ON was associated with better visual and neurological outcomes compared to no treatment. These results support early treatment for patients presenting with ON as the first manifestation of MS.