Faculty Bibliography

BACKGROUND:People with MS (PwMS) and related conditions treated with anti-CD20 and S1P modulating therapies exhibit attenuated immune responses to SARS-CoV-2 vaccines. It remains unclear whether humoral/T-cell responses are valid surrogates for postvaccine immunity. OBJECTIVE:To characterize COVID-19 vaccine-breakthrough infections in this population. METHODS:We conducted a prospective multicenter cohort study of PwMS and related CNS autoimmune conditions with confirmed breakthrough infections. Postvaccination antibody response, disease-modifying therapies (DMTs) at the time of vaccination, and DMT at the time of infection were assessed. RESULTS: = 0.0533). However, neither use of anti-CD20 agents at the time of vaccination nor postvaccination antibody response was associated with hospitalization risk. Anti-CD20 therapies were relatively overrepresented compared to a similar prevaccination-era COVID-19 cohort. CONCLUSION:Use of anti-CD20 therapies during vaccine breakthrough COVID-19 infection is associated with higher severity. However, the attenuated postvaccination humoral response associated with anti-CD20 therapy use during vaccination may not drive increased infection severity. Further studies are necessary to determine if this attenuated vaccine response may be associated with an increased likelihood of breakthrough infection.

The purpose of this study was to develop and test a 3D multi-parameter MR fingerprinting (MRF) method for brain imaging applications. The subject cohort included 5 healthy volunteers, repeatability tests done on 2 healthy volunteers and tested on two multiple sclerosis (MS) patients. A 3D-MRF imaging technique capable of quantifying T ₁ , T ₂ and T _1ρ was used. The imaging sequence was tested in standardized phantoms and 3D-MRF brain imaging with multiple shots (1, 2 and 4) in healthy human volunteers and MS patients. Quantitative parametric maps for T ₁ , T ₂ , T _1ρ , were generated. Mean gray matter (GM) and white matter (WM) ROIs were compared for each mapping technique, Bland-Altman plots and intra-class correlation coefficient (ICC) were used to assess repeatability and Student T-tests were used to compare results in MS patients. Standardized phantom studies demonstrated excellent agreement with reference T ₁ /T _2/ T _1ρ mapping techniques. This study demonstrates that the 3D-MRF technique is able to simultaneously quantify T ₁ , T ₂ and T _1ρ for tissue property characterization in a clinically feasible scan time. This multi-parametric approach offers increased potential to detect and differentiate brain lesions and to better test imaging biomarker hypotheses for several neurological diseases, including MS.

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.

OBJECTIVE:To determine outcomes of COVID-19 in patients with Multiple Sclerosis (MS) and related conditions, and to determine predictors of these outcomes. METHODS:This was a multicenter, observational cohort study of patients with MS or related CNS autoimmune disorders who developed confirmed or highly suspected COVID-19 infection from 2/1/2020 to 12/31/2020. MAIN OUTCOME AND MEASURE/UNASSIGNED:The primary outcome measure was hospitalization status due to COVID-19. Severity of infection was measured using a 4-point ordinal scale: 1. home care; 2. hospitalization without mechanical ventilation; 3. hospitalization and mechanical ventilation, and 4. death. RESULTS:Of 474 patients in the study, 63.3% had confirmed COVID-19 infection and 93.9% were diagnosed with an MS phenotype. Mean age was 45 ± 13 (mean±SD) years, 72% were female, and 86% were treated with a DMT at the time of infection. 58 patients (12.2%) were hospitalized. 24 patients (5.1%) were critically ill (requiring ICU care or outcome of death), of which 15 patients (3.2%) died. Higher neurological disability and older age independently predicted hospitalization. 85% (102/120) of patients with known antibody results not treated with anti-CD20 therapies were seropositive while only 39.5% (17/43) of patients treated with anti-CD20 demonstrated seropositivity (p < 0.0001). Only 25% (2/8) of patients with PCR-confirmed COVID-19 being treated with anti-CD20 therapies demonstrated seropositivity. CONCLUSIONS:Neurological disability and older age independently predicted hospitalization due to COVID-19. Additionally, the results demonstrate that anti-CD20 therapies significantly blunt humoral responses post-infection, a finding that carries implications with regards to natural or vaccine-mediated immunity.

PURPOSE OF REVIEW:The newer, higher-efficacy disease-modifying therapies (DMTs) for multiple sclerosis (MS)-orals and monoclonals-have more profound immunomodulatory and immunosuppressive properties than the older, injectable therapies and require risk mitigation strategies to reduce the risk of serious infections. This review will provide a systematic framework for infectious risk mitigation strategies relevant to these therapies. RECENT FINDINGS:We classify risk mitigation strategies according to the following framework: (1) screening and patient selection, (2) vaccinations, (3) antibiotic prophylaxis, (4) laboratory and MRI monitoring, (5) adjusting dose and frequency of DMT, and (6) behavioral modifications to limit the risk of infection. We systematically apply this framework to the infections for which risk mitigations are available: hepatitis B, herpetic infections, progressive multifocal leukoencephalopathy, and tuberculosis. We also discuss up-to-date recommendations regarding COVID-19 vaccinations for patients on DMTs. We offer a practical, comprehensive, DMT-specific framework of derisking strategies designed to minimize the risk of infections associated with the newer MS therapies.