Cellular and Humoral Immunity to SARS-CoV-2 Infection in Multiple Sclerosis Patients on Ocrelizumab and Other Disease-Modifying Therapies: A Multi-Ethnic Observational Study.

OBJECTIVE: The objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection. METHODS: Patients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity. RESULTS: Between January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized. INTERPRETATION: DMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022;91:782-795.

Vaccine-breakthrough SARS-CoV-2 infections in people with multiple sclerosis and related conditions: An observational study by the New York COVID-19 Neuro-Immunology Consortium (NYCNIC-2).

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: Two hundred nine patients had 211 breakthrough infections. Use of anti-CD20 agents at time of infection was associated with increased infection severity (p = 0.0474, odds ratio (OR) = 5.923) for infections during the Omicron surge and demonstrated a trend among the total cohort (p = 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.

Patient Preference for Subcutaneous Versus Intravenous Administration with Every-6-Week Natalizumab (Tysabri®) Dosing: NOVA Phase IIIb Extension Study (Part 2).

INTRODUCTION: Following NOVA (part 1) and the approval of the subcutaneous (SC) route of administration of natalizumab by the European Medicines Agency, an extension phase of the NOVA phase IIIb study (part 2) was initiated to collect patient preference data for SC versus intravenous (IV) dosing in patients receiving every-6-week (Q6W) dosing of natalizumab. This study was performed to evaluate patient preference for SC versus IV natalizumab administration and explore the efficacy, safety, and pharmacology characteristics of both routes of administration. METHODS: In part 2, participants received natalizumab (Tysabri®) 300 mg via IV infusion Q6W for 36 weeks and then were randomized to 48 weeks of crossover treatment (24 weeks SC Q6W and 24 weeks IV Q6W, or vice versa). The primary endpoint was the proportion of participants who indicated a preference for natalizumab SC administration on the Patient Preference Questionnaire. RESULTS: A total of 153 participants were randomized in NOVA part 2. Of 123 with patient preference data, 108 (87.8%) preferred the SC route of administration for natalizumab over the IV route; 102 (82.9%) specified "requires less time in the clinic" as the reason for the SC preference. CONCLUSION: In NOVA (part 2), most participants on Q6W dosing of natalizumab preferred SC administration versus IV administration. CLINICALTRIALS: GOV: NCT03689972. INFOGRAPHIC.

Outcomes of COVID-19 infection in multiple sclerosis and related conditions: One-year pandemic experience of the multicenter New York COVID-19 Neuroimmunology Consortium (NYCNIC).

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: 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.

Pharmacodynamics of natalizumab extended interval dosing in MS.

OBJECTIVE: To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS: In a cross-sectional assessment of patients with multiple sclerosis (MS) who received standard interval dosing (every 4 weeks) or EID, serum NTZ concentrations were measured using ELISA, and α4-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS: Trough serum concentration was above the "therapeutic" concentration of 2.0 µg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS: Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

Mirabegron Versus Solifenacin in Multiple Sclerosis Patients With Overactive Bladder Symptoms: A Prospective Comparative Nonrandomized Study.

OBJECTIVE: To determine the patient-perceived effectiveness and tolerability of mirabegron compared to solifenacin in a multiple sclerosis (MS) population with overactive bladder (OAB) symptoms. MATERIALS AND METHODS: MS patients with OAB symptoms who were not on medication for their urinary symptoms at enrollment were prospectively recruited. Patients enrolled in years 1-2 were prescribed mirabegron, whereas patients enrolled in years 3-4 were prescribed solifenacin. At enrollment and 6-week follow-up, patients completed several patient reported outcome measures. The primary outcome was change in OAB Questionnaire Short Form (OAB-q SF) symptom severity and minimal clinically important difference (MCID) achievement. The Patient Assessment of Constipation Symptoms (PAC-SYM) was used to assess bowel function over the treatment period. RESULTS: Sixty-one patients were enrolled. The majority of the mirabegron (70%) and the solifenacin (69%) group achieved the OAB-q SF symptom severity MCID. The solifenacin group had a statistically significant greater decrease in its end of study OAB-q SF score (Δ = -37.87 vs -20.43, P = .02). Constipation improved in the mirabegron group and worsened in the solifenacin group (ΔPAC-SYM = -0.38 vs +0.22; P = .02), with 30% of patients prescribed solifenacin experiencing worsening above the MCID threshold. CONCLUSION: Among MS patients, we demonstrated similar response rates to mirabegron and solifenacin, with approximately 50%-70% achieving each patient reported outcome measure's MCID. Though this small study showed some short-term evidence that improvement in urinary symptom severity was greater with solifenacin, this potential benefit must be weighed against the observed risk of worsening constipation. Further studies are needed to confirm these findings.

COVID-19 outcomes in MS: Observational study of early experience from NYU Multiple Sclerosis Comprehensive Care Center.

OBJECTIVE: To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness. METHODS: From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records. RESULTS: We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders). Thirty-seven underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome. CONCLUSIONS: Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at-risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample.

Efficacy and tolerability of dimethyl fumarate in White-, African- and Hispanic- Americans with multiple sclerosis.

BACKGROUND: Dimethyl fumarate (DMF) was approved by the US Food and Drug Administration (FDA) for treatment of relapsing-remitting multiple sclerosis (RRMS) based on two phase III randomized clinical trials (RCTs). There were not enough non-White patients enrolled in these RCTs to allow for subgroup analysis based on race. Efficacy and tolerability of DMF therapy across various racial groups is unknown. METHODS: Retrospective chart review was performed on all patients with RRMS who were started on DMF in two tertiary multiple sclerosis (MS) clinics. Efficacy and tolerability of DMF was compared across three self-identified racial groups: White-American (WA), African-American (AA) and Hispanic-American (HA). RESULTS: A total of 390 RRMS patients were included in the study: 261 (66.9%) WA, 69 (17.7%) AA and 52 (13.3%) HA. When comparing 'pre-DMF' (1 year) and 'on DMF' (mean follow up of 14 months) periods, statistically significant reduction in rates of annualized relapses (WA from 0.44 to 0.19, AA from 0.39 to 0.15, and HA from 0.39 to 0.14; no differences between groups), new T2 lesions (WA from 45% to 23%, AA from 39% to 23%, HA from 52% to 26%; no difference between groups), and Gd+ lesions (WA from 25% to 13%, AA from 24% to 7%, HA from 23% to 12%; no difference between groups) were seen. DMF was relatively well tolerated across all groups, with an overall discontinuation rate of 20% (no difference between the three groups). CONCLUSION: Efficacy of DMF in our clinic population did not differ across three major ethnic groups, WA, AA and HA, and was comparable with results observed in the pivotal studies. These 'real-life' data suggest that race is not a factor that needs to be taken into account when initiating DMF.

Adult-onset spastic paraparesis: an approach to diagnostic work-up.

Adult-onset, chronic progressive spastic paraparesis may be due to a large number of causes and poses a diagnostic challenge. There are no recent evidence-based guidelines or comprehensive reviews to help guide diagnostic work-up. We survey the literature on chronic progressive spastic paraparesis, with special emphasis on myelopathies, and propose a practical, MRI-based approach to facilitate the diagnostic process. Building on neuro-anatomic and radiographic conventions, we classify spinal MRI findings into six patterns: extradural; intradural/extramedullary; Intramedullary; Intramedullary-Tract specific; Spinal Cord Atrophy; and Normal Appearing Spinal Cord. A comprehensive differential diagnosis of chronic progressive myelopathy for each of the six patterns is generated. We highlight some of the more common and/or treatable causes of progressive spastic paraparesis and provide clinical pointers that may assist clinicians in arriving at the diagnosis. We outline a practical, comprehensive MRI-based algorithm to diagnosing adult-onset chronic progressive myelopathy.