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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

Kister, Ilya; Patskovsky, Yury; Curtin, Ryan; Pei, Jinglan; Perdomo, Katherine; Rimler, Zoe; Voloshyna, Iryna; Samanovic, Marie I; Cornelius, Amber R; Velmurugu, Yogambigai; Nyovanie, Samantha; Kim, Joseph J; Tardio, Ethan; Bacon, Tamar E; Zhovtis Ryerson, Lana; Raut, Pranil; Pedotti, Rosetta; Hawker, Kathleen; Raposo, Catarina; Priest, Jessica; Cabatingan, Mark; Winger, Ryan C; Mulligan, Mark J; Krogsgaard, Michelle; Silverman, Gregg J
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/CONCLUSIONS: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.
PMID: 35289960
ISSN: 1531-8249
CID: 5191732

Development and validation of a simple and practical method for differentiating MS from other neuroinflammatory disorders based on lesion distribution on brain MRI

Patel, J; Pires, A; Derman, A; Fatterpekar, G; Charlson, R E; Oh, C; Kister, I
There is an unmet need to develop practical methods for differentiating multiple sclerosis (MS) from other neuroinflammatory disorders using standard brain MRI. To develop a practical approach for differentiating MS from neuromyelitis optica spectrum disorder (NMOSD) and MOG antibody-associated disorder (MOGAD) with brain MRI, we first identified lesion locations in the brain that are suggestive of MS-associated demyelination ("MS Lesion Checklist") and compared frequencies of brain lesions in the "MS Lesion Checklist" locations in a development sample of patients (n = 82) with clinically definite MS, NMOSD, and MOGAD. Patients with MS were more likely than patients with non-MS to have lesions in 3 locations only: anterior temporal horn (p < 0.0001), periventricular ("Dawson's finger") (p < 0.0001), and cerebellar hemisphere (p = 0.02). These three lesion locations were used as predictor variables in a multivariable regression model for discriminating MS from non-MS. The model had area under the curve (AUC) of 0.853 (95% confidence interval: 0.76-0.945), sensitivity of 87.1%, and specificity of 72.5%. We then used an independent validation sample with equal representation of MS and NMOSD/MOGAD cases (n = 97) to validate our prediction model. In the validation sample, the model was 76.3% accurate in discriminating MS from non-MS. Our simple method for predicting MS versus NMOSD/MOGAD only requires a neuroradiologist or clinician to ascertain the presence of lesions in three locations on conventional MRI sequences. It can therefore be readily applied in the real-world setting for training and clinical practice.
PMID: 35525154
ISSN: 1532-2653
CID: 5216572

Is there a link between neuropathic pain and constipation in NMOSD and MOGAD? Results from an online patient survey and possible clinical implications

Lotan, Itay; Romanow, Gabriela; Levy, Michael; Kister, Ilya
BACKGROUND:Neuropathic pain (NP) and constipation are common among people with neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and have a negative impact on quality-of-life measures. The possible association between the two symptoms has not been explored. METHODS:Patients with NMOSD and MOGAD, who were members of a closed international Facebook group, were recruited to complete an anonymous survey on REDCap. Participants were queried regarding demographic and disease-related characteristics, the presence and severity of NP and constipation, and whether they believe there is a relationship between the two symptoms. RESULTS:Of the 317 participants who completed the survey, 213 (67.2%) reported a diagnosis of aquaporin-4 (AQP-4) positive NMOSD, 93 (29.4%) - MOGAD, and 11 (3.4%) - double-seronegative NMOSD. The mean age was 43.9 ± 16.4 years; 259 were female (81.7%). 206 participants (65%) reported NP, of whom 133 (64.6%) were being treated for it with one or more medications. 167 participants (52.7%) reported constipation, of whom 67 (40.2%) received one or more medications. 137 of 206 participants with NP (66%) also had constipation. Both symptoms were significantly more common among patients with a history of myelitis. Among patients with NP and constipation, 47 participants (34.3%) thought there was a relationship between the two conditions, with the majority reporting increased severity of NP when constipation severity was increased and, conversely, alleviation of NP when constipation lessened. CONCLUSIONS:NP and constipation were seen in the majority of NMOSD and MOGAD patients with a history of myelitis. Interestingly, one-third of patients with both symptoms reported a link between them, with the majority reporting that NP severity was increased with worse constipation. The possible association opens a possibility of a new approach to managing NP, which tends to be poorly responsive to symptomatic therapies and is associated with worse quality of life in NMOSD and MOGAD. Further studies are warranted to confirm our results.
PMID: 35537276
ISSN: 2211-0356
CID: 5214302

Faster B-cell repletion after anti-CD20 infusion in Black patients compared to white patients with neurologic diseases [Letter]

Saidenberg, Lucia; Arbini, Arnaldo A; Silverman, Gregg J; Lotan, Itay; Cutter, Gary; Kister, Ilya
This retrospective, single-center study aimed to characterize and compare the kinetics of B-cell reemergence following anti-CD20 infusion (anti-CD20i) in African American (AA) and white patients with MS or NMOSD. In a logistic regression model that included race, time since anti-CD20i, body mass index, and diagnosis, only AA race (p=0.01) and time since anti-CD20i (p=0.0003) were significant predictors of B-cell repletion. However, B-cell subset composition was similar between AA and white patients with detectable CD19+ B-cell counts. These findings highlight the importance of including a diverse study population in future studies of anti-CD20 therapies.
PMID: 35490448
ISSN: 2211-0356
CID: 5215682

The outcomes of total hip arthroplasty in patients with and without multiple sclerosis: a retrospective cohort study

Mai, David H; Blackowicz, Michael E; Kister, Ilya; Schwarzkopf, Ran
BACKGROUND/UNASSIGNED:Multiple sclerosis (MS) is a neuroinflammatory disease with debilitating manifestations that may predispose patients to hip fracture and osteoarthritis, and may affect recovery from total hip arthroplasty (THA). With increased longevity of MS patients and growth in demand for arthroplasty in this population, it is important to understand outcomes of THA in patients with MS. AIM/UNASSIGNED:We sought to compare outcomes of THA among persons with MS and without MS. METHODS/UNASSIGNED:International Classification of Diseases, Ninth Revision Procedure Coding System (ICD-9-PCS) codes for hip arthroplasty (815.1) were used to identify all patients in the New York Statewide Planning and Research Cooperative System (SPARCS) database who underwent THA between 2000 and 2014. Patients with MS, the primary exposure, were identified using ICD-9-Clinical Modification (CM) code 340. The study outcomes of length of stay (days), discharge disposition, index admission mortality, 90-day readmission, 1-year revision arthroplasty, and 1-year all-cause mortality were evaluated using multivariable regression analyses inclusive of basic demographics, admission source, disposition, payer, comorbidity, and socioeconomic status (SES). RESULTS/UNASSIGNED: = 0.035). However, MS patients had similar risk for 90-day readmission and one-year all-cause mortality as compared with non-MS patients. CONCLUSIONS/UNASSIGNED:Although patients with MS who underwent THA had a 90-day complication risk that was similar to those without MS, the risk for requiring revision surgery was more than 2-fold higher. Additional studies are needed to understand the reasons for revision surgery and for developing strategies to mitigate the risk of complications.
PMID: 35437062
ISSN: 1724-6067
CID: 5191762

Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS

Kalincik, Tomas; Kister, Ilya; Bacon, Tamar E; Malpas, Charles B; Sharmin, Sifat; Horakova, Dana; Kubala-Havrdova, Eva; Patti, Francesco; Izquierdo, Guillermo; Eichau, Sara; Ozakbas, Serkan; Onofrj, Marco; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Sola, Patrizia; Ferraro, Diana; Alroughani, Raed; Terzi, Murat; Boz, Cavit; Grand'Maison, Francois; Bergamaschi, Roberto; Gerlach, Oliver; Sa, Maria J; Kappos, Ludwig; Cartechini, Elisabetta; Lechner-Scott, Jeannette; van Pesch, Vincent; Shaygannejad, Vahid; Granella, Franco; Spitaleri, Daniele; Iuliano, Gerardo; Maimone, Davide; Prevost, Julie; Soysal, Aysun; Turkoglu, Recai; Ampapa, Radek; Butzkueven, Helmut; Cutter, Gary
BACKGROUND/UNASSIGNED:The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. OBJECTIVE/UNASSIGNED:To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS/UNASSIGNED:The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients' demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. RESULTS/UNASSIGNED:A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. CONCLUSION/UNASSIGNED:Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.
PMID: 35373638
ISSN: 1477-0970
CID: 5191742


COVID and Multiple Sclerosis: What have we learned since the start of the pandemic?

Kister, Ilya
CID: 5192292

Risk of COVID-19 infection and severe disease in MS patients on different disease-modifying therapies

Smith, Tyler E; Madhavan, Maya; Gratch, Daniel; Patel, Aneek; Saha, Valerie; Sammarco, Carrie; Rimler, Zoe; Zuniga, Guadalupe; Gragui, Dunia; Charvet, Leigh; Cutter, Gary; Krupp, Lauren; Kister, Ilya; Ryerson, Lana Zhovtis
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.
PMID: 35398713
ISSN: 2211-0356
CID: 5191752

Case Conference: When '3-for-5' Is Not Enough

Kister, Ilya; Biller, Jose
ISSN: 1540-1367
CID: 5192272

Vaccine against SARS-CoV2-generated Immunity in Ocrelizumab-treated Patients: Longitudinal Assessments (VIOLA): Study design and early results [Meeting Abstract]

Kister, I; Piquet, A; Patskovsky, Y; Voloshyna, I; Ferstler, N; Curtin, R; Yogambigai, V; Nyovanie, S; Rimler, Z; Perdomo, K; Borko, T; Selva, S; Parra, Gonzalez J; Bacon, T; Zhovtis, Ryerson L; Raposo, C; Priest, J; Winger, R; Silverman, G J; Krogsgaard, M
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
ISSN: 1477-0970
CID: 5179832