Longitudinal study of immunity to SARS-CoV2 in ocrelizumab-treated MS patients up to 2 years after COVID-19 vaccination.

OBJECTIVES: (1) To plot the trajectory of humoral and cellular immune responses to the primary (two-dose) COVID-19 mRNA series and the third/booster dose in B-cell-depleted multiple sclerosis (MS) patients up to 2 years post-vaccination; (2) to identify predictors of immune responses to vaccination; and (3) to assess the impact of intercurrent COVID-19 infections on SARS CoV-2-specific immunity. METHODS: Sixty ocrelizumab-treated MS patients were enrolled from NYU (New York) and University of Colorado (Anschutz) MS Centers. Samples were collected pre-vaccination, and then 4, 12, 24, and 48 weeks post-primary series, and 4, 12, 24, and 48 weeks post-booster. Binding anti-Spike antibody responses were assessed with multiplex bead-based immunoassay (MBI) and electrochemiluminescence (Elecsys®, Roche Diagnostics), and neutralizing antibody responses with live-virus immunofluorescence-based microneutralization assay. Spike-specific cellular responses were assessed with IFNγ/IL-2 ELISpot (Invitrogen) and, in a subset, by sequencing complementarity determining regions (CDR)-3 within T-cell receptors (Adaptive Biotechnologies). A linear mixed-effect model was used to compare antibody and cytokine levels across time points. Multivariate analyses identified predictors of immune responses. RESULTS: The primary vaccination induced an 11- to 208-fold increase in binding and neutralizing antibody levels and a 3- to 4-fold increase in IFNγ/IL-2 responses, followed by a modest decline in antibody but not cytokine responses. Booster dose induced a further 3- to 5-fold increase in binding antibodies and 4- to 5-fold increase in IFNγ/IL-2, which were maintained for up to 1 year. Infections had a variable impact on immunity. INTERPRETATION: Humoral and cellular benefits of COVID-19 vaccination in B-cell-depleted MS patients were sustained for up to 2 years when booster doses were administered.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

OBJECTIVE: The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS: We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS: The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION: CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024.

Heart Rate Variability (HRV) serves as an objective correlate of distress and symptom burden in multiple sclerosis.

Background: Autonomic nervous system (ANS) dysfunction is frequently seen in people living with multiple sclerosis (MS). Heart rate variability (HRV) is an easy and objective index for evaluating ANS functioning, and it has been previously used to explore the association between ANS and the experience of symptom burden in other chronic diseases. Given ANS functioning can be influenced by physical and psychological factors, this study investigated whether emotional distress and/or the presence of ANS dysfunction is associated with symptom severity in people living with MS. Methods: Participants with MS and healthy controls (HC) with no history of cardiac conditions were recruited to self-collect HR data sampled from a chest strap HR monitor (PolarH10). Short-term HR signal was collected for five minutes, and time and frequency HRV analyses were performed and compared between groups. HRV values were then compared to self-reported distress (Kessler Psychological Distress Scale) and MS participants' self-reported measures of symptom burden (SymptoMScreen). Results: A total of n = 23 adults with MS (51 ± 12 years, 65 % female, median Patient Determined Disease Steps [PDDS]: 3.0) and n = 23 HCs (43 ± 18 years, 40 % female) completed the study procedures. All participants were able to complete the chest strap placement and HR data capture independently. Participants with MS, compared to the HC participants, had a significantly lower parasympathetic activation as shown by lower values of the root mean square of successive differences between normal heartbeats (RMSSD: 21.86 ± 9.84 vs. 43.13 ± 20.98 ms, p = 0.002) and of high-frequency (HF) power band (HF-HRV: 32.69 ± 12.01 vs. 42.39 ± 7.96 nu, p = 0.016), indicating an overall lower HRV in the MS group. Among individuals with MS, HF-HRV was significantly correlated with the severity of self-reported MS symptoms (r = -0.548, p = 0.010). Participants with MS also reported higher levels of distress compared to HC participants (18.32 ± 6.05 vs. 15.00 ± 4.61, p = 0.050), and HRV correlated with the severity of distress in MS participants (r = -0.569, p = 0.007). A significant mediation effect was also observed, with emotional distress fully mediating the association between HRV and symptom burden. Conclusions: These findings suggest the potential for ANS dysfunction, as measured by HRV (i.e., lower value of HF power), to be utilized as an objective marker of symptom burden in people living with MS. Moreover, it is apparent that the relationship between HRV and symptom burden is mediated by emotional distress.

Relapsing White Matter Disease and Subclinical Optic Neuropathy: From the National Multiple Sclerosis Society Case Conference Proceedings

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

Immune Checkpoint Inhibitors in Patients with Pre-existing Neurologic Autoimmune Disorders.

PURPOSE OF REVIEW: The use of immune checkpoint inhibitors (ICIs) for oncologic indications is associated with immune-related adverse events (irAEs). Patients with pre-existing autoimmune diseases are at increased risk of irAEs and have largely been excluded from clinical trials of ICIs. Therefore, there is limited data on the safety of safety of ICIs in patients with pre-existing neurologic autoimmune diseases (nAIDs) such as myasthenia gravis and multiple sclerosis. This review aims to synthesize the literature on the post-marketing experience with ICI in patients with pre-existing nAID and to discuss possible strategies for mitigating the risk of post-ICI nAID relapses. RECENT FINDINGS: Patients with pre-existing myasthenia gravis (MG), myositis, and paraneoplastic encephalitis appear highly susceptible to neurologic relapses of their underlying neurologic disorder following ICI initiation; these relapses can cause considerable morbidity and mortality. In patients with multiple sclerosis (MS), the risk and severity of MS relapses following ICI appears to be relatively lower compared to MG. Preliminary evidence suggests that older MS patients with no recent focal neuroinflammatory activity may be safely treated with ICI. Among the several case reports of ICI in patients with a history of Guillain-Barre syndrome (GBS), neurologic worsening was only recorded in one patient who was in the acute phase of GBS at the time of ICI start. Initiating an ICI in a patient with pre-existing nAID involves a complex risk-benefit discussion between the patient, their oncologist, and neurologist. Relevant issues to consider before ICI include the choice of disease-modifying therapy for nAID (if any) and strategies for promptly identifying and managing nAID relapses should they occur. Currently, the literature consists mainly of case reports and case series, subject to publication bias. Prospective studies of ICI in patients with nAID are needed to improve the level of evidence.

African American patients with Multiple Sclerosis (MS) have higher proportions of CD19+ and CD20+ B-cell lineage cells in their cerebrospinal fluid than White MS patients.

OBJECTIVES: To compare proportions of B-cell lineage CD19+ and CD20+ cells in CSF of African-American (AA) and White (W) patients with MS. BACKGROUND: AA MS patients are more likely to have oligoclonal bands in CSF, higher IgG index in CSF, and higher circulating plasmablasts in blood than W MS patients. It is unknown whether the proportion of B-cells in CSF differs between AA and W patients in MS. METHODS: Demographics, disease-related information, treatment history were retrospectively collected on patients with MS who self-identified as AA or W and underwent flow cytometry of CSF during diagnostic work-up. Proportion of B-lymphocytes, T-lymphocytes, NK cells, monocytes, and plasma cells were analyzed with flow cytometry. RESULTS: 20 AA and 56 W MS patients fulfilled our inclusion criteria. The groups had similar demographics, CSF cell counts, protein and glucose CSF concentrations, and oligoclonal band number. IgG index was higher in AA compared to W (1.08 vs. 0.85, p = 0.031). AA had higher proportions of CD19+ (5.46 % AA vs. 2.26 % W, p = 0.006) and CD20+ (4.64 % AA vs. 1.91 % W, p = 0.004) cells but did not significantly differ in proportion of CD4+, CD8+, CD38+ bright B-cells, NK cells and monocytes. CONCLUSIONS: B-cells are overrepresented in the CSF of African American patients with MS relative to Whites.

No Increase in Symptoms Toward the End of the Ocrelizumab Infusion Cycle in Patients With Multiple Sclerosis: Symptom Burden on Ocrelizumab: A Longitudinal Study (SymBOLS).

Background and Objectives: Some patients with multiple sclerosis (MS) receiving ocrelizumab (OCR) report worsening symptoms toward the end of the 6-month infusion cycle ('wearing off'). The objective of our study was to comprehensively assess changes in symptom burden across 2 consecutive OCR infusion cycles. Methods: SYMptom Burden on Ocrelizumab, a Longitudinal Study (SymBOLS; NCT04855617) was an investigator-initiated, 2-center study of patients with MS starting or receiving OCR. Patients' symptoms were assessed with NeuroQoL short forms, SymptoMScreen, and Work Productivity and Activity Impairment Questionnaire at the start-cycle, mid-cycle, and end-cycle time points in each of the 2 infusion cycles. Symptom scores at the 3 time points within each cycle were compared with repeated-measures ANOVA or the Friedman rank-sum test for non-normal variables. The proportions of patients with a meaningful symptomatic change from the start to the end of each infusion cycle were calculated, and patients whose symptoms improved, worsened, and stayed the same from the start to the end of the cycle were compared with respect to demographic and clinical characteristics. Results: One hundred three patients with MS provided longitudinal data for analyses (mean age [SD]: 46.7 [12.2] years, 68% female, 33% non-White, disease duration: 15.5 [5] years, 41% with the Extended Disability Status Scale score >3). On a group level, NeuroQoL and SymptoMScreen scores mostly remained stable or even improved slightly toward the end of each cycle. On an individual level, symptoms remained unchanged across either cycle for most patients, and meaningful symptom worsening from the start to the end of the cycle was no more common than improvement. Meaningful change in symptoms in both cycles was very rare and generally in the direction of improvement toward the end cycle. Despite the lack of evidence for symptom worsening with a longer time from infusion, 54% of patients endorsed feeling of "wearing off" at least sometimes, most commonly as an increase in fatigue. Discussion: Our prospective study failed to uncover evidence for the worsening of symptoms with a longer time from OCR infusion. These findings cast doubt on the existence of wearing off as a physiologic phenomenon in OCR-treated patients with MS. The perception of wearing off is likely the result of natural fluctuations in MS symptoms and attribution bias.

Pearls & Oy-sters: CSF1R-Related Leukoencephalopathy With Spinal Cord Lesions Mimicking Multiple Sclerosis.

CSF1R-related leukoencephalopathy is an autosomal dominant neurologic disorder causing microglial dysfunction with a wide range of neurologic complications, including motor dysfunction, dementia, and seizures. This case report highlights an unusual presentation of CSF1R-related leukoencephalopathy with radiographic spinal cord involvement initially diagnosed as multiple sclerosis. This case highlights the importance of considering adult-onset neurogenetic disorders in the setting of white matter disease. Genetic testing provides a confirmatory diagnosis for an expanding number of adult-onset leukoencephalopathies and informs therapeutic decision-making.

Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): a multicentre, randomised, single-blind, phase 4, non-inferiority trial.

BACKGROUND: Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. METHODS: DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov, NCT03073603, and is completed. FINDINGS: 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6-15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. INTERPRETATION: We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. FUNDING: Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society.

Two cases of MT-ND5-related mitochondrial disorder misdiagnosed as seronegative neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease primarily affecting the optic nerves and spinal cord, which is usually associated with anti-aquaporin-4 antibodies. Here, we present two individuals who were negative for anti-aquaporin-4 antibodies and were initially diagnosed with seronegative NMOSD. Each patient's clinical course and radiographic features raised suspicion for an alternative disease process. Both individuals were found to have pathogenic variants of MT-ND5, encoding subunit 5 of mitochondrial complex I, ultimately leading to a revised diagnosis of a primary mitochondrial disorder. These cases illustrate the importance of biochemical and genetic testing in atypical cases of NMOSD.

Three-dimensional multi-parameter brain mapping using MR fingerprinting.

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 T1, T2 and T1ρ 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 T1, T2, T1ρ, 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 T1/T2/T1ρ mapping techniques. This study demonstrates that the 3D-MRF technique is able to simultaneously quantify T1, T2 and T1ρ 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.

Volumetric brain changes in MOGAD: A cross-sectional and longitudinal comparative analysis.

BACKGROUND: Relatively little is known about how global and regional brain volumes changes in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) compare with Multiple Sclerosis (MS), Neuromyelitis optica spectrum disorder (NMOSD), and healthy controls (HC). OBJECTIVE: To compare global and regional brain volumes in MOGAD, MS, NMOSD, and HC cross-sectionally as well as longitudinally in a subset of patients. METHODS: We retrospectively reviewed all adult MOGAD and NMOSD patients with brain MRI performed in stable remission and compared them with MS patients and HC. Volumetric parameters were assessed using the FDA-approved icobrain software. adjusted for age and sex. RESULTS: Twenty-four MOGAD, 47 NMOSD, 40 MS patients, and 37 HC were included in the cross-sectional analyses. Relative to HC, the age-adjusted whole brain (WB) volume was significantly lower in patients with MOGAD (p=0.0002), NMOSD (p=0.042), and MS (p=0.01). Longitudinal analysis of a subset of 8 MOGAD, 22 NMOSD, and 34 MS patients showed a reduction in the WB and cortical gray matter (CGM) volumes over time in all three disease groups, without statistically significant differences between groups. The MOGAD group had a greater loss of thalamic volume compared to MS (p=0.028) and NMOSD (p=0.023) and a greater loss of hippocampal volumes compared to MS (p=0.007). CONCLUSIONS: Age-adjusted WB volume loss was evident in all neuroinflammatory conditions relative to HC in cross-sectional comparisons. In longitudinal analyses, MOGAD patients had a higher thalamic atrophy rate relative to MS and NMOSD, and a higher hippocampal atrophy rate relative to MS. Larger studies are needed to validate these findings and to investigate their clinical implications.

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

BACKGROUND: 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: We sought to compare outcomes of THA among persons with MS and without MS. METHODS: 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: Compared to patients without MS, those with MS had marginally longer lengths of stay (mean ratio [MR] 1.05; 95% confidence interval [CI], 1.01-1.10; p = 0.0142), higher risk for institutional discharge disposition (odds ratio [OR] 2.03; 95% CI, 1.54-2.70; p < 0.0001) and higher risk of readmission for revision hip arthroplasty (OR 2.60; 95% CI, 1.07-6.35; p = 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: 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.

Hybrid and vaccine-induced immunity against SAR-CoV-2 in MS patients on different disease-modifying therapies.

OBJECTIVE: To compare "hybrid immunity" (prior COVID-19 infection plus vaccination) and post-vaccination immunity to SARS CoV-2 in MS patients on different disease-modifying therapies (DMTs) and to assess the impact of vaccine product and race/ethnicity on post-vaccination immune responses. METHODS: Consecutive MS patients from NYU MS Care Center (New York, NY), aged 18-60, who completed primary COVID-19 vaccination series ≥6 weeks previously were evaluated for SARS CoV-2-specific antibody responses with electro-chemiluminescence and multiepitope bead-based immunoassays and, in a subset, live virus immunofluorescence-based microneutralization assay. SARS CoV-2-specific cellular responses were assessed with cellular stimulation TruCulture IFNγ and IL-2 assay and, in a subset, with IFNγ and IL-2 ELISpot assays. Multivariate analyses examined associations between immunologic responses and prior COVID-19 infection while controlling for age, sex, DMT at vaccination, time-to-vaccine, and vaccine product. RESULTS: Between 6/01/2021 and 11/11/2021, 370 MS patients were recruited (mean age 40.6 years; 76% female; 53% non-White; 22% with prior infection; common DMT classes: ocrelizumab 40%; natalizumab 15%, sphingosine-1-phosphate receptor modulators 13%; and no DMT 8%). Vaccine-to-collection time was 18.7 (±7.7) weeks and 95% of patients received mRNA vaccines. In multivariate analyses, patients with laboratory-confirmed prior COVID-19 infection had significantly increased antibody and cellular post-vaccination responses compared to those without prior infection. Vaccine product and DMT class were independent predictors of antibody and cellular responses, while race/ethnicity was not. INTERPRETATION: Prior COVID-19 infection is associated with enhanced antibody and cellular post-vaccine responses independent of DMT class and vaccine type. There were no differences in immune responses across race/ethnic groups.

Toward Precision Phenotyping of Multiple Sclerosis.

The classification of multiple sclerosis (MS) has been established by Lublin in 1996 and revised in 2013. The revision includes clinically isolated syndrome, relapsing-remitting, primary progressive and secondary progressive MS, and has added activity (i.e., formation of white matter lesions or clinical relapses) as a qualifier. This allows for the distinction between active and nonactive progression, which has been shown to be of clinical importance. We propose that a logical extension of this classification is the incorporation of additional key pathological processes, such as chronic perilesional inflammation, neuroaxonal degeneration, and remyelination. This will distinguish MS phenotypes that may present as clinically identical but are driven by different combinations of pathological processes. A more precise description of MS phenotypes will improve prognostication and personalized care as well as clinical trial design. Thus, our proposal provides an expanded framework for conceptualizing MS and for guiding development of biomarkers for monitoring activity along the main pathological axes in MS.

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

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.

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

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.

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

BACKGROUND: 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: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. METHODS: 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: 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: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

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

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.

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.