Author Of 1 Presentation
SS02.02 - Comparison of COVID-19 outcomes between racial groups in the COViMS registry
Abstract
Background
Risk factors previously identified for worse outcomes with SARS-CoV-2 infections include older age, male sex and specific comorbid conditions. An increased risk for poorer COVID-19 outcomes in people with multiple sclerosis (MS) are similar to the general population, but less is known about outcomes in minority groups with MS.
Objectives
To evaluate differences in outcomes of SARS-CoV-2 infection in non-Hispanic White and Black persons with multiple sclerosis.
Methods
COViMS is a North American registry for health care providers to report persons with MS who are infected with SARS-CoV-2, the virus that causes COVID-19 (cases). Cases are reported after 7 days and when the outcome of infection is reasonably certain. MS and clinically isolated syndrome cases were categorized using the Center for Disease Control and Prevention races (non-Hispanic Whites, and Black). Comorbidities related to COVID-19 outcomes were collected. Clinical outcomes examined were mortality alone, mortality and/or admissions to the intensive care unit (ICU) and mortality, ICU admissions and/or hospitalization. Age-adjusted mortality rates as of August 3, 2020 and 95% confidence intervals (CI) were calculated. Multivariable logistic regression was used to assess adjusted differences between races using odds ratios (OR) and 95% CIs. Covariates included sex, age, smoking (current, past, never), MS clinical course (relapsing, progressive), disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy use (yes vs no).
Results
Of 734 patients reported, 421 (57.4%) Whites, and 194 (26.5%) Black patients were reported. Black cases were more likely to be younger (p=0.002), never smokers (p=0.002), have shorter MS duration (p<0.001), a relapsing MS course (p=0.03) and have comorbidities (p<0.001) compared to Whites. A higher proportion of Black patients had hypertension (40.2% vs 19.5%, p<0.001), and morbid obesity (17.0% vs 9.5%, p=0.007). Mortality rates increased with age and were not statistically different between Whites and Blacks (p=0.156). Black race was associated with increased odds of mortality and/or ICU admission (OR 3.8 [95%CI: 1.60, 8.96], p=0.002) and mortality, ICU admission and/or hospitalization (OR 2.0 [95%CI: 1.14, 3.54], p=0.016) after adjustment for covariates.
Conclusions
Within the COViMS registry, Black MS patients were younger and more likely to have comorbidities than White MS patients. Black MS patients had an increased risk for poorer outcomes compared to Whites even after adjusting for comorbidities at the time of COVID-19.
Author Of 4 Presentations
LB1242 - COViMS Registry: Clinical Characterization of SARS-CoV-2 Infected Multiple Sclerosis Patients in North America (ID 2128)
Abstract
Background
Emergence of SARS CoV-2 causing COVID-19 provoked the need to gather information on the overall outcomes and potential risks associated with morbidity and mortality in multiple sclerosis (MS) patients with COVID-19 infections. The COViMS registry was initiated as a rapid and efficient means to collect this data from North American health care providers.
Objectives
To describe the spectrum of outcomes in SARS CoV-2 infected North American MS patients and to ascertain characteristics associated with severe COVID-19 outcomes.
Methods
The COViMS registry requested that MS, neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and radiographically isolated syndrome (RIS) patients with SARS-CoV-2 infection be reported after the outcome was reasonably certain. Data were de-identified and cross-sectional. Effort was made to harmonize with other international registries for COVID-19. Poor clinical outcomes assessed were: mortality, mortality and/or admission to the intensive care unit (ICU), and mortality, ICU admission and/or hospitalization. Associations between patient characteristics and these outcomes were evaluated using multivariable logistic regression. Covariates included sex, age, race, smoking, MS clinical course (relapsing, progressive), MS disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy (DMT) use.
Results
As of Aug 3, 2020, 764 patients from over 140 different practices were reported; 734 MS, 21 NMO, 4 MOGAD, and 5 RIS. MS patients were 73.4% female (73.4%), 65.2% Caucasian, with mean (SD) age of 48.2 (±13.5) years. Mean disease duration was 13.8 (±9.9) years. 70.9% were fully ambulatory. Ocrelizumab and dimethyl fumarate (DMF) were the top two DMTs used. Most (77.1%) were laboratory confirmed for SARS-CoV-2. Of MS cases, 6.1% died, 13.8% were admitted to the ICU and/or died, and 31.2% were either hospitalized, admitted to the ICU or died. Older age, non-ambulatory status and cardiovascular disease were associated with increased risk of poor outcomes. No specific DMT was associated with increased odds of mortality and mortality and/or ICU admission. Anti-CD20 DMT use showed an increased odds of mortality, ICU admission and/or hospitalization compared to DMF (OR: 2.53 95%CI [1.17, 5.50]).
Conclusions
The data provide reassurance that the MS registry population aligns with reported COVID-19 outcomes in the general North American population. While reported deaths are few, no clear association between a specific therapy and mortality has been seen after adjustment for age, sex, ambulatory status and comorbidities. Data collection continues.
P0125 - Ocrelizumab treatment induces a sustained blood NfL reduction in patients with PPMS and RMS (ID 1865)
Abstract
Background
Blood neurofilament light chain (NfL) is a biomarker of neuroaxonal injury associated with acute disease activity and may be prognostic for disability progression in patients with multiple sclerosis (MS). Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody indicated for relapsing MS (RMS) and primary progressive MS (PPMS).
Objectives
To assess the impact of OCR on blood NfL distribution in patients with RMS from the OPERA I and II trials and those with PPMS from ORATORIO.
Methods
Pretreatment and posttreatment NfL levels (measured using the SiMOA assay) with OCR vs interferon β-1a (OPERA I and II; n=1,421) or placebo (ORATORIO; n=596) were compared using geometric mean (GM) and GM ratios (GMR). Patients were stratified by presence/absence of acute disease activity at baseline (BL) (T1 gadolinium [Gd]-enhancing lesions and/or relapse in prior 3 months for RMS; T1 Gd-enhancing lesions for PPMS). Age-adjusted NfL distributions (using a linear model for log-NfL and age derived from a healthy donor [HD] cohort) at BL and after OCR were compared with HD using the Kolmogorov-Smirnov test.
Results
Significant reductions in NfL were observed 3 months after OCR initiation (RMS, GMR=0.80; PPMS, GMR=0.89) and sustained through the end of controlled treatment (RMS [96 weeks], GMR=0.56; PPMS [120 weeks], GMR=0.81; all p<0.0001). Age-adjusted BL serum NfL was elevated in patients with RMS disease activity (GM [95% CI]=12.7 [11.9–13.6] pg/mL) vs those without (5.5 [5.3–5.7] pg/mL) and HD (4.1 [3.9–4.4] pg/mL; all p<0.0001). In OCR-treated patients with RMS, GM [95% CI] serum NfL levels after 96 weeks (with activity at BL, 4.4 [4.2–4.6] pg/mL; without activity at BL, 4.1 [4.0–4.3] pg/mL) were comparable to HD (4.1 [3.9–4.4] pg/mL; all p>0.1). Age-adjusted BL plasma NfL was also elevated in PPMS patients with disease activity (GM [95% CI]=8.7 [7.5–10.1] pg/mL) vs those without (4.9 [4.6–5.2] pg/mL) and HD (3.1 [2.9–3.3] pg/mL; all p<0.0001). In OCR-treated patients with PPMS, GM [95% CI] plasma NfL levels after 120 weeks (with activity at BL, 4.6 [4.1–5.1] pg/mL; without activity at BL, 4.2 [4.0–4.4] pg/mL) were reduced from BL (all p<0.005) but remained elevated vs HD (all p<0.001).
Conclusions
NfL is highly elevated in patients with acute MS disease activity, and more subtle elevations are observed in RMS and PPMS patients without detectable disease activity. Ocrelizumab significantly reduces NfL in RMS and PPMS patients with and without detectable disease activity.
P0581 - Gradient echo magnetic resonance imaging to detect central vein sign in patients with Multiple Sclerosis (ID 1528)
Abstract
Background
Diagnostic criteria for multiple sclerosis (MS) have undergone several iterations in the past 20 years, resulting in increased sensitivity and earlier diagnosis, but also increased misdiagnoses due to reduced specificity. Biomarkers are needed to distinguish MS from its mimics and between MS subtypes. MS lesions in white matter (WM) typically form around a central vein, which can be visualized with FLAIR* imaging (Sati, et al, 2012). Central vein sign (CVS) presence on MRI can help differentiate MS from other diseases with WM T2-weighted hyperintensities and may increase the sensitivity and specificity of MS diagnosis.
Objectives
To apply MRI-based gradient echo plural contrast imaging (GEPCI) approach (Luo, et al, 2012) to generate FLAIR*-like images and detect CVS in patients with progressive MS (PMS) and relapsing remitting MS (RRMS). To quantitatively evaluate tissue damage in lesions with and without CVS using tissue-specific GEPCI R2t* metric (Xiang, et al, 2019).
Methods
MRI scans of PMS (n=39) and RRMS subjects (n=30) were analyzed for the CVS within WM lesions. Presence of CVS, lesion volume, and anatomic location were determined. To quantitatively evaluate the severity of brain-tissue damage in MS lesions, mean R2t* was calculated. R2t* is a quantitative measure that correlates with brain tissue cellular density and is decreased in areas of reduced tissue integrity. The proportion of total lesions with CVS was calculated, excluding confluent lesions and lesions with more than 1 central vein. Median proportions in PMS and RRMS subjects were compared using the Wilcoxon sign rank test. Individual lesion CVS status was examined using generalized linear models. Linear mixed models adjusted for age were used to evaluate predictors of mean R2t* in nonconfluent lesions with only one central vein of sufficient size. Associations of CVS and clinical data from time of MRI scan, including Expanded Disability Status Scale (EDSS), symbol digit modality test (SDMT), and multiple sclerosis functional composite (MSFC) were made using Spearman correlations.
Results
The PMS group had significantly higher EDSS scores and poorer performance on SDMT and MSFC than the RRMS group. There were no significant differences in total CVS and percentage of CVS per lesion between MS subtypes. Controlling for age, EDSS, and lesion volume did not increase the odds of either group having CVS. Lesions with CVS had lower R2t* (greater tissue damage). However, accounting for MS type, age, and lesion count reduced significance (p = 0.09). Mean R2t* was significantly lower in PMS than RRMS (p = 0.027) and declined with age (p = 0.023).
Conclusions
This study did not find that the presence of CVS could distinguish between patients with RRMS and PMS. Our data suggest that lesions with CVS have more tissue damage. Due to reduced significance after accounting for additional variables, further studies with more patients are needed.
P0947 - CD11c+CD88+CD317+ myeloid cells are critical mediators of persistent CNS autoimmunity (ID 1199)
Abstract
Background
Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c+ cells should curtail their migration to the CNS and ameliorate experimental autoimmune encephalomyelitis (EAE).
Objectives
We intended to invesigate the effects of α4-integrin antagonism among CD11c+ cells on the clinical outcomes in a mouse model of EAE.
Methods
We generated CD11c.Cre+/-ITGA4fl/fl C57BL/6 mice to selectively delete α4-integrin in CD11c+ cells. Active immunization and adoptive transfer EAE models were employed and compared with wild type controls. Multi-parameter flow cytometry was utilized to immunophenotype leukocyte subsets. Results from murine model analyses were reconfirmed via single-cell RNA sequencing (scRNA-seq) of human blood and cerebrospinal fluid (CSF) samples to profile individual cells
Results
In our mouse model α4-integrin expression by CD11c+ cells was significantly reduced in primary and secondary lymphoid organs in CD11c.Cre+/-ITGA4fl/fl mice. In active EAE, a delayed disease onset was observed in CD11c.Cre+/-ITGA4fl/fl mice, during which CD11c+CD88+ cells were sequestered in the blood. Upon clinical EAE onset, CD11c+CD88+ cells appeared in the CNS and expressed CD317+. In adoptive transfer experiments, CD11c.Cre+/-ITGA4fl/fl mice had ameliorated clinical disease phenotype associated with significantly diminished numbers of CNS CD11c+CD88+CD317+ cells. In human CSF from subjects with neuroinflammation, microglia-like cells display coincident expression of ITGAX (CD11c), C5AR1 (CD88), and BST2 (CD317). In mice, we show that only activated, but not naïve microglia expressed CD11c, CD88, and CD317. Finally, anti-CD317 treatment prior to clinical EAE substantially enhanced recovery in mice.
Conclusions
CD11c+CD88+CD317+ myeloid cells in the CNS promote inflammatory damage with direct temporal correlation with the clinical phase of the disease in EAE model in mice. Transcriptional analysis identifies ITGAX (CD11c) C5AR1 (CD88) BST2 (CD317) expressing cells as a distinct myeloid subset in human CSF collected from patients with neuroinflammation. The disease-propagating effects of these cells in EAE can be effectively antagonized using anti-CD317 mAb therapy.