A pilot trial for ozanimod therapy in hospitalized COVID19 patients

Background: Sphingosine-1-phosphate (S1P) receptor ligands reduce lung damage and endothelial activation in models of virus-induced pneumonia. Feasibility of initiating S1P receptor ligand therapy during pneumonia needs confirmation. Objective(s): Evaluate safety/efficacy outcomes of ozanimod therapy in COVID-19 patients. Method(s): In a prospective multicentric open-label pilot trial, adults with COVID-19 requiring O were recruited (3 Canadian centres, starting Sept. 2020). Patients were randomized to standard of care (SOC) or SOC + ozanimod (per os). Modified WHO-adapted 6-points ordinal scale for clinical improvement was computed daily and adverse events were recorded. Result(s): As of Jan. 2022, 41 patients (out of 48) were enrolled and 18 received ozanimod. Stratification at randomization balanced groups for risk factors of poor outcome and initial O2 requirement. No serious drug reaction was reported. Asymptomatic bradycardia occurred with ozanimod. So far, 36 patients completed the study-ending phone call (day 90). Ordinal scale-related outcomes are shown in Table 1. Since enrollment is ongoing, data is shown for the whole cohort. Conclusion(s): This small scale trial provides the very first evidence supporting the possibility of initiating S1P receptor ligand therapy during active COVID-19 pneumonia.

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS

Objective: COVID19 is associated with vascular inflammation. IFN-alpha (IFNa) and IFN-lambda3 (IFNl3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways Design and methods: Human ECs were stimulated with S1P (1 mg/mL), IFNa (100ng/mL) or IFNl3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 mM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice. Results: S1P increased expression of IFNa (3-fold), IFNl3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNa (ISG15: 16-fold) were greater than to IFNl3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFa (6.2-fold) and IL-1b (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNa and IFNl3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNa (1,230pg/mL) and IFNl3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNa (40%) and IFNl3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNa (67%) and IFNl3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNa (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05). Conclusions: In ECs, S1P, IFNa and IFNl3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.

The effect of Fingolimod on patients with moderate to severe COVID-19.

Hyper-inflammation, cytokine storm, and recruitment of immune cells lead to uncontrollable endothelial cell damage in patients with coronavirus disease 2019 (COVID-19). Sphingosine 1-phosphate (S1P) signaling is needed for endothelial integrity and its decreased serum level is a predictor of clinical severity in COVID-19. In this clinical trial, the effect of Fingolimod, an agonist of S1P, was evaluated on patients with COVID-19. Forty patients with moderate to severe COVID-19 were enrolled and divided into two groups including (1) the control group (n = 21) receiving the national standard regimen for COVID-19 patients and (2) the intervention group (n = 19) that prescribed daily Fingolimod (0.5 mg) for 3 days besides receiving the standard national regimen for COVID-19. The hospitalization period, re-admission rate, intensive care unit (ICU) administration, need for mechanical ventilation, and mortality rate were assessed as primary outcomes in both groups. The results showed that re-admission was significantly decreased in COVID-19 patients who received Fingolimod compared to the controls (p = .04). In addition, the hemoglobin levels of the COVID-19 patients in the intervention group were increased compared to the controls (p = .018). However, no significant differences were found regarding the intubation or mortality rate between the groups (p > .05). Fingolimod could significantly reduce the re-admission rate after hospitalization with COVID-19. Fingolimod may not enhance patients' outcomes with moderate COVID-19. It is necessary to examine these findings in a larger cohort of patients with severe to critical COVID-19.

Sphingolipid metabolism and its relationship with cardiovascular, renal and metabolic diseases.

Sphingolipids (sphingomyelin, glycolipids, gangliosides) are located in cell membranes, plasma, and lipoproteins. In patients with cardiovascular, renal, and metabolic diseases, the profile of sphingolipids and their metabolites (ceramide, sphingosine, and sphingosine-1-phosphate) is modified, and these changes may explain the alterations in some cellular responses such as apoptosis. Furthermore, sphingosine and sphingosine-1-phosphate have been suggested to prevent COVID-19. This review also briefly mentions the techniques that allow us to study sphingolipids and their metabolites.

Los esfingolípidos (esfingomielina, glucolípidos y gangliósidos) se localizan en las membranas celulares, el plasma y las lipoproteínas. En pacientes con enfermedades cardiovasculares, renales y metabólicas, el perfil de los esfingolípidos y sus metabolitos (ceramida, esfingosina y esfingosina-1-fosfato) se modifica, y estos cambios pueden explicar las alteraciones en algunas respuestas celulares, como la apoptosis. Además, se ha sugerido que la esfingosina y la esfingosina-1-fosfato previenen la COVID-19. En esta revisión también se mencionan brevemente las técnicas que permiten el estudio de los esfingolípidos y sus metabolitos.

Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, immunity, angiogenesis, vascular permeability, and lymphocyte trafficking through G-protein coupled S1P receptors. Reduction of the circulating S1P level correlates with COVID-19 severity. S1P binding to sphingosine-1-phosphate receptor 1 (S1PR1) elicits endothelial protection and anti-inflammatory effects during SARS-CoV-2 infection, by limiting excessive INF-α response and hindering mitogen-activated protein kinase and nuclear factor kappa B action. However, binding to S1PR2 opposes the effect of S1PR1 with vascular inflammation, endothelial permeability, and dysfunction as the concomitant outcome. This binding also promotes nod-like receptor pyrin 3 (NLRP3) inflammasome activation, causing liver inflammation and fibrogenesis. Thus, higher expression of macrophage S1PR2 contributes to the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines. In conclusion, S1PR1 agonists and S1PR2 antagonists might effectively manage COVID-19 and its severe effects. Further studies are recommended to elucidate the potential conflict in the effects of S1P in COVID-19.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. CONCLUSIONS: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

OA Biology

Purpose: The field of osteoarthritis (OA) biology is rapidly evolving and brilliant progress has been made this year as well. Methods: Landmark studies of OA biology published in 2021 and early 2022 were selected through PubMed searches and classified by their molecular mechanisms, and it was largely divided into the intra-cellular mechanisms and the inter-compartment or inter-cellular interaction in OA progression. Results: The intra-cellular mechanisms involving OA progression included 1) Piezo1/TRPV4-mediated calcium signaling, 2) low grade inflammation by TLR-CD14-LBP complex and IKKβ-NFkB signaling, 3) PGRN/TNFR2/14-3-3ε/Elk-1 anabolic cascade, 4) G protein-coupled receptor (GPCR) signaling, 5) mechanical loading-cilia/Ift88-hedgehog signaling, 6) mitochondrial fission by ERK1/2-DRP1 pathway, and 7) hypoxia-DOT1L-H3K79 methylation pathway. The studies on inter-compartment or inter-cellular interaction in OA progression included the following subjects: 1) the anabolic role of Lubricin, a proteoglycan from superficial zone cells, 2) osteoclast-chondrocyte interaction via exosomal miRNA and sphingosine 1-phosphate (S1P), 3) αV integrin-mediated TGFβ activation by mechanical loading, 4) TGFβ-mediated suppression of sclerostin in osteocytes, 5) catabolic role of Flightless I as a DAMPs-triggering molecule, and 6) catabolic role of paracrine signaling from fat. Conclusions: Despite the disastrous Covid-19 pandemic situation, many outstanding studies have expanded the boundary of OA biology. They give us not only critical insight on pathophysiology, but also clue for the treatment of OA.

Protective and therapeutic potentials of HDL and ApoA1 in COVID-19 elderly and chronic illness patients.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease-2019 (COVID-19). Elderly subjects, obese, and patients with chronic illnesses, are the most affected group. HDL has pleiotropic physiological functions that are affected with alteration(s) in its structure. Main text: Inflammation whether septic, immune, or other affects HDL structure and function. COVID-19 is associated with systemic immune-inflammation due to cytokine surge. Viral interaction with erythrocytes and hemoglobin-related compounds (may cause anemia and hypoxia) and other factors may affect HDL function. Trials have been conducted to resume HDL functions using peptide preparation, nutritional, and herbal elements. Conclusions: In this review article, I'll discuss the use of reconstituted HDL (rHDL), Apo-A1 mimetic peptide D-4F, ω-3 polyunsaturated fatty acids, and the powdered roots and/or extract of Saussurea lappa (costus) to avoid comorbidity and mortality of COVID-19 in patients with chronic illness or elderly-age mortality.

IMMUNE DYSREGULATION INDUCED BY SPIKE PROTEIN 1 OF SARS-COV-2 INCREASES ENDOTHELIAL CELL DYSFUNCTION VIA TYPE I AND TYPE III INTERFERON ACTIVATION PATHWAYS

Objective: COVID19-associated immunopathology is associated with increased production of interferon (IFN)-alpha (IFNα) and lambda3 (IFNL3). Effects of IFNs are mediated by interferon-stimulated genes (ISGs) and influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. Increasing evidence indicates vascular inflammation in cardiovascular sequelae of COVID19. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFNα and IFNL3. Design and method: Human ECs were stimulated with S1P (1 μg/mL), IFNα (100ng/mL) or IFNL3 (100IU/mL). Because ACE2, metalloproteinase domain-17 (ADAM17) and type-II transmembrane serine protease (TMPRSS2) are important for SARS-CoV-2 infection, cells were treated with inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 μM). Gene and protein expression was investigated by real-time PCR immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive mice and in ISG15-deficient (ISG15KO) mice. Results: EC stimulated with S1P increased expression of IFNα (3-fold), IFNL3 (4-fold) and ISG (2-fold)(p < 0.05). EC exhibited higher responses to IFNα (ISG15: 16-fold) than to IFNL3 (ISG15: 1.7-fold)(p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFα (6.2-fold) and IL-1β (3.3-fold), effects that were maximized by IFNs. Only marimastat inhibited S1P effects. IL-6 was increased by IFNα (1,230pg/mL) and IFNL3 (1,124pg/mL) vs control (591pg/ mL). This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). Nitric oxide production and eNOS phosphorylation (Ser1177) were reduced by IFNα and (40%) and IFNL3 (40%). Reduced endothelium relaxation maximal response (%Emax) was observed in vessels from WTmice stimulated with IFNα (67%) and IFNL3 (71%) vs control (82%)(p < 0.05) but not in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNα (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN, p < 0.05). Conclusions: In ECs, S1P, IFNα and IFNL3 increased ISG15 and IL-6, processes that involve ADAM17. Inflammation induced by S1P was amplified by IFNs. IFNs induce vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This is especially important in the presence of cardiovascular risk factors, including hypertension.

Effect of Subacute Angiotensin II Elevations on Sphingolipid Levels and Lung Injury in Mice

Background: There is a paucity of therapies for acute lung injury (ALI) induced by respiratory viruses. A previously demonstrated key mechanism of ALI, particularly in the setting of severe acute respiratory syndrome coronavirus infections, has been ascribed to decreased cell surface angiotensin converting enzyme 2 (ACE2) leading to increased circulating levels of angiotensin II (Ang2). In turn, supraphysiological Ang2 levels trigger a cascade of events that culminates with endothelial injury in the systemic circulation via acid sphingomyelinase (ASMase) activation. ASMase has been implicated in several models of ALI, but its specific involvement in Ang2-induced ALI is unknown. ASMase hydrolyzes sphingomyelin to pro-apoptotic, edemagenic ceramide, which can be metabolized to endothelial-protective sphingosine-1-phosphate (S1P). Therefore, the ratio of ceramide/S1P can determine endothelial cell fate and lung vascular permeability. We hypothesized that ceramide levels are increased relative to S1P in mice with Ang2-induced ALI. Methods: Following a published protocol of Ang2-induced ALI (Wu et al, 2017), we delivered Ang2 via osmotic pumps (1 ug/kg/min, 7 days;Ang2-mice), using saline (sham) or untreated C57BL/6 mice as controls. We evaluated pulmonary function (FlexiVent);albumin, IgM (ELISA), and inflammatory cell abundance in bronchoalveolar lavage fluid (BALF);and lung parenchyma inflammation and fibrosis (Ashcroft score) on H/E-stained lungs. Sphingolipid levels in lungs and plasma were measured by tandem liquid chromatography/mass spectrometry. Results: Inspiratory capacity, lung compliance, and body weight all decreased in Ang2-mice (by 13-14%, p<0.05 each) compared to sham. Lung pressure-volume loops exhibited a right-shift in Ang2- vs. sham or untreated mice. There was no significant change in BALF albumin, IgM, or inflammatory cells, or in lung histology inflammation or fibrosis scores in Ang2-mice. Compared to sham, S1P levels were significantly increased in plasma and unlavaged lung in Ang2-mice, decreasing ceramide/S1P ratios (from 3.1 to 2.0, and 26 to 20, respectively, p<0.05 each). Conclusions: Sustained subacute systemic elevations of Ang2 increased lung stiffness, but did not cause severe ALI in mice. Lung and circulatory elevations of S1P but not ceramide may have protected against lung edema and inflammatory injury. Although the cause of increased lung stiffness in this model remains to be elucidated, it is notable that chronic (months) supraphysiological elevations of either Ang2 or S1P have been associated with lung fibrosis. In conclusion, a second-hit injury may be necessary to augment the susceptibility of murine lung to Ang2-induced endothelial damage and inflammation relevant to coronavirus.

Adaptive B-cell and T-cell responses to SARS-CoV-2 vaccination in patients with Multiple Sclerosis on disease modifying immunotherapy

Objective: To expand understanding of the human immunological response to SARS-CoV-2 vaccination in patients with Multiple Sclerosis (MS) treated with anti-CD20 monoclonal therapy and sphingosine-1-phosphate (S1P) modulators. Background: Immunomodulatory therapy prescribed for patients with MS has been associated with decreased or absent anti-SARS-CoV-2 immunoglobulin production following COVID-19 vaccination. We investigate broader adaptive immune responses to SARS-CoV-2 vaccination measuring IgG immunoglobulin production and T-cell reactivity in a small cohort. Design/Methods: We used the Stanford Research Repository database to identify 55 MS patients by ICD10 code who were tested for B-cell and T-cell responses via SARS-CoV-2-IgG and SARS-CoV-2 Interferon Gamma Release Assay (IGRA), respectively. 96% (53/55) of patients were fully vaccinated (98% mRNA/2% Janssen). A Chi-square test compared differences in vaccine response between 3 different disease modifying treatment (DMT) groups: anti-CD20 therapy (n=24), S1P modulators (n=11), and off DMT/other MS therapies (n=20). Results: In patients on anti-CD20 therapy, 71% (17/24) were positive for SARS-CoV-2 IGRA but negative for SARS-CoV-2 IgG, among which 65% (11/17) had low CD-19 levels (0-64 cells/uL, normal 100-500 cells/uL) with normal absolute lymphocyte count (ALC). Among patients who delayed vaccination by 4-6 months following anti-CD20 therapy, 13% (3/24) expressed SARS-CoV-2-IgG. 82% (9/11) of patients on S1P modulators showed absent SARS-CoV-2-IgG and SARS-CoV-2 IGRA responses, in association with low ALC (range 210-600 cells/uL, normal 1000-3000 cells/uL). 95% (19/20) of patients off DMT/on other MS therapies showed positive SARS-CoV-2-IgG and SARS-CoV-2 IRGA responses. All vaccinated patients were assessed between 4 weeks and 6 months post-vaccination. These differential responses between treatment groups were significant (p<0.05). Conclusions: We demonstrate that among MS patients treated with anti-CD20 therapy, T-cell response was largely preserved despite greatly reduced B-cell response to SARS-CoV-2 vaccination. MS patients on S1P modulators demonstrated absence of both B-cell and T-cell response. The clinical correlation of this is to be determined.

COVID19 infections in patients with Multiple Sclerosis(MS) on Various treatments at Kaiser Permanent Mid-Atlantic States(KPMAS)

Objective: To assess how many of our patients compliant on MS medicines developed COVID19 infection during the early pandemic. Background: MS is a debilitating progressive disease, and a variety of treatments are available including B cell depleting (BDT), interferons (IFN), glatiramer acetate (GA), adhesion inhibitors (NAT), S1P modulators (S1P), dimethyl fumarate (DM), and teriflunomide (TF). These treatments modulate the immune response and can predispose patients to infections like COVID19. It is postulated that patients on BDT group are at higher risk of COVID19 infection and may have poor outcomes. Design/Methods: In our neurology clinics at KPMAS, we followed 684 patients with MS compliant on treatment during the pandemic. As part of quality measures, we evaluated how many MS patients in various treatment groups developed COVID19 infection and their outcomes from January 1, 2020 to October 31, 2020. Results: The mean age of the 684 patients was 49.4 years;360 blacks and 283 whites;519 females and 165 males. 240 patients were on BDT, 222 on GA, 115 on IFN, 59 on DM, 29 on NAT, 11 on TF and 8 on S1P. 18 (2.6%) patients tested positive for COVID19. 6 patients (2.5%) were in BDT group, 6 (2.7%) in GA, 5 (4.3%) in IFN group, and 1 (9%) in the TF group tested positive for COVID19. 2 in the BDT group, and 1 in the GA group died. Those who died had significant comorbidities (including excessive smoking, obesity, obstructive sleep apnea, and aspiration pneumonia), prior to the infection. Conclusions: We found that the rates of COVID19 infection in patients with MS in the BDT group were not out of proportion when compared to those on other treatments for MS. The poor outcomes were more likely to be related to underlying comorbidities.

SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs

Objective: To describe antibody and T-cell responses to the three SARS-CoV-2 vaccines available in the United States (U.S.) in patients with relapsing multiple sclerosis (RMS) on ozanimod or other disease modifying therapies (DMTs). Background: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel, zoonotic coronavirus that emerged in late 2019 in patients with pneumonia of unknown cause;the disease caused by SARS-CoV-2 is termed COVID-19 (coronavirus disease 2019). Recent reports have suggested that RMS patients on certain DMTs may have a blunted humoral response to the available COVID-19 vaccinations. Sphingosine-1-phosphate (S1P) receptor modulators may control RMS via sequestration of circulating lymphocytes, thus raising questions about vaccination response in RMS on ozanimod and other S1P receptor modulators. Design/Methods: Prospective observational trial following patients with RMS who are going to be vaccinated against COVID-19. The primary endpoint is the proportion of subjects treated with ozanimod with SARS-CoV-2 anti-spike IgG positivity (Elecsys® Anti-SARS-CoV-2) 4 weeks after full vaccination as compared to pre-vaccination levels. To ensure a geographic distribution across the U.S., RMS patients were recruited online (under the care of various neurologists), and all study-related proceures were performed at the patient's home. Results: Descriptive statistics of antibody and T-cell response for sixty subjects (30 treated with ozanimod and 30 treated with various other FDA-approved RMS DMTs) assessed prior to and 28 days after full vaccination will be presented. Additionally, all subjects will complete follow-up questionnaires every 3 months until a year has passed from the second (or only) vaccine dose Conclusions: In this study, RMS patients treated with ozanimod had an antibody and T-cell response to the three available COVID-19 vaccines in the U.S. This trial is ongoing, with 48- weeks of follow-up expected in December 2022.

Neutralizing Antibody Response to SARS-CoV-2 Vaccination in Multiple Sclerosis

Objective: To investigate the humoral immune response following SARS-CoV-2 vaccination in patients with multiple sclerosis (pwMS) and to determine the effect of disease modifying therapies (DMT) on the vaccination response. Background: Coronavirus disease 19 (COVD-19), a highly transmissible and potentially fatal illness caused by SARS-CoV-2, emerged as a global pandemic in early 2020. Several vaccines, including 2 innovative mRNA vaccines, were developed against this virus. To reduce relapse rates and slow disability accumulation, pwMS are often treated with DMTs which have anti-inflammatory properties and regulate adaptive immunity. An important clinical issue concerns the impact of DMTs on the efficacy of SARS-CoV-2 vaccination, and the eventual need for booster doses. In this study, we measured the titers of anti-SARS-CoV-2 neutralizing antibodies (nAbs) in pwMS following SARS-CoV-2 vaccination. Design/Methods: We conducted a prospective longitudinal study in pwMS at the Ohio State University (OSU) MS Center. Longitudinal serum samples were obtained from pwMS prior to and after the administration of the SARS-CoV-2 vaccine. These samples were analyzed for nAbs against SARS-CoV-2 spike protein using a novel pseudotyped-lentivirus-based virus neutralization assay. OSU health care workers (HCWs) served as healthy controls. Results: Of eighty-three consented subjects, fifty-two had post vaccination serum samples analyzed. Although pwMS did not exhibit drastically different nAb titers compared to HCWs, 21% (n=11) did not have detectable nAb titers post-vaccination (NT50 < 40)-including 9 patients on B-cell depleting therapies, 1 on sphingosine 1-phosphate modulator, and 1 on no DMT. Compared to patients not on DMT, pwMS on B-cell depleting therapies exhibited 7-fold lower nAb titers, while those on fumarates or beta-interferon exhibited no significant difference to patients not on DMT. Conclusions: Humoral immune response to the SARS-CoV-2 vaccine may be attenuated by certain DMTs, most notably B-cell depleting drugs. Further studies are underway to determine the effect of booster vaccine on nAb levels.

Immune responses to SARS-CoV-2 vaccination in multiple sclerosis: a systematic review and meta-analysis

Objective: To examine response of SARS-CoV-2 vaccination in patients with MS (pwMS) by a systematic review. Background: Varying responses to the SARS-CoV-2 vaccines have been reported in pwMS on disease modifying therapies (DMTs). We performed a meta-analysis and systematic review of pwMS and rates of immune response to SARS-CoV-2 vaccines by DMT and by vaccine type. Design/Methods: A systematic review was conducted for manuscripts from January 1, 2019 until October 1, 2021 by two independent reviewers (M.D. and G.G.). Search terms in PubMed, Google Scholar and Embase included “multiple sclerosis,” “SARS-CoV-2”, “Coronavirus-19”, “vaccines”, and “vaccinations.” Data from publications reporting on antibody or cellular vaccine response data in pwMS were included. Antibody response was defined as positive or negative, based upon assay cutoffs. Immune response to prior COVID infections were excluded. Descriptive statistics was performed using STATA. Results: We included 16 out of 589 articles and 186 healthy controls and 1,239 pwMS. Protective antibody responses were detected in 99% of healthy controls (184/186), 100% untreated pwMS (169/169), 99% pwMS on beta-interferons (79/80), and 100% pwMS on glatiramer acetate (39/39), dimethyl fumarate (116/116), natalizumab (127/127), alemtuzumab (19/19), and teriflunomide (72/72). Ninety-three percent of pwMS on cladribrine (69/74), 70% of sphingosine 1-phosphate modulators (S1PM) (108/155) and forty-six percent of pwMS on anti-CD20 treatments had an antibody response (177/388). PwMS on rituximab had a higher antibody response (23/37 = 62%) as compared to ocrelizumab (107/205 = 39%), with unknown anti-CD20 in 76. This difference may be attributable to the vaccination received (mRNA-1273 vs BNT162b2) as mRNA-1273 results in higher antibodies. However, 46/49 (94%) on anti-CD20 had T cell responses to SARS-CoV-2 vaccines. Conclusions: Varying rates of vaccine response are reported in pwMS. Humoral responses appear to be blunted in S1PM and anti-CD20 treatments;however, the majority develop cellular responses. Further investigation into how DMT affects immune response are needed.

Lowered COVID-19 mRNA vaccine antibody response in MS patientstreated with B-cell depleting and S1P-receptor-targeting therapies compared to controls: interim analysis

Objective: Assess the SARS-CoV2 Spike antibody response in multiple sclerosis (MS) patients on high efficacy immunotherapies. Background: There is limited knowledge about SARS-CoV2 mRNA vaccine response in MS patients on immunotherapy. Design/Methods: Patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV2 vaccine (Pfizer or Moderna) were offered enrollment. A cohort of healthy controls who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV2 Spike antibody (Anti-SARS-CoV2 S, RocheElecsys) were collected 2-3 months after the second mRNA vaccine. The proportion who seroconverted (antibody>0.4 U/ml), and SARS-CoV2 Spike antibody levels were assessed. Results: A total of 39 MS patients (6 fingolimod, 33 ocrelizumab) and 31 controls were included in this interim analysis. 33%(13/39) of MS patients seroconverted, compared to 100%(31/31) in the control group, with an estimated risk difference of -0.67,(95% confidence interval: -0.81, -0.52;Fisher's exact test, p=9.0∗10-10 ). There was no difference in seroconversion rates between MS patients who received the Pfizer (34%, 10/29) versus the Moderna vaccine (30%, 3/10) (95% confidence interval -0.38, 0.29;Fisher's exact test=1). Seroconversion was found in 100% (31/31) of controls, 66.7% (4/6) of fingolimod-treated patients, and 27.3% (9/33) of ocrelizumab-treated patients (three group comparison, Fisher's exact test p-value =2.7∗10 -10). The median Spike antibody level was <0.4 U/ml in MS patients, and 1,663 U/ml in controls (Wilcoxon rank sum test, p-value= 1.0∗10-12 ). The median Spike antibody level in the ocrelizumab group was <0.4 U/ml, 3.45 U/ml in the fingolimod group, and 1,663 U/ml in the control group (Kruskal Wallis test, p-value=5.9∗10-12 ). Total IgG correlated with Spike antibody levels in the ocrelizumab-treated group only (Spearman correlation, p=0.025). Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median Spike antibody levels in response to the mRNA SARS-CoV2 vaccines compared to controls.

Are different degrees of lymphopenia for FTY720 associated with serious infectious-type events? No

Objective: Describing the occurrence of infections in patients with relapsing-remitting multiple sclerosis (RRMS) treated with fingolimod and with different degrees of lymphopenia in our unit. Patients and Methods: Observational, descriptive, longitudinal, and retrospective study in the Hospital Centro Médico Nacional Siglo XXI. Patients with RRMS and treatment with fingolimod were grouped based on lymphocyte count and infections. Quantitative variables were expressed as mean, standard deviation, and interquartile range;qualitative variables were expressed as frequencies and percentages. Results: 110 patients, 76 (69.1%) female, 34 (30.9%) male, mean age 38.3 years (17-63, SD 9.85). Mean of initial expanded disability status scale 1.59 (0-5.5, SD 1.15) with a mean diagnosis time of 63.6 months (3-252, SD 50.96). Prior to starting fingolimod, 90.09% of patients had lymphocyte count >1,000. At six months of treatment, 35.64% had lymphocyte >1,000. At twelve months 32.95% had lymphocyte from 501 to 700. At 24 months, 34.21% had lymphocyte from 701 to 1,000. Of the 110 patients, 31.8% had mild infections, of which pharyngitis was reported in 10%, gastroenteritis 2.7%, urinary tract infection 10.9%, HPV infection 0.9%, SARS-CoV-2 infection 3.6%, ophthalmic herpes 0.9%, molluscum contagiosum 0.9%, oral candidiasis 0.9%. 68.18% did not present infections of any kind, no serious infections were reported even with lymphocyte levels below 200. Conclusions: Selective lymphopenia caused by fingolimod was not associated with infections of any kind in this population even at levels of 200-500 cells/mm³. (English) [ FROM AUTHOR] Objetivo: Describir la ocurrencia de infecciones severas en pacientes con EMRR tratados con fingolimod y con diferentes grados de linfopenia en nuestra unidad Métodos: Estudio observacional, descriptivo, longitudinal y retrospectivo realizado en el Hospital Centro Médico Nacional Siglo XXI. Pacientes con EMRR tratados con fingolimod, se agruparon por grados de linfopenia e infecciones. Las variables cuantitativas se expresaron como media, desviación estándar y rango intercuartil;las variables cualitativas se expresaron en frecuencias y porcentajes. Resultados: 110 pacientes, 76 mujeres (69.1%), 34 hombres (30.9%), media de edad 38.39 (17-63 DE 9.85). Media EDSS inicial 1.59 (0-5.5, DE 1.15), tiempo diagnóstico medio 63.67 meses (3-252, DE 50.96). Previo al inicio de fingolimod, 90.09% de los pacientes tenía linfocitos absolutos >1,000. A los 6 meses de tratamiento, 35.64% tenía >1,000 linfocitos. A los 12 meses el 32.95% tenía 501-700 linfocitos, a los 24 meses el 34.21% tenía 701-1,000 linfocitos. De los 110 pacientes, el 31.8% presentó infecciones leves, de las cuales se informó faringitis en 10%, gastroenteritis 2.7%, infección del tracto urinario 10.9%, infección por VPH 0.9%, infección por SARS-CoV-2 3.6%, herpes oftálmico 0.9%, molusco contagioso 0.9%, candidiasis oral 0.9%. El 68.18% no presentó infecciones de ningún tipo, no se reportó infecciones graves incluso con niveles de linfocitos inferiores a 200. Conclusiones: La linfopenia selectiva causada por fingolimod no se asoció a infecciones severas en esta población incluso en niveles de 200 a 500 células/mm³. (Spanish) [ FROM AUTHOR] Copyright of Revista Mexicana de Neurociencia is the property of Academia Mexicana de Neurologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Skeletal Muscle and COVID-19: The Potential Involvement of Bioactive Sphingolipids.

SARS-CoV-2 virus infection is the cause of the coronavirus disease 2019 (COVID-19), which is still spreading over the world. The manifestation of this disease can range from mild to severe and can be limited in time (weeks) or persist for months in about 30-50% of patients. COVID-19 is considered a multiple organ dysfunction syndrome and the musculoskeletal system manifestations are beginning to be considered of absolute importance in both COVID-19 patients and in patients recovering from the SARS-CoV-2 infection. Musculoskeletal manifestations of COVID-19 and other coronavirus infections include loss of muscle mass, muscle weakness, fatigue or myalgia, and muscle injury. The molecular mechanisms by which SARS-CoV-2 can cause damage to skeletal muscle (SkM) cells are not yet well understood. Sphingolipids (SLs) represent an important class of eukaryotic lipids with structural functions as well as bioactive molecules able to modulate crucial processes, including inflammation and viral infection. In the last two decades, several reports have highlighted the role of SLs in modulating SkM cell differentiation, regeneration, aging, response to insulin, and contraction. This review summarizes the consequences of SARS-CoV-2 infection on SkM and the potential involvement of SLs in the tissue responses to virus infection. In particular, we highlight the role of sphingosine 1-phosphate signaling in order to aid the prediction of novel targets for preventing and/or treating acute and long-term musculoskeletal manifestations of virus infection in COVID-19.