Research COVID-19 and its Outcomes in Multiple Sclerosis Patients

Background: Coronavirus Disease 2019 (COVID-19) is a highly contagious disease that resulted in 4533645 deaths until September first, 2021. Multiple Sclerosis (MS) patients receive immunosuppressive drugs. Thus, there is a concern that these drugs will reduce the patient's immune system resistance against COVID19. Objective(s): This study aimed to evaluate the epidemiology of COVID19 and its impact on MS patients in our university hospital in Tehran City, Iran. Material(s) and Method(s): A cross-sectional study was conducted based on hospital-based registry data from May 2020 to March 2021. Among more than 500 registered MS patients in Imam Khomeini Hospital in Tehran City, Iran, referring within our study period, 84 patients reported SARS-COV2 infection. The diagnosis of MS was confirmed by the McDonald criteria. Moreover, the diagnosis of COVID-19 in MS patients was established by the real-time-PCR technique and chest computed tomography. Result(s): Out of 84 MS patients with SARS-COV2 infection, 55(65.5%) were women, and their mean age was 37.48 years. The most commonly used medications by MS patients were Rituximab 20 (26.3%) and Dimethyl Fumarate 14(18.4%). Totally, 9(10.8%) of the patients needed to be hospitalized due to COVID-19, with a mean hospitalization duration of 5.88 days. A total of 1 (1.2%) death was reported. Conclusion(s): Compared to the healthy population, COVID-19 is not more serious in MS patients. Most MS patients with COVID-19 infection were not hospitalized and continued their medication during the infection.Copyright © 2022 The Authors. This is an open access article under the CC-By-NC license. All Rights Reserved.

Teriflunomide and COVID-19: A Friend or Foe?!

Unfortunately, the coronavirus disease 2019 (COVID-19) pandemic has become an irritating universal crisis. Thus, the discovery/identification of prospective drug candidates to disband the branched health issues caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become urgent. This current research sheds light on the repositioning possibility of the potent antirheumatic drug teriflunomide to act as an efficient anti-SARS-CoV-2/anti-COVID-19 remedy. Herein, a motivating in silico molecular docking/modeling study of teriflunomide explores its potential inhibitory actions on the novel coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp) enzyme/protein was reported. Interestingly, the computational analysis of the teriflunomide superior inhibitory binding mode in the binding cavity of one of the active sites of the nCoV-RdRp detected that teriflunomide molecule shows considerably stronger inhibitory binding interactions and better inhibitory binding affinities (it shows lower binding energies which reached-9.70 kcal/mol) than both used references. It was reported that teriflunomide potently impairs viral replication/reproduction by employing two distinct action mechanisms. Thus, the existing study's findings surprisingly uphold teriflunomide's double mode of action. In conclusion, the presented research work paves the way to biologically and clinically begin exploring the promising properties of teriflunomide to strongly hit the SARS-CoV-2 particles of the different strains and inhibit their pathogenic replication in an integrative triple mode of action. Hopingly, the potential sextet COVID-19 attacker teriflunomide can be rapidly subjected to the various in vitro/in vivo/clinical anti-COVID-19 assays/trials in a serious attempt to assess its comprehensive bioactivities against COVID-19 to be effectively used in SARS-CoV-2 infections therapy soon. © 2022 by the authors.

Role of Type 1 Interferons therapy on Adverse Clinical Outcomes on COVID-19 in Hospitalized Multiple Sclerosis Patients

Objective(s): Type 1 Interferons (IFNs) modulate the antiviral immune response and have been used for the treatment of coronaviruses. This study aimed to determine any possible effects and safety concerns of the two most promising exogenously administrable interferons (IFNbeta1a and IFNbeta1b) on the severity outcomes of COVID-19 in multiple sclerosis (MS) patients hospitalized with COVID-19. Material(s) and Method(s): Using the electronic health records systems;this is a cross-sectional study of two years of hospital admissions in terms of COVID-19 in Iran from March 2019 to August 2021. The severities of COVID-19 outcomes were admitted to ICU, hospitalization days, and in-hospital mortality. MS patients with positive results from PCR were included. The data included demographic information, admission, and discharge dates, initial and final diagnoses, hospital inpatient services, including all drugs, admitted wards, procedures, and hospital mortality. A questionnaire was filled out with information on their MS diagnosis, MS medications at the time of COVID-19 admission, history of other chronic illnesses, history of smoking, height and weight, co-morbidity, and MS course (MS type, EDSS, MS duration) and disease-modifying therapies (DMT) at the time of COVID-19 admission (Rituximab, Fingolimod, IFNs, Glatiramer acetate, Dimethyl fumarate, Teriflunomide, Tysabri, and Azathioprine). Result(s): A total of 993 hospitalized MS patients were included in the study. IFNs were used in 28.8% of patients for the treatment of SARS-CoV-2 infection;26% IFNbeta1a and 3.5% IFNbeta1b. Among studied patients, 5.6% did not receive any DMT before their hospital admission. Almost half of the patients were under Rituximab(50.3%). The data were classified based on consuming DMTs. Except for patients who received Rituximab;there was not any significant association between taking IFNs and reducing the severity of COVID-19 outcomes in each DMT sub-group. In patients who were under Rituximab;taking IFNbeta1a for COVID-19 treatment had a significant association with longer hospitalization than patients not receiving it (median (IQR);8(7) vs. 6(4) days, respectively, p=0.000). In the logistic regression model, after adjusting confounding factors, there was a constant association between receiving IFNbeta1a and the risk of longer hospitalization (adjusted OR=2.46 95%CI: 1.46, 4.13). Conclusion(s): The current data suggest that MS healthcare providers should consider specific risks of exogenously IFNbeta1a for the treatment of COVID-19 based on MS medication therapies.Copyright © 2022

The immune response to SARS-COV-2 MRNA vaccines in siponimod-treated patients with secondary progressive multiple sclerosis

Objective: We aimed to understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and SPMS treatment. Background(s): SARS-CoV-2 mRNA vaccines are a key factor in fighting the COVID-19 pandemic. However, data are lacking on the efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs), both over time and after a booster vaccination. Design/Methods: AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment in clinical routine. Cohort 1 received SARS-CoV-2 mRNA vaccination while continuing current siponimod treatment, cohort 2 interrupted siponimod treatment for the purpose of a full vaccination cycle, and cohort 3 received vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. The primary endpoint was the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies 1 week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells was evaluated in all patients. Both parameters were analyzed in week one and months one and six after the initial vaccination cycle and 1 month after a potential booster vaccination. Result(s): After a positive first interim analysis showing both SARSCoV- 2 neutralizing antibodies and T-cell responses 1 week after complete vaccination in siponimod patients, data will be available in early 2022 for all patients at week one and later timepoints, including first booster vaccinations. Conclusion(s): This analysis will provide the first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimodtreated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

Effectiveness and safety of switching to teriflunomide in older patients with relapsing multiple sclerosis: A real-world retrospective multicenter analysis.

BACKGROUND: The prevalence of multiple sclerosis (MS) in older people is increasing due to population aging and availability of effective disease-modifying therapies (DMTs). Treating older people with MS is complicated by age-related and MS-related comorbidities, immunologic effects of prior DMTs, and immunosenescence. Teriflunomide is a once-daily oral immunomodulator that has demonstrated efficacy and acceptable safety in clinical trials of adults with relapsing forms of MS (RMS). However, there are limited clinical trial and real-world data regarding teriflunomide use in people with MS aged >55 years. We analyzed real-world data to assess the effectiveness and safety of teriflunomide in older people with RMS who had switched to this agent from other DMTs. METHODS: People with RMS (relapsing remitting and active secondary progressive MS) aged ≥55 years who had switched from other DMTs to teriflunomide (7 mg or 14 mg) for ≥1 year were identified retrospectively by chart review at four sites in the United States. Data were extracted from medical records from 1 year pre-index to 2 years post-index (index defined as the teriflunomide start date). Assessments of effectiveness included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging (MRI) outcomes. Assessments of safety included lymphocyte counts, infections, and malignancies. We examined the effectiveness outcomes and lymphocyte counts within sub-groups defined by age (55-64, ≥65 years), sex, MS type, and prior route of DMT administration (oral, injectable, infusible). RESULTS: In total, 182 patients with RMS aged ≥55 years who switched from other DMTs to teriflunomide were identified (mean [SD] age: 62.5 [5.4] years). Mean ARR decreased from the start of teriflunomide treatment (mean [SD]: 0.43 [0.61]) to year 1 post-index (0.13 [0.65]) and year 2 post-index (0.05 [0.28]). Mean EDSS score remained unchanged from index (mean [SD]: 4.5 [1.8]) to 1 year post-treatment (4.5 [1.8]) and increased slightly at 2 years post-treatment (4.7 [1.7]). MRI scans from index and years 1 and 2 post-index compared with scans from the previous year indicated that most patients had stable or improved MRI outcomes at index (87.7%) and remained stable or improved at years 1 (96.0%) and 2 (93.6%). Lymphopenia decreased at years 1 (21.4%) and 2 post-index (14.8%, compared to index (23.5%). By 1 year post-index, fewer patients had grade 3 or 4 lymphopenia, and at 2 years post-index, there were no patients with grade 3 or 4 lymphopenia. Infection incidence was low (n = 40, 22.0%) and none were related to teriflunomide. The decreases in lymphopenia were driven by decreases among people who switched from a prior oral DMT; there were no notable differences in lymphopenia across the other sub-groups examined. ARR, EDSS score, and MRI outcomes across all sub-groups were similar to the results of the overall population. CONCLUSION: Our multicenter, longitudinal, retrospective study demonstrated that patients with RMS aged 55 or older switching to teriflunomide from other DMTs had significantly improved ARR, stable disability, and stable or improved MRI over up to 2 years' follow up. Safety results were acceptable with fewer patients exhibiting lymphopenia at years 1 and 2 post-index.

In-depth characterization of long-term humoral and cellular immune responses to COVID-19m-RNA vaccination in multiple sclerosis patients treated with teriflunomide or alemtuzumab.

BACKGROUND: The impact of disease-modifying therapies on the efficacy to mount appropriate immune responses to COVID-19 vaccination in patients with multiple sclerosis (MS) is currently under investigation. OBJECTIVE: To characterize long-term humoral and cellular immunity in mRNA-COVID-19 MS vaccinees treated with teriflunomide or alemtuzumab. METHODS: We prospectively measured SARS-COV-2 IgG, memory B-cells specific for SARS-CoV-2 RBD, and memory T-cells secreting IFN-γ and/or IL-2, in MS patients vaccinated with BNT162b2-COVID-19 vaccine before, 1, 3 and 6 months after the second vaccine dose, and 3-6 months following vaccine booster. RESULTS: Patients were either untreated (N = 31, 21 females), under treatment with teriflunomide (N = 30, 23 females, median treatment duration 3.7 years, range 1.5-7.0 years), or under treatment with alemtuzumab (N = 12, 9 females, median time from last dosing 15.9 months, range 1.8-28.7 months). None of the patients had clinical SARS-CoV-2 or immune evidence for prior infection. Spike IgG titers were similar between untreated, teriflunomide and alemtuzumab treated MS patients both at 1 month (median 1320.7, 25-75 IQR 850.9-3152.8 vs. median 901.7, 25-75 IQR 618.5-1495.8, vs. median 1291.9, 25-75 IQR 590.8-2950.9, BAU/ml, respectively), at 3 months (median 1388.8, 25-75 1064.6-2347.6 vs. median 1164.3 25-75 IQR 726.4-1399.6, vs. median 837.2, 25-75 IQR 739.4-1868.5 BAU/ml, respectively), and at 6 months (median 437.0, 25-75 206.1-1161.3 vs. median 494.3, 25-75 IQR 214.6-716.5, vs. median 176.3, 25-75 IQR 72.3-328.8 BAU/ml, respectively) after the second vaccine dose. Specific SARS-CoV-2 memory B cells were detected in 41.9%, 40.0% and 41.7% of subjects at 1 month, in 32.3%, 43.3% and 25% at 3 months, and in 32.3%, 40.0%, 33.3% at 6 months following vaccination in untreated, teriflunomide treated and alemtuzumab treated MS patients, respectively. Specific SARS-CoV-2 memory T cells were found in 48.4%, 46.7% and 41.7 at 1 month, in 41.9%, 56.7% and 41.7% at 3 months, and in 38.7%, 50.0%, and 41.7% at 6 months, of untreated, teriflunomide-treated and alemtuzumab -treated MS patients, respectively. Administration of a third vaccine booster significantly increased both humoral and cellular responses in all patients. CONCLUSIONS: MS patients treated with teriflunomide or alemtuzumab achieved effective humoral and cellular immune responses up to 6 months following second COVID-19 vaccination. Immune responses were reinforced following the third vaccine booster.

In vitro evaluation of the activity of teriflunomide against SARS-CoV-2 and the human coronaviruses 229E and OC43

Previous data have suggested an antiviral effect of teriflunomide, including against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the agent underlying the ongoing COVID-19 pandemic. We undertook an in vitro investigation to evaluate the inhibitory activity of teriflunomide against SARS-CoV-2 in a cell-based assay. Teriflunomide was added to Vero (kidney epithelial) cells that had been infected with SARS-CoV-2. A nucleocapsid immunofluorescence assay was performed to examine viral inhibition with teriflunomide and any potential cytotoxic effect. The 50% effective concentration (EC(50)) for teriflunomide against SARS-CoV-2 was 15.22 μM. No cytotoxicity was evident for teriflunomide in the Vero cells (i.e., the 50% cytotoxic concentration [CC(50)] was greater than the highest test concentration of 100 μM). The data were supported by additional experiments using other coronaviruses and human cell lines. In the SARS-CoV-2-infected Vero cells, the prodrug leflunomide had an EC(50) of 16.49 μM and a CC(50) of 54.80 μM. Our finding of teriflunomide-mediated inhibition of SARS-CoV-2 infection at double-digit micromolar potency adds to a growing body of evidence for a broad-ranging antiviral effect of teriflunomide.

In vitro evaluation of the activity of teriflunomide against SARS-CoV-2 and the human coronaviruses 229E and OC43

Previous data have suggested an antiviral effect of teriflunomide, including against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the agent underlying the ongoing COVID-19 pandemic. We undertook an in vitro investigation to evaluate the inhibitory activity of teriflunomide against SARS-CoV-2 in a cell-based assay. Teriflunomide was added to Vero (kidney epithelial) cells that had been infected with SARS-CoV-2. A nucleocapsid immunofluorescence assay was performed to examine viral inhibition with teriflunomide and any potential cytotoxic effect. The 50% effective concentration (EC50) for teriflunomide against SARS-CoV-2 was 15.22 μM. No cytotoxicity was evident for teriflunomide in the Vero cells (i.e., the 50% cytotoxic concentration [CC50] was greater than the highest test concentration of 100 μM). The data were supported by additional experiments using other coronaviruses and human cell lines. In the SARS-CoV-2-infected Vero cells, the prodrug leflunomide had an EC50 of 16.49 μM and a CC50 of 54.80 μM. Our finding of teriflunomide-mediated inhibition of SARS-CoV-2 infection at double-digit micromolar potency adds to a growing body of evidence for a broad-ranging antiviral effect of teriflunomide.

Multiple sclerosis associated with Balo-like lesions post-Coronavirus disease 2019

Background and Purpose: Balo's concentric sclerosis (BCS) is a rare inflammatory demyelinating disorder of the central nervous system (CNS) characterized pathologically and radiologically by concentric lamella of alternating demyelinated and partially myelin-preserved white matter. Whether BCS is a variant of multiple sclerosis (MS) or a distinct entity remains debatable. Here, we report an unusual case of MS complicated by Balo's lesions, post-Coronavirus disease 2019 (COVID-19), focusing on the evolution ofMRI findings. Methods: Single-case study. Results: The patient is a 42-year-old woman with relapsing-remitting MS diagnosed at age of 19 who was treated with teriflunomide for the past 5 years. She developed a febrile illness and arthralgia for a week;however, COVID-19 testing was deferred. Two weeks later, she presented with vertigo followed by profound right-hemiparesis, gait impairment, and encephalopathy. Cerebrospinal fluid analysis revealed a protein of 56 mg/dl, increased immunoglobulinG(IgG) index, and>l10 unique oligoclonal bands. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG was detected in serum, but viral ribonucleic acid was absent in the CSF. BrainMRI demonstrated, for the first time, several Balo-like and tumefactive lesions, with contrast enhancement and restricted diffusion. She received plasma exchange alternating with pulse steroids, yet was left with ataxic hemiparetic gait. She was later switched to an anti-CD20 monoclonal antibody therapy. Followup brain MRIs showed continuous regression of the tumefactive and Balo-like lesions. Conclusion: This case adds to the emerging spectrum of COVID-19- associated radiological findings regarding inflammatory demyelination in the CNS. It remains unknown whether potential neurotropism of SARS-CoV-2 or parainfectious mechanisms might have contributed to the fulminant disease in our patient.

Humoral Immune Response to SARS-CoV-2 Vaccination in MS Patients

Objective(s): The aim of this study was to study the humoral immune response to SARS-CoV-2 following vaccination in MS patients. Material(s) and Method(s): We performed a prospective study including all MS patients receiving one of the approved COVID-19 vaccines since January to September 2021. Demographic characteristics, MS treatments and adverse events reports after COVID-19 vaccination of vaccinated MS patients were collected. We analyzed the antibody response to SARS-CoV-2 vaccines with a chemiluminescent microparticle immunoassay (CMIA) from Abbot in MS patients with different DMTs at week 3, week 6 and month 3 after the first dose. The positivity cutoff is ≥50 AU/ml (manufacturer defined). 200 Healthy healthcare professionals were the control group. Result(s): We analyzed 165 vaccinated MS patients: 106 with Pfizer, 14 with Moderna, 42 with both doses of Astra zeneca and 3 with Jannsen. The mean age of patients was 45 (range: 21-71) and 46 for the controls. The most frequent adverse events were pain at injection site, headache and fatigue for 24-48 hours. No differences between MS patients and controls. No increased risk of relapse was noted in the first six months. 120 patients have received both doses of mRNA vaccine. Overall, mean antibody titers response to SARS-CoV-2 SARS-CoV-2 at three weeks was 7910,3 AU/mL (range 0-74947), at 6 weeks 16347,9 UA/mL (range:0-52380,5) and at 3 months 8182,10 UA/ml (range:0-33752,4) in mRNA vaccinated patients. By the mRNA vaccinated control group mean antibody titers response to SARS-CoV-2 SARS-CoV-2 at three weeks was 9397 AU/mL and at 6 weeks 18120 UA/mL Performing a subanalysis of the different DMTs: Only 3 out of 20 patients treated with ocrelizumab developed antibodies. Six vaccinated patients treated with rituximab had no antibody response. Four from 16 patients treated with fingolimod failed to develop a post-vaccination humoral response (< 50 AU/ml). 4 of 5 patients treated with ofatumumab developed have an adequate humoral response. Patients treated with interferon Beta, glatiramer acetate, teriflunomide, dimethyl fumarate, vaccinated with mRNA vaccines developed a similar post vaccination humoral response than healthy controls. Conclusion(s): Most of MS treated patients developed enough antibodies to SARS-CoV-2. The adverse events on MS patients were similar to the general population. No increase of relapse activity was observed. Some patients treated with ocrelizumab, rituximab and fingolimod have no developed a humoral response to SARS-CoV-2 vaccination. Hence we conclude that all approved COVID-19 vaccines are safe in MS patients and effective in most patients. However vaccine strategy in patients treated with anti-CD20 and fingolimod need further studies.

The Effect of Disease Modifying Drugs of Multiple Sclerosis on the Effectiveness of BBIBP-CorV COVID19 Vaccine

Background: Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic. There are many concerns about the effectiveness of vaccination in patients with multiple sclerosis (MS). Few studies have examined the effectiveness of mRNA COVID vaccine in MS patients treated with high potency disease modifying therapies (DMTs). The aim of this study was to evaluate the efficacy of BBIBP-CorV (Sinopharm) vaccine in patients treated with 7 different DMTs. Material(s) and Method(s): This quasi-experimental study was conducted on the patients of MS clinics of Imam Hossein hospital in Tehran (capital of Iran) and Ghaem hospital in Mashhad (northeast of Iran). MS patients with:1- no history of COVID infection in the past 6 month, 2- no history of relapse or steroid use in the past 4 weeks, 3- regular use of a DMT for at least 6 months (9 month for glatiramer acetate) and 4- at least 2 months interval between the previous rituximab infusion and vaccination, were enrolled and vaccinated with Sinopharm vaccine (2 doses, 4 weeks apart). In the case of relapse, COVID infection, or If any of the antibodies (anti neucleocapsid IgM and IgG and anti RBD IgG) were positive at the first injection of the vaccine, the patient was excluded from the study. The amount of IgG class antibodies against virus RBD were measured using ELISA SARS-CoV-2 IgG DIAZIST after 28 days of the first vaccination and on the day 56 (28 days after the second vaccination). An index value higher than 1.1 was considered reactive for anti RBD antibodies. Result(s): Out of the 208 patients included in the study, 91 patients were excluded and 117 patients were finally analyzed. Humoral response to vaccination based on the DMT used by the patient was as follows: beta interferons: 89.47% (17 out of 19 patients), dimethyl fumarate: 85.71% (12 out of 14 patients), patients without DMT treatment:83.33% (5 out of 6 patients), Natalizumab 83.33% (5 out of 6 patients), glatiramer acetate:71.42% (5 out of 7 patients), teriflunomide: 50% (4 out of 8 patients), rituximab: 38.46% (15 out of 39 patients), and fingolimod: 21.05% (4 out of 19 patients). Conclusion(s): According to our findings, the response to vaccination is maintained in patients treated with beta interferons, dimethyl fumarate and natalizumab, but is less than acceptable in patients treated with rituximab and fingolimod.

Saliva as Blood Alternative in Therapeutic Monitoring of Teriflunomide-Development and Validation of the Novel Analytical Method.

Therapeutic drug monitoring (TDM) is extremely helpful in individualizing dosage regimen of drugs with narrow therapeutic ranges. It may also be beneficial in the case of drugs characterized by serious side effects and marked interpatient pharmacokinetic variability observed with leflunomide and its biologically active metabolite, teriflunomide. One of the most popular matrices used for TDM is blood. A more readily accessible body fluid is saliva, which can be collected in a much safer way comparing to blood. This makes it especially advantageous alternative to blood during life-threatening SARS-CoV-2 pandemic. However, drug's saliva concentration is not always a good representation of its blood concentration. The aim of this study was to verify whether saliva can be used in TDM of teriflunomide. We also developed and validated the first reliable and robust LC-MS/MS method for quantification of teriflunomide in saliva. Additionally, the effect of salivary flow and swab absorptive material from the collector device on teriflunomide concentration in saliva was evaluated. Good linear correlation was obtained between the concentration of teriflunomide in plasma and resting saliva (p < 0.000016, r = 0.88), and even better between plasma and the stimulated saliva concentrations (p < 0.000001, r = 0.95) confirming the effectiveness of this non-invasive method of teriflunomide's TDM. The analyzed validation criteria were fulfilled. No significant influence of salivary flow (p = 0.198) or type of swab in the Salivette device on saliva's teriflunomide concentration was detected. However, to reduce variability the use of stimulated saliva and synthetic swabs is advised.

Assessing the immune response to SARSCoV- 2 mRNA vaccines in SPMS patients treated with siponimod (clinical trial)

Background and aims: SARS-CoV-2 mRNA vaccines are a key factor for fighting the COVID-19 pandemic across the globe. However, data are lacking on the efficacy of these vaccines to induce cellular and humoral immune responses in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. Methods: AMA-VACC is prospective, open-label, threecohort study including 41 multiple sclerosis patients at ten sites in Germany. Cohort 1 receives SARS-CoV-2 mRNA vaccination during continuous siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 is vaccinated during continuous treatment with first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Development of neutralizing antibodies (primary endpoint) as well as detection of SARS-CoV-2 specific T-cells (secondary endpoint) are assessed after initial and booster vaccination and monitored for up to 6 months. Results: Results of previous interim analysis showed that the majority of patients treated with siponimod can mount an immune response after SARS-CoV-2 mRNA vaccination. Here, longitudinal data will be presented describing for the first time the level of cellular and humoral immune response for up to 6 months after vaccination and the effect of booster vaccines in siponimod treated patients. Conclusion: This analysis will provide data on the maintenance of humoral and cellular immune response after SARS-CoV-2 vaccination in siponimod treated patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA (booster) vaccination and SPMS treatment.

IMPACT OF IMMUNOSUPPRESSIVE THERAPIES ON ANTIBODY DECAY FOLLOWING MRNA VACCINATION TO SARS-COV-2 IN A PROSPECTIVE COHORT OF PATIENTS WITH CHRONIC INFLAMMATORY DISEASES

Background: Waning levels of anti-SARS-CoV-2 Spike (S) antibodies, particularly neutralizing, are associated with the risk of breakthrough infections. The impact of immunosuppression on antibody decay kinetics is unclear. We have previously reported a strong correlation between total anti-S antibodies and neutralization titers. Here, we report the decay kinetics in anti-S IgG antibodies across various immunosuppressive medications used in patients with CID. Methods: We recruited a volunteer sample of adults with confirmed CID eligible for SARS-CoV-2 vaccination in a prospective observational cohort study at two United States CID referral centers. All study participants received two doses of mRNA vaccine to SARSCoV- 2. To assess the durability of immunogenicity, anti-S IgG were measured at 7 (visit 3), 90 (visit 5), and 120 (visit 6) days after the 2nd dose of mRNA vaccine. The impact of various medications was assessed in repeated measures mixed model with the patient as a random effect, adjusting for gender and age, and using the group of patients on sulfasalazine, NSAIDs, or on no medications as a reference, using STATA. The half-life of anti-S IgG for a 50 percent reduction in titers at visit 3 was calculated for each medication class. Results: A total of 316 CID patients were recruited of which 148 (46.8%) had inflammatory bowel disease (IBD). Durability was assessed in 495 samples obtained in 293 patients. The arithmetic mean of anti-S IgG antibodies for each medication class at visits 3, 5, and 6 is shown in Figure 1. Overall, a 2-fold reduction in titers was observed from 7 to 90 days and 90 to 120 days (Table 1). The strongest decline was observed among patients on B cell depleting/ modulating therapies followed by those on combinations of biologics and/or small molecules and antimetabolites (methotrexate, leflunomide, thiopurines, mycophenolate mofetil, and teriflunomide). There was modest decline seen with TNFi (half-life 430.5 days, -2.15, 95% CI - 4.31 to - 1.07, p = 0.03). There was also a modest, but not significant, decline seen with Janus Kinase inhibitor (JAKi). No decline was seen with anti-IL-23 or anti-integrin medication classes. Conclusions: Antibody decay in patients with CID is not observed in patients on anti-integrins or anti-IL-23 while it is seen among patients on TNFi, JAKi, antimetabolites, and combinations of biologics and/or small molecules. Our data and those from other cohorts may be used to prioritize medication classes for boosting immunogenicity with additional doses of vaccination against SARS-CoV-2. Collection of antibody titers after booster doses is currently ongoing.(Table Presented) (Figure Presented) Figure 1: Durability of anti-spike IgG antibodies after vaccination against SARS-CoV-2 in patients with Chronic Inflammatory Disease

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.

AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccinesin siponimod treated patients with secondary progressive multiple sclerosis

Objective: We are aiming to understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and SPMS treatment. Background: SARS-CoV-2 mRNA vaccines are a key factor fighting the COVID-19 pandemic across the globe. However, data are lacking on efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. Design/Methods: AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, first-line DMT or without treatment in clinical routine. Cohort 1 receives SARS-CoV-2 mRNA vaccination while continuing their current siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 receives vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one and month one and six after initial vaccination cycle and one month after a potential booster vaccination. Results: After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients data will be available in early 2022 for all patients at week one and later time points including first booster vaccinations. If possible, AMA-VACC results will be compared to findings from other clinical SARS-CoV-2 vaccination studies in patients with MS. Conclusions: This analysis will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimod treated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

Impact of Covid-19: Preserving Services for Patients with Multiple Sclerosis during a Global Pandemic

Objective: To survey the impact of the Covid-19 pandemic, (April 2020-April 2021), on access to specialist care for people with multiple sclerosis (PwMS) within the Belfast Health and Social Care (HSC) Trust. Background: The challenges of healthcare service provision have been significantly heightened during the covid-19 pandemic. For PwMS, access to healthcare is of permanent importance, and has been greatly challenged during this timeframe. Design/Methods: In March/April 2021, we posted an anonymised survey to 2342 pwMS receiving care in the Belfast HSC Trust. Data was analysed on returns received by mid-May 2021. Results: In total, 1072 (45.8%) pwMS responded, mean age 53 years, female: male 2.6:1. Of these, 895 (84.2%) were ambulant with or without aid. Wheelchair use was reported in 14.6%. Relapsing remitting MS, Secondary progressive MS and primary progressive MS patients made up 67.7%, 15.5% and 5.9% of indicative responses, respectively. In all, 179 (17%) experienced a confirmed relapse during the pandemic, with 37.4% of these receiving steroids. Perceived delays in appointments were most frequent in: clinic review (17.9%), imaging (13.3%), physiotherapy (11.6%). Over half (52.8%) reported no delays. In total, 64.5% were taking disease-modifying therapy (DMT), most frequently: dimethyl fumarate (34.9%), betainterferon (18.0%), teriflunomide (12.4%). With new DMT commencement during the pandemic, 11.5% experienced delay. In those already DMT-established, 6.6% had a delay with infusion, 4.3% in switching DMT, whilst 89% experienced no delay. Only 2.0% of pwMS on DMT had their treatment stopped directly due to Covid-19. During the pandemic, 13.8% pwMS reported difficulty contacting the MS team, while 40.7% reported physical deconditioning. A majority (88%) had received a covid-19 vaccine dose. Conclusions: Whilst most patients experienced normal standard care, Covid-19 has impacted service provision for some pwMS, with delays reported across a multi-faceted service. The downstream effects of this may be seen moving beyond the pandemic.

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.

Impact of Multiple Sclerosis Disease-Modifying Therapies on Effectiveness of SARS-Cov-2 Vaccines: A Longitudinal Total Population Study of National Health Service (NHS) England

Objective: To compare the risk of SARS-CoV-2 infection before and after mass vaccination among patients with multiple sclerosis (pwMS) taking different disease-modifying therapies (DMTs) compared to the general population (GP). Background: Real-world data in the GP show that SARS-CoV-2 vaccines are effective in preventing infections, but it is still unclear whether vaccination offers the same level of protection for pwMS taking immunomodulatory DMTs. Design/Methods: National Health Service (NHS) England and NHS Improvement (NHSE/I) hold prescribing data on all MS DMTs in England. Public Health England (PHE) collected data on all SARS-CoV-2 tests in England. Datasets of NHE/I and PHE were merged to estimate the monthly rates of SARS-CoV-2 infections in the entire population of pwMS taking DMTs in England. Publicly available data were used for the same analysis in the GP. The relative risk (RR) of infection in pwMS taking DMTs compared to the GP was calculated during two waves of the pandemic: before (November 2020-January 2021) and after (July-September 2021) mass vaccination. Results: All 42,402 pwMS taking DMTs in England were included. A total of 28,113 (66.3%) patients were tested for SARS-CoV-2 out of whom 4,104 (14.6%) tested positive. Pre-vaccination, the RR (95%CI) of infection was beta-interferon: 0.75(0.65-0.87), cladribine: 0.93(0.75-1.14), dimethyl fumarate: 1.15(1.05-1.25), fingolimod: 0.88(0.76-1.02), glatiramer acetate: 1.05(0.93-1.19), natalizumab: 1.08(0.96-1.21), ocrelizumab: 1.20(1.07-1.34), teriflunomide 0.79(0.63-0.99). Post-vaccination, it was beta-interferon: 0.73(0.63-0.85), cladribine: 1.21(1.02-1.45), dimethyl fumarate: 1.34(1.24-1.45), fingolimod: 1.63(1.47-1.82), glatiramer acetate: 0.85(0.74-0.98), natalizumab: 1.22(1.10-1.36), ocrelizumab: 2.18(2-2.36), teriflunomide: 1.04 (0.85-1.27). Conclusions: The risk of SARS-CoV-2 infection in patients taking ocrelizumab and fingolimod substantially increased compared to the general population following vaccination which agrees with the suppressed humoral immune response observed with these DMTs. The changes associated with other DMTs are less clear. Further analysis of data collected longitudinally over a longer period will reveal their impact on the effectiveness of SARS-CoV-2 vaccines.