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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.
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Introduction Lymphopenia is a known adverse event of dimethyl fumarate (DMF) with treatment dis-continuation recommended for patients with severe prolonged (>=6 months) lymphopenia. Because of the COVID-19 pandemic burden on healthcare systems, we retrospectively examined the impact of absolute lymphocyte count (ALC) monitoring frequency (every-3-months vs every-6-months) on lym-phopenia detection. Methods Samples from patients enrolled in phase 3 trials (DEFINE/CONFIRM) and the extension study (ENDORSE) were retrospectively analysed using 3-month or 6-month intervals. Lymphopenia was defined as ALC <0.91x109/L and severe lymphopenia as ALC <0.5x109/L. Times to the first lymphopenia event and first severe lymphopenia event were estimated using Kaplan-Meier methods. Results The analysis included 741 patients. There were 355 lymphopenia cases (76 severe) with 3-month monitoring, and 314 cases (70 severe) with 6-month monitoring. Over 120 months, incidence of first lympho-penia event was significantly different for 3-month vs 6-month monitoring (difference range: 2.64%-6.54%;P=0.0088). Incidence of first severe lymphopenia event was not significantly different for the two intervals (P=0.5866). Proportions of patients with severe prolonged lymphopenia with 3-month and 6-month moni-toring were similar (4.0% vs 4.2%). Conclusions The results of this study may be informative to clinicians managing pandemic-related health-care resource burdens.
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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
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Background: Dimethyl fumarate (DMF) is an approved treatment for multiple sclerosis (MS). Due to its efficacy and safety profile, DMF is the most prescribed oral medication for relapsing remitting (RR) MS. Given the long-term course of treatment with DMF in MS, continuous surveillance of opportunistic infections is fundamental. Case presentation: We report the occurrence of facial herpes zoster (HZ) associated with MS disease reactivation in a person with RRMS after 6 years of DMF therapy. Case report: A 44-year-old woman with RRMS developed right temple pain and blisters over the right cheek, suggestive of facial HZ. A normal lymphocyte count with however relatively lower proportions of CD8+ T cells and higher percentages of natural killer cells were detected in blood. The patient failed oral treatment and required hospitalization for intravenous acyclovir. She eventually developed symptoms of an MS exacerbation featured by lower extremities weakness and urinary retention. Conclusion(s): Our case highlights the importance of counseling patients on the possibility of HZ reactivation even in the setting of a normal lymphocyte count, the risk of MS exacerbation possibly associated with HZ occurrence and the importance of timely vaccination.Copyright © 2022
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BACKGROUND: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) impair responses to vaccines, emphasizing the importance of understanding COVID-19 vaccine immune responses in people with MS (PwMS) receiving different DMTs. METHODS: This prospective, open-label observational study enrolled 45 participants treated with natalizumab (n = 12), ocrelizumab (n = 16), fumarates (dimethyl fumarate or diroximel fumarate, n = 11), or interferon beta (n = 6); ages 18-65 years inclusive; stable on DMT for at least 6 months. Responder rates, anti-SARS-CoV-2 spike receptor-binding domain IgG (anti-RBD) geometric mean titers (GMTs), antigen-specific T cells, and vaccination-related adverse events were evaluated at baseline and 8, 24, 36, and 48 weeks after first mRNA-1273 (Moderna) dose. RESULTS: At 8 weeks post vaccination, all natalizumab-, fumarate-, and interferon beta-treated participants generated detectable anti-RBD IgG titers, compared to only 25% of the ocrelizumab cohort. At 24 and 36 weeks post vaccination, natalizumab-, fumarate-, and interferon beta-treated participants continued to demonstrate detectable anti-RBD IgG titers, whereas participants receiving ocrelizumab did not. Anti-RBD GMTs decreased 81.5% between 8 and 24 weeks post vaccination for the non-ocrelizumab-treated participants, with no significant difference between groups. At 36 weeks post vaccination, ocrelizumab-treated participants had higher proportions of spike-specific T cells compared to other treatment groups. Vaccine-associated side effects were highest in the ocrelizumab arm for most symptoms. CONCLUSIONS: These results suggest that humoral response to mRNA-1273 COVID-19 vaccine is preserved and similar in PwMS treated with natalizumab, fumarate, and interferon beta, but muted with ocrelizumab. All DMTs had preserved T cell response, including the ocrelizumab cohort, which also had a greater risk of vaccine-related side effects.
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BACKGROUND: Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR). METHODS: Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures. RESULTS: After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01). CONCLUSION: DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.
Subject(s)
Dimethyl Fumarate , Multiple Sclerosis , Antibodies, Monoclonal, Humanized/adverse effects , Dimethyl Fumarate/therapeutic use , Health Care Costs , Humans , Multiple Sclerosis/chemically induced , Multiple Sclerosis/complications , Multiple Sclerosis/drug therapy , Retrospective StudiesABSTRACT
Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder of the central nervous system. Disease-modifying drugs (DMDs) and subsequent adherence are crucial for preventing reversible episodes of neurological dysfunction and delayed onset of progressive accumulation of irreversible deficits. Yet, side effects may limit their usage in clinical practice. Gastrointestinal (GI) side effects are a significant limitation of the use of dimethyl fumarate (DMF), the most frequently prescribed oral DMD in MS worldwide. Diroximel fumarate (DRF) is a second-generation oral fumaric acid ester (FAE) that was developed as a formulation with better GI tolerability. The improved tolerability is assumed to be related to a lower synthesis of gut-irritating methanol. Other explanations for DRF's lower extent of GI irritation include a more modest off-target activity due to its chemical structure. The superior GI tolerability of DRF compared to DMF could be proven in clinical trials and lead to approval of DRF for the treatment of relapsing forms of MS/relapsing-remitting MS (United States Food and Drug Administration and European Medicines Agency, respectively). Here, we summarize the mode of action of oral FAE and compare the chemical and physiological characteristics of DMF and DRF. Moreover, we discuss the adverse effects of FAE and introduce the emerging preclinical and trial data leading to the approval of DRF in MS. This article additionally reviews our current understanding of coronavirus disease 2019 (COVID-19) and the efficacy of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in people treated with FAE.
Subject(s)
Dimethyl Fumarate , Multiple Sclerosis , Humans , COVID-19 , Dimethyl Fumarate/adverse effects , Drug-Related Side Effects and Adverse Reactions/drug therapy , Immunosuppressive Agents/adverse effects , Multiple Sclerosis/drug therapy , SARS-CoV-2 , United StatesABSTRACT
Background: Recent Covid-19 outbreak around the world turned into an international public health concern. Generally, people who receives immunosuppressive treatments or have an underlying disease are more likely to be infected. Multiple sclerosis (MS) patients also may have higher risk of infection due to the taking immunosuppressive or immunomodulatory drugs. Our objectives were to identify the epidemiological characteristics of Covid-19 in patients with MS for improve quality of care and achievement to better diagnosis and treatment in MS patients in Iran. Material(s) and Method(s): The present data were obtained from a hospital-based registry in Imam Khomeini hospital, Tehran, Iran. Totally, 88 MS patients who was infected by Covid-19 were registered from May, 2020 to March 2021. Demographic and clinical data was collected (2). Result(s): 55 (65.5%) of participants were female by the mean age (SD) of 37.48 ± 10.05 years. Covid-19 diagnosis of 4 (4.5%) of patients was based on positive PCR test. The most MS treatment was receiving by patients was Rituximab (20 (22.7%)) following by Dimethyl Fumarate (14 (15.9%)), Fingolimod (10 (11.4%)), Glatiramer acetate (8 (9.1%)), Interferon β-1a (IM) (5 (5.7%)), Interferon β-1a (SQ) (5 (5.7%)), Interferon β-1b (3 (3.4%)), Triflunomide (2 (2.3%)) and Natalizumab (1 (1.1%)). The mean (SD) interval from the last Rituximab injection to Covid-19 infection was 3.80 ± 3.40 months. 37 (42.0%) MS patients continued to take their drugs after Covid-19 infection, while 10 (11.4%) of them stopped taking MS medicine and 7 (8.0%) of them was taking no treatment for controlling MS. 2 (2.3%) of participants was diagnosed by MS after Covid-19 infection. 9 (9.7%) subjects hospitalized due to Covid-19 infection. The mean (SD) duration of hospitalization was 5 ± 7.81 days. One (1.1%) death cases was reported. Conclusion(s): Our findings revealed valuable data of Covid-19 characteristics in patients with MS which could be useful for improving health services for MS patients during the Covid-19 pandemic (3-4).
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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.
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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.
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Background and aims: Evobrutinib, a Bruton's tyrosine kinase inhibitor, was well tolerated and effective in a double-blind, randomised Phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Objective: report evobrutinib safety and efficacy data 2.5 years into an open-label extension (OLE). Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily, W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ∼48W) then 75mg twice-daily. We report the latest available OLE data. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W OLE treatment. Treatmentemergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE (six were serious;Table). Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);three (not treatment related;Covid pneumonia [n=2]) were fatal. Most patients had normal IgG (91%), IgA (88%) and IgM (82%) levels (OLE W120). Mean CD19+ B cells levels were 0.218x106cells/mL (OLE baseline) and 0.122x106cells/ mL (OLE W96). ALT/AST elevations only occurred in patients previously receiving DMF/evobrutinib 25mg, and within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, without clinical signs and symptoms. ARR, for patients receiving 75mg twice-daily in the DBP, was 0.12 (95%CI 0.07-0.20 [all available OLE data]). Conclusion: Evobrutinib safety and efficacy data over 2.5 years shows acceptable tolerability, no new safety signals and maintained efficacy in pwRMS.
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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.
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Objective: To assess symptoms, severity, outcome of Covid 9 in Multiple sclerosis patients ( including NeuroMyelitis Optica )and to assess the prognostic factors for severe Covid19 Background: Covid 19 pandemic came with its own challenges of novelty, lack of information uncertainty of treatment and its effect on chronic autoimmune diseases like Multiple sclerosis. The outcome of covid 19 with immunosuppressive and immunomodulatory treatment in multiple sclerosis was not known till this year. We share our observation of multiple sclerosis patients including neuromyelitis optics who contracted Covid 19 in Dubai UAE, during April 2020 to Sep 2021 in 2 major hospitals treating multiple sclerosis. Design/Methods: All Multiple sclerosis Patients following in Rashid hospital and Alzahra Hospital Neurology apartment who had Covid 19 were included in this observational study. Results: 55 MS patient with Covid 19 ( including 2 NMO) were studied. Age of the patients ranged from 19 to 58years. There were 39 females and 16 males. 43 were RRMS, 6 -SPMS,4- CIS, 1- PPMS and 2 NMOSD. 6 were on interferons, 2 on teriflunamide, 8 on dimethylfumarate, 12 on fingolimod, 3 on natalizumab, 1 on alemtuzumab, 1 on rituximab, 9 on cladribine, 12 on ocrelizumab and 1 on azathioprine. 47 had fever, 30 anosmia, 28 had fatigue and 42 had sorethroat and cough, 5/55 had pneumonia.39/55 had mild covid, 13/55 had moderate and 3 had severe covid 19. 3/55 needed ICU. There were 2 deaths, first with MS, EDSS 6.5 on ocrelizumab and second with NMO (EDSS 7.0)on rituximab Conclusions: The disease course and outcomes were mostly favorable with most patients not requiring hospitalization. A higher EDSS score, progressive disease, use of rituximab, and ocrelizumab(antiCD20 therapy) were associated with the mortality encountered. Age, sex, smoking history, and duration of MS were not independent risk factors for increased severity or adverse COVID-19 disease outcomes.
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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.
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Objective: To examine the temporal trends of humoral and cell-mediated immune responses to SARS-CoV-2 mRNA vaccines among multiple sclerosis (MS) patients on different immunomodulatory therapies. Background: The impact of various MS medications on the immune responses to SARS-CoV-2 vaccine is of acute interest to patients and clinicians. Design/Methods: 22 MS patients treated with ocrelizumab (OCR, n=9), natalizumab (NTZ, n=8), fumarates (FUM, n=5;diroximel fumarate, 3 and dimethyl fumarate, 2) received BNT162b2 (Pfizer, n=15) or mRNA-1273 (Moderna, n=7) vaccines. Blood samples were collected before and after each of the two vaccine doses, and 2 months after second vaccine dose. AntiSARS-CoV-2 spike protein titers were measured using quantitative assay (Labcorp). Antibody neutralization was measured with a lentivirus-based pseudovirus particle expressing the D614 spike protein (Labcorp-Monogram Biosciences). T-cell reactivity was determined by measuring interferon-gamma and interleukin-2 in response to stimulation with SARS-CoV-2 peptides. Results: All patients in NTZ and FUM cohorts, but only 22% (2/9) of OCR cohort developed anti-spike and neutralizing antibodies. The highest titers were measured after the second vaccine dose, without significant difference between the NTZ and FUM cohorts in anti-spike IgG (69.7+/-55.1 vs 56.0+/-36.7 arbitrary units/ml) or neutralizing ID50 (1513+/-1317 vs 942+/ -566). Two months after the second vaccine, the antibody titers and neutralizing ID50 decreased by 72% and 79% in NTZ cohort, respectively, and by 45% and 49% in FUM cohort. T-cell reactivity was observed in all cohorts as early as 7 days after the first vaccine, and further increased following the second vaccine. Conclusions: Patients on NTZ and FUM mounted robust antibody responses to SARS-CoV-2 mRNA vaccines, in contrast to OCR-treated patients. T-cell responses were comparable among all three treatment cohorts. Two months after the second vaccine, the serological responses decreased by 45-79%. These findings may inform the optimal timing of additional vaccine doses for MS patients.
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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.
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Objective: Report the safety and efficacy of evobrutinib over 2.5 years in an open-label extension (OLE). Background: Evobrutinib, a covalent, blood-brain barrier-penetrating Bruton's tyrosine kinase inhibitor, was well tolerated and effective at reducing gadolinium-enhancing lesions in a double-blind, randomized phase II trial in patients with relapsing multiple sclerosis (pwRMS;NCT02975349). Design/Methods: In the 48-week (W) double-blind period (DBP), pwRMS (n=267) received placebo (switched to evobrutinib 25mg once-daily at W24), evobrutinib 25mg once-daily, 75mg once-daily, or 75mg twice-daily, or open-label dimethyl fumarate (DMF;240mg twice-daily). At W48 patients could enter the OLE (DMF: 4-8W washout);evobrutinib 75mg once-daily (median ~48W) then 75mg twice-daily. The latest available OLE data are now reported. Results: Of 267 DBP patients, 213 (80%) entered the OLE;164 (61%) completed ≥132W of OLE treatment. Treatment-emergent adverse events (TEAEs) were reported by 165/213 patients (77.5%);59 (27.7%) had a treatment-related TEAE. Six serious TEAEs were deemed treatment-related. Severe/opportunistic infections (≥Grade 3) were reported by 9/213 patients (4.2%);3 were fatal (Covid-19 pneumonia [n=2] and E. coli sepsis [n=1];not considered treatment-related). At OLE W120, most patients had IgG (91%), IgA (88%) and IgM (82%) within normal ranges. Overall mean CD19+ B cells levels were 0.218×10 cells/mL (OLE baseline) and 0.122×10 cells/mL (OLE W96). ALT/AST elevations were observed only in patients previously receiving DMF/evobrutinib 25mg and occurred within 12W of OLE initiation. Amylase/lipase increases occurred in 6 (2.8%)/24 (11.3%) patients, but without clinical signs and symptoms. Based on all available OLE data, ARR was 0.12 (95%CI 0.07-0.20) for patients receiving 75mg twice-daily in the DBP. 6 6 Conclusions: Evobrutinib safety and efficacy data over 2.5 years in pwRMS continue to show acceptable tolerability, with no new safety signals, and maintained efficacy.
ABSTRACT
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.
ABSTRACT
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.