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.

Natalizumab extended-interval dosing in a real-life setting.

BACKGROUND: Natalizumab is a high-efficacy therapy for recurrent multiple sclerosis (RMS) with a four-week administration interval. Controlled trials have shown that extending this interval to six weeks led to better safety without increasing the risk of relapse. We aimed to analyze the safety of extending the natalizumab interdose interval from 4 to 6 weeks in a real-life setting. METHODS: This monocentric retrospective self-controlled study included adult patients with RMS treated with natalizumab with a four-week interval between infusions for a minimum of six months, before switching to a six-week interval. The main outcomes were the incidence of MS relapse, new MRI lesions, and MRI activity signs during the two periods, with patients being their own controls. RESULTS: Fifty-seven patients were included in the analysis. The mean (95%CI) annualized relapse rate (AAR) before natalizumab introduction was 1.03 (0.52; 1.55). During the four-week interval dosing period, no patient presented with an MS relapse, and seven (13.5%) patients had new MRI lesions. During the six-week interval dosing period, no relapse was observed and two (3.6%) patients had new MRI lesions. CONCLUSION: We did not observe more relapses or signs of MRI activity when extending the interval between natalizumab infusions from four to six weeks.

Evaluation of risk management in a natalizumab home infusion procedure.

Natalizumab is a well-established disease-modifying therapy used in active multiple sclerosis (MS). The most serious adverse event is progressive multifocal leukoencephalopathy. For safety reasons, hospital implementation is mandatory. The SARS-CoV-2 pandemic has deeply affected hospital practices leading French authorities to temporarily authorize to administer the treatment at home. The safety of natalizumab home administration should be assessed to allow ongoing home infusion. The aim of the study is to describe the procedure and assess the safety in a home infusion natalizumab model. Patients presenting relapsing-remitting MS treated by natalizumab for over two years, non-exposed to John Cunningham Virus (JCV) and living in the Lille area (France) were included from July 2020 to February 2021 to receive natalizumab infusion at home every four weeks for 12 months. Teleconsultation occurrence, infusion occurrence, infusion cancelling, JCV risk management, annual MRI completion were analyzed. The number of teleconsultations allowing infusion was 365 (37 patients included in the analysis), all home infusions were preceded by a teleconsultation. Nine patients did not complete the one-year home infusion follow-up. Two teleconsultations canceled infusions. Two teleconsultations led to a hospital visit to assess a potential relapse. No severe adverse event was reported. All 28 patients who have completed the follow-up benefited from biannual hospital examination and JCV serologies and annual MRI. Our results suggested that the established home natalizumab procedure was safe using the university hospital home-care department. However, the procedure should be evaluated using home-based services outside the university hospital.

Current and Future Trends in MS Management: Near East Perspective

Objective(s): The objectives were to provide an overview of the current practices of Near East (NE) healthcare practitioners (HCPs) by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers Material(s) and Method(s): A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling Result(s): The survey included 98 neurologists from the included NE countries, the majority of whom had more than 15 years of experience in the field, and 39% were seeing more than 40 MS patients a month. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. In the treatment of mild to moderate RRMS in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. According to 80.7% of participants, interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. Conclusion(s): Most neurologists in the NE region followed MENACTRIMS recommendations for prescribing treatment. The treatment choice also depended on the availability of DMTs in the region. Regarding the use of upcoming DMTs such as Ofatumumab, Siponimod, Ozanimod, and BTK inhibitors, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MSCopyright © 2022

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

Fifteen-year experience with natalizumab in the treatment of multiple sclerosis - a description of 15 clinical cases.

Natalizumab, a humanized anti-alpha4-integrin antibody, is a valuable therapeutic option for relapsing-remitting multiple sclerosis and has been widely used in this indication since 2006. The growing body of data on its high efficacy and safety profile, both from randomised trials and clinical practice, has allowed to identify risk factors for progressive multifocal leukoencephalopathy and to develop a preventive algorithm, which increased the therapeutic safety. Natalizumab also seems relatively safe in pregnant women as there is no indication in the available literature suggesting that exposure to this drug has a significant impact on pregnancy outcomes. However, adequate and well-controlled studies are still lacking and natalizumab should only be used in pregnancy if clearly needed. The mechanism of action of natalizumab also proved successful during the COVID-19 pandemic. Most patients receiving this therapy experienced only mild infection and developed normal vaccine-induced immunity after immunisation. We present a description of 15 patients with relapsing-remitting multiple sclerosis treated with natalizumab in 15 different centres throughout Poland. The drug was included both due to first-line treatment failure and in cases of rapidly progressing, severe form of multiple sclerosis. The patients differed in terms of disease duration, the length of natalizumab therapy, and JCV serological status. The described cases include patients from the natalizumab registration trial, women who became pregnant while on the therapy, and patients who developed COVID-19. The presented case reports summarise the experience to date with the use of natalizumab in the treatment of relapsing-remitting multiple sclerosis in PolandCopyright © 2022 Buchajewicz et al.

Switching from natalizumab administration at the day hospital to administration at home. A 1 year prospective study of patient experience and quality of life in 30 consecutive patients with multiple sclerosis (TYSAD-35).

BACKGROUND: In the context of the COVID-19 pandemic, French health authorities allowed the home administration of natalizumab by a healthcare-at-home service. We evaluated the patients' perception of care quality following the transition from day-hospital to home natalizumab administration. METHODS: Thirty relapsing-remitting multiple sclerosis (MS) patients treated with natalizumab were prospectively evaluated for one year after changing onto a home treatment procedure, using MusiCare, the first MS-specific questionnaire to evaluate patient experience and MusiQol. A numerical rating scale score for satisfaction and a dedicated questionnaire concerning patient experience were completed after each infusion. The primary endpoint was the mean difference in MusiCare score between baseline and 12 months. RESULTS: From June 2020 to November 2021, 306 infusions were performed at home. Three patients withdrew from the study (one lost to follow-up and two preferred to return at the day hospital). No worsening of patient experience or quality of life was observed. The mean scores of the Musicare dimensions were higher at 12 months than at baseline, significantly for the "relationship with healthcare professionals" (p = 0.0203). The MusiQol global score remained stable but the coping and friendship dimensions were significantly better at M12 than at baseline (p = 0.0491 and p = 0.0478, respectively). The satisfaction questionnaire highlighted some pain during the infusions (21.8%) and contradictions between healthcare professionals (17.2%). The mean score for satisfaction with care was 9.1/10. No safety concerns were identified. CONCLUSION: The positive experience of patients with home natalizumab administration provides an important opportunity to improve the quality of patient care.

COVID-19 Vaccine Response in People with Multiple Sclerosis Treated with Dimethyl Fumarate, Diroximel Fumarate, Natalizumab, Ocrelizumab, or Interferon Beta Therapy.

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.

Natalizumab wearing-off symptoms: effect of extend interval dosing during Sars-CoV-2 pandemic.

BACKGROUND: Many patients treated with Natalizumab experience wearing-off symptoms (WoS) towards the end of the administration cycle. During the pandemic we advised and asked patients undergoing treatment with Natalizumab if they wanted to be shifted from a standard interval dosing (StID of 4 weeks) to an extended interval dosing (ExID of 5-6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of WoS when ExID was adopted. METHODS: We enrolled 86 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on WoS, Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and MRI. RESULTS: Among the 86 patients, 32 (37.2%) reported WoS. Most common one was fatigue (93.7%). Mean EDSS was higher in the group reporting WoS (3.8 WoS vs 3.1 non-WoS, p < 0.05). Sphincterial function was the EDSS item that significantly differed between the WoS group and the non-WoS group (1.4 WoS vs 0.6 non-WoS, p < 0.001). WoS correlate with the FSS scale (p < 0.001). CONCLUSION: Adopting an extended interval dosing does not result in significantly different occurrence of WoS between the ExID and the StID populations, in our cohort of patients. Interestingly, there is a strong correlation between WoS and a higher EDSS and FSS. Safety and efficacy of Natalizumab with ExID are relatively preserved in our study.

B- and T-Cell Responses After SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis Receiving Disease Modifying Therapies: Immunological Patterns and Clinical Implications.

Background: Vaccination campaign to contrast the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has raised the issue of vaccine immunogenicity in special populations such as people with multiple sclerosis (PwMS) on highly effective disease modifying treatments (DMTs). While humoral responses to SARS-CoV-2 mRNA vaccines have been well characterized in the general population and in PwMS, very little is known about cell-mediated responses in conferring protection from SARS-CoV-2 infection and severe coronavirus disease-2019 (COVID-19). Methods: PwMS on ocrelizumab, fingolimod or natalizumab, vaccinated with two doses of mRNABNT162b2 (Comirnaty®) vaccine were enrolled. Anti-Spike (S) and anti-Nucleoprotein (N) antibody titers, IFN-gamma production upon S and N peptide libraries stimulation, peripheral blood lymphocyte absolute counts were assessed after at least 1 month and within 4 months from vaccine second dose administration. A group of age and sex matched healthy donors (HD) were included as reference group. Statistical analysis was performed using GraphPad Prism 8.2.1. Results: Thirty PwMS and 9 HDs were enrolled. All the patients were negative for anti-N antibody detection, nor reported previous symptoms of COVID-19. Peripheral blood lymphocyte counts were assessed in PwMS showing: (i) reduction of circulating B-lymphocytes in PwMS on ocrelizumab; (ii) reduction of peripheral blood B- and T-lymphocyte absolute counts in PwMS on fingolimod and (iii) normal B- and T-lymphocyte absolute counts with an increase in circulating CD16+CD56+ NK-cells in PwMS on natalizumab. Three patterns of immunological responses were identified in PwMS. In patients on ocrelizumab, anti-S antibody were lacking or reduced, while T-cell responses were normal. In patients on fingolimod both anti-S titers and T-cell mediated responses were impaired. In patients on natalizumab both anti-S titers and T-cell responses were present and comparable to those observed in HD. Conclusions: The evaluation of T-cell responses, anti-S titers and peripheral blood lymphocyte absolute count in PwMS on DMTs can help to better characterize the immunological response after SARS-CoV-2 vaccination. The evaluation of T-cell responses in longitudinal cohorts of PwMS will help to clarify their protective role in preventing SARS-CoV-2 infection and severe COVID-19. The correlation between DMT treatment and immunological responses to SARS-CoV-2 vaccines could help to better evaluate vaccination strategies in PwMS.

Epidemiology of COVID-19 in Patients with MS: A Hospital-Based Registry

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).

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.

Controversies in neuroimmunology: multiple sclerosis, vaccination, SARSCoV-2 and other dilemas

Neuroimmunology is a discipline that increasingly broadens its horizons in the understanding of neurological diseases. At the same time and in front of the pathophysiological links of neurological diseases and immunology, specific diagnostic and therapeutic approaches have been proposed. Despite the important advances in this discipline, there are multiple dilemmas that concern and filter into clinical practice. This article presents 15 controversies and a discussion about them, which are built with the most up-to-date evidence available. The topics included in this review are: steroid decline in relapses of multiple sclerosis (MS), therapeutic recommendations in MS in light of the SARS-CoV2 pandemic, evidence of vaccination in MS and other demyelinating diseases, overview current situation of isolated clinical and radiological syndrome, therapeutic failure in MS as well as criteria for suspension of disease-modifying therapies, evidence of the management of mild relapses in MS, recommendations for prophylaxis against strongyloides stercolaris, usefulness of a second course of immunoglobulin in the syndrome Guillain-Barre (GBS), criteria to differentiate an acute-onset inflammatory demyelinating chronic polyneuropathy versus GBS and the utility of angiotensin-converting enzyme in neurosarcoidosis. In each of the controversies, the general problem is presented and specific recommendations are offered that can be adopted in daily clinical practice.

Has the pandemic changed treatment strategy in multiple sclerosis? Insights from an Austrian registry

Background and aims: Social distancing measures during the Covid-19 pandemic reduced access to health care and concerns were raised over the safety of immunosuppressive disease modifying treatments (DMT) for multiple sclerosis (MS). Here, we aimed to investigate changes in DMT prescription before and during the pandemic in a large and well-characterized real-world cohort of MS patients. Methods: From the Vienna MS database (VMSD) we extracted MS patients who were initiated on a new DMT (both treatment-naïve and switching) between January 1st 2017 and December 31st 2021. Two time periods were defined: 1) the preCovid-19 era (January 1st 2017 to March 15th 2020, i.e. the day of the first lockdown in Austria) and the Covid-19 era (March 16th 2020 to December 31st 2021). Average annualized DMT prescription rates were descriptively compared between the two periods. Results: The average annualized number of prescriptions in the preCovid-19 era was 90.3/year and dropped to 74.8/year (-17.2%) in the Covid-19 era, driven by a marked reduction to 41.7/year (-54%) in the first nine months of the Covid-19 era, partly offset by a rise to 101 in 2021. Use of alemtuzumab (-64%), antiCD20 (-49%), cladribine (-46%), and S1PM (-38%) was reduced, while natalizumab increased by 24%. Lower efficacy treatments remained stable. Conclusion: The pandemic coincides with a drop in DMT prescription, most markedly for immunosuppressive highefficacy treatments, strongly suggesting the pandemic as the causal factor. If and how much this affects long-term outcome is yet to be determined. (Figure Presented).

Infectious issues of therapeutic monoclonal antibodies in multiple sclerosis and neuromyelitis optica spectrum disorders

Various effective monoclonal antibodies (mAbs) have been approved for both multiple sclerosis (MS) and anti-aquaporin-4-seropositive neuromyelitis optica spectrum disorders worldwide, including in Japan. As these newer mAbs have distinct modes of action that effectively suppress the recurrence of inflammation and slow disability progression, they can modulate and interfere with the protective immune response against pathogens, resulting in various infectious complications. Among various mAbs, natalizumab (NTZ) has the highest risk of causing progressive multifocal leukoencephalopathy (PML), a rare but fatal opportunistic brain infection caused by John Cunningham polyomavirus. Switching from NTZ to B-cell-depleting mAbs, such as ocrelizumab, is also a possible risk factor for PML development. Alemtuzumab carries the risk of reactivation of varicella-zoster virus (VZV);therefore, prophylactic acyclovir treatment is required. NTZ has also been associated with VZV reactivation. Eculizumab can cause severe meningococcal infection due to Neisseria meningitis, and vaccination prior to treatment induction is required. Attention to the reactivation of hepatitis B or Mycobacterium tuberculosis is also needed during mAb therapy. Additionally, in the era of severe acute respiratory syndrome coronavirus 2 infection (COVID-19), the risk for of developing severe COVID-19 may be associated with some mAbs, such as B-cell-depleting agents. Thorough understanding and mitigation strategies for infectious risks are essential.

Covid19 in Multiple Sclerosis Patients in Dubai: Observational Study

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.

Temporal Trendsin Humoral and Cellular Immune Responsesto SARS-CoV-2 mRNA Vaccines Among Multiple Sclerosis Patients TreatedWith Natalizumab, Ocrelizumab or Fumarates

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.

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.