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

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

Decentralised clinical trials in multiple sclerosis research.

Randomised controlled trials (RCTs) play an important role in multiple sclerosis (MS) research, ensuring that new interventions are safe and efficacious before their introduction into clinical practice. Trials have been evolving to improve the robustness of their designs and the efficiency of their conduct. Advances in digital and mobile technologies in recent years have facilitated this process and the first RCTs with decentralised elements became possible. Decentralised clinical trials (DCTs) are conducted remotely, enabling participation of a more heterogeneous population who can participate in research activities from different locations and at their convenience. DCTs also rely on digital and mobile technologies which allows for more flexible and frequent assessments. While hospitals quickly adapted to e-health and telehealth assessments during the COVID-19 pandemic, the conduct of conventional RCTs was profoundly disrupted. In this paper, we review the existing evidence and gaps in knowledge in the design and conduct of DCTs in MS.

Response to COVID-19 booster vaccinations in seronegative people with multiple sclerosis.

BACKGROUND: People with MS treated with anti-CD20 therapies and fingolimod often have attenuated responses to initial COVID-19 vaccination. However, uncertainties remain about the benefit of a 3rd (booster) COVID-19 vaccine in this group. METHODS: PwMS without a detectable IgG response following COVID-19 vaccines 1&2 were invited to participate. Participants provided a dried blood spot +/- venous blood sample 2-12 weeks following COVID-19 vaccine 3. Humoral and T cell responses to SARS-CoV-2 spike protein and nucleocapsid antigen were measured. RESULTS: Of 81 participants, 79 provided a dried blood spot sample, of whom 38 also provided a whole blood sample; 2 provided only whole blood. Anti-SARS-CoV-2-spike IgG seroconversion post-COVID-19 vaccine 3 occurred in 26/79 (33%) participants; 26/40 (65%) had positive T-cell responses. Overall, 31/40 (78%) demonstrated either humoral or cellular immune response post-COVID-19 vaccine 3. There was no association between laboratory evidence of prior COVID-19 and seroconversion following vaccine 3. CONCLUSIONS: Approximately one third of pwMS who were seronegative after initial COVID-19 vaccination seroconverted after booster (third) vaccination, supporting the use of boosters in this group. Almost 8 out of 10 had a measurable immune response following 3rd COVID-19 vaccine.

Recovery From COVID-19 in Multiple Sclerosis: A Prospective and Longitudinal Cohort Study of the United Kingdom Multiple Sclerosis Register.

BACKGROUND AND OBJECTIVES: To understand the course of recovery from coronavirus disease 2019 (COVID-19) among patients with multiple sclerosis (MS) and to determine its predictors, including patients' pre-COVID-19 physical and mental health status. METHODS: This prospective and longitudinal cohort study recruited patients with MS who reported COVID-19 from March 17, 2020, to March 19, 2021, as part of the United Kingdom MS Register (UKMSR) COVID-19 study. Participants used online questionnaires to regularly update their COVID-19 symptoms, recovery status, and duration of symptoms for those who fully recovered. Questionnaires were date stamped for estimation of COVID-19 symptom duration for those who had not recovered at their last follow-up. The UKMSR holds demographic and up-to-date clinical data on participants as well as their web-based Expanded Disability Status Scale (web-EDSS) and Hospital Anxiety and Depression Scale (HADS) scores. The association between these factors and recovery from COVID-19 was assessed using multivariable Cox regression analysis. RESULTS: Of the 7,977 patients with MS who participated in the UKMSR COVID-19 study, 599 reported COVID-19 and prospectively updated their recovery status. Twenty-eight hospitalized participants were excluded. At least 165 participants (29.7%) had long-standing COVID-19 symptoms for ≥4 weeks and 69 (12.4%) for ≥12 weeks. Participants with pre-COVID-19 web-EDSS scores ≥7, participants with probable anxiety and/or depression (HADS scores ≥11) before COVID-19 onset, and women were less likely to report recovery from COVID-19. DISCUSSION: Patients with MS are affected by postacute sequelae of COVID-19. Preexisting severe neurologic impairment or mental health problems appear to increase this risk. These findings can have implications in tailoring their post-COVID-19 rehabilitation.

Mental health of people with multiple sclerosis during the COVID-19 outbreak: A prospective cohort and cross-sectional case-control study of the UK MS Register.

BACKGROUND: People with MS (pwMS) have had higher rates of anxiety and depression than the general population before the COVID-19 pandemic, placing them at higher risk of experiencing poor psychological wellbeing during the pandemic. OBJECTIVE: To assess mental health and its social/lifestyle determinants in pwMS during the first wave of the outbreak in the United Kingdom. METHODS: This is a community-based, prospective longitudinal cohort and cross-sectional case-control online questionnaire study. It includes 2010 pwMS from the UK MS Register and 380 people without MS. RESULTS: The Hospital Anxiety and Depression Scale scores of pwMS for anxiety and depression during the outbreak did not change from the previous year. PwMS were more likely to have anxiety (using General Anxiety Disorder-7) and/or depression (using Patient Health Questionnaire-9) than controls during the outbreak (OR: 2.14, 95% CI: 1.58-2.91). PwMS felt lonelier (OR: 1.37, 95% CI: 1.04-1.80) reported worse social support (OR: 1.90, 95% CI: 1.18-3.07) and reported worsened exercise habits (OR: 1.65, 95% CI: 1.18-2.32) during the outbreak than controls. CONCLUSION: Early in the pandemic, pwMS remained at higher risk of experiencing anxiety and depression than the general population. It is important that multidisciplinary teams improve their support for the wellbeing of pwMS, who are vulnerable to the negative effects of the pandemic on their lifestyle and social support.

Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.

BACKGROUND: Contradicting assumptions have been made about the effectiveness of SARS-CoV-2 vaccines in patients with multiple sclerosis (MS) receiving immunomodulatory disease-modifying therapies (DMTs) based on the quantification of humoral and cellular immune responses. This study aimed to understand changes in the risk of SARS-CoV-2 infection among the total population of patients receiving MS DMTs in England following mass vaccination. METHODS: This is a retrospective analysis of national data collected prospectively and longitudinally. National Health Service (NHS) England and NHS Improvement (NHSE/I) hold prescribing data on all commissioned MS DMTs in England. United Kingdom Health Security Agency (UKHSA) has been collecting data on all registered SARS-CoV-2 test results, including polymerase chain reaction and rapid antigen tests. All patients receiving MS DMTs were identified using NHSE/I datasets. All patients receiving MS DMTs with SARS-CoV-2 infection (i.e., positive test) from March 2020 to August 2021 were identified by merging NHSE/I and UKHSA datasets. Similar data for the general population were captured using publicly available datasets of the United Kingdom government. The incidence rate ratios (IRR) of SARS-CoV-2 infection among patients receiving MS DMTs compared to the general population during the pre-vaccination (November 2020 to January 2021) and post-vaccination (June to August 2021) periods were calculated. RESULTS: A mean (standard deviation) of 41,208 (4,301) patients received an MS DMT in England during each month from March 2020 to August 2021. The IRR (95% confidence interval) of infection in patients taking ocrelizumab versus the general population increased from 1.13 (0.97-1.31) during the pre-vaccination period to 1.79 (1.57-2.03) during the post-vaccination period. For patients on fingolimod, it increased from 0.87 (0.73-1.02) to 1.40 (1.20-1.63) during the same periods. There were no significant changes for patients on other MS DMTs. CONCLUSION: SARS-CoV-2 vaccines offer less protection against infection to patients taking ocrelizumab or fingolimod, who have an impaired immune response to vaccines, than the general population. These findings will have implications for vaccination policies.

COVID-19 Vaccine Response in People with Multiple Sclerosis.

OBJECTIVE: The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS). METHODS: Four hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. RESULTS: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01-0.06, p < 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01-0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses. INTERPRETATION: Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 20219999:n/a-n/a.

Challenges of developing, conducting, analysing and reporting a COVID-19 study as the COVID-19 pandemic unfolds: an online co-autoethnographic study.

OBJECTIVES: To capture the complexities and unique experience of a newly formed multidisciplinary and multicentre research team developing and deploying a COVID-19 study and to identify lessons learnt. DESIGN: Co-autoethnographic study. SETTING: Staff at two UK academic institutions, a national charity and two major UK hospitals. PARTICIPANTS: Researchers, clinicians, academics, statisticians and analysts, patient and public involvement representatives and national charity. METHODS: The sampling frame was any content discussed or shared between research team members (emails, meeting minutes, etc), standard observational dimensions and reflective interviews with team members. Data were thematically analysed. RESULTS: Data from 34 meetings and >50 emails between 17 March and 5 August 2020 were analysed. The analysis yielded seven themes with 'Managing our stress' as an overarching theme. CONCLUSIONS: Mutual respect, flexibility and genuine belief that team members are doing the best they can under the circumstances are essential for completing a time-consuming study, requiring a rapid response during a pandemic. Acknowledging and managing stress and a shared purpose can moderate many barriers, such as the lack of face-to-face interactions, leading to effective team working.

COVID-19 is associated with new symptoms of multiple sclerosis that are prevented by disease modifying therapies.

BACKGROUND: Infections can trigger exacerbations of multiple sclerosis (MS). The effects of the coronavirus disease 2019 (COVID-19) on MS are not known. The aim of this study was to understand the impact of COVID-19 on new and pre-existing symptoms of MS. METHODS: The COVID-19 and MS study is an ongoing community-based, prospective cohort study conducted as part of the United Kingdom MS Register. People with MS and COVID-19 were invited by email to complete a questionnaire about their MS symptoms during the infection. An MS exacerbation was defined as developing new MS symptoms and/or worsening of pre-existing MS symptoms. RESULTS: Fifty-seven percent (230/404) of participants had an MS exacerbation during their infection; 82 developed new MS symptoms, 207 experienced worsened pre-existing MS symptoms, and 59 reported both. Disease modifying therapies (DMTs) reduced the likelihood of developing new MS symptoms during the infection (OR 0.556, 95%CI 0.316-0.978). Participants with a higher pre-COVID-19 webEDSS (web-based Expanded Disability Status Scale) score (OR 1.251, 95%CI 1.060-1.478) and longer MS duration (OR 1.042, 95%CI 1.009-1.076) were more likely to experience worsening of their pre-existing MS symptoms during the infection. CONCLUSION: COVID-19 infection was associated with exacerbation of MS. DMTs reduced the chance of developing new MS symptoms during the infection.