ABSTRACT
Background: The immune response to COVID-19 vaccines varies between people with multiple sclerosis (pwMS) receiving different disease-modifying therapies (DMTs). Objective(s): To assess the clinical effectiveness of COVID-19 vaccines in preventing infections and their severe outcomes among pwMS receiving DMTs. Method(s): National Health Service England and United Kingdom Health and Security Agency datasets were used to analyse data on all COVID-19 tests, outcomes, and vaccines among the total population of pwMS receiving DMTs in England. Publicly available data were used for the general population. Monthly COVID- 19 incidence was compared between pwMS receiving DMTs and the general population. COVID-19 related hospitalisation and in-hospital mortality following full vaccination, with at least two doses, were compared between pwMS receiving different DMTs. These results are from March 2020 to December 2021 and will be updated. Result(s): A mean (standard deviation) of 44,170 (4,951) pwMS taking DMTs per month were included. Monthly COVID-19 incidence among pwMS receiving all DMTs, except for fingolimod and ocrelizumab, followed the pattern among the general population, before and after mass vaccination. COVID-19 incidence in pwMS on fingolimod and ocrelizumab compared to the general population increased despite mass vaccination (incidence rate ratio [95% confidence interval]: from 0.50 [0.37-0.66] to 0.91 [0.80-1.03] for fingolimod, and from 1.01 [0.79-1.26] to 1.57 [1.44-1.72] for ocrelizumab, in January 2021 [when vaccination started] to December 2021 [when over 80% of the populations were vaccinated]). COVID-19 related hospitalisation (per 10,000 people) was higher among vaccinated pwMS on fingolimod (94) and ocrelizumab (140) than other DMTs (ranging from 0 to 37). COVID-19 related in-hospital mortality (per 1,000 people) was 0.3 for fingolimod, 2 for ocrelizumab, and 0-1.2 for other DMTs. Conclusion(s): PwMS taking ocrelizumab and fingolimod are at increased risk of contracting COVID-19 and hospitalisation due to COVID-19 compared to the general population and other DMTs using current vaccination protocols.
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.
ABSTRACT
The COVID-19 study (clinicaltrials.gov:NCT04354519) is a prospective observational cohort launched on 17 March 2020 as part of the UKMSR. As of 24 April, out of 3910 participants, 237 (6.1% (95% CI 5.3% to 6.8%)) reported self-diagnosed COVID-19 among whom 54 (22.8% (17.5% to 28.2%)) also had a diagnosis by a healthcare professional based on symptoms and 37 (15.6% (11.2% to 20.6%)) a confirmed diagnosis by testing. Three participants reported hospitalisation due to COVID-19. No deaths were reported. Among 1283 siblings without MS, 79 (6.2%) had a reported diagnosis of COVID-19. Adjusting for age and gender, the likelihood of contracting COVID-19 in pwMS was similar to siblings (OR 1.180 (0.888 to 1.569)). Seven hundred and fifty-nine of 3812 participants reported that they were self-isolating and that they had been self-isolating for at least 2 weeks before symptom onset if they had COVID-19. Of these, 2 (0.3% (0% to 0.7%)) had self-diagnosed COVID-19 whereas 137 of 3053 participants not self-isolating (4.5% (3.8% to 5.2%)) had the disease. Participants on DMTs were less likely to have self-diagnosed COVID-19 (OR 0.640 (CI 0.428 to 0.957)), which remained significant after removing self-isolating participants (OR 0.633 (0.402 to 0.998)). High-efficacy DMTs reduced the likelihood of self-diagnosed COVID-19 compared with no DMTs (OR 0.540 (0.311 to 0.938)) but not compared with moderate-efficacy DMTs. Including webEDSS (n=2808) and physical MSIS-29v2 (n=3192) as additional predictors in the analysis showed no significant association with the likelihood of contracting COVID-19. The gender distribution was similar between participants with and without COVID-19. More participants with self-diagnosed COVID-19 reported themselves as having any ethnicity other than white compared with those without the disease (6.9% (3.9% to 10.1%) vs 3.8% (3.2% to 4.4%), p=0.019). Gender and ethnicity did not affect the likelihood of having COVID-19.
ABSTRACT
Introduction: The COVID-19 pandemic potentially affected decisions around prescribing MS disease modifying therapies (DMTs) due to concerns about the safety of their use and disruptions to healthcare services. Objectives: To depict prescribing trends of MS DMTs during the COVID-19 outbreak in England and compare it to DMT use in other countries. Aims: To understand the effect of the pandemic on prescribing MS DMTs in England compared to other countries. Methods: National Health Service (NHS) England and NHS Improvement data on all issued MS DMT prescriptions during (1/03/2020 to 31/12/2020) and before (1/05/2019 to 29/02/2020) the outbreak was analysed. Interrupted time series analysis was used to depict the effect of the outbreak in England on prescribing trends of total and individual DMTs which will be presented as diagrams. Results: The outbreak had not affected the stationary trend of total DMT prescriptions;median (interquartile range) number of prescriptions per month was 20789 (2489) before and 21102 (1824) during the outbreak. COVID-19 significantly accelerated the pre-pandemic decline of alemtuzumab prescriptions, which dropped from 219 (85) to 63 (31) per month and remained low. The upward trend of cladribine and ocrelizumab prescriptions before the outbreak was interrupted by the first wave with their nadir during the first peak (April-May 2020). The monthly prescriptions of cladribine and ocrelizumab were 249 (47) and 641 (297) before the outbreak and dropped to 18 and 191 in May 2020, respectively. During the first 10 months of the pandemic, there was a 16% reduction in the number of MS patients treated with their firstever DMT from 3847 before to 3241 during the outbreak. These changes were mostly due to significant reductions in prescription of alemtuzumab, cladribine, and ocrelizumab especially during the peaks of the first and second (November 2020) waves of the outbreak which were not compensated by other DMTs. There was an increase in monthly natalizumab prescriptions as first-ever treatment from 32 (18) before to 61 (24) during the outbreak. Conclusion: These changes reflect recommendations of published guidelines on MS DMT use. Comparison of prescribing trends of MS DMTs in England with those from other countries highlights the interplay of different factors in altering DMT prescription practices. These observations have implications in population- based studies involving MS disease activity including the period of the COVID-19 pandemic.
ABSTRACT
Background: The effects of MS disease modifying therapies (DMTs) on COVID-19 morbidity and mortality have been studied in clinician-reported registries, but the true prevalence of SARSCoV-2 infection and its outcomes in the MS population receiving DMTs are unknown. Objectives: To assess the prevalence of SARS-CoV-2 infection and its outcomes, and their association with individual DMTs among all MS patients receiving DMTs in England. Aims: To understand the magnitude of COVID-19's impact on a population of MS patients receiving DMTs. Methods: We analysed merged national databases to ascertain the rate of SARS-CoV-2 positive tests and COVID-19 in-hospital mortality among all MS patients receiving DMTs in England from 1/02/2020 to 27/03/2021. The National Health Service (NHS) England and NHS Improvement collect prescribing and dispensing data on all MS DMTs. Public Health England collects data on all SARS-CoV-2 tests and COVID-19 in-hospital deaths. Further clinical data collection on a random sample of patients who tested positive (cases) or were not tested (controls) for SARS-CoV-2 is ongoing in multiple centres to establish risk factors of adverse COVID-19 outcomes without selection bias. Results: A total of 35556 MS patients had received a DMT. Their mean (standard deviation) age was 44 (12) years. A total of 16,108 patients (45.3%) were tested for SARS-CoV-2, and 2000 (5.6%) tested positive with a mean age of 42 (12) years. Twentysix patients with a positive test (1.3%) died in hospital. Their mean age was 54 (16) years. The age-standardised mortality ratio (95% confidence interval) of the MS versus the general population was 1.2 (0.7-1.7). There was no clear difference between individual DMTs in their rates of positive tests or inhospital mortality. Detailed data on 79 randomly selected patients with a positive test has been collected at two centres so far. Their mean age is 44 (11) years and 55 (69.6%) are women. Five were hospitalised due to COVID-19 out of whom one was admitted to an intensive therapy unit and died. Data will be updated and reanalysed prior to ECTRIMS 2021. Conclusions: So far, COVID-19 does not appear to significantly increase the risk of mortality in MS patients on DMTs compared to the general population, in this large population study.
ABSTRACT
Introduction: Remyelination has emerged as a critical therapeutic target in multiple sclerosis (MS) that has the potential to restore function and protect demyelinated axons. The Cambridge Centre for Myelin Repair trial One (CCMR One, ISRCTN14265371) recently showed that 6-months of bexarotene reduces visual evoked potential (VEP) latency in people with relapsing remitting MS. Objectives: To conduct a follow-up study of the CCMR One participants to examine the durability of the VEP latency improvements that were seen on trial. Aims: To explore the long-term effects of bexarotene. Methods: We re-examined full-field VEP, alongside multifocal- VEP (MF-VEP), using a Vision-Search Plus, and repeated an expanded disability status scale (EDSS) assessment, in MS participants from CCMR One. Treatment effects between follow-up and baseline were tested using multiple regression of the outcome measure on a group indicator with the baseline value of the outcome and the trial minimisation factors (age (≤ 40 /> 40 years), gender, and EDSS (≤ 4.0/> 4.0)) as covariates. Results: From all 31 Cambridge-based CCMR One participants, at a time of COVID-19, 20 consented to be studied, and were seen on average 750 days after their trial involvement. In an analysis of all eyes with recordable signal (24 bexarotene and 14 placebo) there was a statistically significant difference between the followup and baseline P100 latencies of the trial arms: the adjusted bexarotene- placebo treatment difference was -7.79 (95% CI -14.76, -0.82) ms, p=0.044. In line with previous research, there was a good correlation between the P100 latency of the full-field VEP and the latency of the MF-VEP: coefficient of correlation (r) was 0.81 (p<0.0001). 3 participants - all from the bexarotene group - had had an improvement in EDSS, but there was no treatment difference between the two groups: the EDSS difference, adjusted for age and gender, was -0.31 (95% CI -1.37, 0.74), p=0.569. Conclusions: This follow-up study to CCMR One shows that the full-field VEP latency improvements observed in the original trial are durable, suggests long-term benefits from exposure to a remyelinating drug, and supports the potential importance of MF-VEP assessments in remyelination trials. While these data support the original trial finding that bexarotene has a biological effect to promote remyelination in humans, they should be interpreted in light of the significant adverse events that were observed on the trial.