Updated Results of the COVID-19 in MS Global Data Sharing Initiative: Anti-CD20 and Other Risk Factors Associated With COVID-19 Severity.

BACKGROUND AND OBJECTIVES: Certain demographic and clinical characteristics, including the use of some disease-modifying therapies (DMTs), are associated with severe acute respiratory syndrome coronavirus 2 infection severity in people with multiple sclerosis (MS). Comprehensive exploration of these relationships in large international samples is needed. METHODS: Clinician-reported demographic/clinical data from 27 countries were aggregated into a data set of 5,648 patients with suspected/confirmed coronavirus disease 2019 (COVID-19). COVID-19 severity outcomes (hospitalization, admission to intensive care unit [ICU], requiring artificial ventilation, and death) were assessed using multilevel mixed-effects ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were individually compared with glatiramer acetate, and anti-CD20 DMTs with pooled other DMTs and with natalizumab. RESULTS: Of 5,648 patients, 922 (16.6%) with suspected and 4,646 (83.4%) with confirmed COVID-19 were included. Male sex, older age, progressive MS, and higher disability were associated with more severe COVID-19. Compared with glatiramer acetate, ocrelizumab and rituximab were associated with higher probabilities of hospitalization (4% [95% CI 1-7] and 7% [95% CI 4-11]), ICU/artificial ventilation (2% [95% CI 0-4] and 4% [95% CI 2-6]), and death (1% [95% CI 0-2] and 2% [95% CI 1-4]) (predicted marginal effects). Untreated patients had 5% (95% CI 2-8), 3% (95% CI 1-5), and 1% (95% CI 0-3) higher probabilities of the 3 respective levels of COVID-19 severity than glatiramer acetate. Compared with pooled other DMTs and with natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. All associations persisted/enhanced on restriction to confirmed COVID-19. DISCUSSION: Analyzing the largest international real-world data set of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab), as well as male sex, older age, progressive MS, and higher disability are associated with more severe course of COVID-19.

Multiple Sclerosis International Federation guideline methodology for off-label treatments for multiple sclerosis.

BACKGROUND: A total of 2.8 million people are living with multiple sclerosis and due to disparities in access to medicines, the ability to treat this condition varies widely. Off-label disease-modifying therapies are sometimes more available or affordable in different health systems. Appropriate methodology is integral in creating high-quality and trustworthy guidelines. In this article, we outline Multiple Sclerosis International Federation's (MSIF) approach to creating guidelines for off-label treatments for multiple sclerosis. METHODS: We use the Guidelines International Network (GIN)-McMaster Guideline Development Checklist and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) Evidence-to-Decision (EtD) framework. We developed detailed health descriptors for health outcomes and the panel drafted PICO (Population, Intervention, Comparator, Outcome) questions and prioritised outcomes. We collaborate with independent organisations, which systematically review and collate the information. We are actively engaging stakeholders and consulting with relevant organisations, boards, working groups and individuals. RESULTS: The draft guideline recommendations will be published for open comment and stakeholders will be encouraged to endorse and disseminate the guidelines. Our methodology ensures integrity and transparency in the criteria, evidence and judgement used to make recommendations. CONCLUSIONS: This approach will facilitate transparent creation of high-quality and trustworthy guidelines, and allow the global guidelines to be adopted or adapted into national settings.

Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. METHODS: Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1-12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. RESULTS: Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01-2.41; aOR 2.43, 95% CI 1.48-4.02) and ICU admission (aOR 2.30, 95% CI 0.98-5.39; aOR 3.93, 95% CI 1.56-9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54-10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (aOR 1.75, 95% CI 1.29-2.38; aOR 2.76, 95% CI 1.87-4.07) and ICU admission (aOR 2.55, 95% CI 1.49-4.36; aOR 4.32, 95% CI 2.27-8.23), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13-3.07; aOR 2.88, 95% CI 1.68-4.92) and ICU admission (aOR 2.13, 95% CI 0.85-5.35; aOR 3.23, 95% CI 1.17-8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71-17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. DISCUSSION: Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Changes on the health care of people with multiple sclerosis from Latin America during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in uncertain access to medical treatment for people with multiple sclerosis (pwMS) all over the world. However, there is no data regarding its impact on access to health care of pwMS from Latin America. OBJECTIVES: We investigated and described changes in health care delivery for pwMS from Latin America during the COVID-19 pandemic. METHODS: PwMS from 18 patient organizations of the region completed a web-based survey hosted from May to October 2020. RESULTS: A total of 602 pwMS completed the questionnaire. Changes in disease-modifying therapies (DMTs) use: 6.7% of pwMS on continuous DMTs claimed to stopped them; 14.1% of those on infusion therapies declared to postpone their dosing; 68.8% declared delaying the initiation of a DMT. Disruptions in accessing rehabilitation services were reported by 65.7%. Changes in laboratory and MRI monitoring were reported by 30% and 33%, respectively. In a multivariable-adjusted logistic regression model, changes in laboratory monitoring were significantly associated with increased odds of postponing MRI monitoring (OR 4.09 CI95% 2.79-6.00, p < 0.001). CONCLUSIONS: The COVID-19 pandemic has disrupted all aspects of the routine care for pwMS from Latin America. Consequences are yet to be determined.

Ethical use of off-label disease-modifying therapies for multiple sclerosis.

BACKGROUND: Off-label disease-modifying therapies (DMTs) for multiple sclerosis (MS) are used in at least 89 countries. There is a need for structured and transparent evidence-based guidelines to support clinical decision-making, pharmaceutical policies and reimbursement decisions for off-label DMTs. OBJECTIVES/RESULTS: The authors put forward general principles for the ethical use of off-label DMTs for treating MS and a process to assess existing evidence and develop recommendations for their use. CONCLUSION: The principles and process are endorsed by the World Federation of Neurology (WFN), American Academy of Neurology (AAN), European Academy of Neurology (EAN), Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Middle-East North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) and Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (PACTRIMS), and we have regularly consulted with the Brain Health Unit, Mental Health and Substance Use Department at the World Health Organization (WHO).

Rising prevalence of multiple sclerosis worldwide: Insights from the Atlas of MS, third edition.

BACKGROUND: High-quality epidemiologic data worldwide are needed to improve our understanding of disease risk, support health policy to meet the diverse needs of people with multiple sclerosis (MS) and support advocacy efforts. OBJECTIVES: The Atlas of MS is an open-source global compendium of data regarding the epidemiology of MS and the availability of resources for people with MS reported at country, regional and global levels. METHODS: Country representatives reported epidemiologic data and their sources via survey between September 2019 and March 2020, covering prevalence and incidence in males, females and children, and age and MS type at diagnosis. Regional analyses and comparisons with 2013 data were conducted. RESULTS: A total of 2.8 million people are estimated to live with MS worldwide (35.9 per 100,000 population). MS prevalence has increased in every world region since 2013 but gaps in prevalence estimates persist. The pooled incidence rate across 75 reporting countries is 2.1 per 100,000 persons/year, and the mean age of diagnosis is 32 years. Females are twice as likely to live with MS as males. CONCLUSIONS: The global prevalence of MS has risen since 2013, but good surveillance data is not universal. Action is needed by multiple stakeholders to close knowledge gaps.

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

BACKGROUND: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale. OBJECTIVES: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible. METHODS: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale. RESULTS: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process. CONCLUSIONS: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.

World Health Organization Essential Medicines List: Multiple sclerosis disease-modifying therapies application.

INTRODUCTION: The World Health Organization (WHO) publishes a biennial Essential Medicines List (EML) to assist governments in low-resource settings to prioritize their spending on medicines. Currently, no medicines on the EML have a multiple sclerosis (MS) indication. Multiple Sclerosis International Federation (MSIF) prepared an application for inclusion of MS disease-modifying therapies (DMTs) for the 2019 EML together with the regional Committees for Treatment and Research in Multiple Sclerosis (TRIMS) and the World Federation of Neurology. RATIONALE: The MSIF taskforce categorized 15 DMTs according to their efficacy and risk profiles to ensure the ability to treat as many different clinical scenarios as possible. Three DMTs were selected: glatiramer acetate, fingolimod, and ocrelizumab. OUTCOME: The WHO Expert Committee did not recommend the addition of any of the DMTs to the EML. They acknowledged the public health burden of MS, the need for effective and affordable MS medications, and the high volume of letters received in support of the application but requested a revised application. DISCUSSION: Despite the negative outcome, the repeated recognition of MS as a global public health burden is sending a powerful message to governments globally that a range of affordable and good quality medications need to be available to health systems and people affected by MS.

Future MS care: a consensus statement of the MS in the 21st Century Steering Group.

The "MS in the 21st Century" initiative was established with the purpose of (1) defining how multiple sclerosis (MS) treatment and standards of care should look in the 21st century; (2) developing a minimum standard of care across the world; and (3) motivating the broad MS community to align standards of care and challenge the current treatment paradigm. The aim was to develop a consensus statement to reach and influence the broader MS community. An expert steering group from Europe and Canada-consisting of neurologists, patient advocates, a pharmacoepidemiologist/pharmacoeconomist, and representatives from national MS centers-participated in a series of workshop-driven meetings between February 2011 and 2012. After three phases of discussions, the steering group identified that the overall vision for future care of MS should be full access to personalized treatment, with reimbursement, to achieve freedom from disease. They constructed seven overall principles that support this vision: personalized care, patient engagement, commitment to research, regulatory body education and reimbursement issues, new endpoints in clinical trials, more therapy options, and MS centers of excellence. This consensus statement outlines the key aspects of the seven principles that need to be addressed. The "MS in the 21st Century Steering Group" hopes that this consensus statement acts as a call to action for healthcare providers and decision-makers to address simultaneously the overarching principles that will guide patient management in order to improve outcomes for people with MS.