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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.

Recommendations about the comparison of multiple interventions should ideally be based on direct evidence. Issues may arise in a guideline development group (GDG) if the intervention of interest is compared with an alternative, widely accepted intervention, and direct evidence suggests that the former may be at least as effective as the latter. In this report, we present our experience during the development of evidence-based recommendations, according to the Grading of Recommendations Assessment, Development and Evaluation methodology, on azathioprine as an off-label treatment for multiple sclerosis in settings with limited resources. Direct evidence from small studies on critical outcomes (relapse and worsening of disability) probably favored, with very low certainty, azathioprine over interferon (IFN), a widely accepted labeled treatment for multiple sclerosis. Indirect evidence on IFN compared to placebo, despite being supported by larger trials, favored IFN with very low certainty. These observations were surprising for some GDG members and challenged their confidence in the seemingly established health effects of IFN and on how they should comparatively evaluate azathioprine. De facto, the long-established treatment that before the availability of newer disease-modifying treatments had been considered for years as a standard of care, was only based on very low certainty evidence, which was paired by very low certainty evidence in favor of another treatment. To not deviate from the mandate and scope of the guideline, through discussion and voting, conditional recommendations supporting the use of azathioprine were made where IFN and/or other treatments were not available and affordable. Although the GDG concluded that there was insufficient evidence to recommend azathioprine ahead of IFN, some of its members would have preferred to rank azathioprine ahead of IFN, based on the published evidence. An alternative solution may have been to add a new question and rediscuss the role of the established treatment, that is, IFN. Recommendations should be developed according to the target recommendation question and the scope of the guideline. Scenarios that question the perceived health effects of long-established interventions must be met by an openness to reconsider such standards of care. If directed by the GDG, external, indirect evidence on the widely accepted intervention may have to be assessed and this should be considered when planning a guideline recommendation. Potential alternative approaches on how to formulate the final recommendation should be carefully weighted in relation to the context and setting to which recommendations are targeted. •A widely accepted treatment may be available as the main comparator to a new treatment.•Evidence may suggest that the new treatment is at least as effective as the comparator.•Confidence in the perceived benefits of widely accepted treatments may be challenged.•Guideline panel may need to reconsider the role of a widely used existing treatment.•Context-specific considerations are needed while formulating target recommendations.

The Lancet Neurology's December Editorial featured the Multiple Sclerosis International Federation application to add multiple sclerosis treatments to the WHO Essential Medicines List (EML).1 The WHO EML Expert Committee recognised the health burden of multiple sclerosis in its review of applications in 20152 and 2019,3 but no medications have yet been included on the EML. The American Cancer Society, together with the Clinton Health Access Initiative (CHAI), have created harmonised regional guidelines to address the dynamic nature of resource availability (ie, the daily changes in resources depending on location, drug availability, shortages, equipment breakdown, and patient's ability to pay), and address the aim for a high standard of cancer care. To create resource-relevant multiple sclerosis guidelines, the affordability, availability, level of evidence, and risk or efficacy profiles of disease-modifying therapies that are readily supported by evidence should be integrated into proposals for sustainable improvement of care.

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.

ObjectivesSome disease-modifying therapies (DMTs) have been associated with COVID-19 severity in people with MS. Comprehensive exploration of these relationships in large international samples is needed.MethodsClinician-reported demographic/clinical data from 27 countries were aggregated into a dataset of 5,648 patients with suspected/confirmed COVID-19. COVID-19 severity outcomes (hospitalisation, admission to ICU, requiring artificial ventilation, death) assessed using multilevel mixed-effect ordered probit and logistic regression, adjusted for age, sex, disability, and MS phenotype. DMTs were compared to glatiramer acetate, dimethyl fumarate, pooled other DMTs, and natalizumab.ResultsOf 5,648 patients (83.4% confirmed COVID-19) were included. Compared to glatiramer acetate, ocrelizumab and rituximab were associated with higher probability of hospitalisation (4%(95%CI=1–7) & 7%(95%CI=4–11)), ICU/artificial ventilation (2%(95%CI=0–4) & 4%(95%CI=2–6)), and death (1%(95%CI=0–2) & 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 three respective levels of COVID-19 severity than glatiramer acetate. Compared to pooled other DMTs and to natalizumab, the associations of ocrelizumab and rituximab with COVID-19 severity were also more pronounced. Evaluation of interferon associations with COVID-19 severity found these only apparent in comparison with the untreated but not vs individual or pooled other DMTs. All associations persisted/enhanced on restriction to confirmed COVID-19.ConclusionsAnalysing the largest international real-world dataset of people with MS with suspected/confirmed COVID-19 confirms that the use of anti-CD20 medication (both ocrelizumab and rituximab) are associated with more severe course of COVID-19, while interferon-based DMTs have no intrinsic protective benefit from other treatment.