From the School of Rehabilitation Therapy, Faculty of Health Sciences, Queen’s University, Kingston, ON, Canada (MF); Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy (SP, IMB, MR); Patient and Public Involvement Partner, Italian MS Society, Scientific Research Area, Genoa, Italy (FB); Italian MS Foundation, Scientific Research Area, Genoa, Italy (GB, JP); Department of Neurology, Haukeland University Hospital, Bergen, Norway (LB); University of Bergen, Bergen, Norway (LB); Exercise Biology, Department of Public Health, Aarhus University, Aarhus, Denmark (UD); Departments of Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, UK (NE, LAT, RdN); Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK (AF); Faculty of Health, University of Plymouth, Plymouth, UK (JF); Patient and Public Involvement Partner, UK (HJ); KU Leuven, Department of Rehabilitation Sciences, Leuven, Belgium (DK); National MS Center Melsbroek, Melsbroek, Belgium (DK); The Melbourne School of Population and Global Health, The University of Melbourne, Australia (CHM); Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH (DO); Research and Innovation, Nottingham University Hospitals NHS Trust, Nottingham, UK (PS); School of Health, Education, Policing and Sciences, University of Staffordshire, Stoke-on-Trent, UK (PS); Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, UK (ET); Health Division, SINTEF, Trondheim, Norway (RdN). 

Roshan das Nair, PhD, Department of Health Research, SINTEF, Vangslundsgate 10, 7030 Trondheim, Norway; 

Well-being captures an individual’s capacity to lead a meaningful and engaged life. Interventions to address well-being go beyond managing symptoms or supporting daily activity performance. Designing trials to evaluate the effectiveness of such well-being interventions can be challenging. One such challenge is determining what the comparator or control arm should be. Several trials of complex interventions use usual care as a comparator, but this can be particularly challenging when planning trials across multiple countries and health care systems. Therefore, trial design decisions must be informed by a good understanding of what constitutes usual or routine well-being interventions across locations. Our international, multidisciplinary team’s efforts to develop this understanding across our 8 countries found that efforts to support the well-being of people with progressive multiple sclerosis vary widely. This variability emphasizes the importance of having a consistent way to collect data and report on the components of usual well-being care to inform trial design.

 This editorial stems from the project “Living Well With Progressive Multiple Sclerosis” (chief investigator: Roshan das Nair) funded by the International Progressive MS Alliance (Grant PA-2304-41125).

 Marcia Finlayson, PhD, has received funding from MS Canada (2023-2025). Claudia H. Marck, PhD, has received funding from MS Australia (Grant 20-216). Roshan das Nair, PhD, has received funding (speakers’ bureau) from Biogen, Merck, and Novartis. All other authors have disclosed no pertinent interests.

Marcia Finlayson, PhD

Silvia Poli, PhD

Federico Bozzoli, MD

Giampaolo Brichetto, MD, PhD

Lars Bø, MD, PhD

Isolde Martina Busch, PhD

Ulrik Dalgas, PhD

Nikos Evangelou, PhD, MRCP

Amanda Farrin, MSc

Jennifer Freeman, PhD

Helena Jidborg, BA

Daphne Kos, PhD

Claudia H. Marck, PhD

Daniel Ontaneda, MD, PhD

Jessica Podda, PhD

Michela Rimondini, PhD

Polly Swain, MS

Emma Tallantyre, MD, PhD, FRCP

Lauren A. Taylor, PhD

Roshan das Nair, PhD

For people with progressive forms of multiple sclerosis (MS), there are few disease-modifying treatments available,

 leaving much of MS care focused on the management of symptoms and cumulative disability. Research indicates that pharmaceutical approaches to symptom management can reduce the frequency and severity of symptoms and delay progression

 and rehabilitation and self-management approaches can help people with progressive MS reduce the impact of symptoms,

and manage everyday life despite disability.

 Approaches tested through research are often applied in clinical practice under the assumption that they will improve the overall well-being of people with progressive MS, even if available evidence has not included this subgroup of the MS population or explicitly reported this broader outcome.

Well-being (or wellness) is an individual’s capacity to lead a life that is purpose filled and engaged and embraces their full potential, including physical, emotional, spiritual, intellectual, social, environmental, and vocational functioning.

 Therefore, well-being is not just the absence of symptoms or the ability to perform daily activities but also about thriving in a balanced, meaningful, and fulfilling life. This implies that interventions focused on well-being require a holistic, multidimensional approach and intervention targets that go beyond specific symptoms, physiological parameters, or behaviors.

The importance of broader targets for MS care is apparent in the results of a recent international survey

 that found more than 40% of people with MS reported worsening of their ability to perform activities of daily living during the previous 24 months and that more than 60% reported negative changes in physical functioning. Furthermore, respondents indicated that these negative changes were associated with factors beyond symptoms (eg, emotional and social factors, future outlook, emotional well-being, coping, self-esteem, and relationships with friends and family).

This brief background supports the need for a novel approach to address the well-being of people with MS, particularly those with progressive MS, whose symptoms and their impact may be particularly burdensome and/or intractable.

We are an international multidisciplinary consortium of MS researchers and clinicians from 8 countries who are developing and evaluating a well-being intervention for people with progressive MS.

 One of the challenges we faced while designing our study was in understanding the similarities and differences in usual care across our settings and what that means for evaluating our intervention. The intent of this editorial is to share our insights regarding the usual care challenge.

To evaluate our intervention, we are planning a comparative trial with the exact design still under consideration. Comparative studies, including randomized controlled trials, rely on comparisons between the experimental condition (intervention to be tested) and a control or comparator condition. In MS rehabilitation trials focused on symptom management, the comparator is often described as 

 care, suggesting that participants randomly assigned to this trial arm receive what is typically or routinely provided to patients in that clinic or region. Although published treatment guidelines can encourage the harmonization of comparator trial arms in medical trials, the commitment in rehabilitation to patient-centered, goal-directed, and tailored interventions can make such harmonization challenging. Standardized comparators may be more challenging for well-being interventions because the ways in which individuals achieve a meaningful, purpose-filled, and engaged life vary socioculturally and individually.

 Further, usual care can vary widely regionally and nationally, making the generalization of trial findings difficult without details about usual care comparators.

Notably, the practice characteristics of rehabilitation and the breadth of interventions addressing well-being are both consistent with the definition of a 

. Complex interventions include several interacting components, require engagement with multiple behaviors by both the provider and the recipient, have multiple targets and outcomes, and offer a degree of delivery flexibility. Thus, a single intervention can vary considerably depending on the recipient, their goals, the provider’s implementation of the tailoring process, and the resources made available by the health care system, health insurance, or individual.

 Complexity is further affected by service-level factors and by an individual’s clinical characteristics.

Given these multiple factors, what constitutes usual care to support and promote well-being for people with progressive MS is largely unknown. This gap has also been identified in stroke rehabilitation.

 However, in situations where a trial uses a usual care comparator or when the experimental intervention is added to usual care, a good understanding of what constitutes usual care is needed to accurately interpret results and their relevance to a particular setting. Although the importance of describing a usual care comparator is recognized in the context of trial reporting,

 we argue that understanding and documenting usual care also need to be part of trial planning and implementation. Gathering information about usual care in potential study sites will facilitate decision-making about which sites to use, enhance understanding about the overlap between the intervention to be tested and usual care at each site, guide thinking about how to maximize generalizability, and support future implementation if the trial is successful. Indeed, a methodological review summarizing the current approaches to determining the components of usual care comparators highlighted the importance of researchers understanding the context in which a trial is going to be implemented.

 we aimed to describe usual care to support improved well-being among people with progressive MS across sites in Norway, the United Kingdom, the United States, Canada, Australia, Belgium, Italy, and Denmark. We developed a brief survey for this purpose, with the goal of using the results to inform trial design and planning. We did not intend to conduct formal comparisons across countries but wanted to understand what services and resources were available to support well-being (eg, disciplines and programs available, service funding models, referral requirements, care coordination) and what this might mean for our trial comparators. We also wanted to know about the modes of service delivery available, the extent of the use of digital technologies, and the outcomes being monitored. We received ethical approval of our survey from the Queen’s University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board (Canada; No. 6041507). An invitation to participate that included a link to the online survey was sent to all members of our study team, who then purposefully distributed it to colleagues who might be invited to operate a study site for our trial in the future.

In total, 50 individuals responded, with half from the UK. We also had responses from Italy, Australia, Denmark, Belgium, Canada, and Norway. Respondents were primarily neurologists (41%) and nurses (23%), with others being physiotherapists (14%), occupational therapists (12%), psychologists (2%), continence specialists (2%), or other profession (5%). Most (50%) worked in an academic hospital, with tertiary care settings and community-based hospitals or practices being the next most common. The vast majority (85%) reported that their workplace was an MS specialty center. Although 98% considered themselves to be MS specialists within their discipline, one-third of respondents reported serving fewer than 100 people with progressive MS annually and 16% reported serving more than 1000 annually.

Despite responses from different countries, 90% of respondents indicated that traditional health care services were publicly funded, likely due to the preponderance of European respondents. In comparison, less than one-third of respondents reported that well-being services were publicly funded. Instead, a mixed model that included both public and private funding sources was most common, followed by private pay (eg, private insurance or out-of-pocket payments). Of concern is that 56% reported that less than 25% of their patients with progressive MS have private health insurance to access services that support well-being.

Respondents were asked about the sources of the referrals to their service, and they could choose more than 1 option. Primary care physicians were the most common referral source (56%), followed by general (ie, non-MS) neurologists (50%) and then other health care providers 40%). Just over 25% of respondents also reported receiving self-referrals from people with MS. Given our respondents’ settings, it is not surprising that the majority (47%) reported that nurses were the team members most likely to coordinate the connections between people with progressive MS and services or resources to support well-being. Only 3% had a case manager or coordinator who offered such coordination services for people with progressive MS.

The proportion of time respondents spent delivering services to support the well-being of people with progressive MS was limited: The majority (58%) reported that they spent 25% or less of their time addressing well-being. The availability of other disciplines, services, or resources to address well-being was also limited; for example, fewer than 25% of respondents indicated that their center offered exercise programs for people with physical disabilities and a smaller proportion had a social worker (18%) or offered mental health programs (14%), spiritual support (12%), or assistive technology services (8%). Service providers such as physiotherapists, occupational therapists, dietitians, speech therapists, continence advisers, and psychologists were sometimes available through a center or through external agencies, where referrals were often required. Availability of digital health care technologies (DHCTs) to support well-being was not common, except for telehealth technologies, which were available to 56% of respondents. All other DHCTs were available to fewer than one-third of respondents. Even when available, DHCTs were integrated into care 40% or less of the time.

Our survey results uncovered several issues that we must consider as we develop our intervention to improve well-being for people with progressive MS. Attending to these issues may be useful to others interested in supporting the well-being of people with progressive MS and may improve future research.

We asked about what services were available, primarily focusing on the person/discipline or service (eg, nurse, social worker, support group). We cannot assume that the people providing services are focused on well-being, consistent with the broad definition provided earlier. However, based on what we found, service provision focused on well-being appears to be relatively sparse for people with progressive MS. This may be due to funding structures, time available during appointments, or other service factors. We are left wondering the extent to which well-being services reach people with progressive MS and whether any subgroups (eg, racially or ethnically minoritized individuals) are particularly disadvantaged given extant literature.

Care to support well-being is often coordinated by nurses in the centers where our respondents worked. Nevertheless, we cannot assume that the availability of nurses is ubiquitous.

 Even when nurses are available, they may not have time to address well-being given the ever-increasing pressures they are under to provide support for disease-modifying treatments and other medical issues. Overall, our findings suggest that focusing on well-being issues represents a small fraction of most neurologists’ and nurses’ clinical time. Although case coordinators or link workers have become a useful resource in other areas of health care, and social prescribing

 are used to complement traditional health care professionals’ roles, very few MS centers have such personnel or offer these models of care provision.

We need to consider whether the types of supports and services needed to address well-being—we thought of this as thriving in a balanced, meaningful, and fulfilling life—are aligned with traditional health care settings, which primarily operate in a medical model of care. If we think broadly about usual care for well-being, we need to recognize that care can be obtained from services that are not commonly linked to health care (eg, recreation, leisure, and social programs) and from informal systems of support. These aspects of care can be invisible if they are not consistently recorded in patient records or during clinical trials. Our survey captured only aspects of usual care that were provided in the context of the clinical setting. We need to capture other aspects of well-being support when describing usual care comparator arms.

Despite growth in the use of DHCTs in neurological trials,

 our findings indicated limited use of such technologies in clinical care. We need a better understanding of the factors contributing to this implementation gap so that evidence-based DHCTs can be considered as an adjuvant or alternative option to traditional in-person services.

 Given technological improvements and increased technological literacy, providing patientswithchoicesin accessing and receiving services that include evidence-based DHCTs is worth considering. The use of DHCTs is particularly relevant if we want to provide accessible well-being services in the community.

Finally, in a trial, we can often control aspects such as access to the intervention, the method and timing of its delivery, and the training of personnel providing it. As our survey results revealed, usual care to support the well-being of people with progressive MS varies widely. This highlights the need for a consistent way to collect data and report on the components of usual care (see the definition of complex interventions previously) so that we fully understand the comparator arm of our well-being trials.

Our consortium is committed to developing and evaluating a program to support people with progressive MS to live well and thrive in daily life. Our small survey of clinicians at potential study sites has helped inform our thinking and planning. Although our approach and sample size have limitations, our findings highlighted variability in available services, care team composition, and access to well-being support. Understanding these variations is a critical step to design interventions that are feasible, able to be implemented at scale, and centered on the diverse needs of people with progressive MS. For a clinical audience, our team’s efforts highlight that usual care looks different across clinics, regions, and countries, which highlights the importance of interpreting the results of trials with usual care comparators carefully. Our work also highlights the potential value of monitoring and addressing gaps in the provision and coordination of well-being–focused services in routine care.

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Designing Well-Being Intervention Trials for People With Progressive Multiple Sclerosis: The Importance of Understanding Usual Care Comparators

From the Université Saint Joseph de Beyrouth and Hôtel-Dieu de France Hospital, Beirut, Lebanon (JC, GM); the Neurology Institute, Harley Street Medical Center, Abu Dhabi, United Arab Emirates (JM, BY); the Department of Neurology, Clinical Investigation Centre Neurosciences and Mental Health LR 18SP03, Razi University Hospital–Manouba, Tunis, Tunisia (SM); the Faculty of Medicine of Tunis, University of Tunis El Manar, Tunisia (SM); and the Department of Neurology, Centre Hospitalier de l’Université de Montréal, Montreal, Quebec, Canada (GM). 

Gabrielle Macaron; 1000 St Denis Street, Montreal, QC, Canada, H2X 0C1; email: gabrielle.macaron@umontreal.ca; gabrielle.macaron.med@ssss.gouv.qc.ca

The prevalence of multiple sclerosis (MS) is increasing in the Middle East and North Africa (MENA), in part due to better access to earlier diagnosis. Many MENA countries are now considered to fall in moderate to high MS risk zones. MS in MENA populations occurs at a younger age and is more severe, specifically in North African populations. Large disparities in MS care have been observed among MENA countries. Access to care remains a significant obstacle in countries with low incomes, active wars, and a large number of refugees. The MENA MS population could serve as participants in the evaluation of several genetic, epigenetic, and environmental risk factors for MS. Indeed, low vitamin D levels due to reduced sun exposure in hijab-wearing women might explain the striking rising prevalence in Iran after the Islamic revolution, and the prevention of MS with vitamin D could be evaluated in this community. Moreover, because immigration is part of the history of MENA populations, it can serve as an archetype for the study of the impact of immigration on MS risk and severity. Unfortunately, MENA populations are underrepresented in clinical trials, limiting our understanding of this group. However, with the creation of the Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis and the emergence of highly specialized MS centers in several countries, better access to care and collaborative research efforts are expanding.

Jad Costa, MD, reports no conflicts of interest. Joelle Massouh, MSCN, has received honoraria for lectures and advisory boards from AbbVie, Biogen, Biologix, Janssen, Lundbeck, Merck, Novartis, Roche, and Sanofi. Saloua Mrabet, MD, received a Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis clinical fellowship grant in 2020. Bassem Yamout, MD, received lecture honoraria from Bayer, Biogen, Genpharm, Genzyme, Merck-Serono, and Novartis; research grants from Bayer, Biogen, Merck-Serono, Novartis, and Pfizer; and advisory board honoraria from Bayer, Biogen, Genpharm, Genzyme, Merck-Serono, and Novartis. Gabrielle Macaron, MD, received an Innovations in Well- Being Award from the National Multiple Sclerosis Society/International Progressive Multiple Sclerosis Alliance (grant #PA-2304-41062) (2024-2025). She has been on advisory boards for Genentech-Roche, Merck/EMD Serono, and Novartis, and has participated in educational programs for Biogen, Johns Hopkins e-Literature review, MedEdge, 

Jad Costa, MD

Joelle Massouh, MSCN

Saloua Mrabet, MD

Bassem Yamout, MD

Gabrielle Macaron, MD

Several genetic and environmental risk factors for multiple sclerosis (MS) have been identified, such as human leukocyte antigen (HLA) complex (particularly with HLA-DRB1*15:01

), reduced sun exposure and low vitamin D,

 Other environmental risk factors include smoking, obesity, diet, and microbiome.

 Although the prevalence of MS varies along a geographic gradient, MS prevalence has increased in every world region in the past 2 decades. According to the Atlas of MS data,

the global MS prevalence increased from 29.26 to 43.95 per 100,000 people between 2013 and 2020, with the highest MS prevalence recorded in North America (approximately 300 per 100,000) and European countries (142.8 per 100,000), and the lowest in Western Pacific regions (4.79 per 100,000). A rapid increase in the female-to-male ratio has also been observed over the past century, supporting an interaction of sex and environmental factors on the development of MS in women.

 Genetic, epigenetic, and environmental factor interaction is complex, but explains the differences in MS risk, phenotype, and severity across different populations. Phenotypic differences between predominant ethnic categories in the United States and Europe have been studied, but unfortunately, the Arab population of individuals with MS in the Middle East and North Africa (MENA) has received little research interest. The clinical and demographic aspects of MS in the MENA region are, therefore, less characterized. The aim of this narrative review is to highlight epidemiological and phenotypic characteristics of MS in the MENA region, discuss the main challenges in accessing care, and highlight research questions relevant to the MENA population.

Epidemiological Particularities of MS in the MENA Region 

Middle Eastern populations have heterogeneous ethnic origins mixed with Western (Anatolian, Levantine) and Eastern (Iranian, Caucasian) ancestry, with a relatively homogeneous racial background and a common Arabic language.

 It is of note that genetic differences between different populations of the same race might sometimes be greater than between different races. North Africans, natively Berbers, have received genetic contributions from their Middle Eastern, European, and sub-Saharan/African ancestry.

 The MENA region is located at a latitude of 12° to 42° and a longitude of 35° to 54°.

 Based on epidemiological studies prior to 2000, the MENA region was considered to be in the low-moderate MS prevalence zone, with rates ranging between 3 and 20 cases per 100,000 persons.

 However, consistent with the rising incidence and prevalence rates worldwide, a similar increase has been seen in the MENA region. This may be due to advances in MS diagnosis because of, among other factors, increased access to MRIs and specialized MS centers, and/or earlier diagnosis with revised diagnostic criteria, which have been validated in MENA populations.

However, aging of the general population and increased urbanization (implying less sun exposure and increased obesity, stress, and smoking) might also contribute to an increase in MS incidence.

 The most recent reported MS prevalence rates in different MENA countries are shown in the 

MS prevalence is highly variable, with the lowest rates reported in Libya (data from 1985), Oman, and Iraq, and the highest rates in Iran, with a 2017 prevalence of 148 per 100,000.

 Familial MS is particularly prevalent in Iran.

 Interestingly, the MS incidence in Iran has been steadily increasing since 1990, faster than the rise in other MENA and Western European countries.

 Lebanon has also seen increasing prevalence. In 2018, the prevalence was 62.9 per 100,000 people, placing Lebanon in the category of moderate to high risk for MS.

 Similarly, the 2019 crude prevalence rate in the West Bank of Palestine was 51.9 per 100,000, with an overall increase between 2010 and 2019.

 In Kuwait, the crude 2018 prevalence was 105 per 100,000, an increase of 1.6 times compared with 2013.

 In Saudi Arabia, the 2018 prevalence was 40.4 per 100,000, and 62 per 100,000 when accounting for Saudi nationals only.

 In Tunisia, the 2020 prevalence was 58.3 per 100,000 vs 20.2 per 100,000 in 2000.

 In Oman, the 2021 prevalence estimate was 15.9 per 100,000, significantly higher than previously reported (< 5 per 100,000).

 A similar increase was seen in Iraq (11.7 per 100,000).

 However, the latter estimates were based on hospital registries, which are less reliable than national registries. Little is known about the prevalence and incidence of MS in several Arab countries, including Algeria and Syria.

Multiple Sclerosis Prevalence in MENA Countries

Phenotypic Particularities of MS in the MENA Region

Clinical MS onset tends to occur at an earlier age in MENA patients, most commonly 25 to 29 years of age.

 In an epidemiological meta-analysis carried out in 2015, the mean age at onset was 28.5 years, ranging from 25 years in Kuwait to 32 years in Iran and Saudi Arabia.

 Similarly, in 2020, Yamout et al reported a mean age at onset of 27.8 years across several MENA countries, with 60% manifesting before age 30 and 17% before age 20.

 In comparison, the mean age at onset in predominantly White populations from European and North American studies was 32 to 34 years of age.

An earlier age of onset in North African descendants living in France compared with White French residents was also observed.

According to the Middle East and North Africa Committee for Treatment and Research in Multiple Sclerosis (MENACTRIMS) registry, the presenting symptoms were optic or spinal in two-thirds of cases. MS onset was relapsing in 96% and progressive in only 3.2% of cases.

 The clinical presentation, severity, and disability progression vary widely. In North Africa, people with MS tend to have more severe disease, more incomplete recovery after first relapse, and more rapidly progressing disability, despite earlier onset and often equal access to care when compared with European cohorts.

 This has been consistently observed in MS registries from Algeria, Tunisia, and Morocco.

 In other countries, such as Lebanon, Egypt, Kuwait, Oman, Saudi Arabia, Iran, and the United Arab Emirates, a milder phenotype is observed, comparable to the MS population in Western countries, at least based on the large MSBase registry.

 However, symptoms are reportedly more severe and time to secondary progression (SPMS) is shorter in Muslim and Druze Arabs when compared with Christian Arabs in the region. This further emphasizes the importance of genetic factors, as religion is a relatively fixed heritage in the region.30 SPMS risk seems higher in Oman, Iran, and Tunisia, according to a large (> 50,000 patients) worldwide MSBase study, even after taking into account disability, relapse rate, national prevalence, government health expenditure, and time on moderate- to high-efficacy disease-modifying therapies (DMTs).

 Of note, Canada was among the countries with the highest SPMS risk. However, there was no association between MENA ethnicities and risk of SPMS in this study. The prevalence of primary progressive MS appears to be the highest in Saudi Arabia.

 Studies addressing biologic and radiologic biomarkers of MS in the MENA region are still missing from the current literature. Serum and cerebral spinal fluid neurofilament light chains and central vein sign test results seem to be comparable to Western cohorts in 2 studies from Tunisia and Egypt.

Access to MS care, especially DMTs, varies widely across MENA countries. Between 2009 and 2018, platform injectable therapies were the most commonly used DMTs in Egypt, Iran, and Turkey (53%-86%), whereas oral DMTs and monoclonal antibodies were most commonly used in Kuwait, Lebanon, and the United Arab Emirates (59%-87%).

 Specifically, fingolimod was the most widely accessible oral DMT in almost all MENA countries.

 Access to DMTs for patients with SPMS was limited to a few countries such as Kuwait and Egypt. Consistent with the global increase in prescribing high-efficacy DMTs, a similar trend was observed across the MENA region but at a slower rate. These differences may be attributable to variabilities in gross domestic product per capita, as countries with higher income have better access to newer (and more expensive) treatments.

In addition to inequities in socioeconomic status, political unrest, wars, and refugee crises have further widened the gap among countries. The most recent data based on the Atlas of MS indicate widespread use of off-label DMTs such as azathioprine, mycophenolate mofetil, and rituximab.

 The disparities are further highlighted when considering the case of Sudan, for example, which has no access to any approved DMTs and no access to off-label, high-efficacy DMTs. In 40% of MENA countries (but no Gulf countries), new DMTs are either not registered or not fully reimbursed by governments, and the high cost of treatment is the most significant barrier to care.

 Other barriers include substantial co-payments (coverage by national health system or insurance), lack of MRI access, and paucity of MS specialists, all of which can equally impede care. Indeed, significant difficulties for consistent DMT access due to supply and reimbursement concerns were observed in 56% of MENA countries, specifically in low-income countries and those experiencing political unrest.

Displacement, which has long been an outcome of war and conflicts in the MENA region, has resulted in a sizable number of refugees in countries such as Jordan and Lebanon, posing an unparalleled burden on their health care systems. As of 2023, Lebanon, a country of 4.5 million Lebanese citizens, is hosting 1.5 million Syrians and 300,000 Palestinians refugees, 90% of whom live in extreme poverty, according to the United Nations High Commissioner of Refugees. These 2 groups make up 40% of the population, making Lebanon the country with the highest number of refugees per capita worldwide. DMT access is limited for refugees, with sporadic supply of interferons from the Syrian Ministry of Health (requiring possibly unsafe travel to Syria) and from the United Nations Relief and Works Agency for Palestine Refugees in the Near East. Host governments are also unable to carry the cost of DMTs for refugees. To improve access, key MS centers in Lebanon have secured funds from various entities to offer first-line rituximab free of charge to refugees.

 This is in a country where 61.7% of Lebanese people with MS reported an interruption in or inability to access DMTs, with a significant impact on their quality of life.

In spite of these struggles, optimism prevails with the establishment of multidisciplinary collaborative MS centers of excellence in several countries to refine MS management in the MENA region.

 Another positive step is the addition of 3 DMTs (glatiramer acetate, cladribine, rituximab) on the World Health Organization Essential Medicines List; this is a significant milestone for people with MS across the globe, but it does not necessarily imply real-world feasibility in countries with socioeconomic challenges and political instability.

Founded in 2012, MENACTRIMS aims to improve MS care and research efforts among MENA MS specialists. Its founding led to an increase in the number of specialized MS centers and a rising interest in participation in clinical trials.

 The MENACTRIMS registry, a regional MSBase substudy, was created through a collaborative effort in 2016.

 Other noteworthy endeavors include the publication of the MENACTRIMS treatment guidelines

; the development of criteria and evaluation processes for certification of MS centers; the organization of the annual MENACTRIMS congress and associated workshops and educational forums; and the availability of annual research grants, fellowship grants, and internships for physiotherapists in European MS centers. In collaboration with the International Organization of Multiple Sclerosis Nurses and the Consortium of Multiple Sclerosis Centers, annual MS certification exams for MS nurses and other MS specialists have also been offered, leading to an increased the number of certified health care providers in the MENA region.

Contemporary Topics Relevant to the MENA Region 

Vitamin D deficiency during childhood and adolescence is a risk factor for MS.

The majority of Arab countries are predominantly Muslim, and women wearing the hijab or niqab is a common practice that leads to less sun exposure and, consequently, lower vitamin D levels. This has been observed in several countries. A recent study evaluating low vitamin D levels in Palestinian young adults showed that the majority of men had sufficient/optimal levels vs only 7% of women (of whom 98% wear the hijab).

 After the Iranian revolution of 1979, all Iranian women were legally required to wear the hijab and loose-fitting clothes covering their arms and legs. Between 1989 and 2006, Iran recorded an 8.3-fold increase in the incidence of MS with an increasing female predominance.

 It is highly likely that this substantial and rapid rise may be due to genetic changes and may be linked to reduced sun exposure and associated low vitamin D levels.

 Early vitamin D repletion as a primary prevention strategy may be considered in the hijab-wearing population, but its effectiveness in reducing MS incidence requires further investigation.

The MENA population could serve as an archetype for the study of immigration and the understanding of the pathophysiological bases of MS, particularly the interplay among genetic, epigenetic, and environmental factors on MS risk and phenotype. Several environmental factors for MS are similarly observed between MENA and Western countries.

 Although results are heterogeneous across studies, it is generally accepted that immigration from high- to low-risk regions reduces MS risk if relocation occurs before individuals are 15 years of age.

 Genetic factors may also have a determining role in the occurrence and phenotype of the disease. Seyman et al evaluated MS characteristics in patients of MENA descent residing in the Canadian province of Ontario.

 These patients displayed higher disease severity and greater disability progression despite similar annualized relapse rates and new/enlarging T2 lesions over time when compared with MS patients of European descent.

 Sidhom et al compared disability progression in first- and second-generation North Africans living in France with those living in Tunisia, and with White patients born and living in France.

 Second-generation North African patients had the most severe disease despite no difference in access to care, delay in diagnosis, or use of higher efficacy DMTs.

 In fact, they were more likely to be diagnosed early and treated with high-efficacy DMTs compared with other groups, probably secondary to their more severe phenotype at disease onset. North Africans living in Tunisia had less severe disease compared with those living in France, which highlights the impact of environmental factors. These immigration studies have substantial potential to inform on the importance of epigenetics and environmental factors associated with MS pathogenesis, risk, and prognosis.

According to a large 2018 retrospective study using data from the MENACTRIMS registry, almost half of people with MS in the MENA region were treated with interferon beta. Fingolimod was the most prescribed oral DMT (14.9%), followed by dimethyl-fumarate (4.8%). Natalizumab was used in 8.5% of patients, whereas CD20-targeted therapies were used in nearly 6% of patients.

 Of note, cladribine was recently recommended as a first-line agent in the treatment of moderately to highly active disease in the MENACTRIMS 2023 consensus for treatment of relapsing-remitting MS.

Volume 27, Issue Theme

Designing Well-Being Intervention Trials for People With Progressive Multiple Sclerosis: The Importance of Understanding Usual Care Comparators

Multiple Sclerosis in the Middle East and North Africa: Perspectives and Challenges

Multiple Sclerosis Care in a Low/Middle-Income Setting in South West India

Current Practices, Challenges, and Future Directions in Multiple Sclerosis Management in Sub-Saharan Africa

Unique Health Care Delivery Considerations in Rural America

Multiple Sclerosis Care in Latin America

LETTER FROM THE GUEST EDITOR - Volume 27, Issue Theme - December 2024