Personal and Societal Burden

Impact and Research

Although multiple sclerosis (MS) symptoms are often not a direct cause of death in patients with MS, the disability associated with progressive disease in particular (including physical dependence, reduced mobility and decreased workplace and social participation) is a major burden on individuals, healthcare systems and the overall economy. Compounding the burden of MS symptoms are the various comorbid conditions, of which the most common are depression (24%), anxiety (22%), hypertension (19%) and alcohol abuse (15%). An interview-based study of people with MS revealed that 27% have considerable worries about basic economic security (i.e., affording food, housing and utilities) and the same proportion relies only on social security disability insurance (SSDI) for income. Caregivers – typically family members such as parents or partners – also bear a significant portion of the burden of MS, including taking time off work or quitting altogether to care for their loved one. The burden on the healthcare system is likewise substantial. A retrospective cohort analysis of the Medstat MarketScan Commercial Claims and Encounters database revealed that, compared to healthy controls, patients with MS had a 3.5-fold increased risk of hospitalization, 2.4-fold increased risk of ≥1 visit for physical, occupational, or speech therapy and 2-fold increased risk of ≥1 emergency room visit.

One study of the cost burden of MS in the United States used health insurance claims to estimate direct costs and a conducted a survey of 946 patients with MS to collect indirect costs (including productivity loss, caregiver costs, and home modification). The authors estimated the total economic burden of MS in the United States at $85.4 billion, of which $63.3 billion was attributed to direct and $22.1 billion to indirect medical costs. The largest component of the direct costs was retail prescription medication (54%), followed by clinic-administered drugs (12%) and outpatient care (8%). In British Columbia, Canada, a retrospective-matched cohort study of 17,071 patients with MS and 85,355 matched controls also found a substantial excess cost of MS, which was largely driven by DMT use.

Impact on the Patient

Multiple sclerosis reduces the patient’s physical ability, cognitive function and emotional well-being. Physical disability may include reduced general mobility (as a result of muscle weakness/spasticity, fatigue and loss of balance) and manual dexterity, both of which negatively impact the patient’s independence. Patients with advanced MS often require mobility aids (canes, wheelchairs, mobility scooters) to maintain a degree of independence. The most common cognitive deficits in patients with MS include a decline in cognitive processing speed and in episodic memory; impairments in executive function, verbal fluency and visuospatial analysis also commonly occur. Cognitive impairment often starts early in the disease course, but becomes more pronounced with progressive disease. Emotional and mood disorders are also common in patients with MS; the most common mood disorder is depression, which is associated with increased suicide risk, decreased treatment adherence and reduced quality of life. Other, less common but prevalent disorders associated with MS include anxiety, bipolar disorder, apathy and pseudobulbar affect (bouts of inappropriate and involuntary crying or laughter).

Because MS causes possibly irreversible central nervous system (CNS) tissue loss from the earliest stages of the disease, a timely diagnosis is essential to slow the accumulation of CNS damage. Early diagnosis allows for early treatment with disease-modifying therapy (DMT), which can reduce inflammation and prevent the development of lesions. Furthermore, the innate regenerative capacity of CNS tissue decreases with age, underscoring the importance of starting treatment early, when the physiological potential for repair and remyelination is higher. Early treatment with interferon β was shown to reduce mortality in patients with MS by 46% (P <0.001) over a long-term (21 year) follow-up period. Early treatment is also effective at limiting disability; early and continuing treatment with natalizumab was shown to significantly reduce EDSS scores (P <0.0001) compared to the placebo, a difference that was maintained for 240 weeks as long as natalizumab was administered throughout that time period.

Advances in Multiple Sclerosis Research

In the period since the early 2000s, multiple theoretical and practical advances have radically improved the theoretical and clinical understanding of multiple sclerosis; this has yielded new therapeutic options with which MS relapses can be minimized and disease progression slowed. One important theoretical advance is a better understanding of the immune events that drive demyelination, shifting from a T cell-centric view of MS pathophysiology to one in which the contribution of B cells and CNS-resident immune cells (microglia and astrocytes) to the pathologic process is better appreciated. The emergence of Epstein-Barr virus (EBV) infection as a critically important (and potentially causative) factor also represents a major advance in the understanding of MS pathogenesis. As mentioned in the Etiology and Risk Factors section above, advances in genotyping technology enabled the use of genome-wide association studies (GWAS) to identify 233 genomic loci associated with MS risk, which are consistent with the involvement of innate and adaptive immunity in the pathophysiology of MS. Diagnostic criteria (see Presentation and Diagnosis) continue to be refined, with the most recent (2017) McDonald criteria markedly improving diagnostic specificity.

Notable advances in therapeutics also characterized the past two decades. Some examples include the 2004 approval of natalizumab (a monoclonal antibody [mAb] targeted against the VLA-4 receptor), which doubled the relapse rate reduction efficacy compared to other treatment options available at the time; the 2010 approval of fingolimod (a sphingosine-1-phosphate receptor that prevents lymphocyte movement out of lymphoid organs), the first oral therapy for MS; the 2014 approval of alemtuzumab (a mAb that targets CD52 and depletes lymphocytes); and the 2017 approval of ocrelizumab (a mAb that targets CD20), the first specifically B cell-targeted therapy and the first and to date only agent approved for the management of PPMS. See Assessment and Treatment for an overview of available DMTs.

Ongoing areas of research for novel therapeutics include remyelination/functional restoration, autologous hematopoietic stem cell transplantation (AHSCT) and expanding the range of lymphocyte-targeted neurotherapeutics. Repair of existing lesions is mediated by oligodendrocyte precursor cells (OPCs), which differentiate into oligodendrocytes at sites of injury. A significant research effort is devoted to finding and developing agents that increase the differentiation of OPCs into oligodendrocytes, although no successful drug has yet been developed. Another area of research is AHSCT, which aims to re-populate the immune system with autologous but non-autoreactive lymphocytes following chemical immunoablation of autoreactive lymphocytes. This is an aggressive form of treatment and is being investigated for patients with disease refractive to pharmacological interventions. In the domain of pharmacotherapy, Bruton's tyrosine kinase (BKT) inhibitors are a new class of agents that target an enzyme crucial for the activation of microglia, macrophages and B cells. Three BTK inhibitors – remibrutinib, tolebrutinib and fenebrutinib – are currently being investigated for the treatment of MS.