Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), affecting more than 2 million people worldwide.
Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system (CNS), affecting more than 2 million people worldwide.1 MS primarily affects younger adults, with the average age of onset at 30 years; women are affected at 3 times the rate of men.2 Long-term prognosis is poor: At 25 years after diagnosis, about half of patients will require permanent use of a wheelchair.3 Risk factors of MS are still largely unknown, although they are believed to be a combination of genetic susceptibility and environmental factors.4
Classified as an autoimmune disease, MS occurs when components of the patient’s immune system cross the blood-brain barrier (BBB), leading to inflammation and demyelination of neurons.3 The primary pathological characteristic of MS are areas of demyelination called plaques; these can occur in both the white and grey matter throughout the CNS.4 Extensive cortical demyelination in grey matter, such as the forebrain and cerebellum, can occur in the earliest phases of the disease. It is more widespread in patients with progressive forms of MS, in which 60% or more of the cortex can be affected.4
MS has 4 distinct subtypes: clinically isolated syndrome (CIS), relapsing–remitting MS (RRMS), secondary progressive MS (SPMS), and primary progressive MS (PPMS).5 Standardized and consistent definitions of these subtypes are critical for a variety of reasons—among them, to define patient parameters for the inclusion in groups for demographic studies and clinical trials, as well as to clarify communications among clinicians who treat patients with MS.6 The most recent revisions of the definitions of MS subtypes in 2013 added CIS, which is recognized as the first clinical presentation of MS demonstrating characteristic inflammatory demyelination that has yet to fulfill the diagnostic criteria of MS.6 If CIS becomes clinically active and fulfills the diagnostic criteria, the patient is then diagnosed with RRMS, which is characterized by neurological deficits known as relapses that can last for days or weeks.4 In patients with RRMS, there is often a progression of clinical disability over 10 to 15 years that becomes prominent and is eventually diagnosed as SPMS.4,7 Approximately 5% to 15% of all patients with MS will be classified as having PPMS, the initially progressive form of MS. Instead of distinct neurological relapses, PPMS presents with a gradual progression of neurological disability, often involving 1 dominant neuronal system.7
Although early and accurate diagnosis is critical,there is no single diagnostic test for MS.2 Diagnosis is instead based on a myriad of clinical information including clinical history and presentation, MRI, and blood and cerebral spinal fluid (CSF) analyses.1,2 Because MS is a disease of the CNS, symptoms are not homogenous and vary widely among patients. The symptoms are neurologically based and can involve the sensory, motor, visual, and brainstem pathways, depending on the lesion location.3,4 When a patient presents with symptoms indicative of MS, a complete MRI evaluation is recommended, as MRI is among the most important tools for early MS diagnosis. Not only can MRI help confirm diagnosis, it can also assist in differentiating from other diseases with similar clinical presentations.2,8
The Burden of MS: Comorbidities, Quality of Life, and Economic Considerations
Comorbidities are more prevalent among patients with MS compared with the general population.9 A growing body of literature suggests that comorbidities significantly affect patients with MS, impacting their overall quality of life, diagnostic delay, and risk of hospitalization, among other difficulties.10 Some of the most frequent comorbidities include thyroid disease, rheumatoid arthritis, psoriasis, cardiovascular disorders, hypertension, depression, anxiety, diabetes mellitus, chronic lung disease, and irritable bowel syndrome.9 Some comorbidities may be autoimmune in nature, while others are not immune-mediated.
It has been suggested that these diverse comorbidities can help explain the variability in clinical course among patients with MS.11,12 For example, findings from one study found that patients with MS with comorbidities exhibited more severe brain damage, particularly those patients with psoriasis, type 2 diabetes mellitus, and thyroid disease.9 Other results suggest that patients with 1 vascular comorbidity are at a 50% higher risk for early gait disability, while patients with 2 vascular comorbidities were at a 228% increased risk.12 When patients exhibit at least 1 vascular comorbidity, they are at increased risk for increased lesion burden and more advanced brain atrophy.13 The vascular conditions that put patients with MS at the highest risk for disability progression include diabetes, hypertension, hypercholesterolemia, and peripheral vascular disease.12 The effect of comorbidities on relapse rate has also been investigated; relapse rate tends to increase with the number of comorbidities. Higher relapse rates have also been noted among in patients who have migraine or hyperlipidemia compared with others who do not.11
Psychiatric comorbidities in MS have a major impact on patient quality of life but can be overlooked in clinical practice. Results from a large survey of patients with MS indicated that 60% of patients reported mental health problems, but less than half of these patients had received treatment.10 The reported rate of depression among patients with MS is variable; it is generally between 20% and 40%, but it can be up to 50% depending on the definition.14 Although the reported rate of depression is highly variable, it is consistently approximately 2 to 3 times higher compared with the general population.15 Furthermore, diagnosis of depression in patients with MS is challenging, as many symptoms of depression, such as fatigue and altered sleep patterns, also align with MS symptoms.10 Depression can affect patients in numerous ways, including in lowered energy, cognition, and overall perception of health. Additionally, patients with depression may have worse long-term outcomes due to decreased adherence to prescribed therapies.10 Also, there is a loss of identity or “self” associated with MS due to physical changes and functional limitations, which can occur particularly when the patient can no longer perform valued activities or an occupation.16 Results from one study found that the rate of unemployment among patients with MS was as high as 75% within 10 years of diagnosis.16
The economic burden of MS is also quite significant, as it is considered the second-most expensive chronic condition behind congestive heart failure. It is roughly 7.5 times more expensive compared with having no chronic condition.17 The estimated total mean costs for patients with MS are quite variable, but one estimate puts them at between $8528 and $52,244 per patient per year.17 Furthermore, costs increase in patients with PPMS and as disability worsens throughout the disease course.17
Current treatments for MS seek to modify the disease course, manage relapses, and manage ongoing symptoms. Disease-modifying therapies (DMTs) are aimed at suppressing CNS inflammation and reducing exacerbation rates; most are therefore primarily indicated in the treatment of RRMS.18 The first DMTs, approved in 1993, were 3 different preparations of interferon-beta (IFNβ). Shortly thereafter, glatiramer acetate (GA) was approved as well. These approvals subsequently triggered intense pharmaceutical research, leading to the numerous options available today that have varying mechanisms of action and delivery.19
The most common treatment strategy for patients with RRMS is an injectable monotherapy such as IFNβ or GA.20 IFNβ has several formulations, including IFNβ-1a, IFNβ-1b, and the recently approved pegylated IFNβ-1a. This latest formulation of IFNβ is designed to be more convenient for patients, with administration just once every 2 weeks, and it is associated with fewer reported adverse effects (AEs).21 IFNβ induces an anti-inflammatory effect by inhibiting T-cell activation and decreasing the activity of matrix metalloproteinases.22 GA has anti-inflammatory effects similar to those of IFNβ, as it induces anti-inflammatory T cells while downregulating inflammatory T cells.19,22 Since GA’s initial approval, 2 additional generic versions have become available, including a formulation taken 3 times weekly instead of daily.19
The first oral treatment, fingolimod, was introduced in 2010; it is also the only DMT approved for the treatment of MS in pediatric patients aged over 10 years.19,22 Fingolimod is an analogue of sphingosine; it works to alter the migration and sequestration of lymphocytes in the lymph nodes. Other oral sphingosine modulators have been subsequently approved, including siponimod in 2019 and ozanimod in 2020.22,23
Teriflunomide, an oral drug that inhibits the biosynthesis of pyrimidine, causing a disruption in the interaction between T cells and antigen-presenting cells, was introduced in 2012.22 Dimethyl fumarate (DMF) was introduced in 2013; it activates the nuclear factor erythroid 2–related factor 2 pathways. DMF has high efficacy but is associated with a high rate of gastrointestinal (GI) AEs. This led to the development and approval of diroximel fumarate, which has the same pharmacologically active metabolite as DMF—monomethyl fumarate (MMF)—but fewer associated GI AEs. Then, in 2020, MMF was approved, also demonstrating fewer GI AEs compared with DMF.22,24,25
The final oral agent, cladribine, has immune-suppressing effects derived from inhibiting DNA synthesis; it was approved by the FDA in 2019. Due to its safety profile, cladribine is recommended only for patients who have had inadequate response to other therapies. Nonetheless, cladribine is considered highly efficacious, with one trial demonstrating that 75% of patients who took it remained relapse-free for up to 2 years following treatment.19,26
The last category of therapeutic options include intravenous infusions. Most of these agents are monoclonal antibodies (mAbs) that suppress the immune system by acting against B cells. Approved in 2005, the first was natalizumab, a mAb that binds to a cellular component of lymphocytes and does not cross the blood-brain barrier.19,22 Natalizumab showed a significant increase in treatment efficacy compared with injectables; however, there was also a substantial increase in AEs, such as progressive multifocal leukoencephalopathy, a potentially deadly infection.19 Other approved mAbs are alemtuzumab and ocrelizumab. Alemtuzumab targets and depletes CD52-expressing cells, including various T and B cells, natural killer cells, and monocytes. Ocrelizumab targets CD20, a B-cell marker, leading to the depletion of B cells.22 Mitoxantrone, another intravenous therapy, works by using several mechanisms to induce immune suppression, including inhibiting topoisomerase, intercalating DNA, and suppressing cytokine secretion and immune cells.22 Although it is available for use in MS, mitoxantrone is recommended only as a “last resort” treatment due to the high frequency of associated AEs, including cardiomyopathy and malignancy.27
Treatment Challenges and Future Directions
One of the most pronounced difficulties in the current MS treatment spectrum is the lack of reliable biomarkers to identify the best therapies for specific patients. Nevertheless, novel markers found in CSF and blood serum in preliminary studies offer promise. For example, it has been found that when neurological disability occurs, many structural cellular proteins, including neurofilament light chains (NFLs), are released into the CSF. It has been demonstrated that serum NFLs (sNFLs) are closely correlated with CSF levels, which is important, given that sampling of CSF has to be done with lumbar puncture, and repeated lumbar punctures are impractical.28 In a recently concluded 12-year study, sNFL levels were shown to be associated with age, disease subtype, relapses, brain atrophy, disease activity, and DMT treatment status.28
Although early results for certain emerging biomarkers are compelling, the MS landscape is still characterized overall by a lack of proven biomarkers. Therefore, the decision regarding how to treat a specific patient relies on disease characteristics and preferences of the patient and physician.19 Given the complexities of MS and the difficulties in treatment decision-making when considering DMTs, the American Academy of Neurology (AAN) released guidelines in 2018, encompassing 30 recommendations to assist clinicians when they start, switch, and stop DMTs for their patients.27 The guidelines’ authors, however, acknowledged that the recommendations emerged from short-term outcomes of trials and that the heterogeneity of the real-world MS population is not perfectly replicated in the patient pool in randomized trials.27
The AAN has also provided suggestions for future research to improve decision-making for DMT selection; the suggestions include comparative DMT studies that include transparent reporting in different MS subpopulations; evaluating DMT benefit in patients with SPMS who are nonambulatory; comparing highly active DMTs against one another for MS treatment; and comparing DMTs for CIS treatment.27
In addition to challenges in treatment selection, difficulties concerning clinical terminology remain, particularly when it comes to the emerging therapeutic spectrum for SPMS. Although phenotype characterizations are widely used, inconsistency has been increasing with regard to how these terms are applied, especially by regulatory authorities, including the terms “activity,” “progression,” and “worsening.”29 Standardized terminology helps to facilitate communication among clinicians, reduce heterogeneity in populations recruited for clinical trials, and apply clinical trial results to the correct patient population.29 In 2020, the International Advisory Committee on Clinical Trials in MS released a clarification regarding the definition of activity for SPMS, stating that the full definition of activity should be used and should also include relapses or imaging features of inflammatory activity. Previously, many regulatory agencies such as the FDA had limited the definition of “activity” to clinical relapses and did not mention MRI activity. In addition to including MRI activity, regulators should also specify a time frame for disease activity, which is critical for effective decision-making.29 Although a defined time frame was never specified in the original definitions of SPMS, the committee recommended reaffirming disease activity annually (at a minimum) to monitor changes over time.29 In addition to the definition of “activity,” the committee recommended that clinicians use the general term “worsening” to define any increase of impairment or disability as a result of relapses, and to reserve the term “progressing” for patients in the progressive phase of MS.29
As characterizations of the MS disease course continue to be elucidated, improving technology may also assist in both the identification and subsequent treatment of MS. Diagnostic tools have continued to improve and will presumably identify promising biomarkers that could aid in selection of therapy. MRI has been the fundamental imaging tool in MS diagnosis, prognosis, and assessment of treatment response.30 Research continues to expand on the use of MRI to not only differentiate MS from other neurological disorders, but to identify imaging biomarkers that reflect pathological processes occurring in SPMS.30
As our understanding of MS disease onset and progression continue to expand, so will the treatment landscape: an optimistic scenario, but one that will lead to increasingly difficult decisions to be made by providers and patients in selecting optimal therapies. Still, by continuing to improve imaging and diagnostic technologies, and by standardizing clinical definitions and clinical trial proceedings, more accurate and clearer prognoses at diagnosis may emerge, aiding in the development of more reliable treatment algorithms.