Clinical Review

Disease-Modifying Therapies in Multiple Sclerosis: Overview and Treatment Considerations

Controlling symptoms can slow the physical and emotional disabilities associated with multiple sclerosis and help patients attain the highest quality of life possible for as long as possible.

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Multiple sclerosis (MS) is a disorder characterized by inflammation, demyelination, and degeneration of the central nervous system (CNS). The hallmark of the disorder is relapses and remissions of neurologic symptoms occurring early in the disease course, which are often associated with areas of CNS inflammation and myelin loss.1-3 The inciting cause for this inflammation is unknown but is believed to be multifactorial, with environmental and genetic influences creating an adaptive, T cell-mediated autoimmune response against the CNS.4 Separate from the acute attacks, progressive neurodegeneration can occur more chronically and is characterized by axonal loss and grey matter atrophy thought to be due to direct cytotoxic activity of the innate immune system as well as toxic intermediates, such as nitric oxide.4,5 Despite the multiple insults early on, neurologic disability typically becomes more apparent over time.6 The disability threshold theory argues that neurologic function compensates for brain tissue loss until a threshold of accumulated damage is exceeded.7

Background

The incidence of MS follows a geographic gradient; rates rise as the distance from the equator increases.8,9 This is thought to be due to the gradient of relative sun exposure and its role in the production of vitamin D, which plays an important role in immune regulation when converted to its active hormonal form. Multiple sclerosis is more prevalent in non-Hispanic white patients than it is in other racial groups, and women are affected nearly 2 to 3 times more often than are men.10 About 450,000 individuals in the U.S. and more than 2 million worldwide have MS.11-14

Multiple sclerosis is the most common cause of nontraumatic neurologic disability in young adults. It is typically diagnosed in the third and fourth decades of life, and those who are diagnosed after age 50 years often can recount neurologic symptoms that began years before. However, pediatric-onset and new-onset cases in the elderly have been reported. It has been estimated that up to 10% of patients with MS have onset before 18 years of age.15-17 Compared with adult-onset MS, pediatric-onset is associated with a longer period between initial attack and physical disability, although the average age of disability onset is about 10 years younger.17,18

Disease Courses

Relapsing-remitting MS (RRMS) is the most common disease course overall, and this pattern affects 97% of individuals with disease onset before age 18 years.15-17 The clinically isolated syndrome disease course leads to clinically definite MS in one-third of patients within 1 year and in one-half of patients within 2 years.19 In the majority of cases, the RRMS course transitions over time to secondary-progressive MS (SPMS), which is a disease pattern of progressively worsening disability with few neurologic relapses. Although inflammation is present at all stages, the difference is in the predominance of cell types involved.5 Why the shift from active to chronic inflammation occurs and how to prevent it remain central questions in MS research.4 Regardless, tentative evidence suggests that prevention of relapses may reduce disability accumulation and risk of conversion to progressive MS.20

A minority of patients with MS are diagnosed with primary-progressive MS (PPMS) at onset, which is characterized by a disease pattern that follows a relatively steady progression of neurologic symptoms over time, without clear relapses or remissions of these symptoms, though phases of stability or fluctuations in disability may still occur.21 It is typically diagnosed at an older age than is RRMS, and it is rare in children; suspicion of PPMS in this age group should prompt detailed assessment of alternative diagnoses.17,22 Primary-progressive MS is more equally distributed in men and women than is RRMS.

Regardless of onset type, disability progression seems to occur at the same rate among all patients with MS after a certain threshold is reached. The established assessment scale for disability progression in MS is the Kurtzke Expanded Disability Status scale (EDSS), which has a scoring range from 0 to 10. Data from several patient registries have shown that once EDSS step 4 is reached, progression thereafter occurs at a predictable rate that is similar across MS phenotypes.23 The time it takes patients to subsequently reach higher EDSS steps may be independent of preceding factors.23

MS Symptom Burden

The neurologic symptoms that patients experience are fluctuating and disabling throughout the disease course, irrespective of onset type. Typical MS symptoms include mobility impairment, changes in cognition and mood, pain and other sensation disturbances, bowel and bladder dysfunction, fatigue, and visual disturbances. The burden of these symptoms can significantly impact quality of life (QOL) for patients and their families. The symptom burden can pose a direct threat to a patient’s autonomy, necessitating adaptation to an unpredictable disease that requires frequent health care visits to many different health care providers (eg, neurologists; primary care providers; physiatrists; urologists; ophthalmologists; and speech, physical, and occupational therapists), periodic testing, and often costly medications.24

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