MS: Past, Present, and Future

Stuart D. Cook, MD, and Abdul Rahman Alchaki

Dr. Cook is the Ruth Dunietz Kushner and Michael Jay Serwitz Professor of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark. Dr. Alchaki is a resident in the Deptartment of Neurology/Neurosciences at Rutgers, the State University of New Jersey, Newark.

Disclosure: Stuart Cook has received honoraria for lectures from Bayer HealthCare and Merck Serono. He has served as a consultant for Merck Serono, Bayer HealthCare, Teva, Novartis, Sanofi-Aventis, Biogen Idec, and Actinobac Biomed. He has served on steering committees for the BEYOND and CLARITY Studies and as a member of Advisory Boards for Merck Serono, Bayer HealthCare, Teva, Biogen Idec, Sanofi Aventis, and Actinobac Biomed.

Stuart D. Cook, MD

The Initial Years (1838 to 1930s)

The earliest recognition of MS clinical features and pathology was attributed to Jean-Martin Charcot, Robert Carswell, and Jean Cruveilhier in Europe from 1838 to 1868. Beyond those early descriptions, relatively few MS breakthroughs occurred until the 1930s, when Thomas Rivers discovered experimental autoimmune encephalomyelitis (EAE), a demyelinating disease, in animals. His insightful concepts were widely cited and ultimately contributed to undestanding of the immune mechanisms of MS and acute disseminated encephalomyelitis (ADEM).

Advances in Diagnosis (1965 to 1992)

In 1965, Schumacher et al provided the essential clinical criteria for MS diagnosis. Poser et al refined these criteria in 1983. In 2001, McDonald et al added neuroimaging, CSF analysis, and evoked potentials to further complement MS clinical diagnosis. For the first time, the disease could generally be recognized.

Early Treatments

Various treatments for MS were tried over the years, without great success. However, in 1953, a small descriptive trial by Miller and Gibbons reported clinical benefits in patients using intramuscular (IM) adrenocorticotropic hormone (ACTH) for MS and disseminated encephalomyelitis. This was followed in 1970 by a Cooperative Study of IM ACTH versus placebo by Rose et al, which resulted in ACTH, and subsequently oral corticosteroids, being widely used to treat MS, particularly for acute exacerbations of the disease. However, robust evidence of long-term steroids remain limited, even to the present.

High-Dose Steroids

By 1980, the initial descriptive treatment of high-dose intravenous (IV) steroids for demyelinating diseases, including MS and transverse myelitis, by Dowling et al resulted in rapid clinical improvement in some patients. This result was ultimately confirmed by others. High-dose IV steroids became the gold standard for acute attacks, particularly those aggressive in nature. In the mid 1980s, work by Troiano et al, as well as others, showed that the rapid use of high-dose IV as well as oral steroids showed similar effects, with reduction or elimination of CT contrast-enhancing lesions within as few as eight hours, while lower doses or alternative-day treatments were less effective. In addition, descriptive studies of immune modulatory and immunosuppressive drugs, as well as small randomized studies, were published. These agents did not receive FDA approval.

The Golden Age of Therapy (1993 to 2018)

A remarkable era in MS prognosis and treatment began with immunomodulation injections of Betaseron (INFβ-1b), Avonex (INFβ-1a), and Copaxone (glatiramer acetate). This can be attributed, at least in part, to advances in molecular biology, genetics, and neuroimaging, and support by corporate, private, and public funding. Since the initial FDA approval of INFβ-1b, 15 MS therapies have become clinically available, including eight injectables, three orals, and four infusion treatments (see Table 1). In addition, two other drugs have been FDA approved for uses other than MS: rituximab (approved for lymphoma) and cladribine (for hairy cell leukemia), with the latter now approved by the European Medicines Agency for MS. Table 1 depicts characteristics of these therapies approved by US or European agencies (or for other disorders increasingly used off label for MS) in an attempt to compare annual relapse rates (ARR) and decreases in the percent of gadolinium-enhancing MS lesions versus placebo. This information was chosen because ARR has been uniformly selected and defined for such trials, while percent decrease of gadolinium-enhancing lesions on MRI has been the most sensitive barometer available for assessing acute clinical activity. As a result, risk-benefit considerations have been critical in evaluating these drug treatments, with efficacy improving greatly over time, whereas risks have been more variable.