TAKE-HOME POINTS
■ In late 2010, the first oral medication for MS, fingolimod (Gilenya), was approved; it reduces gadolinium-enhancing lesions and significantly lowers relapse rates at 1 year.
■ At least three IV antibody therapies, ocrelizumab, alemtuzumab, and daclizumab, are currently in clinical trials.
■ Several agents that treat MS by modulating immune function have emerged, including teriflunomide and dimethyl fumarate acid. Cladribine is still in clinical trials.
Multiple sclerosis (MS), a chronic inflammatory
autoimmune disease that targets tracts in the CNS, is characterized by plaques composed of demyelination, axonal and neuronal degeneration, and astrocytic scars (sclerosis).1 Effective management requires early, individualized application of disease-modifying therapies (DMT) that reduce the number of attacks and minimize CNS lesions, slowing the progression of disease and promoting neuroprotection and restoration in the near future.2 This article reviews the types of MS as well as the modifying therapeutic strategies currently in use and under development.
SUBTYPES OF MS
MS has four subtypes marked by varying symptoms, rates of manifestation, and frequency of attacks. Relapsing-remitting multiple sclerosis (RRMS) is the most common type, manifesting in more than 80% of cases with periods of exacerbation and remission. Most patients with RRMS progress to secondary progressive MS (SPMS), characterized by insidious progressive neurologic deterioration and few to no further exacerbations. Patients who develop primary progressive MS (PPMS), a wholly progressive form of MS, do not experience a single attack of neurologic dysfunction. A small minority of patients with PPMS develop bona fide exacerbations, the defining symptom of the least common form of MS: progressive-relapsing MS (PRMS).
CURRENT DISEASE-MODIFYING THERAPIES
Because RRMS constitutes the most common form of MS and most of these cases transition to SPMS, therapy development has focused on treating this subtype of MS. Multiple drugs are currently approved for treating RRMS.
Interferon beta-1a (Avonex), interferon beta-1b (Betaseron), and glatiramer acetate (Copaxone) are the first-line therapies that work by reducing MS attacks by about 30% and modestly slowing disease progression. The three drugs reduce MRI-defined lesions by about 50% to 90%. Oral and IV corticosteroids help reduce the impact of acute exacerbations, but they have a limited role as a DMT in the long-term management of MS patients.
Mitoxantrone (Novantrone, generics), an IV chemotherapeutic immunosuppressive agent, is used as a second-line treatment for very active relapsing disease after a severe exacerbation. Risks of mitoxantrone include cardiotoxicity at a lifetime cumulative dose greater than 100 mg/m2 and a significantly higher risk of leukemia.
Natalizumab (Tysabri) is a monoclonal IV antibody that binds to the adhesion molecule VLA-4 on circulating mononuclear cells (T and B cells and macrophages) before the mononuclear cell surface receptor interacts with an endothelial cell surface epitope—vascular cell adhesion molecule 1 (VCAM-1)—thereby reducing trafficking into the CNS. Natalizumab reduces MS-related exacerbations by 67% to 81%, depending on the patient's baseline characteristics. Natalizumab also decreases MRI measures of MS activity by decreasing gadolinium-enhancing lesions by more than 90%. This therapy reduces the progression of disability by 42% to 65% and is the most effective DMT for MS available.
The most serious adverse event with natalizumab is the potentially fatal infection caused by the polyomavirus (or John Cunningham virus [JCV]), which can produce progressive multifocal leukoencephalopathy (PML). A new simple blood test links the presence of the JCV antibody to a greater risk of PML. Prognostic information should determine both the benefits and potential risks of MS immunotherapy.3-5
FIRST ORAL TREATMENT AGENT
Fingolimod (Gilenya) was approved as the first oral medication for MS in late 2010. A structural analog of sphingosine, fingolimod binds to the sphingosine-1-phosphate receptor-1 (S1P1) as an agonist. After the S1P1 receptor is activated, fingolimod depletes it, which inhibits lymphocytes from exiting the lymph nodes and reduces the circulating lymphocytes. Patients on fingolimod had fewer gadolinium-enhancing lesions than the placebo group and much lower relapse rates than patients on weekly IM interferon beta-1b.6,7
Patients who take fingolimod should be monitored for bradycardia for 6 hours after the first dose. Fingolimod treatment increases the risk for infection, macular edema, skin cancer, and respiratory problems, primarily in predisposed persons. It should be considered in those who continue to exhibit disease activity with injectable medications or in those who do not tolerate other MS medications.
Before starting fingolimod, patients should have an ECG to evaluate for conduction abnormalities; an eye examination with optical coherence tomography to rule out macular edema and establish baseline thickness; and a serology test for varicella-zoster virus (VZV), as this agent can cause dangerous disseminated viremia in those not immunized. If VZV test results are negative, the VZV vaccine should be given and therapy should be delayed for 4 weeks.