Rituximab, a murine B-cell-depleting monoclonal antibody that targets CD20 lymphocytes, has been tested in several trials and found to be effective in reducing relapses and the accumulation of MRI lesions of relapsing–remitting cases over 4 years, but long-term safety is still being established (Hauser et al, 2008). A similar, fully humanized anti-CD20 drug, ocrelizumab, has been introduced and has similar effects to rituximab (Kappos et al, 2011). In addition to its indication for relapsing remitting MS, it has tentatively been shown to have some effect on primary progressive MS. Appropriate use in patients should be balanced by consideration of its risks, which include opportunistic infection as well as malignancy.
Another monoclonal antibody that has been introduced for the treatment of MS is alemtuzumab, which targets CD-52 antigen expressed on T and B lymphocytes, thereby reducing the number of circulating B cells and for a longer period, T cells. It is used in an annual cycle of intravenous administration for 5 consecutive days. A randomized trial conducted over 36 months comparing the drug to interferon-β-1a found it to be superior in preventing relapses and in reducing the accumulation of disability (CAMMS223 Trial Investigators). A series of subsequent trials have confirmed its effectiveness in comparison to interferon (Cohen et al). The drug can produce idiopathic thrombocytopenic purpura and autoimmune thyroiditis that results in either hyperor hypothyroidism. At the time of this writing, it is being used in Europe but has not yet been approved in the United States for patients with MS. It is associated with increased risk of infections and autoimmune conditions, including thyroid dysregulation and immune thrombocytopenic purpura (ITP).
Oral therapies Since 2010, several novel oral agents have become available for the treatment of MS. Many patients with a new diagnosis of MS are now treated with one of these oral medications. While these drugs have idiosyncratic side effects, for the most part, tolerability and ease of adherence have been main reasons they have been preferred by patients to injectable medications.
Dimethyl fumarate, an oral drug of uncertain mode of action, reduces annualized relapse rates by approximately one-third to one-half and has gastrointestinal side effects as well as causing flushing (Gold et al). Its effect on MS was discovered coincidentally during use to treat psoriasis.
Fingolimod is a sphingosine-1 phosphate 1 (S1P1) receptor analogue that interferes with egress of mature lymphocytes from lymph nodes. Two large phase 3 clinical trials (FREEDOMS and TRANSFORMS) showed a significant effect on MRI lesion burden and relapse rate that is comparable or superior to injectable agents (Cohen and colleagues, 2010; Kappos and colleagues, 2006 and 2010). The approved 0.5 mg daily dose showed 54 percent reduction in relapse rate and 17 percent reduction in risk of disability progression in these 2 year trials. The systemic side effects of fingolimod likely relate to consequences of S1P1 inactivation in several nonneural tissues. Discontinuation of the drug is sometimes required because of extremes of bradycardia or atrioventricular block, macular edema, herpes infections, occurrence of melanoma, or elevations in liver function tests, the last of these, in approximately 10 percent of patients. Patients are monitored for bradyarrhythmias for 6 hours following the first dose, including an electrocardiogram before and after the observation period. Eye examinations to screen for macular edema should occur before and 3 months after initiation of the drug.