—Alina Rabinovich, MD, MS Fellow, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark
Multiple sclerosis (MS) is an autoimmune condition in which autoreactive T cells cross the blood-brain barrier and attack the CNS, causing demyelination and axonal damage. Natalizumab, the newest medication approved for relapsing-remitting MS, is a humanized monoclonal antibody that binds to alpha-4 integrin molecule and prevents T and B cells from entering the brain, thereby decreasing inflammation and thus CNS damage. It has shown great promise in two large-scale multicenter trials with proven effectiveness in decreasing disease relapse rate, as well as accumulation of disability. In general, natalizumab has been well tolerated. Liver abnormalities, allergic reactions, and fatigue are some of its mild side-effects. However, occurrence of progressive multifocal leukoencephalopathy (PML) among patients using natalizumab as part of combination treatment or as monotherapy has caused considerable apprehension among patients and health care professionals about its safety.
PML is a devastating but rare opportunistic viral infection, caused by the JC virus, seen most commonly in patients with HIV, leukemia, and organ transplantation. A novel presentation of PML in MS emerged as a result of natalizumab. Some of the proposed mechanisms are compromised brain immunosurveillance versus mobilization of bone marrow cells carrying the JC virus. Due to surfacing of this infection, natalizumab was taken off the market in 2005. However, careful risk-benefit analysis and studies showing a much greater health gain over the risk of developing PML allowed the drug to be reapproved by the FDA in 2006. Proper use is mandated, such that it is used primarily as a second-line agent in patients with relapsing forms of MS, close clinical surveillance of patients is maintained, and it remains a monotherapy only, as using it in combination with other immunosuppressive agents may greatly increase chances of opportunistic infections, especially PML.
To date, 14 cases of PML have been reported, with the last two published in the New England Journal of Medicine in September. All cases occurred after 12 or more months of treatment, and the majority of cases occurred after 14 months. It appears that natalizumab is very safe for the first year, with the risk of developing PML increasing thereafter. The overall risk of PML after the first 12-month period of treatment with natalizumab appears to be approximately one in 2,000 to 3,000, given the limited information we have available to date. The key is to use natalizumab correctly and with appropriate surveillance. Close patient observation and clinical vigilance are necessary for early detection of PML. As the diagnosis is made early, the drug discontinued and residual drug removed by plasmapheresis, some patients have done well despite the potential deleterious effects of immune reconstitution syndrome on the brain as the virus is eliminated. Patients must be informed that individual susceptibility is not known, and regular laboratory surveillance of the JC virus in the blood and urine is of limited use with current techniques. Therefore, clear risk assessment is difficult at this time. Each patient must be clearly informed of the symptoms of PML. In the future, ongoing analysis will clarify the true safety profile of natalizumab and better define its role in the treatment of MS.