Best practice in the use of natalizumab in multiple sclerosis

Natalizumab is approved for the treatment of patients with relapsing-remitting multiple sclerosis who have failed first-line treatment with traditional disease-modifying therapies or who have highly active disease. The drug has proved highly effective, both in a clinical trial setting and in clinical practice, with marked reductions in the rate of clinical relapses and slowed disease progression. These clinical outcomes are mirrored by a marked reduction in disease activity as evidenced by magnetic resonance imaging of the brain. However, natalizumab treatment has been associated with a risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus (JCV) activation. When this condition was detected in a clinical trial shortly after approval, the drug was immediately and voluntarily withdrawn from the market. As a condition of its reinstatement, stringent pharmacovigilance measures and a risk management plan were enforced. The recent availability of a two-step enzyme-linked immunosorbent assay (ELISA) test for the presence of anti-JCV antibodies (free testing is available in a central laboratory for registered centers), along with an ever-improving understanding of other risk factors such as prior immunosuppressant use and duration of treatment, allow an increasingly refined stratification of the risk of PML. This improved stratification of risk can help guide decisions about treatment. This review will also deal with other topics of relevance to clinical practice such as the development of antinatalizumab antibodies and their negative implications in terms of hypersensitivity reactions and loss of efficacy, withdrawal of treatment, and compassionate pediatric use.