Patients with MS show a threefold to fourfold increase in the expression of the α4 subunit of the integrin VLA-4, which is normally expressed on activated lymphocytes, monocytes, and other cell types in the CSF and circulation [119] . Elovaara et al. confirmed that methylprednisolone reduces the adhesion molecules in the blood and CSF in patients with MS [120] , implying that targeting leukocyte trafficking may be a possible therapeutic strategy for MS [121] . Therefore, natalizumab, a humanized mAb directed against the VLA-4 adhesion complex, has been introduced into the treatment of MS and reduces the risk of sustained progression of disability and the rate of clinical relapse in patients with relapsing MS [122] . However, during clinical trials, two natalizumab-treated MS patients developed progressive multifocal leukoencephalopathy (PML), which resulted in the voluntary removal of the drug from the market in February 2005 [123, 124] . A retrospective safety evaluation was subsequently conducted, and natalizumab was consequently returned to the market as a monotherapy in July 2006 for the treatment of relapsing MS; however, there were 111 cases of PML reported subsequently in natalizumab-treated MS patients as of April 2011 [125] . More evidently, the risk of developing PML for a MS patient on natalizumab (Tysabri) is almost 100 times higher if the patient (1) has been taking the drug for more than two years, (2) has a prior history of immunosuppressant use, and (3) tests positive for antibodies to the JC virus [126] , compared to a patient with none of these three risk factors [127] . Instead, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease-modifying or immunosuppressive agents [128] . Nevertheless, natalizumab use must be restricted to the indicated patients.