Monoclonal antibodies One approach to treatment has been the use of monoclonal antibodies to various components of the inflammatory response. Natalizumab is directed against alpha-integrin in order to block lymphocyte and monocyte adhesion to endothelial cells and their migration through the vessel wall. It has been used in rheumatoid arthritis and fistulizing Crohn disease. In a study that ran for 6 months, Miller and colleagues (2003) were able to demonstrate a reduction in the number of relapses and a slowing of the accumulation of MRI lesions. A double-blind, placebo-controlled study of 942 patients with relapsing–remitting MS (Polman et al, 2006; the AFFIRM study) showed a 68 percent reduction in relapses, an 80 percent reduction in new or enlarging T2 cerebral lesions and a 96 percent reduction in gadolinium-enhancing lesions on MRI after a year. This represents a twofold improvement in efficacy compared to what has been reported with interferon and glatiramer acetate. There was a 2 percent rate of anaphylactic reactions. Another study suggested that the use of interferon and natalizumab may give better results (Rudick et al, 2006; the SENTINEL study) but this study was terminated early because 2 patients receiving the combination therapy developed PML.
The advantages of this drug are once monthly intravenous treatment and a virtual lack of acute side effects. However, the appearance of cases of progressive multifocal leukoencephalopathy (PML as discussed in Chap. 32) has led to a restriction on its use. Programs are in place to facilitate the early detection of PML since recovery may be possible if the drug is stopped promptly and removed by plasma exchange. However, the methods to detect the infection and to predict which patients will become symptomatic are imperfect. It can be stated that the absence of both JC virus in the urine and of serum antibodies to JC virus makes it very unlikely that PML will occur but there still may be rare cases. In those who have anti-JC virus antibodies, the risk is dependent on the duration of use of natalizumab (particularly if over 24 months) and the prior or concurrent use of other immunosuppressive medications. With both of these factors present, the risk of PML is approximately 11 per 1,000 patients (Bloomgren et al). Serum JC virus antibody ELISA testing is performed for all patients in whom treatment with natalizumab is being considered; periodic retesting is important to reduce false-negative results or detect seroconversion, but the optimal frequency of retesting is unknown.
One remarkable observation has been that in cases of PML associated with the use of natalizumab, plasma exchange to rapidly clear the has reversed the clinical syndrome and led to disappearance of JC virus from the CSF. There may be an immune reconstitution inflammatory syndrome (IRIS) soon after the exchanges, which may be ameliorated by corticosteroids (Wenning et al; Lindå et al). Some patients have survived PML using this approach, 71 percent in one series reported by Vermersch and colleagues, in distinction to the almost uniform fatality in other circumstances. The potential treatments for PML, in addition to ceasing natalizumab or other disease modifying drug for MS, are reviewed in Chap. 32.