To assess clinical consequences of temporary natalizumab dosage suspension.

Background Progressive multifocal leukoencephalopathy (PML) occurs in a fraction of patients with multiple sclerosis who were treated with natalizumab. Most adults who are infected with the JC virus, the etiologic agent in PML, do not have symptoms. We sought to determine whether exposure to natalizumab causes subclinical reactivation and neurotropic transformation of JC virus. Methods We followed 19 consecutive patients with multiple sclerosis who were treated with natalizumab over an 18-month period, performing quantitative polymerase-chain-reaction assays in blood and urine for JC virus reactivation; BK virus, a JC virus–related polyomavirus, was used as a control. We determined JC virus–specific T-cell responses by means of an enzyme-linked immunospot assay and antibody responses by means of an enzyme-linked immunosorbent assay and analyzed JC virus regulatory-region sequences. Results After 12 months of natalizumab therapy, the prevalence of JC virus in the urine of the 19 patients increased from a baseline value of 19% to 63% (P = 0.02). After 18 months of treatment, JC virus was detectable in 3 of 15 available plasma samples (20%) and in 9 of 15 available samples of peripheral-blood mononuclear cells (60%) (P = 0.02). JC virus regulatory-region sequences in blood samples and in most of the urine samples were similar to those usually found in PML. Conversely, BK virus remained stable in urine and was undetectable in blood. The JC virus–specific cellular immune response dropped significantly between 6 and 12 months of treatment, and variations in the cellular immune response over time tended to be greater in patients in whom JC viremia developed. None of the patients had clinical or radiologic signs of PML. Conclusions Subclinical reactivation of JC virus occurs frequently in natalizumab-treated patients with multiple sclerosis. Viral shedding is associated with a transient drop in the JC virus–specific cellular immune response.

The primary clinical outcome for the IFN beta-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFN beta-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.

The objective of this work was to assess the effect of interferon beta-1a (Avonex) on the rate of development of clinically definite multiple sclerosis and brain magnetic resonance imaging changes in subgroups based on type of presenting event, baseline brain magnetic resonance imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial. After the onset of a first demyelinating event, 383 patients with brain magnetic resonance imaging evidence of subclinical demyelination were treated with corticosteroids and randomly assigned to receive weekly intramuscular injections of 30 microg interferon beta-1a or placebo. The treatment effect within subgroups was assessed in proportional hazards models both for the development of clinically definite multiple sclerosis and for a combined outcome of development of clinically definite multiple sclerosis or >1 new or enlarging T2 lesions on brain magnetic resonance imaging. A beneficial effect of treatment was noted in all subgroups evaluated. Adjusted rate ratios for the development of clinically definite multiple sclerosis in the optic neuritis, brainstem-cerebellar, and spinal cord syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01) and for the development of the combined clinically definite multiple sclerosis/magnetic resonance imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively. A treatment benefit on both outcome measures also was seen in subgroups based on baseline brain magnetic resonance imaging parameters, gender, and age. Interferon beta-1a is beneficial when initiated at the first clinical demyelinating event in patients with brain magnetic resonance imaging evidence of subclinical demyelination. The beneficial effect is present for optic neuritis, brainstem-cerebellar syndromes, and spinal cord syndromes.

The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.