Abstract
Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression.Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case.Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.
Highlights
The use of natalizumab, a highly effective therapy approved for the treatment of active relapsing-remitting multiple sclerosis [1], is limited by the risk of progressive multifocal leucoencephalopathy (PML), a serious opportunistic infection of the central nervous system caused by John Cunninghan virus (JCV), appearing in about 1/250 treated patients [2, 3].The factors most frequently used to stratify PML risk in multiple sclerosis patients treated with natalizumab are the presence of anti-JCV antibodies or high anti-JCV indexes in serum; prior immunosuppressive therapies; and duration of natalizumab treatment [3,4,5,6,7]
Univariate tests based on logistic regression were used to explore variables associated to PML risk and to calculate odds ratios (OR) and confidence intervals (CI)
Significant results obtained in the univariate analyses were explored by multivariate tests, and minimal models were established by eliminating variables loosing statistical significance
Summary
The factors most frequently used to stratify PML risk in multiple sclerosis patients treated with natalizumab are the presence of anti-JCV antibodies or high anti-JCV indexes in serum; prior immunosuppressive therapies; and duration of natalizumab treatment [3,4,5,6,7]. These factors have proven to be effective in reducing the risk of PML in the clinical setting [8, 9]. It remains unknown if clinical data indicating high inflammatory course prior natalizumab onset can predict PML risk
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