New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab

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.

Keywords: biomarkers; demyelinating diseases; disease modifying treatments; multiple sclerosis; natalizumab; progressive multifocal leucoencephalopathy.

Figure 1

Nomogram for predicting progressive multifocal leukoencephalopathy (PML) onset in individual MS patients. The multivariate logistic regression analysis assigns a score to every variable included in the minimal model. The sum of the scores obtained by a patient is interpolated in the total score point-probability line at the bottom of each nomogram and gives the individual PML risk. (A) PML risk in the total cohort. Having a relapse rate lower than 0.5 gives a score of 5 and showing anti-John Cunningham virus antibody levels (anti-JC levels) higher than 0.9 provides a score of 10. Individual patient scores range from 0 to 15 and their PML risk from <1/3,300 to 1/50, respectively. (B) PML risk in the patients with lipid-specific oligoclonal IgM band (LS-OCMB) detection. Being negative (Neg) for LS-OCMB gives a score of 10. Showing anti-JC levels higher than 0.9 provides a score of 5.75. Being older than 45 years gives a score of 5.75. Individual patient scores range from 0 to 21.5 and their PML risk from <1/10,000 to 1/30, respectively.

Figure 2

Illustration of predicting progressive multifocal leukoencephalopathy (PML) risk depending on the results of the nomograms. (A) In the whole cohort PML risk associates with the anti-John Cunningham virus antibody levels (JC) and the relapse rate (RR). (B) In patients with lipid-specific oligoclonal IgM band (LS-OCMB) detection, PML risk associated with the LS-OCMB, and JC status, and the age at natalizumab onset (ANO).