Proportionate and disproportionate reporting of different infectious complications of disease modifying therapy in multiple sclerosis

Introduction Progessive multifocal leukoencephalopathy (PML) is a complication of immunoincompetence due to disease or immunosuppressive therapy and in particular due to disease modifying therapy (DMT) in multiple sclerosis. It is not clear however, whether there is a specific vulnerability to PML or whether this is due to immunosuppression per se. The same holds for the combination of cryptococcal disease and Fingolimod. Methods We used the reporting odds ratio (ROR) as calculated from entries to Vigibase for a sample of drugs used for DMT (Alemtuzumab, Cladribine, Fingolimod, Dimethyl fumarate, Glatirameracetat, Interferon beta-1a, Interferon beta-1b, Natalizumab, Ocrelizumab, Ofatumumab, Ozanimod, Peginterferon-beta-1a, Ponesimod, Siponimod, and Teriflunomide) and infections with the varicella zoster virus (VZV), PML, and cryptococcal and pneumococcal disease as a surrogate for the frequency of these events. Principal component analysis was used to identify outliers of the general relation between the RORs for the 4 infections studied. A plot of log(ROR) for the other infections as a function of log(ROR) of VZV infections was used to characterize the outliers more clearly. Results The associations of PML/Natalizumab and Cryptococcal disease/Fingolimod were reported significantly more frequently than expected from the general reporting pattern as extracted from the PCA. They were the only combinations which were outside the confidence intervals of the otherwise linear correlations of log(ROR) with log(ROR) for VZV. Conclusion These associations are candidates for which specific effects of Natalizumab and Fingolimod should be identified that increase vulnerability to respective infections.