gms | German Medical Science

MAINZ//2011: 56. GMDS-Jahrestagung und 6. DGEpi-Jahrestagung

Deutsche Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie e. V.
Deutsche Gesellschaft für Epidemiologie e. V.

26. - 29.09.2011 in Mainz

Immunosuppressants associated with progressive multifocal leukoencephalopathy: A disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS)

Meeting Abstract

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  • Niklas Schmedt - University of Bremen, Bremen Institute for Prevention Research and Social Medicine (BIPS), Bremen
  • Frank Andersohn - Charité Berlin, Institute for Social Medicine, Epidemiology and Health Economics, Berlin
  • Edeltraut Garbe - University of Bremen, Bremen Institute for Prevention Research and Social Medicine (BIPS), Bremen

Mainz//2011. 56. Jahrestagung der Deutschen Gesellschaft für Medizinische Informatik, Biometrie und Epidemiologie (gmds), 6. Jahrestagung der Deutschen Gesellschaft für Epidemiologie (DGEpi). Mainz, 26.-29.09.2011. Düsseldorf: German Medical Science GMS Publishing House; 2011. Doc11gmds237

doi: 10.3205/11gmds237, urn:nbn:de:0183-11gmds2376

Published: September 20, 2011

© 2011 Schmedt et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.



Background: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system. In the last years, it has gained particular attention as an adverse drug reaction (ADR) of immunosuppressive drugs, especially with the use of the monoclonal antibodies natalizumab, rituximab and efalizumab. We aimed to investigate the association of PML and other immunosuppressants using a disproportionality analysis of spontaneous reports.

Methods: Within the US Adverse Event Reporting System (AERS), we analysed all reports of adverse drug reactions, submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. As cases, we identified all patients with a code for PML according to the Medical Dictionary for Regulatory Activities (MedDRA). Patients with other ADRs were considered as “non-cases”. Reports with implausible data and possible duplicates of PML ADR reports were excluded. As possible exposures, we analysed all drugs categorized as ‘immunosuppressants’ (L04) according to the Anatomical Therapeutic Chemical (ATC) classification system. All patients were classified as either exposed or not exposed to all analysed substances. For all immunosuppressants, we calculated reporting odds ratios (ROR) of PML for the respective immunosuppressive drug compared to all other drugs with 95% confidence intervals using logistic regression analysis. In addition to crude estimates, we conducted a multivariate analysis including all immunosuppressants reported with PML to the AERS. A signal for a drug was defined by the following: a ROR>2, p<0.05 and ADR reports for the drug in at least three PML cases.

Results: After exclusion of implausible reports and duplicates, N=1,998,604 patients were eligible for analysis. N=817 were PML cases, N=1,997,787 had another ADR. The majority of PML cases were reported in patients with lymphoproliferative disorders or leukemias (33.3%) and autoimmune disorders (29.9%). Compared to all other ADR, the reporting of PML cases was constant over time until 2009 with a strong increase in 2010. In univariate analyses, we found a signal for nine out of 34 immunosuppressants (azathioprine, cyclosporine, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, sirolimus and tacrolimus). In the multivariate analysis, a signal was no longer present for cyclosporine and sirolimus.

Discussion: Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far, e.g. leflunomide or azathioprine. In most drug-associated PML cases, several immunosuppressive and immunomodulating agents were involved. Further research is needed to quantify possible interactions and the influence of individual drugs.


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