title: Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS).
abstract: OBJECTIVE
  Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the central nervous system that has been reported as rare adverse drug reaction (ADR) of immunosuppressive drugs. We aimed to study signals of PML for immunosuppressants using a disproportionality analysis of spontaneous adverse event reports.
  
  
  METHODS
  Within the US Adverse Event Reporting System, we analyzed all reports of ADRs submitted to the US Food and Drug Administration between January 1, 2004 and September 30, 2010. We used univariate and multivariate logistic regression analysis to calculate reporting odds ratios with 95% confidence intervals of PML for immunosuppressants according to the Anatomical Therapeutic Chemical classification system (L04), rituximab and cyclophosphamide compared to all other drugs.
  
  
  RESULTS
  We identified 635 PML cases in a total of 1,978,706 patients eligible for analysis. Altogether, 21 out of 36 analyzed immunosuppressants were reported at least once with PML. In the univariate analyses, we found a signal for 11 of these drugs (azathioprine, cyclosporine, cyclophosphamide, efalizumab, leflunomide, methotrexate, mycophenolate mofetil, natalizumab, rituximab, tacrolimus and sirolimus). In the multivariate analysis, the signal was no longer present for sirolimus, leflunomide and methotrexate.
  
  
  CONCLUSIONS
  Our study revealed signals of PML for a substantial number of immunosuppressants, including some drugs less considered so far as a risk factor of PML, especially when used for the treatment of autoimmune disorders. These drugs and possible interactions between different immunosuppressants should be studied more closely in future studies.
authors: BIPS-Institute for Epidemiology and Prevention Research, Germany.
authors: Niklas
authors: N
authors: Schmedt
authors: Frank
authors: F
authors: Andersohn
authors: Edeltraut
authors: E
authors: Garbe
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D003627:Data Interpretation, Statistical; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D015999:Multivariate Analysis; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
chemical_list: D007166:Immunosuppressive Agents