Progressive Multifocal Leukoencephalopathy (PML): only immunosuppressive complication or also drug adverse reaction?

Background: PML is becoming a safety concern for monoclonal antibodies (MAbs), as also recently warned by regulatory agencies. The aim of this study is to review available reports of drug-induced-PML from different sources to identify drugs involved in PML occurrence. Methods: From international spontaneous report databases, FDA-AERS (2004–2008) and WHO-VigiBase (2004–2008), we searched druginduced- PML cases. From MEDLINE database, we selected case-report/case-series published until 2008 and containing the MESH term ‘Leukoencephalopathy, Progressive Multifocal/chemically induced’. In order to assess PML-drug relationship, we analysed drug-reaction-pairs in terms of patient characteristics, basal diseases and co-suspected drugs, if any. Results: We collected 214 PML cases in FDA-AERS, 118 in WHOVigiBase and 140 in MEDLINE. Drugs more frequently involved in PML cases belong to ‘antineoplastic/immunomodulating’ or ‘antiviral’. Substances more frequently reported as the only suspected drug were rituximab (20 in WHO-VigiBase, 28 in FDA-AERS and 5 in MEDLINE), natalizumab (4, 9 and 3), tacrolimus (7, 8 and 2). Concerning basal diseases, lymphoproliferative diseases, autoimmune disorders and transplants were recorded in about 28%, 20% and 10%, without differences among sources. HIV/AIDS was more represented in FDA-AERS (27%) and WHO-VigiBase (19%), rather than in MEDLINE (10%). Conclusions: In HIV/AIDS, the role of drugs in PML occurrence is difficult to establish because of polypharmacy, whereas in autoimmune disorders, we found a strong relationship between PML and MAbs (natalizumab in multiple sclerosis and rituximab in rheumatoid arthritis). Before the MAbs advent, evidence of drug-induced PML among old immunosuppressants was very poor; thus, the risk ofMAbs-induced PML gains strength.