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In 2010, our analysis of spontaneous and published reports of Progressive Multifocal Leukoencephalopathy (PML) coming from different sources (FDA Adverse Event Reporting System–AERS, WHO VigiBase and MEDLINE) suggested a possible strong relationship between PML and Monoclonal Antibodies (MAbs), especially when used in autoimmune diseases. Recently, Schmedt and colleagues, by using the public version of FDA AERS, have performed the first disproportionality analysis for the possible association between PML and immunosuppressive drugs, and found disproportionality signals for several immunosuppressants, especially MAbs (e.g. natalizumab, efalizumab and rituximab). This study prompted us to refine our analysis by applying a similar disproportionality method, in order to confirm or reject our previous speculation. Therefore, we performed a step-by-step disproportionality analysis for PML in the FDA AERS database by checking disproportionality for: (i) immunosuppressants vs. other drugs; (ii) among immunosuppressants, MAbs vs. Non-MAbs and (iii) each MAb, separately.

AIM: The aim of the present study was to collect and compare cases of drug-induced PML in order to contribute to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence. METHODS: We searched for drug-induced PML cases in two international spontaneous adverse drug reaction (ADR) report databases, FDA-AERS and WHO-VigiBase. From MEDLINE, we retrieved case reports and case series containing the MESH term "leukoencephalopathy, progressive multifocal/chemically induced". In order to assess the PML-drug relationship, we analysed drug-reaction pairs in terms of the patients' underlying diseases and co-suspected drugs. RESULTS: Overall, 214 cases in FDA-AERS, 118 in WHO-VigiBase and 140 in MEDLINE were collected. Therapeutic groups more frequently involved in PML cases were monoclonal antibodies (MAbs), conventional immunosuppressive drugs and anti-HIV drugs. The most frequent underlying diseases were lymphoproliferative diseases (28%), autoimmune disorders (20%) and transplants (10%). MAbs were more often reported in cases where they were the only suspected drugs, whereas for the other therapeutic groups, concomitant drugs were reported. CONCLUSIONS: We found a strong relationship between PML and MAbs, especially when used in autoimmune diseases. PML is becoming a crucial issue of MAbs, since they can cause severe ADRs through the imbalance of the immune system. Based on these results, patients treated with MAbs should be carefully monitored for early signs and symptoms of PML.