Progressive Multifocal Leukoencephalopathy: an effect of immunodeficiency or an adverse drug reaction?

Background. Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating disease affecting the Central Nervous System associated with a high rate of mortality. The interest in PML, a known HIV complication, reappeared when natalizumab, a new immunomodulating agent for multiple sclerosis, was withdrawn from US market because of PML cases. As well as with other monoclonal antibodies (MAbs) many PML cases were recently reported and warned by regulatory agencies. The aim of the present study was to collect and compare cases of drug-induced PML as reported in main international spontaneous ADR databases, in order to offer a contribution to the debate about the role of the underlying diseases and/or drug immunosuppression in PML occurrence. Methods. From international spontaneous report databases, FDA-AERS (2004-2008) and WHO-VigiBase (2004-2008), we retrieved drug-induced-PML cases. From MEDLINE database, we selected the case-reports and case-series 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, underlying diseases and co-suspected drugs, if any. Multiple records were detected within each source and removed before the analysis. No pooling was made of records coming from the two ADR databases (FDA and WHO) as well those mentioned in the literature, since possible duplicates of the same ADRs could be present. Results. We collected 214 PML cases in FDA-AERS, 118 in WHO-VigiBase and 140 in MEDLINE. Therapeutic groups more frequently involved in PML cases were “MAbs”, “conventional immunosuppressive drugs” and “antiviral anti-HIV”. “MAbs” were more often reported in cases where they were the single suspected drugs, whereas for the other groups the drugs were more often reported as multiple suspected drugs. This difference resulted statistically significant both in FDA (c2= 44.17 p<0.0001) and WHO (c2=30.05 p<0.0001) sources. Concerning specific active substances, rituximab (20 in WHO-VigiBase and 28 in FDA-AERS), natalizumab (4 and 9), tacrolimus (7 and 8) were more frequently reported as the single suspected drug. The most frequent underlying diseases were lymphoproliferative diseases (28%), autoimmune disorders (20%) and transplants (10%), without differences among sources. Concerning autoimmune disorders, multiple sclerosis was the most represented: 16 cases in FDA-AERS, 10 in WHO-VigiBase and 2 in MEDLINE, followed by Systemic Lupus Erythematosus (9, 4 and 3) and rheumatoid arthritis (7, 3 and 1). Conclusions. In HIV/AIDS, the role of drugs in PML occurrence is difficult to establish because of polypharmacy and the immunodepressive underlying disease, 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 of MAbs-induced PML gains strength. In the past, PML has never been associated with autoimmune disorders, while, recently it became a crucial issue of biological drugs, because of they could cause severe ADRs through the imbalance of immune system. Based on these results, careful monitoring of patients treated with any biological drugs should be recommended for early signs and symptoms of PML.