Background Progressive Multifocal Leukoencephalopathy (PML) is a rare and often fatal opportunistic infection recently associated with several biologic therapies. However, ascribing risk to individual therapies has been problematic. A previous study of the aggregate experience of PML reported in association with autoimmune rheumatic diseases (ARD) in the FDA Adverse Event Reporting System (AERS) database, through March 31, 2010 identified 15 cases associated with biologic therapies for ARD.
Objectives To provide an updated analysis of the FDA AERS database of cases of PML in patients treated with biologic therapies for ARD.
Methods A Freedom of Information Act request was submitted for all cases of PML within FDA AERS through August 27, 2012. MedWatch forms with identified ARD were selected for further analysis. Exclusions included:  cases where the ARD was not the primary indication for biologic therapy  where another condition was the key underlying factor for PML (e.g. HIV)  where PML was unconfirmed. A case was considered as confirmed PML once there was a clear description of compatible clinical and neuroimaging findings AND positive identification of the JC virus by PCR in cerebrospinal fluid AND/OR compatible findings on brain biopsy/autopsy. Relevant data collected included drug treatment and disease association cofactors of PML.
Results 30 confirmed cases of PML associated with biologic therapy for ARD were identified (11 SLE, 11 RA, 5 dermato/polymyositis, 3 other). Median age was 53 yrs (range 28–76yrs), 25 were female. Rituximab (RTX) and anti-TNF therapies were the most recently administered biologic therapy in 26 and 4 cases respectively. There were no cases in which abatacept, tocilizumab, belimumab or anakinra was the most recently administered biologic therapy. PML developed after a median of 2 courses of RTX (range 1–5). The median interval between the first and last infusion of RTX and the development of PML was 15 months (range 1–66) and 5 months (range 0–66), respectively. 4 patients were receiving concomitant cyclophosphamide (CYC), 5 additional patients had previously received CYC. 18/26 were receiving one or more additional immunosuppressive therapies at the time of diagnosis of PML. 7/26 had received an anti-TNF therapy prior to treatment with rituxmab. Two RTX-treated patients had received chemotherapy for malignancy (1 oropharyngeal cancer, 1 MALT lymphoma), 1 had a prior history of breast cancer, 5 additional patients had documented significant lymphopenia. 4 patients developed PML during treatment with anti-TNF therapy, 1 receiving concomitant CYC and 1 treated with CYC prior.
Conclusions PML is a rare event overall in ARD patients treated with biologic immunosuppressive therapies. The small numbers of cases involved and existence of confounders in many cases precludes definitive attribution of causality. However, the relative paucity of confirmed cases in patients recently treated with anti-TNF therapy, despite their widespread use, suggests that a causal relationship is less likely. In contrast, albeit rare, there is a discordant signal regarding the association between rituximab and PML, requiring continued pharmacovigilance.
Disclosure of Interest E. Molloy Consultant for: GSK, Pfizer, L. Calabrese Consultant for: GSK, Biogen Idec, Genentech, Pfizer