Background Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML.
Objective/methods A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority.
Results The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty.
Conclusions The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.
- Progressive multifocal leukoencephalopathy
- monoclonal antibodies
- case definition
- Guillain–Barre syndrome
- multiple sclerosis
- peripheral neuropathology
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Competing interests All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare RG and HPH have received financial support for the submitted work. RG has received consulting fees or honorariums from Biogen Idec, TEVA, Merck Serono, Novartis and Bayer Schering; the institution of RG has received grants from the above mentioned companies; RG has obtained financial support for travels to meetings for the study or other purposes from Biogen Idec and fees for participation in review activities from TEVA. HPH has received consulting fees or honorariums from Grifols and Baxter. In addition, relevant financial activities exist outside the submitted work: RG has received payment from Biogen Idec, TEVA, Merck Serono, Novartis and Bayer Schering for board membership, consultancy and lectures; the institution of RG has received grants from TEVA; RG has been paid from Novartis for the development of educational presentations; HPH has been paid from Biogen Idec, Novartis Pharma, Genzyme, Bayer HealthCare and Merck Serono for consultancy. There are no other relationships or activities that could appear to have influenced the submitted work.
Ethics approval The data referring to human subjects (suspected cases of progressive multifocal leukoencephalopathy following treatment with monoclonal antibodies) were reported to the Paul-Ehrlich-Institute as the national competent authority that is responsible for the safety of monoclonal antibodies in Germany according to German and European legislation. The data, which are included in the adverse drug reaction database of the Paul-Ehrlich-Institute, were analysed in this study. The database has been audited by the National Data Protection Officer. An Ethics Committee approval is not necessary for analysis of adverse drug reaction reports.
Provenance and peer review Not commissioned; externally peer reviewed.