Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents
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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.
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.
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.
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.
KeywordsProgressive multifocal leukoencephalopathy Adverse drug reaction Reporting system Database Monoclonal antibody
- 6.Yousry TA, Major EO, Ryschkewitsch C, Fahle G, Fischer S, Hou J, Curfman B, Miszkiel K, Mueller-Lenke N, Sanchez E, Barkhof F, Radue EW, Jager HR, Clifford DB (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354:924–933CrossRefPubMedGoogle Scholar
- 7.Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:899–910CrossRefPubMedGoogle Scholar
- 9.U.S. Food and Drug Administration (FDA) (2009) FDA-AERS Adverse Event Reporting System. http://www.fda.gov/cder/aers/default.htm. Accessed 23 Feb 2009
- 10.Northrup Grumman (2009) The Medical Dictionary for Regulatory Activities (MedDRA). Available via http://www.meddramsso.com/MSSOWeb/index.htm. Accessed 23 Feb 2009
- 11.World Health Organization (WHO) (2009) WHO-VigiBase.Uppsala Monitoring Centre. http://www.umc-products.com/DynPage.aspx?id=4910&mn=1107. Accessed 23 Feb 2009
- 12.World Health Organization (WHO) (2009) WHO Collaborating Centre for Drug Statistics Methodology. http://www.whocc.no/atcddd/. Accessed 23 Feb 2009
- 19.Falco V, Olmo M, del Saz SV, Guelar A, Santos JR, Gutierrez M, Colomer D, Deig E, Mateo G, Montero M, Pedrol E, Podzamczer D, Domingo P, Llibre JM (2008) Influence of HAART on the clinical course of HIV-1-infected patients with progressive multifocal leukoencephalopathy: results of an observational multicenter study. J Acquir Immune Defic Syndr 49:26–31CrossRefPubMedGoogle Scholar
- 22.U.S. Food and Drug Administration (FDA) (2006) Tysabri - FDA approval letter. http://www.fda.gov/cder/foi/appletter/2006/125104s015LTR.pdf. Accessed 23 Feb 2009
- 23.U.S. Food and Drug Administration (FDA) (2006) Tysabri - risk minimization action plan. http://www.fda.gov/cder/foi/appletter/2006/125104s015LTR.pdf. Accessed 23 Feb 2009
- 24.Mancardi GL, Amato MP, D'Alessandro R, Drago F, Milanese C, Popoli P, Provinciali L, Rossi P, Savettieri G, Tedeschi G, Tola MR, Vanacore N, Covezzoli A, De Rosa M, Piccinni C, Montanaro N, Periotto L, Addis A, Martini N (2008) Natalizumab: a country-based surveillance program. Neurol Sci 29(Suppl 2):S235–S237CrossRefPubMedGoogle Scholar
- 26.Carson KR, Focosi D, Major EO, Petrini M, Richey EA, West DP, Bennett CL (2009) Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a review from the Research on Adverse Drug Events and Reports (RADAR) project. Lancet Oncol 10:816–824CrossRefPubMedGoogle Scholar
- 29.Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V (2006) Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 295:2275–2285CrossRefPubMedGoogle Scholar
- 32.Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P (2005) Natalizumab induction and maintenance therapy for Crohn's disease. N Engl J Med 353:1912–1925CrossRefPubMedGoogle Scholar
- 34.European Agency for the Evaluation of Medicinal Products (EMEA) (2009) European Medicines Agency recommends suspension of the marketing authorisation ofRaptiva (efalizumab). EMEA/CHMP/20857/2009. http://www.emea.europa.eu/humandocs/PDFs/EPAR/raptiva/2085709en.pdf. Accessed 1 Apr 2009
- 36.National Institute for Health and Clinical Excellence (NICE) (2007) Natalizumab for the treatment of adults with highly active relapsing- remitting multiple sclerosis. www.nice.org.uk
- 37.Naldi L, Addis A, Chimenti S, Giannetti A, Picardo M, Tomino C, Maccarone M, Chatenoud L, Bertuccio P, Maggese E, Cuscito R (2008) Impact of body mass index and obesity on clinical response to systemic treatment for psoriasis. Evidence from the Psocare project. Dermatology 217:365–373CrossRefPubMedGoogle Scholar