European Journal of Clinical Pharmacology

, Volume 66, Issue 2, pp 199–206

Stronger association of drug-induced progressive multifocal leukoencephalopathy (PML) with biological immunomodulating agents

  • Carlo Piccinni
  • Chiara Sacripanti
  • Elisabetta Poluzzi
  • Domenico Motola
  • Lara Magro
  • Ugo Moretti
  • Anita Conforti
  • Nicola Montanaro
Pharmacoepidemiology and Prescription



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.


Progressive multifocal leukoencephalopathy Adverse drug reaction Reporting system Database Monoclonal antibody 


  1. 1.
    Koralnik IJ (2004) New insights into progressive multifocal leukoencephalopathy. Curr Opin Neurol 17:365–370CrossRefPubMedGoogle Scholar
  2. 2.
    Koralnik IJ (2006) Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 60:162–173CrossRefPubMedGoogle Scholar
  3. 3.
    Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353:375–381CrossRefPubMedGoogle Scholar
  4. 4.
    Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353:369–374CrossRefPubMedGoogle Scholar
  5. 5.
    Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, Verbeeck J, Geboes K, Robberecht W, Rutgeerts P (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 353:362–368CrossRefPubMedGoogle Scholar
  6. 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. 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
  8. 8.
    Berger JR (2007) Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep 7:461–469CrossRefPubMedGoogle Scholar
  9. 9.
    U.S. Food and Drug Administration (FDA) (2009) FDA-AERS Adverse Event Reporting System. Accessed 23 Feb 2009
  10. 10.
    Northrup Grumman (2009) The Medical Dictionary for Regulatory Activities (MedDRA). Available via Accessed 23 Feb 2009
  11. 11.
    World Health Organization (WHO) (2009) WHO-VigiBase.Uppsala Monitoring Centre. Accessed 23 Feb 2009
  12. 12.
    World Health Organization (WHO) (2009) WHO Collaborating Centre for Drug Statistics Methodology. Accessed 23 Feb 2009
  13. 13.
    Hammond IW, Gibbs TG, Seifert HA, Rich DS (2007) Database size and power to detect safety signals in pharmacovigilance. Expert Opin Drug Saf 6:713–721CrossRefPubMedGoogle Scholar
  14. 14.
    Furberg CD, Levin AA, Gross PA, Shapiro RS, Strom BL (2006) The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med 166:1938–1942CrossRefPubMedGoogle Scholar
  15. 15.
    Pariente A, Gregoire F, Fourrier-Reglat A, Haramburu F, Moore N (2007) Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias. Drug Saf 30:891–898CrossRefPubMedGoogle Scholar
  16. 16.
    Motola D, Vargiu A, Leone R, Conforti A, Moretti U, Vaccheri A, Velo G, Montanaro N (2008) Influence of regulatory measures on the rate of spontaneous adverse drug reaction reporting in Italy. Drug Saf 31:609–616CrossRefPubMedGoogle Scholar
  17. 17.
    Hartnell NR, Wilson JP (2004) Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy 24:743–749CrossRefPubMedGoogle Scholar
  18. 18.
    Hauben M, Reich L, DeMicco J, Kim K (2007) ‘Extreme duplication’ in the US FDA Adverse Events Reporting System database. Drug Saf 30:551–554CrossRefPubMedGoogle Scholar
  19. 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
  20. 20.
    Aksamit AJ (2006) Review of progressive multifocal leukoencephalopathy and natalizumab. Neurologist 12:293–298CrossRefPubMedGoogle Scholar
  21. 21.
    Boren EJ, Cheema GS, Naguwa SM, Ansari AA, Gershwin ME (2008) The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases. J Autoimmun 30:90–98CrossRefPubMedGoogle Scholar
  22. 22.
    U.S. Food and Drug Administration (FDA) (2006) Tysabri - FDA approval letter. Accessed 23 Feb 2009
  23. 23.
    U.S. Food and Drug Administration (FDA) (2006) Tysabri - risk minimization action plan. Accessed 23 Feb 2009
  24. 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
  25. 25.
    Giezen TJ, Mantel-Teeuwisse AK, Straus SM, Schellekens H, Leufkens HG, Egberts AC (2008) Safety-related regulatory actions for biologicals approved in the United States and the European Union. JAMA 300:1887–1896CrossRefPubMedGoogle Scholar
  26. 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
  27. 27.
    Uetrecht J (2009) Immune-mediated adverse drug reactions. Chem Res Toxicol 22:24–34CrossRefPubMedGoogle Scholar
  28. 28.
    Hamilton CD (2004) Infectious complications of treatment with biologic agents. Curr Opin Rheumatol 16:393–398CrossRefPubMedGoogle Scholar
  29. 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
  30. 30.
    Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A (2009) Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 301:737–744CrossRefPubMedGoogle Scholar
  31. 31.
    Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW (2006) Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 354:911–923CrossRefPubMedGoogle Scholar
  32. 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
  33. 33.
    Hartung HP (2009) New cases of progressive multifocal leukoencephalopathy after treatment with natalizumab. Lancet Neurol 8:28–31CrossRefPubMedGoogle Scholar
  34. 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. Accessed 1 Apr 2009
  35. 35.
    Wu VC, Huang JW, Lien HC, Hsieh ST, Liu HM, Yang CC, Lin YH, Hwang JJ, Wu KD (2006) Levamisole-induced multifocal inflammatory leukoencephalopathy: clinical characteristics, outcome, and impact of treatment in 31 patients. Medicine (Baltimore) 85:203–213CrossRefGoogle Scholar
  36. 36.
    National Institute for Health and Clinical Excellence (NICE) (2007) Natalizumab for the treatment of adults with highly active relapsing- remitting multiple sclerosis.
  37. 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
  38. 38.
    Nijsten T, Wakkee M (2008) Psocare: Italy shows the way in postmarketing studies. Dermatology 217:362–364CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Carlo Piccinni
    • 1
  • Chiara Sacripanti
    • 1
  • Elisabetta Poluzzi
    • 1
  • Domenico Motola
    • 1
  • Lara Magro
    • 2
  • Ugo Moretti
    • 2
  • Anita Conforti
    • 2
  • Nicola Montanaro
    • 1
  1. 1.Department of PharmacologyUniversity of BolognaBolognaItaly
  2. 2.Clinical Pharmacology UnitUniversity of VeronaVeronaItaly

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