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01-12-2015

A risk classification for immunosuppressive treatment-associated progressive multifocal leukoencephalopathy

Authors: Salim Chahin, Joseph R. Berger

Published in: Journal of NeuroVirology | Issue 6/2015

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rare, complex opportunistic infection of the central nervous system caused by the JC virus. This past decade, PML was increasingly recognized to be associated with the use of immunosuppressive and biologic agents. The risk for PML differs among these agents and remains difficult to quantify because of the complex pathogenesis of PML and the presence of confounding factors. This paper explores and updates the association of PML with different biologic and immunosuppressive agents and proposes an expanded classification system for the risk of PML. We identify three classes of drug that vary by PML risk, latency to infection, and underlying illness. We also review some of the most common agents with known associations to PML and explore risk mitigation strategies that aim to inform the decision-making process for clinicians and patients in the face of the changing incidence of PML and the growing landscape of immunologic agents.

Armuzzi A, Lionetti P, Blandizzi C, Caporali R, Chimenti S, Cimino L, Gionchetti P, Girolomoni G, Lapadula G, Marchesoni A, Marcellusi A, Mennini FS, Salvarani C, Cimaz R (2014) anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab. Int J Immunopathol Pharmacol 27:11–32PubMed

Berger JR (2010) Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 33:969–983CrossRefPubMed

Berger JR, Khalili K (2012) The pathogenesis of progressive multifocal leukoencephalopathy. Discov Med 12:495–503

Berger JR, Pall L, Lanska D, Whiteman M (1998) Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 4:59–68CrossRefPubMed

Berger JR, Houff SA, Gurwell J, Vega N, Miller CS, Danaher RJ (2013) JC virus antibody status underestimates infection rates. Ann Neurol 74:84–90PubMedCentralCrossRefPubMed

Brinkmann V, Billich A, Baumruker T, Heining P, Schmouder R, Francis G, Aradhye S, Burtin P (2010) Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov 9:883–897CrossRefPubMed

Brooks BR, Walker DL (1984) Progressive multifocal leukoencephalopathy. Neurol Clin 2:299–313PubMed

Calabrese LH, Molloy ES, Huang D, Ransohoff RM (2007) Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum 56:2116–2128CrossRefPubMed

Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL (2009) Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 113:4834–4840PubMedCentralCrossRefPubMed

Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, Perry A, Yerra R, Schmidt R, Alvarez E, Tyler KL (2011) Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol 68:1156–1164PubMedCentralCrossRefPubMed

Cross AH, Stark JL, Lauber J, Ramsbottom MJ, Lyons JA (2006) Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 180:63–70PubMedCentralCrossRefPubMed

del Pilar Martin M, Cravens PD, Winger R, Frohman EM, Racke MK, Eagar TN, Zamvil SS, Weber MS, Hemmer B, Karandikar NJ, Kleinschmidt-DeMasters BK, Stuve O (2008) Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol 65:1596–1603CrossRefPubMed

Ermis U, Weis J, Schulz JB (2013) PML in a patient treated with fumaric acid. N Engl J Med 368:1657–1658CrossRefPubMed

Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT, Investigators CS (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367:1087–1097CrossRefPubMed

Fredericks C, Kvam K, Bear J, Crabtree G, Josephson S (2014). A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus

Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT, Investigators DS (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367:1098–1107CrossRefPubMed

Gonzalez H, Bolgert F, Camporo P, Leblond V (1999) Progressive multifocal leukoencephalitis (PML) in three patients treated with standard-dose fludarabine (FAMP). Hematol Cell Ther 41:183–186CrossRefPubMed

Gordon FH, Lai CW, Hamilton MI, Allison MC, Srivastava ED, Fouweather MG, Donoghue S, Greenlees C, Subhani J, Amlot PL, Pounder RE (2001) A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn’s disease. Gastroenterology 121:268–274CrossRefPubMed

Gordon FH, Hamilton MI, Donoghue S, Greenlees C, Palmer T, Rowley-Jones D, Dhillon AP, Amlot PL, Pounder RE (2002) A pilot study of treatment of active ulcerative colitis with natalizumab, a humanized monoclonal antibody to alpha-4 integrin. Aliment Pharmacol Ther 16:699–705CrossRefPubMed

Gordon KB, Papp KA, Hamilton TK, Walicke PA, Dummer W, Li N, Bresnahan BW, Menter A (2003) Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 290:3073–3080CrossRefPubMed

Gorelik L, Lerner M, Bixler S, Crossman M, Schlain B, Simon K, Pace A, Cheung A, Chen L, Berman M (2010) Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 68(3):295–303CrossRefPubMed

Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, Chen F, Magliocco M, Krueger JG (2005) TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 175:2721–2729CrossRefPubMed

Gurcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR (2009) A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 9:10–25CrossRefPubMed

Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J, Group IS (2011) Alemtuzumab induction in renal transplantation. N Engl J Med 364:1909–1919CrossRefPubMed

Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S, Langer-Gould A, Smith CH (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688CrossRefPubMed

Hersh CM, Cohen JA (2014) Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Immunotherapy 6:249–259CrossRefPubMed

Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J (2007) Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 25:5616–5623CrossRefPubMed

Holman RC, Janssen RS, Buehler JW, Zelasky MT, Hooper WC (1991) Epidemiology of progressive multifocal leukoencephalopathy in the United States: analysis of national mortality and AIDS surveillance data. Neurology 41:1733–1736CrossRefPubMed

Isidoro L, Pires P, Rito L, Cordeiro G (2014) Progressive multifocal leukoencephalopathy in a patient with chronic lymphocytic leukaemia treated with alemtuzumab. BMJ Case Rep

Jacobi AM, Huang W, Wang T, Freimuth W, Sanz I, Furie R, Mackay M, Aranow C, Diamond B, Davidson A (2010) Effect of long-term belimumab treatment on B cells in systemic lupus erythmatosus: extension of a phase II, double-blink, placebo-controlled, dose-ranging study. Arthritis Rheum 62:201–210PubMedCentralCrossRefPubMed

Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, Group FS (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362:387–401CrossRefPubMed

Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB (1989) Fludarabine: a new agent with major activity against chronic lymphocytic leukemia. Blood 74:19–25PubMed

Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353:369–374CrossRefPubMed

Klotz L, Meuth SG, Wiendl H (2012) Immune mechanisms of new therapeutic strategies in multiple sclerosis-a focus on alemtuzumab. Clin Immunol 142:25–30CrossRefPubMed

Knowles WA, Pipkin P, Andrews N, Vyse A, Minor P, Brown DW, Miller E (2003) Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol 71:115–123CrossRefPubMed

Kothary N, Diak IL, Brinker A, Bezabeh S, Avigan M, Dal Pan G (2011) Progressive multifocal leukoencephalopathy associated with efalizumab use in psoriasis patients. J Am Acad Dermatol 65:546–551CrossRefPubMed

Krumbholz M, Meinl I, Kumpfel T, Hohlfeld R, Meinl E (2008) Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 71:1350–1354CrossRefPubMed

Kumar D, Bouldin TW, Berger RG (2010) A case of progressive multifocal leukoencephalopathy in a patient treated with infliximab. Arthritis Rheum 62:3191–3195CrossRefPubMed

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 353:375–381CrossRefPubMed

Langley RG, Carey WP, Rafal ES, Tyring SK, Caro I, Wang X, Wetherill G, Gordon KB (2005) Incidence of infection during efalizumab therapy for psoriasis: analysis of the clinical trial experience. Clin Ther 27:1317–1328CrossRefPubMed

Leandro MJ, Cambridge G, Ehrenstein MR, Edwards JC (2006) Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 54:613–620CrossRefPubMed

Lee P, Plavina T, Castro A, Berman M, Jaiswal D, Rivas S, Schlain B, Subramanyam M (2013) A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol 57:141–146CrossRefPubMed

Lejniece S, Murovska M, Chapenko S, Breiksa B, Jaunmuktane Z, Feldmane L, Ziedina I, Gomez-Roman J, Garcia-Cabeza M, Lejnieks A (2011) Progressive multifocal leukoencephalopathy following fludarabine treatment in a chronic lymphocytic leukemia patient. Exp Oncol 33:239–241PubMed

Leonard S, Hulin C, Anxionnat R, Grignon Y, Taillandier L, Vespignani H (2002) Multifocal progressive leukoencephalitis in a patient given fludarabine for chronic lymphoid leukemia. Rev Neurol (Paris) 158:1121–1123

Leonardi CL (2004) Current concepts and review of efalizumab in the treatment of psoriasis. Dermatol Clin 22:427–435, ixCrossRefPubMed

Lindberg RL, Achtnichts L, Hoffmann F, Kuhle J, Kappos L (2008) Natalizumab alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients. J Neuroimmunol 194:153–164CrossRefPubMed

Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182–1190CrossRefPubMed

Maini RN, Feldmann M (2002) How does infliximab work in rheumatoid arthritis? Arthritis Res 4(Suppl 2):S22–S28PubMedCentralCrossRefPubMed

Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR (2006) Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 43:16–24CrossRefPubMed

Matos A, Duque V, Beato S, da Silva JP, Major E, Melico-Silvestre A (2010) Characterization of JC human polyomavirus infection in a Portuguese population. J Med Virol 82:494–504CrossRefPubMed

Menter A (2009) The status of biologic therapies in the treatment of moderate to severe psoriasis. Cutis 84:14–24PubMed

Molloy ES, Calabrese LH (2008) Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun Rev 8:144–146CrossRefPubMed

Molloy ES, Calabrese LH (2012) Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum 64:3043–3051CrossRefPubMed

O’Connor PW (2012) Natalizumab risk stratification: role of a two- step anti-JCV antibody assay. Can J Neurol Sci 39:670–675CrossRefPubMed

Palazzo E, Yahia SA (2012) Progressive multifocal leukoencephalopathy in autoimmune diseases. Jt Bone Spine 79:351–355CrossRef

Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B (2014) Anti-JCV antibody levels in serum or plasma further define risk of natalizumab-associated PML. Ann Neurol

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 354:899–910CrossRefPubMed

Putzki N, Clifford DB, Bischof D, Moore A, Weinshenker BG, Freedman MS (2014) Characteristics of PML cases in multiple sclerosis patients switching to fingolimod from natalizumab. Presentation at ECTRIMS 2014

Ransom JT (1995) Mechanism of action of mycophenolate mofetil. Ther Drug Monit 17:681–684CrossRefPubMed

Saumoy M, Castells G, Escoda L, Mares R, Richart C, Ugarriza A (2002) Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 43:433–436CrossRefPubMed

Schneider-Hohendorf T, Philipp K, Husstedt IW, Wiendl H, Schwab N (2014) Specific loss of cellular L-selectin on CD4+ T cells is associated with progressive multifocal leukoencephalopathy development during HIV infection. AIDS 28:793–795CrossRefPubMed

Schwab N, Schneider-Hohendorf T, Posevitz V, Breuer J, Göbel K, Windhagen S, Brochet B, Vermersch P, Lebrun-Frenay C, Posevitz-Fejfár A, Capra R, Imberti L, Straeten V, Haas J, Wildemann B, Havla J, Kümpfel T, Meinl I, Niessen K, Goelz S, Kleinschnitz C, Warnke C, Buck D, Gold R, Kieseier BC, Meuth SG, Foley J, Chan A, Brassat D, Wiendl H (2013) L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 81(10):865–871CrossRefPubMed

Siddiqi T, Thomas SH, Chen R (2014) Role of brentuximab vedotin in the treatment of relapsed or refractory Hodgkin lymphoma. Pharmgenomics Pers Med 7:79–85PubMedCentralPubMed

Sorensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E, Kappos L, Kieseier BC, Montalban X, Olsson T (2012) Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 18:143–152CrossRefPubMed

Steinman L (2012) The discovery of natalizumab, a potent therapeutic for multiple sclerosis. J Cell Biol 199:413–416PubMedCentralCrossRefPubMed

Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM (2001) The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol 144:1114–1120CrossRefPubMed

Stuve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Jerome KR, Cook L, Grand’Maison F, Hemmer B, Monson NL, Racke MK (2006a) Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 63:1383–1387CrossRefPubMed

Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Hemmer B, Monson NL, Racke MK (2006b) Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 59:743–747CrossRefPubMed

Sweetser MT, Dawson KT, Bozic C (2013) Manufacturer’s response to case reports of PML. N Engl J Med 368:1659–1661CrossRefPubMed

Treumer F, Zhu K, Glaser R, Mrowietz U (2003) Dimethylfumarate is a potent inducer of apoptosis in human T cells. J Investig Dermatol 121:1383–1388CrossRefPubMed

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 353:362–368CrossRefPubMed

van Oosten BW, Killestein J, Barkhof F, Polman CH, Wattjes MP (2013) PML in a patient treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med 368:1658–1659CrossRefPubMed

Vermersch P, Kappos L, Gold R, Foley JF, Olsson T, Cadavid D, Bozic C, Richman S (2011) Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 76:1697–1704CrossRefPubMed

Villarroel MC, Hidalgo M, Jimeno A (2009) Mycophenolate mofetil: an update. Drugs Today (Barc) 45:521–532

von Andrian UH, Engelhardt B (2003) Alpha4 integrins as therapeutic targets in autoimmune disease. N Engl J Med 348:68–72CrossRef

Vugmeyster Y, Kikuchi T, Lowes MA, Chamian F, Kagen M, Gilleaudeau P, Lee E, Howell K, Bodary S, Dummer W, Krueger JG (2004) Efalizumab (anti-CD11a)-induced increase in peripheral blood leukocytes in psoriasis patients is preferentially mediated by altered trafficking of memory CD8+ T cells into lesional skin. Clin Immunol 113:38–46CrossRefPubMed

Waggoner J, Martinu T, Palmer SM (2009) Progressive multifocal leukoencephalopathy following heightened immunosuppression after lung transplant. J Heart Lung Transplant 28:395–398PubMedCentralCrossRefPubMed

Wagner-Johnston ND, Bartlett NL, Cashen A, Berger JR (2012) Progressive multifocal leukoencephalopathy in a patient with Hodgkin lymphoma treated with brentuximab vedotin. Leuk Lymphoma 53:2283–2286CrossRefPubMed

Warnke C, Menge T, Hartung HP, Racke MK, Cravens PD, Bennett JL, Frohman EM, Greenberg BM, Zamvil SS, Gold R, Hemmer B, Kieseier BC, Stuve O (2010) Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 67:923–930PubMedCentralCrossRefPubMed

Weber T (2008) Progressive multifocal leukoencephalopathy. Neurol Clin 26(3):833–854CrossRefPubMed

Zaheer F, Berger JR (2012) Treatment related progressive multifocal leukoencephalopathy: current understanding and future steps. Ther Adv Drug Saf 3:227–239PubMedCentralCrossRefPubMed

Title: A risk classification for immunosuppressive treatment-associated progressive multifocal leukoencephalopathy
Authors: Salim Chahin
Joseph R. Berger
Publication date: 01-12-2015
Publisher: Springer US
Published in: Journal of NeuroVirology / Issue 6/2015
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-014-0303-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A risk classification for immunosuppressive treatment-associated progressive multifocal leukoencephalopathy

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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