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Abstract. Progressive Multifocal Leukoencephalopathy (PML) is a rare and often fatal opportunistic demyelinating disorder secondary to central nervous system ...

Review

Progressive multifocal leukoencephalopathy and antipsoriatic drugs Assessing the risk of immunosuppressive treatments Vito Di Lernia, MD

Department of Dermatology, Arcispedale S. Maria Nuova, Reggio Emilia, Italy Correspondence Vito Di Lernia, MD Department of Dermatology Arcispedale S. Maria Nuova Viale Risorgimento 80 42100 Reggio Emilia Italy E-mail: [email protected]

Abstract Progressive Multifocal Leukoencephalopathy (PML) is a rare and often fatal opportunistic demyelinating disorder secondary to central nervous system infection by the polyomavirus John Cunningham (JC), a common infecting agent in human populations, with 50–70% of healthy individuals having antibodies to the virus. Although human immunodeficiency virus (HIV) infection remains the most common predisposing factor for PML, which can occur also in association with hematologic malignant neoplasms or iatrogenic immunosuppression in the setting of organ transplantations, recently JC virus has been recognized as an important pathogen in patients with autoimmune and rheumatic diseases receiving immunosuppressive treatments. Following the availability of new biologic drugs, additional cases of PML have been reported in dermatologic patients as well. In particular, the occurrence of PML in psoriatic patients who had been taking efalizumab in the absence of any other concurrent immunosuppressive agents resulted in the decision of European Medicine Agency (EMEA) in February 2009 to recommend suspension of the marketing authorization for this drug in Europe. Some months later the manufacturer of the drug decided to voluntarily withdraw the product from the U.S. market. Since PML can occur as a potential side effect of different immunosuppressive drugs, including conventional treatments for psoriasis, and in consideration of the future development of new immunosuppressive biological agents, dermatologists need to become familiar with opportunistic infections including PML.

Epidemiology, pathogenesis and clinical manifestations of PML Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal opportunistic demyelinating disorder secondary to central nervous system (CNS) viral infection that was initially described in patients immunosuppressed because of malignant disease or iatrogenic immunosuppression. Clinical symptoms include cognitive and personality disturbances, motor weakness and seizures. The disease typically progresses very quickly over a course of weeks. PML remained an extremely uncommon condition until the advent of acquired immunodeficiency syndrome (AIDS) in the 1980s, when it was recognized as the cause of death in 4% of HIV-infected patients.1 As no effective treatment is available at present for PML, the prognosis is usually poor. The etiological agent of PML, the polyomavirus John Cunningham (JC), was isolated in 1971. It is an unenveloped DNA virus that is a common infecting agent in human populations, with 50–70% of healthy individuals ª 2010 The International Society of Dermatology

having antibodies to the virus by the age of 65 years.1 Usually the infection is clinically silent: the virus remains inactive in kidneys, and excretion of JC virus (JCV) has been documented in immunologically normal individuals, as well as during pregnancy or immunosuppression.2 The prevailing view of PML pathogenesis is that peripheral site(s) of latent JCV infection operate as a source of viral reactivation when the immune system has been severely debilitated with subsequent infection of the CNS.3 Sites of peripheral reactivation may be kidney and particularly bone marrow, allowing circulating B lymphocytes harboring JCV to reach the brain.3,4 As detection of JCV DNA in brains of patients without PML has also been reported, JCV reactivation within the CNS with decreased immune surveillance, independent of peripheral reactivation, cannot be entirely excluded.3 Thus, infection by polyomavirus JC is a model of chronic active viral infection, closely controlled by the immune system.5 The contributions of predisposing factors to PML, such as underlying disease and immunosuppressive therapy are incompletely understood. Although it is clear that International Journal of Dermatology 2010, 49, 631–635

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dysfunction of cell-mediated immunity is crucial for the development of PML, our knowledge of why PML develops – and, on the other hand, why it does not arise – is incomplete. During the last 25 years, the incidence of PML has significantly increased related to the AIDS pandemic. HIV infection causes an estimated 85% of cases,6 while hematologic malignant neoplasms, in particular chronic lymphocytic leukemia, Hodgkin and non-Hodgkin lymphoma, represent another critical risk factor. PML can occur also in the context of organ transplantation and has been reported in organ transplant recipients whose immune systems have been considerably suppressed to prevent graft rejection. In this setting, drugs associated to PML include cyclosporine, azathioprine, tacrolimus and mycophenolate mofetil.7,8 More recently, JCV has been recognized as an important pathogen in patients with autoimmune and rheumatic diseases, receiving immunosuppressive treatments which include corticosteroids, cyclophosphamide, azathioprine, and cyclosporine. Other infrequently implicated immunosuppressant agents include antimalarials, chlorambucil, leflunomide, methotrexate, and sulfasalazine.4,9–13 However, a critical review of the risk of PML associated with different classes of drugs is complicated by the fact that some of the traditional immunosuppressive therapies have not been subjected to the post marketing surveillance addressed by current FDA and European Medicines Agency’s (EMEA) standards.14 Consequently, the development of PML does not seem to depend on distinct immunosuppressant molecules, although a major risk can be taken in account for certain types of drugs, based on their mechanism of action and the specific subset of immune cells involved. On the other hand, patients with systemic lupus erythematosus (SLE) appear to be at the highest susceptibility with 25 of 41 cases of PML in patients with rheumatologic disease occurring in patients with SLE.10 PML and targeted biologic therapies Following the availability of new classes of immune therapies which target specific inflammatory mediators or pathways that are felt to be critical to the pathogenesis of a specific disease or a group of diseases, additional cases of PML have been reported. At least 25 cases of PML have been described in association with rituximab, a chimeric IgG1 anti-CD20 monoclonal antibody that selectively leads to prolonged B-lymphocyte depletion. Rituximab is approved in the USA for treatment of non-Hodgkin lymphoma and in combination with methotrexate for adult patients with moderate to severe rheumatoid arthritis who have had an inadequate response to one or more tumor necrosis factor (TNF)International Journal of Dermatology 2010, 49, 631–635

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alpha inhibitors; in Europe, it is also approved in combination with chemotherapy for use in patients with previously untreated chronic lymphocytic leukemia. Really two of these patients were affected by SLE,15 while the remaining 23 were treated with rituximab as part of chemotherapy for non-Hodgkin lymphoma. Anti-TNF is not considered to be at risk for PML. Until now only a case of PML has been reported associated with treatment with etanercept in a patient affected with refractory rheumatoid arthritis.16 However, Roos and Ostor17 assumed that PML could be underreported as a complication of treatment with anti-TNF-alfa agents. Indeed, in 18 cases of demyelination reported to the US FDA following treatment with etanercept or infliximab, brain biopsy was performed in only two,18 one of which showed on histopathologic examination, which is considered the definitive way of establishing a diagnosis of PML, morphologic features consistent with encephalopathy rather than demyelination. In this case, Magnetic Resonance Imaging (RMI) findings were also in keeping with PML rather than multiple sclerosis. A depletion of T cells following treatment with infliximab, evoking a possible mechanism for how anti-TNF-alfa therapy may predispose patients to JC virus infection and PML has been described.19 Finally, in consideration of the very high number of patients treated, monotherapy with TNFalfa inhibitors cannot be considered to increase the risk of PML development, as the few cases of PML in antiTNF treated individuals were observed in combination with aggressive cytotoxic drugs. As the approval of efalizumab for psoriatic patients who were candidates for systemic or phototherapy in October 2003, the FDA has received reports of three confirmed cases and one possible case of PML in patients who were 47–73 years of age who were using the antiCD11a inhibitor for the treatment of moderate to severe plaque psoriasis. Two of the patients with confirmed PML and one patient with possible PML died. All four patients were treated with efalizumab continuously for more than 3 years. None of the patients were receiving other treatments that suppress the immune system while taking efalizumab. An unsolved question concerning the extent to which viral as well as host factors might have played a role in the onset of PML in these three cases who resulted in the decision of the EMEA Committee for Medicinal Products for Human Use (CHMP) on February 19, 2009 to recommend suspension of the marketing authorization for efalizumab in Europe. In addition to PML, the drug was associated with other serious side effects, including Guillain-Barré and Miller-Fisher syndromes, encephalitis, encephalopathy, meningitis, sepsis, and opportunistic infections. The CHMP did not believe there was enough evidence to identify a group of patients ª 2010 The International Society of Dermatology

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in which the benefits of efalizumab outweigh its risks. In addition, it was considered that the risk of PML increased with longer and continuous use of efalizumab and there was a lack of data on effectiveness and safety in patients who had no other treatment options and who might already have a weakened immune system as result of the previous treatments. FDA had required a Boxed Warning in October 2008 for the drug to highlight the risks of life-threatening infections, including PML and directed Genentech, the manufacturer of efalizumab, to develop a Risk Evaluation and Mitigation Strategy (REMS), to ensure that patients have risk information about this treatment. On February 2009, a Public Health Advisory informing patients and prescribers of the risk of PML in patients taking Raptivaª was issued and on March 2009, the FDA approved a Medication Guide for Raptivaª and included additional information in Raptiva’s labeling regarding PML. On April 8, 2009, Genentech, the manufacturer of the drug, announced that it has begun a voluntary, phased withdrawal of the product from the US market. The removal of a drug is a moment of great frustration for many people (the drug was only being used by about 2000 people in the United States and by 46 000 people worldwide as it was first introduced in 2003) with psoriasis who had hoped for access to a systemic drug that appeared to be more safe than any conventional treatment with respect to the lack of toxicity in long-term use. The withdrawal of efalizumab from the European market will prevent careful and objective evaluation of additional questions which will remain unanswered: what if the drug had been cyclically stopped for a short period to allow the reconstitution of immune surveillance? What if the drug had been used only for patients who were naive to immunosuppressive drugs? Would it be possible to safely administer the drug with less frequent intervals of time (such as every 2 weeks) in patients who reached remission with a comparable efficacy? Efalizumab is a humanized, monoclonal IgG1 antibody that binds to the alpha-subunit of lymphocyte function associated antigen (LFA)-1, a heterodimeric glycoprotein belonging to the b2-integrin family, also known as aLb2 or CD11a/CD18 which binds intracellular adhesion molecules 1-3 (ICAM-1, ICAM-2, and ICAM-3).20 Blocking these interactions, a reduction in T cell activation, an inhibition of the trafficking and recruitment of T cells to the dermis and epidermis, and a decrease in the reactivation of T cells at several steps in the psoriasis pathogenesis occurs. The history of efalizumab reminds us of another biologic agent, natalizumab, a humanized monoclonal antibody directed against an adhesion molecule on T cells, a4b1 integrin or VLA-4 (Very Late Antigen-4), which, analogally to efalizumab, plays a critical role in leukocyte ª 2010 The International Society of Dermatology

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recruitment21 and migration into tissue at sites of inflammation. It has been widely assumed that the therapeutic effect of both molecules is mainly the effect of the blockade of leukocyte adhesion to endothelium, thus inhibiting extravasation and the inflammatory phenomenon. Natalizumab was approved in 2004 by the US FDA for multiple sclerosis and Crohn’s disease. The development of PML in three patients who received natalizumab resulted in the drug being withdrawn from the market in 2005 until a careful risk management program, the goals of which were to assess the risk of PML in treated patients and promote patient understanding of the risks and benefits involved in the use of the drug, could be developed. Since the return of the drug to the clinical use in 2006, two additional cases of PML have been observed. The drug is now used worldwide, with cautious patient monitoring.1 Treatment with efalizumab and natalizumab has added psoriasis, multiple sclerosis and Crohn’s Disease to the list of conditions that may be complicated by PML.22 The impaired cytotoxic T-cell adhesion and migration natalizumab- or efalizumab-induced, might be primarily responsible by decreasing immune surveillance. As natalizumab (like efalizumab), blocks leukocyte migration across endothelial cells, it is suggested that drug-associated PML occurred as a result of the mobilization of JC virusinfected bone marrow cells, possibly in combination with reduced inflammatory and surveillance trafficking to the CNS;23 in addition, JCV-specific cytotoxic T cells might be useless or prevented from developing, allowing from unchecked replication of JCV. Another possibility is the reactivation of JCV strains already present in the brain, without occurrence of JCV viremia. This assumption is supported by a noteworthy reduction in the presence of T-cells, B-cells and plasma cells in the cerebrospinal fluid (CSF) of patients receiving natalizumab. PML and psoriasis Progressive multifocal leukoencephalopathy had not previously been reported in the setting of psoriasis, except for a case which affected a patient with a concurrent AIDS-related immunosuppression24 and the three cases correlated to efalizumab treatment. However, PML has been reported or suspected in association with drugs, either conventional (cyclosporine, methotrexate), or biologic (etanercept, infliximab) which have made a significant impact on the treatment for moderate to severe psoriasis. Given the rarity of PML, the risk that single antipsoriatic drugs confer is not clearly quantifiable. It is important to take into account that certain mechanisms of immune suppression that affect CNS immunosurveillance can increase the risk. In particular, dermatologists International Journal of Dermatology 2010, 49, 631–635

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should be aware that combination treatment with immunosuppressant agents can be associated with a risk profile which is different with respect to that of the single drugs in monotherapy used independently by the possibility to combine multiple drugs at lowered dosages. In addition, a long history of multiple immunosuppressive treatments could be another important factor increasing the risk of PML, but the significance of this condition is not completely understood. With the development of new targeted immunosuppressive biologic agents for the treatment of psoriasis, continued vigilance is warranted. In particular, dermatologists need to become familiar with opportunistic infections including PML. The new onset or change of cerebral symptoms in immunosuppressed patients should alert us to look carefully for opportunistic infections. To date, survival in PML has been limited to patients who had the chance for immune reconstitution; therefore, discontinuation of immunosuppressive agents should receive a high priority25 in possible cases. Blood cultures and brain MRI should be the first step of the clinical evaluation, while polymerase chain reaction on cerebrospinal fluid being more than 90% sensitive and almost 100% specific should be used to rule out PML in questionable cases. If the clinical suspicion is high, PCR-negative patients should undergo brain biopsy to definitely exclude the diagnosis of PML.14 Finally, a prosecution of registries and post-marketing surveillance, or still better an active continuous monitoring of the safety26 of immunosuppressive treatments, is necessary not only to establish the true incidence rates of opportunistic infections in the long-term use of biologic and conventional antipsoriatic drugs, but also to define a possible profile of patients at risk for opportunistic infections. References 1 Greenlee JE. Progressive Mulifocal Leucoencephalopathy in the era of natalizumab: a review and discussion of implications. Int MS J 2006; 13: 100–107. 2 Markovitz RB, Thompson HC, Mueller JF, et al. Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects. J Infect Dis 1993; 167: 13–20. 3 Bartt RE. Multiple sclerosis, natalizumab therapy, and proressive multifocal leukoencephalopathy. Curr Opin Neurol 2006; 19: 341–349. 4 Marzocchetti A, Wuthrich C, Tan CS, et al. Rearrangement of the JC virus regulatory region sequence in the bone marrow of a patient with rheumatoid arthritis and progressive multifocal leukoencephalopathy. J Neurovirol 2008; 14: 455–458. 5 Gasnault J, Taoufik Y. New trends in progressive multifocal leukoencephalopathy. Rev Neurol 2006; 162: 43–56.

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6 Engsig FN, Hansen AB, Omland LH, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis 2009; 199: 77–83. 7 Shitrit D, Lev N, Bar-Gil-Shitrit A, Kramer MR. Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int 2005; 17: 658–665. 8 Neff RT, Hurst FP, Falta EM, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 2008; 86: 1474–1478. 9 Wang M, Tsai RT, Ou WC, et al. Treatment with cytotoxic immunosuppression agents increases urinary excretion of JCV in patients with autoimmune disease. J Med Virol 2000; 62: 505–510. 10 Calabrese LH, Molloy ES. Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risk of biological immunosuppressive therapies. Ann Rheum Dis 2008; 67 Suppl. 3: iii64–iii65. 11 Warnatz K, Peter HH, Schumacher M, et al. Infectious CNS disease as a differential diagnosis in systemic rheumatic diseases: three case reports and a review of the literature. Ann Rheum Dis 2003; 62: 50–57. 12 Boren EJ, Cheema GS, Naguwa SM, et al. The emergence of progressive multifocal leucoencephalopathy (PML) in rheumatic diseases. J Autoimmun 2008; 30: 90–98. 13 Rahmlow M, Shuster EA, Dominik J, et al. Leflunomideassociated progressive multifocal leukoencephalopathy. Arch Neurol 2008; 65: 1538–1539. 14 Molloy ES, Calabrese LH. Targeted but not trouble free: efalizumab and PML. Nat Rev Rheumatol 2009; 5: 418– 419. 15 Harris E. Progressive multifocal leucoencephalopathy in a patient with systemic lupus erythematosus treated with rituximab. Rheumatology 2008; 47: 224–225. 16 Yamamoto M, Takahashi H, Wakasugi H, et al. Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis. Mod Rheumatol 2007; 17: 72–74. 17 Roos JC, Ostor AJ. Anti-tumor necrosis factor alpha therapy and the risk of JC virus infection. Arthritis Rheum 2006; 54: 381–382. 18 Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001; 44: 2862–2869. 19 Wachi K, Prasertsuntarasai T, Kishimoto M, Uramoto K. T-cell lymphopenia associated with infliximab and cyclophosphamide. Am J Med Sci 2005; 330: 48– 51. 20 Guttman-Yassky E, Vugmeyster Y, Lowes MA, et al. Blockade of CD11a by efalizumab in psoriasis induces a unique state of T-cell hyporesponsiveness. J Invest Dermatol 2008; 128: 1182–1191.

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21 Lobb RR, Hemler ME. The pathophysiologic role of alfa4 integrins in vivo. J Clin Invest 1994; 94: 1722– 1728. 22 Korman BD, Tyler KL, Korman NJ. Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression. A cautionary tale for dermatologists. Arch Dermatol 2009; 145: 937–942. 23 Ransohoff RM. Natalizumab and PML. Nat Neurosci 2005; 8: 1275.

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24 Cotone C, Lucentini M, Garcia G, Anibal Molina H. Psoriasis and progressive multifocal leukoencephalopathy in AIDS. Rev Clin Esp 1992; 191: 285–286. 25 Berger JR. Progressive multifocal leukoencephalopathy. Curr Treat Options Neurol 2000; 2: 361–368. 26 Nijsten T, Spuls P, Naldi L, Stern R. The misperception thata clinical data reflect long-term drug safety. Lessons learned from Efalizumab’s withdrawal. Arch Dermatol 2009; 145: 1037–1039.

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