Mark Gudesblatt, MD

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diseases, which represent an autoimmune inflammatoryprocess, PML may be a direct resultof immune dysfunction but is more likelyto be an indirect consequence of the therapiesthat exert their therapeutic effect by immunosuppressionor by immunomodulation.Treatment duration as well as priorimmunosuppressant exposure have clearlyemerged as important factors in riskstratification.JCV and ImmunomodulatingTherapiesNumerous biologically active therapies havebeen associated with risk of PML. These includebut are not limited to rituximab, natalizumab,infliximab, efalizumab, and tacrolimus. 9 Whilemost of the reported cases of PML associatedwith these therapies have accrued since 2003,it is possible, if not likely, that sporadic earliercases went unrecognized or undiagnosed. Thespecific mechanisms of treatment-related PMLmay vary, but the immunomodulating propertiesof these agents, particularly the changesthey exert on lymphocyte trafficking, are consideredto be a common feature. 10 However, theinfrequency of PML with all of the agents so farimplicated suggests that there are both multipleand complex molecular steps required forthe archetypal JCV to produce PML. Patientspecificsusceptibilities are a focus of intensiveongoing investigation.Early reports of treatment-related PMLincluded use of rituximab in cancer patientsand infliximab in patients with an inflammatorydisease. 11,12 More attention was directed totreatment-related PML when a series of caseswere associated with the anti-inflammatorybiological agents natalizumab, 13 which inhibitsthe cellular adhesion molecular alpha4-integrin,and efalizumab, 9 which exerts its antiinflammatoryeffect by binding to the CD11asubunit of lymphocyte-associated antigen 1.Although there were only a small number ofcases associated with each of these agents, theseries of these unexpected complications overa relatively short period intensified the effort toquantify the risks for this complication.The unadjusted risk of PML with all of theimmunomodulating agents linked to this disorderhas remained very low. By exposure, theincidence of PML on rituximab is an estimated1 per 100,000 when this agent has been usedfor the treatment of rheumatoid arthritis and1 per 5000 patients when used for the treatmentof systemic lupus erythematosus. 6 Fornatalizumab and efalizumab, the risk is alsolow but has been related to treatment duration.Although experience with efalizumab remainslimited, all four cases (three documented andone suspected) occurred in patients who weretaking efalizumab continuously for at leastthree years. 14 The overall incidence of PML innatalizumab-treated patients as of June 1, 2011,is 1.51/1000, with the highest risk occurring between25 to 36 infusions. 15Following the evidence that PML was apossible complication of natalizumab, thisagent was briefly voluntarily withdrawn fromthe market until further analysis of this uncommonand unexpected complicatingproblem. Based on the low rates ofPML and the well-documented benefitsof natalizumab in multiple sclerosis(MS), it was reintroduced in June2006 and is currently available onlythrough the Tysabri Outreach: UnifiedCommitment to Health (TOUCH) prescribingprogram. Since that time, additional cases ofPML have been reported, but the pattern of riskhas remained relatively stable.Treatment duration as well as prior immunosuppressantexposure have clearly emergedas important factors in risk stratification. Thereare likely to be numerous other factors that alsoinfluence risk of PML in patients taking biologicallyactive agents of this nature. Most apparentis the underlying presence of resident JCVinfection. Infection site and potential geneticmutational characteristics of the viral capsidmay well play a role as well. A two-stage ELISAassay has been developed for JCV and will likelybecome a standard annual assessment onceit is commercialized. Moreover, although thepresence of JCV is necessary, biologically ac-S12 July 2011 • Clinical Reviews of JCV and PML
tive therapies appear to exert some change onthe relationship between the virus and the CNSbut impose little or no direct effect on the replicationrate of the pathogen. Although one smallstudy did associate natalizumab with reactivationof JCV, a much larger study was unable todemonstrate any change in JCV-DNA positiveurine specimens after 48 weeks of natalizumabtreatment. 6 In a series of five patients who diddevelop PML, there was no change in JCV DNAlevels prior to disease onset.There are at least 14 currently availablegenotypes, which are determined by the codingregion of JCV. 8 While genotypes have notbeen well matched with virulence, changes inthe hypervariable regulatory region do appearto control the transformation from an archetypelatent JCV to an opportunistic neurotropicinfection with propensity for PML. 5 However,the transformation from the archetype formof the virus to the PML-capable infection doesnot appear to be fully explained by alterationsin the biology of the virus. 16 Rather, in aseries of experiments conducted in the presenceof the JC virus T antigen, the replicationand transcription functions were remarkablysimilar between the archetype and virulentstrains, producing the hypothesis that archetypestrains do not have to convert to PML-typestrains to infect cells in the CNS. This suggeststhat the conversion to the virulent form may, inat least some cases, take place after JCV infectscells in the CNS.The site of the latent JCV infection may alsobe relevant to risk of PML. Low levels of replicationin the bone marrow or lymph tissue, forexample, may pose a much greater risk that thevirus will reach the CNS than latent infection inrenal tissue, particularly when immunomodulatingtherapies alter lymphocyte function. Inone study, JCV virus could be detected in thebone marrow of about twice as many patientswith PML, whether associated with AIDS oranother etiology, than those without PML. 17Although the ability of JCV to reside in the CNSin a latent state is controversial, the potentialfor CNS latency to serve as a risk factor for PMLdeserves further evaluation. If CNS latency isan uncommon but necessary event, this mayexplain the infrequency with which PML isa treatment-related complication. However,autopsy studies suggest that JCV is capable ofcrossing the BBB without producing a demyelinatingdisease, 18 which, again, supports thelikelihood that the presence of JCV in the CNSalone is not a sufficient reason by itself for PMLto occur.One theory is that cell susceptibility to JCVinternalization is required independent of thepresence of receptors known to be used bythis virus for attachment. The nuclear factor-1(NF-1) class X protein, for example, has beenfound at higher levels in JCV-susceptible cellsthan nonpermissive cells, leading to speculationthat expression of this receptor, or additionalreceptors, such as c-Jun, are necessaryfor virus to infect cells critical to PML disease. 19While it has been proposed that activation ofB-lymphocytes by immunomodulating therapies,such as rituximab or natalizumab, play acritical role in transporting JCV across the BBB,this, again, may be one of several molecularevents that must occur for PML to develop.The many unresolved issues complicatethe effort to isolate the steps that permit benign,archetypal JCV to mount a productiveand virulent infection of the CNS. Followinga report of rituximab-related PML, monitoringof blood for JCV and BK virus, anotherpolyomavirus, was performed in 73 consecutivepatients who received rituximab as partof a therapeutic regimen following solid organtransplantation. 20 Over a median 13 months offollow-up, JCV was detected with polymerasechain reaction (PCR) in the blood of four patients(5.5%). Loss of cell-mediated immunityappeared to correspond with JCV detection,but JCV could not be detected in the blood ofany of the four individuals with subsequentmonitoring. None developed PML or any clinicalevidence of neurologic disease. In contrast,all 73 patients developed BK-associated nephropathy,prompting a reduction in the immunosuppressionregimen.In patients who already have PML, an evaluationof the cell-mediated immune responsesuggests that CD8+ cytotoxic T-lymphocytes(CTLs) may play a critical role in the early con-Clinical Reviews of JCV and PML • July 2011 S13
Page 1 and 2: A SUPPLEMENT TO NEUROLOGY REVIEWSCl
Page 3 and 4: An Overview of JC Virusand Progress
Page 5 and 6: cation. Although PML is generally c
Page 7 and 8: JCV exposure than those who are not
Page 9 and 10: 39. Weber F, Goldmann C, Krämer M,
Page 14: tainment of JCV in the CNS as well
Page 17 and 18: Progressive MultifocalLeukoencephal
Page 19 and 20: TABLE 2 Different forms of PMLClass
Page 21 and 22: characteristic brain changes on mag
Page 23 and 24: with HIV-associated PML, recent stu
Page 25 and 26: Natalizumab, the first monoclonal a
Page 27: 22. Lebwohl M, Tyring SK, Hamilton

Mark Gudesblatt, MD

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