Author's Accepted Manuscript
Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice Robert L. Carruthers, Joseph Berger
www.elsevier.com/msard
PII: DOI: Reference:
S2211-0348(14)00008-X http://dx.doi.org/10.1016/j.msard.2014.01.005 MSARD172
To appear in:
Multiple Sclerosis and Related Disorders
Received date: 19 December 2013 Revised date: 30 January 2014 Accepted date: 31 January 2014 Cite this article as: Robert L. Carruthers, Joseph Berger, Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j. msard.2014.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice
Robert L. Carruthers MD1, 2*, Joseph Berger3 Affiliations: 1Department of Neurology, Harvard Medical School, Boston, MA, USA 2Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, MA, USA 3Department of Neurology, University of Kentucky Medical Center, Lexington, KY
Address correspondence to: Dr. Robert Carruthers, Partners MS Center, 1 Brookline Place, Suite 225, Brookline, MA 02445, USA Email: [email protected] Manuscript Number: MSARD-D-13-00137R1 Article Type: Review Article Keywords: progressive multifocal leukoencephalopathy, multiple sclerosis, natalizumab, JCV, JCV serology, PML-IRIS Corresponding Author: Robert L Carruthers, MD Corresponding Author's Institution: Brigham and Women's Hospital First Author: Robert L Carruthers, MD Order of Authors: Robert L Carruthers, MD; Joseph R Berger, MD Abstract: The natural history and clinical import of Progressive Multifocal Leukoencephalopathy has changed enormously in the last thirty years. After a resurgence of PML during the HIV/AIDS epidemic, advances in the treatment of multiple sclerosis created another group of 'at risk' patients. With a focus on issues pertaining to the multiple sclerosis patient population, this review covers pathophysiology of the JC virus, causes of PML, mechanisms by which natalizumab increases the risk of PML, determinants of PML risk in natalizumab-treated patients, risks of natalizumab discontinuation, PML prevention and surveillance, PML imaging features, PML diagnosis and stumbling blocks to making the diagnosis, PML and PML-Immune Reconstitution Inflammatory Syndrome (IRIS) treatment.
Introduction Progressive Multifocal Leukoencephalopathy (PML) is a potentially fatal or disabling infection of the brain by the JC virus that almost always occurs in the setting of immunosuppression. In the past three decades, PML has taken on new importance in the era of HIV/AIDS and monoclonal antibodies used in the treatment of multiple sclerosis (MS) and autoimmune conditions, such as rheumatoid arthritis. PML has particularly impacted the field of multiple sclerosis where 418 cases have been observed among 120,500 patients treated with natalizumab through November 2013 (BiogenIdec, 2013). This humanized monoclonal antibody is effective in MS due to its ability to inhibit alpha-4 beta-1 integrin, preventing transmigration of lymphocytes across the blood brain barrier. Balancing the therapeutic efficacy of natalizumab with the risk of PML has become an issue of great importance for patients and clinicians alike. As the nature of immunosuppression causing PML has changed, so too has the diagnosis and management of PML. Furthermore, the nature of immunosuppression underlying PML determines prognosis, treatment and emergence of PML-related immune reconstitution inflammatory syndrome (PML-IRIS). As there is no established anti-viral treatment, PML-related care is directed at re-institution of immunocompetence. This review will cover the biology of the JC Virus, etiologies of PML, PML diagnosis, PML-IRIS, PML management with a focus on issues pertaining to the multiple sclerosis patient population.
Pathophysiology The etiologic agent, the John Cunningham virus (JCV) is a ubiquitous polyoma virus that exclusively infects humans (Tan and Koralnik, 2010). The enclosed circular genome is comprised of coding (90% of genome) and regulatory regions (10% of genome) that are encoded counterclockwise and clockwise, respectively. Tissue tropism of the virus is determined largely by the hypervariable non-coding control region (regulatory region) while the genomic regions coding for regulatory and structural proteins are largely conserved (Jensen and Major, 2001). JCV found in the brain of patients with PML is referred to as the “prototype” virus and differs from the ubiquitous “archetype” virus due to insertions, deletions, re-arrangements, and importantly, tandem repeats in the regulatory region of the virus. PML occurs when JCV is unchecked by cellular immunity, reactivates, and migrates to the CNS where it infects glial cells. Neurotropism of JCV is not limited to glial cells as JCV can cause a fulminant JCV encephalopathy of cortical pyramidal neurons (Wuthrich et al. , 2009) and a granule cell neuronopathy of the cerebellum (Koralnik et al. , 2005). One group has described JCV Granule cell neuronopathy in a natalizumab-treated MS patient (Schippling et al. , 2013), which if confirmed by other groups could represent a second natalizumb-related JCV syndrome in the MS patient population. Primary exposure to the JC virus occurs asymptomatically in childhood or adolescence, but serological studies indicate that it may also occur in adulthood (Engels et al. , 2005). Thereafter, JCV can be found latent in the kidneys, bone marrow, lymphoid tissue, and other tissues. In a case series of bone marrow specimens, JCV DNA and proteins were more commonly detected in HIV-seropositive than seronegative patients (Tan et al. , 2009a). Whether JCV is latent in brain tissue of healthy controls remains controversial, but one study of brain banked tissue from healthy controls showed that 5/19 brains harbored JCV DNA (Tan et al. , 2010). In a multinational MS cohort, overall JCV seropositivity was 57.6% (Olsson et al. , 2013). JCV seropositivity increased with age: 49.5% seropositive if younger than 30 years old and 66% if 60 years or older. There was regional variation in JCV seropositivity ranging from 47.4% in
Norway to 67.7% in Turkey. JC viremia is infrequently demonstrated, but occasional studies have observed a high prevalence in both healthy controls and untreated MS patients (Delbue et al. , 2007). In HIV-positive patients, JC serology was positive in 59% of PML cases and 49% in disease-matched controls (Viscidi et al. , 2011). In the same study, JC viremia was detected in plasma of 17% of patients with PML and 12% of disease matched controls. After primary exposure, the virus can be intermittently excreted in the urine. JC viruria has been demonstrated in 10-40% of adults (Ling et al. , 2003, Markowitz et al. , 1993, Matos et al. , 2010, Rossi et al. , 2007) and viruria is very frequently observed in older JCV seropositive patients (Chang et al. , 2002). The rarity of PML despite the widespread prevalence of JCV infection in the world’s population implies that there are multiple barriers to the development of the disease. The most common observation is that altered cell-mediated immune dysfunction is a significant predisposing factor for the development of PML. Insights into immune clearance of PML can be gained from neuropathologic studies of PML-IRIS of both HIV-AIDS associated PML-IRIS (Martin-Blondel et al. , 2013) and natalizumab-associated PML-IRIS (Metz et al. , 2012). Typically, there is an intensely inflammatory cellular infiltrate with a preponderance of CD8+ T cells aggregating around infected oligodendrocytes accompanied by CD 20+ B Cells and CD138+ plasma cells. JCVspecific CD8+ T cells are known to play a critical role in JCV suppression and prevention of PML (Koralnik et al. , 2001) and it is likely that JCV-specific CD4+ T cells contribute as well (Gasnault et al. , 2003). In contrast, antibody-mediated immunity seems not to protect against PML as patients with high JCV index are not protected from PML, in fact, the opposite seems to be the case (Plavina T, 2013). Once PML does develop, neurologic symptoms documented in several case series from different PML eras (pre-AIDS era (Brooks and Walker, 1984), AIDS-associated PML (Berger et al. , 1998) and natalizumab-associated PML (Clifford et al. , 2010)) commonly include cognitive and behavioral abnormalities, motor weakness, gait abnormalities and incoordination, sensory loss, visual deficits, headache and seizures.
Causes of PML and Prognosis Immunosuppression is a requisite antecedent for PML. In some patients with no immediate risk factor for PML, idiopathic CD4 T-cell lymphopenia has been described (Chikezie and Greenberg, 1997, Delgado-Alvarado et al. , 2013, Haider et al. , 2000, Iwase et al. , 1998, Puri et al. , 2010). In one study of the US Nationwide Inpatient Sample database, 9113 patients with PML had a clear risk factor (HIV-82%, hematologic malignancy-8.4%, solid malignancy2.83%, SLE-0.44%, rheumatoid arthritis-0.25%) (Molloy and Calabrese, 2009). There were 4 cases of PML per 100,000 SLE patients as compared with 0.4 cases of PML per 100,000 RA patients. Interestingly, 28% of SLE patients with PML had received minimal or no immunosuppressive therapy. PML is a known complication of solid organ and bone marrow transplantation. In one series combining 54 published case reports and 15 PML cases from a multicenter retrospective cohort, the risk of PML at one institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25–3.61)(Mateen et al. , 2011). PML is an AIDS-defining illness that has become less common in the era of antiretroviral therapy. In the EuroSIDA cohort, before antiretroviral therapy, the incidence of PML was 0.7/100 person year of follow up, whereas, it fell afterward to 0.07/100 person year of follow up (d'Arminio Monforte et al. , 2004), though not all studies have demonstrated a significant reduction in PML incidence with the advent of effective antiretroviral therapy. Prognosis in the pre-antiretroviral era was abysmal with 10% 1 year survival (d'Arminio Monforte, Cinque, 2004), in contrast to 50% 1 year survival after availability of HAART (Antinori et al. , 2003). In HIVassociated PML, patients whose CD4 count was < 100cells/microL had an odds ratio of death of
2.71 (95% confidence interval, 1.19-6.15) when compared to patients with CD4 counts > 100 cells/microL(Berenguer et al. , 2003). In multiple sclerosis, PML has been observed in association with natalizumab, an alpha4 beta-1 integrin blocking human IgG monoclonal antibody. The first case reports of PML with MS (Kleinschmidt-DeMasters and Tyler, 2005, Langer-Gould et al. , 2005) and inflammatory bowel disease (Van Assche et al. , 2005) were unanticipated as patients had demonstrated no other evidence of immunsuppression. The PML cases prompted a voluntary suspension of natalizumab in February 2005, months after it was made available to patients. Natalizumab was re-approved by the FDA in June 2006 and is administered under the TOUCH program, a centralized registry of all patients treated with natalizumab that tracks adverse events. Natalizumab remains the most effective MS agent for relapse reduction but its use is limited by concerns of PML.
Mechanisms by which natalizumab potentiates PML Natalizumab treatment has been shown to foster conditions that would promote PML. First, natalizumab precludes effective CNS immunosurveillance by JCV-specific T cells by blocking alpha 4 beta 1 integrin. The administration of natalizumab leads to changes in CSF CD4/8 ratios that parallel those seen in HIV infection for up to 6 months (Stuve et al. , 2006). A recent study demonstrated that RRMS patients treated with natalizumab had not only reduced CSF T cell numbers, but also reduced T-cell receptor heterogeneity compared to other RRMS patients not treated with natalizumab (Warnke, Mausberg et al. 2013). In a series of brain biopsied patients, samples associated with PML were accompanied by a reduction in CD209+ dendritic cells which express MHC class II and contribute to activation and retention of T cells in peripheral tissues (del Pilar Martin, Cravens et al. 2008). Secondly, natalizumab may increase the peripheral expression of JCV and increase the likelihood of the emergence of the neurotropic prototype virus. In one study of 19 MS patients treated with natalizumab, JC viruria increased significantly from 19% of samples to 63% after 12 months and then JCV DNA was detectable in 3/15 plasma samples, and 9/15 peripheral-blood mononuclear cells (60%) (Chen et al. , 2009). This was accompanied by a drop in JCV-specific immunity over 6-12 months as measured by JCV-specific IFN-gamma producing peripheral blood mononuclear cells. Interestingly, the regulatory region sequences found in patient serum samples was similar to those found in PML lesions. Another cross-sectional study of natalizumab-treated MS patients demonstrated that JCV-specific effector T memory cell responses increased with duration of therapy (Hendel-Chavez et al. , 2013), which might suggest ongoing JCV replication in a subset of patients. In another 30 month longitudinal study of 50 RRMS patients treated with natalizumab (Planas et al. , 2012), blood samples demonstrated increased marginal zone B cells. These cells are typically found in the spleen and are susceptible to JCV infection. Natalizumab-related redistribution of marginal zone premature B cells to the circulation harboring JCV could contribute to the development of PML. During the maturation process of these cells, transcriptional factors may transactivate JCV, increasing replication and enhancing the probability that the prototype virus will appear. Determinants of PML Risk in Natalizumab-treated MS patients Industry-sponsored data support a model of PML risk that is impacted by duration of treatment, history of previous immunosuppression, and JCV serology (see Figure 1) (Bloomgren et al. , 2012). When combining safety data from clinical trials and post-marketing studies, the incidence of PML in the first year is low enough (4/99,571 or 0.04/1,000) that some practitioners will treat patients for a year even without checking a JCV serology if warranted. From first year to the second year, the incidence rises to 37/65,981, or 0.56/1,000. Afterward, PML risk plateaus, which suggests that there may be a vulnerable population. The PML risk is also
determined by the history of prior immunosuppressive therapy, such as mitoxantrone, methotrexate, cyclophosphamide and mycophenolate mofetil. It is unclear whether this data applies to patients treated with other agents such as fingolimod and rituximab. This uncertainty should be taken into account when offering natalizumab to patients previously treated with these agents, particularly if the patient is JCV seropositive. JCV serologic testing for clinical use in multiple sclerosis patients was developed to stratify PML risk (Gorelik et al. , 2010), rather than detect for primary exposure. The ELISA test detects antibodies responding to the JCV’s Viral-Like Peptides (VLP) in a first step. For patients with an indeterminate result, a confirmatory test using JCV VLPs to pre-adsorb JCV-specific antibodies demonstrates specificity. The false negative rate of the test was determined in patients with positive urinary JCV DNA PCR and was thought to be 2.5%. While there were no reported cases of JCV sero-negative patients developing PML at the time of publication of Bloomgren’s data (Bloomgren, Richman, 2012), there have been two subsequent cases of PML in patients with negative JCV serology eight and nine months prior to PML diagnosis. This important event prompted a label change of natalizumab requiring JCV serologic testing every six months. The false negative rate of the JCV serologic test has come into question when two separate case series suggested that the false negative rate of JCV serology could be as high as 37% (Berger et al. , 2013b, Major et al. , 2013). Theoretically, even a handful of additional occurrences of PML in JCV seronegative natalizumab-associated patients could prompt the MS community to re-think this risk paradigm (Carruthers et al. , 2013). For the time being, one must remember that JCV seropositive patients accounted for 186 of 188 cases of natalizumabassociated PML where JCV serologic data was available (BiogenIdec, 2013). Additional evidence that JCV serology functions to predict PML risk is that among JCV seropositive patients, a low JCV index (
Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice Robert L. Carruthers, Joseph Berger
www.elsevier.com/msard
PII: DOI: Reference:
S2211-0348(14)00008-X http://dx.doi.org/10.1016/j.msard.2014.01.005 MSARD172
To appear in:
Multiple Sclerosis and Related Disorders
Received date: 19 December 2013 Revised date: 30 January 2014 Accepted date: 31 January 2014 Cite this article as: Robert L. Carruthers, Joseph Berger, Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice, Multiple Sclerosis and Related Disorders, http://dx.doi.org/10.1016/j. msard.2014.01.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Progressive Multifocal Leukoencephalopathy and JC Virus-related Disease in Modern Neurology Practice
Robert L. Carruthers MD1, 2*, Joseph Berger3 Affiliations: 1Department of Neurology, Harvard Medical School, Boston, MA, USA 2Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, MA, USA 3Department of Neurology, University of Kentucky Medical Center, Lexington, KY
Address correspondence to: Dr. Robert Carruthers, Partners MS Center, 1 Brookline Place, Suite 225, Brookline, MA 02445, USA Email: [email protected] Manuscript Number: MSARD-D-13-00137R1 Article Type: Review Article Keywords: progressive multifocal leukoencephalopathy, multiple sclerosis, natalizumab, JCV, JCV serology, PML-IRIS Corresponding Author: Robert L Carruthers, MD Corresponding Author's Institution: Brigham and Women's Hospital First Author: Robert L Carruthers, MD Order of Authors: Robert L Carruthers, MD; Joseph R Berger, MD Abstract: The natural history and clinical import of Progressive Multifocal Leukoencephalopathy has changed enormously in the last thirty years. After a resurgence of PML during the HIV/AIDS epidemic, advances in the treatment of multiple sclerosis created another group of 'at risk' patients. With a focus on issues pertaining to the multiple sclerosis patient population, this review covers pathophysiology of the JC virus, causes of PML, mechanisms by which natalizumab increases the risk of PML, determinants of PML risk in natalizumab-treated patients, risks of natalizumab discontinuation, PML prevention and surveillance, PML imaging features, PML diagnosis and stumbling blocks to making the diagnosis, PML and PML-Immune Reconstitution Inflammatory Syndrome (IRIS) treatment.
Introduction Progressive Multifocal Leukoencephalopathy (PML) is a potentially fatal or disabling infection of the brain by the JC virus that almost always occurs in the setting of immunosuppression. In the past three decades, PML has taken on new importance in the era of HIV/AIDS and monoclonal antibodies used in the treatment of multiple sclerosis (MS) and autoimmune conditions, such as rheumatoid arthritis. PML has particularly impacted the field of multiple sclerosis where 418 cases have been observed among 120,500 patients treated with natalizumab through November 2013 (BiogenIdec, 2013). This humanized monoclonal antibody is effective in MS due to its ability to inhibit alpha-4 beta-1 integrin, preventing transmigration of lymphocytes across the blood brain barrier. Balancing the therapeutic efficacy of natalizumab with the risk of PML has become an issue of great importance for patients and clinicians alike. As the nature of immunosuppression causing PML has changed, so too has the diagnosis and management of PML. Furthermore, the nature of immunosuppression underlying PML determines prognosis, treatment and emergence of PML-related immune reconstitution inflammatory syndrome (PML-IRIS). As there is no established anti-viral treatment, PML-related care is directed at re-institution of immunocompetence. This review will cover the biology of the JC Virus, etiologies of PML, PML diagnosis, PML-IRIS, PML management with a focus on issues pertaining to the multiple sclerosis patient population.
Pathophysiology The etiologic agent, the John Cunningham virus (JCV) is a ubiquitous polyoma virus that exclusively infects humans (Tan and Koralnik, 2010). The enclosed circular genome is comprised of coding (90% of genome) and regulatory regions (10% of genome) that are encoded counterclockwise and clockwise, respectively. Tissue tropism of the virus is determined largely by the hypervariable non-coding control region (regulatory region) while the genomic regions coding for regulatory and structural proteins are largely conserved (Jensen and Major, 2001). JCV found in the brain of patients with PML is referred to as the “prototype” virus and differs from the ubiquitous “archetype” virus due to insertions, deletions, re-arrangements, and importantly, tandem repeats in the regulatory region of the virus. PML occurs when JCV is unchecked by cellular immunity, reactivates, and migrates to the CNS where it infects glial cells. Neurotropism of JCV is not limited to glial cells as JCV can cause a fulminant JCV encephalopathy of cortical pyramidal neurons (Wuthrich et al. , 2009) and a granule cell neuronopathy of the cerebellum (Koralnik et al. , 2005). One group has described JCV Granule cell neuronopathy in a natalizumab-treated MS patient (Schippling et al. , 2013), which if confirmed by other groups could represent a second natalizumb-related JCV syndrome in the MS patient population. Primary exposure to the JC virus occurs asymptomatically in childhood or adolescence, but serological studies indicate that it may also occur in adulthood (Engels et al. , 2005). Thereafter, JCV can be found latent in the kidneys, bone marrow, lymphoid tissue, and other tissues. In a case series of bone marrow specimens, JCV DNA and proteins were more commonly detected in HIV-seropositive than seronegative patients (Tan et al. , 2009a). Whether JCV is latent in brain tissue of healthy controls remains controversial, but one study of brain banked tissue from healthy controls showed that 5/19 brains harbored JCV DNA (Tan et al. , 2010). In a multinational MS cohort, overall JCV seropositivity was 57.6% (Olsson et al. , 2013). JCV seropositivity increased with age: 49.5% seropositive if younger than 30 years old and 66% if 60 years or older. There was regional variation in JCV seropositivity ranging from 47.4% in
Norway to 67.7% in Turkey. JC viremia is infrequently demonstrated, but occasional studies have observed a high prevalence in both healthy controls and untreated MS patients (Delbue et al. , 2007). In HIV-positive patients, JC serology was positive in 59% of PML cases and 49% in disease-matched controls (Viscidi et al. , 2011). In the same study, JC viremia was detected in plasma of 17% of patients with PML and 12% of disease matched controls. After primary exposure, the virus can be intermittently excreted in the urine. JC viruria has been demonstrated in 10-40% of adults (Ling et al. , 2003, Markowitz et al. , 1993, Matos et al. , 2010, Rossi et al. , 2007) and viruria is very frequently observed in older JCV seropositive patients (Chang et al. , 2002). The rarity of PML despite the widespread prevalence of JCV infection in the world’s population implies that there are multiple barriers to the development of the disease. The most common observation is that altered cell-mediated immune dysfunction is a significant predisposing factor for the development of PML. Insights into immune clearance of PML can be gained from neuropathologic studies of PML-IRIS of both HIV-AIDS associated PML-IRIS (Martin-Blondel et al. , 2013) and natalizumab-associated PML-IRIS (Metz et al. , 2012). Typically, there is an intensely inflammatory cellular infiltrate with a preponderance of CD8+ T cells aggregating around infected oligodendrocytes accompanied by CD 20+ B Cells and CD138+ plasma cells. JCVspecific CD8+ T cells are known to play a critical role in JCV suppression and prevention of PML (Koralnik et al. , 2001) and it is likely that JCV-specific CD4+ T cells contribute as well (Gasnault et al. , 2003). In contrast, antibody-mediated immunity seems not to protect against PML as patients with high JCV index are not protected from PML, in fact, the opposite seems to be the case (Plavina T, 2013). Once PML does develop, neurologic symptoms documented in several case series from different PML eras (pre-AIDS era (Brooks and Walker, 1984), AIDS-associated PML (Berger et al. , 1998) and natalizumab-associated PML (Clifford et al. , 2010)) commonly include cognitive and behavioral abnormalities, motor weakness, gait abnormalities and incoordination, sensory loss, visual deficits, headache and seizures.
Causes of PML and Prognosis Immunosuppression is a requisite antecedent for PML. In some patients with no immediate risk factor for PML, idiopathic CD4 T-cell lymphopenia has been described (Chikezie and Greenberg, 1997, Delgado-Alvarado et al. , 2013, Haider et al. , 2000, Iwase et al. , 1998, Puri et al. , 2010). In one study of the US Nationwide Inpatient Sample database, 9113 patients with PML had a clear risk factor (HIV-82%, hematologic malignancy-8.4%, solid malignancy2.83%, SLE-0.44%, rheumatoid arthritis-0.25%) (Molloy and Calabrese, 2009). There were 4 cases of PML per 100,000 SLE patients as compared with 0.4 cases of PML per 100,000 RA patients. Interestingly, 28% of SLE patients with PML had received minimal or no immunosuppressive therapy. PML is a known complication of solid organ and bone marrow transplantation. In one series combining 54 published case reports and 15 PML cases from a multicenter retrospective cohort, the risk of PML at one institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25–3.61)(Mateen et al. , 2011). PML is an AIDS-defining illness that has become less common in the era of antiretroviral therapy. In the EuroSIDA cohort, before antiretroviral therapy, the incidence of PML was 0.7/100 person year of follow up, whereas, it fell afterward to 0.07/100 person year of follow up (d'Arminio Monforte et al. , 2004), though not all studies have demonstrated a significant reduction in PML incidence with the advent of effective antiretroviral therapy. Prognosis in the pre-antiretroviral era was abysmal with 10% 1 year survival (d'Arminio Monforte, Cinque, 2004), in contrast to 50% 1 year survival after availability of HAART (Antinori et al. , 2003). In HIVassociated PML, patients whose CD4 count was < 100cells/microL had an odds ratio of death of
2.71 (95% confidence interval, 1.19-6.15) when compared to patients with CD4 counts > 100 cells/microL(Berenguer et al. , 2003). In multiple sclerosis, PML has been observed in association with natalizumab, an alpha4 beta-1 integrin blocking human IgG monoclonal antibody. The first case reports of PML with MS (Kleinschmidt-DeMasters and Tyler, 2005, Langer-Gould et al. , 2005) and inflammatory bowel disease (Van Assche et al. , 2005) were unanticipated as patients had demonstrated no other evidence of immunsuppression. The PML cases prompted a voluntary suspension of natalizumab in February 2005, months after it was made available to patients. Natalizumab was re-approved by the FDA in June 2006 and is administered under the TOUCH program, a centralized registry of all patients treated with natalizumab that tracks adverse events. Natalizumab remains the most effective MS agent for relapse reduction but its use is limited by concerns of PML.
Mechanisms by which natalizumab potentiates PML Natalizumab treatment has been shown to foster conditions that would promote PML. First, natalizumab precludes effective CNS immunosurveillance by JCV-specific T cells by blocking alpha 4 beta 1 integrin. The administration of natalizumab leads to changes in CSF CD4/8 ratios that parallel those seen in HIV infection for up to 6 months (Stuve et al. , 2006). A recent study demonstrated that RRMS patients treated with natalizumab had not only reduced CSF T cell numbers, but also reduced T-cell receptor heterogeneity compared to other RRMS patients not treated with natalizumab (Warnke, Mausberg et al. 2013). In a series of brain biopsied patients, samples associated with PML were accompanied by a reduction in CD209+ dendritic cells which express MHC class II and contribute to activation and retention of T cells in peripheral tissues (del Pilar Martin, Cravens et al. 2008). Secondly, natalizumab may increase the peripheral expression of JCV and increase the likelihood of the emergence of the neurotropic prototype virus. In one study of 19 MS patients treated with natalizumab, JC viruria increased significantly from 19% of samples to 63% after 12 months and then JCV DNA was detectable in 3/15 plasma samples, and 9/15 peripheral-blood mononuclear cells (60%) (Chen et al. , 2009). This was accompanied by a drop in JCV-specific immunity over 6-12 months as measured by JCV-specific IFN-gamma producing peripheral blood mononuclear cells. Interestingly, the regulatory region sequences found in patient serum samples was similar to those found in PML lesions. Another cross-sectional study of natalizumab-treated MS patients demonstrated that JCV-specific effector T memory cell responses increased with duration of therapy (Hendel-Chavez et al. , 2013), which might suggest ongoing JCV replication in a subset of patients. In another 30 month longitudinal study of 50 RRMS patients treated with natalizumab (Planas et al. , 2012), blood samples demonstrated increased marginal zone B cells. These cells are typically found in the spleen and are susceptible to JCV infection. Natalizumab-related redistribution of marginal zone premature B cells to the circulation harboring JCV could contribute to the development of PML. During the maturation process of these cells, transcriptional factors may transactivate JCV, increasing replication and enhancing the probability that the prototype virus will appear. Determinants of PML Risk in Natalizumab-treated MS patients Industry-sponsored data support a model of PML risk that is impacted by duration of treatment, history of previous immunosuppression, and JCV serology (see Figure 1) (Bloomgren et al. , 2012). When combining safety data from clinical trials and post-marketing studies, the incidence of PML in the first year is low enough (4/99,571 or 0.04/1,000) that some practitioners will treat patients for a year even without checking a JCV serology if warranted. From first year to the second year, the incidence rises to 37/65,981, or 0.56/1,000. Afterward, PML risk plateaus, which suggests that there may be a vulnerable population. The PML risk is also
determined by the history of prior immunosuppressive therapy, such as mitoxantrone, methotrexate, cyclophosphamide and mycophenolate mofetil. It is unclear whether this data applies to patients treated with other agents such as fingolimod and rituximab. This uncertainty should be taken into account when offering natalizumab to patients previously treated with these agents, particularly if the patient is JCV seropositive. JCV serologic testing for clinical use in multiple sclerosis patients was developed to stratify PML risk (Gorelik et al. , 2010), rather than detect for primary exposure. The ELISA test detects antibodies responding to the JCV’s Viral-Like Peptides (VLP) in a first step. For patients with an indeterminate result, a confirmatory test using JCV VLPs to pre-adsorb JCV-specific antibodies demonstrates specificity. The false negative rate of the test was determined in patients with positive urinary JCV DNA PCR and was thought to be 2.5%. While there were no reported cases of JCV sero-negative patients developing PML at the time of publication of Bloomgren’s data (Bloomgren, Richman, 2012), there have been two subsequent cases of PML in patients with negative JCV serology eight and nine months prior to PML diagnosis. This important event prompted a label change of natalizumab requiring JCV serologic testing every six months. The false negative rate of the JCV serologic test has come into question when two separate case series suggested that the false negative rate of JCV serology could be as high as 37% (Berger et al. , 2013b, Major et al. , 2013). Theoretically, even a handful of additional occurrences of PML in JCV seronegative natalizumab-associated patients could prompt the MS community to re-think this risk paradigm (Carruthers et al. , 2013). For the time being, one must remember that JCV seropositive patients accounted for 186 of 188 cases of natalizumabassociated PML where JCV serologic data was available (BiogenIdec, 2013). Additional evidence that JCV serology functions to predict PML risk is that among JCV seropositive patients, a low JCV index (
