anti-JCV Antibody Research Articles

Does risk stratification decrease the risk of natalizumab-associated PML? Where is the evidence?

The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated PML: (1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed.

JC Virus in CD34+and CD19+Cells in Patients With Multiple Sclerosis Treated With Natalizumab

Infection with JC virus (JCV) may lead to development of demyelinating progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS) who are treated with natalizumab. To determine whether mononuclear cells in circulation from MS patients treated with natalizumab harbor JCV DNA. In this prospective investigation, we enrolled 49 MS patients from the Clinical Center for Multiple Sclerosis at The University of Texas Southwestern Medical Center and 18 healthy volunteers. We drew 120-mL blood samples from 26 MS patients at baseline and at approximately 3-month intervals to 10 months during the course of natalizumab infusions. One blood sample was drawn from 23 MS patients receiving natalizumab for more than 24 months and from 18 healthy volunteers. Natalizumab treatment of MS. The blood samples were separated using flow cytometry into CD34+, CD19+, and CD3+ cell subsets; DNA templates were prepared using quantitative polymerase chain reaction for JCV DNA identification. Plasma samples were tested for anti-JCV antibodies by enzyme-linked immunosorbent assays performed at the Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological and Communicative Diseases and Stroke. Thirteen of the 26 patients (50%) with baseline and follow-up blood samples had detectable viral DNA in at least 1 cell compartment at 1 or more points. Ten of the 23 patients (44%) receiving treatment for more than 24 months and 3 of the 18 healthy volunteers (17%) also had detectable viral DNA in 1 or more cell compartment. Fifteen of the 49 MS patients (31%) were confirmed to harbor JCV in CD34+ cells and 12 of 49 (24%) in CD19+ cells. Only 1 of 18 healthy volunteers were viremic in CD34+ cells and none in CD19+ cells. Nine patients and 1 healthy volunteer were viremic but had seronegative test results for JCV antibodies. JC virus DNA was detectable within cell compartments of natalizumab-treated MS patients after treatment inception and longer. JC virus DNA may harbor in CD34+ cells in bone marrow that mobilize into the peripheral circulation at high concentrations. Latently infected cells initiate differentiation to CD19+ cells that favors growth of JCV. These data link the mechanism of natalizumab treatment with progressive multifocal leukoencephalopathy.

JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants

JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10−15) and controls (OR = 0.53, p = 2×10−5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10−5). The German dataset confirmed these findings (OR = 0.54, p = 1×10−4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

Natalizumab treatment for multiple sclerosis: Middle East and North Africa regional recommendations for patient selection and monitoring

BackgroundNatalizumab, a highly specific α4-integrin antagonist, , has recently been registered across the Middle East and North Africa region. It improves clinical and magnetic resonance imaging (MRI) outcomes and reduces the rate of relapse and disability progression in relapsing-remitting multiple sclerosis (MS). Natalizumab is recommended for patients who fail first-line disease-modifying therapy or who have very active disease. Progressive multifocal leukoencephalopathy is a rare, serious adverse event associated with natalizumab.We aim to develop regional recommendations for the selection and monitoring of MS patients to be treated with natalizumab in order to guide local neurological societies.MethodsAfter a review of available literature, a group of neurologists with expertise in the management of MS met to discuss the evidence and develop regional recommendations to guide appropriate use of natalizumab in the region.ResultsDisease breakthrough is defined as either clinical (relapse or disability progression) or radiological activity (new T2 lesion or gadolinium-enhancing lesions on MRI), or a combination of both. Natalizumab is recommended as an escalation therapy in patients with breakthrough disease based on its established efficacy in Phase III studies. Several factors including prior immunosuppressant therapy, anti-John Cunningham virus (JCV) antibody status and patient choice will affect the selection of natalizumab. In highly active MS, natalizumab is considered as a first-line therapy for naive patients with disabling relapses in association with MRI activity. The anti-JCV antibody test is used to assess anti-JCV antibody status and identify the risk of PML. While seronegative patients should continue treatment with natalizumab, anti-JCV antibody testing every 6 months and annual MRI scans are recommended as part of patient monitoring. In seropositive patients, the expected benefits of natalizumab treatment have to be weighed against the risks of PML. Clinical vigilance and follow-up MRI scans remain the cornerstone of monitoring. After 2 years of natalizumab therapy, monitoring should include more frequent MRI scans (every 3–4 months) for seropositive patients, and the risk-benefit ratio should be reassessed and discussed with patients.ConclusionsRecommendations have been developed to guide neurologists in the Middle East and North Africa on patient selection for natalizumab treatment and monitoring.

Prevalence of Anti-JC Virus Antibody in Multiple Sclerosis Patients in Kuwait

Background. Multiple sclerosis (MS) therapeutics entered a new era after the development of anti-JC virus (anti-JCV) antibody assay that assesses the risk of development of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab. Objective. To determine the prevalence of anti-JCV antibody among MS patients in Kuwait. Methods. Using the national MS registry, demographics and disease characteristics of MS patients who were screened for anti-JC virus antibody were collected. The prevalence of anti-JCV antibody seropositivity and its association with demographic and disease characteristics were evaluated. Results. Out of 110 screened MS patients for anti-JCV antibodies, 65.5% were females. Mean age and disease duration were 29.23 ± 8.55 and 5.39 ± 5.04 years, respectively. 47.3% of patients were already on natalizumab and 52.7% of patients were screened for stratification to either natalizumab or a different Disease Modifying Therapy (DMT). The overall prevalence of anti-JC virus antibody was 40%. Gender (P = 0.69), disease duration (P = 0.11), and number of natalizumab infusions (P = 0.64) were not associated with seropositivity. Patients aged ≥30 years were more likely to be seropositive (P = 0.01). Conclusion. The prevalence of anti-JCV antibody is slightly lower than what is reported in published studies. Seropositivity was associated with an increasing age of MS patients.

JCV epidemiology in MS (JEMS)—Epidemiology of anti-JCV antibody prevalence in multiple sclerosis patients—Portuguese data

BackgroundProgressive multifocal leukoencephalopathy, caused by oligodendrocyte lytic infection by JCVirus, is a growing concern for patients undergoing immune modulatory therapies for treatment of autoimmune diseases, such as multiple sclerosis (MS). The objective of JEMS was to describe the prevalence of anti-JCV antibodies in MS patients and to assess the various factors associated to it. MethodsSerum samples were collected and tested for anti-JCV antibody using the STRATIFY JCV™ assay in 131 Portuguese MS patients. Factors potentially associated with prevalence were also evaluated, as well as the effect of established risk factors. ResultsIn the population of 131 Portuguese patients included in the JEMS, the overall anti-JCV antibody prevalence was 69.5% (95% CI, 61.6–77.4). The anti-JCV antibody prevalence did not seem to be influenced by demographic characteristics, although results demonstrate a non-significant trend for increased prevalence with age. Disease characteristics, treatment duration, treatment history, prior immunosuppressive therapy use and natalizumab exposure duration did not seem to be associated with anti-JCV prevalence. ConclusionThe results of Portuguese MS patients participating in the JEMS study present some differences when compared with the global population and literature results. An overall prevalence higher than expected raises awareness for data confirmation with greater sample size studies.

Anti‐JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of JC virus (JCV) infection due to combined host and viral factors. Anti-JCV antibodies provide a means to assess JCV exposure and stratify PML risk. The reported seroprevalence of anti-JCV antibodies varies from 39% to 91% depending on assay methodology and population studied. A two-step anti-JCV antibody assay (STRATIFY JCV™; Focus Diagnostics, Cypress, CA, USA) detected anti-JCV antibodies in approximately 55% of multiple sclerosis (MS) patients. This study describes the prevalence of anti-JCV antibodies in a large, multinational MS population. This cross-sectional epidemiology study was designed to enroll a minimum of 2000 patients with an MS diagnosis of any type, irrespective of treatment, from Europe, Canada and Australia. Anti-JCV antibody prevalence was determined by STRATIFY JCV; the effects of demographic and disease characteristics were evaluated. A total of 7724 patients from 10 countries participated in the study. Overall anti-JCV antibody prevalence was 57.1% (95% confidence interval 56.0%-58.2%). Seroprevalence was significantly associated with increasing age, gender and country of current residence (P<0.0001). No significant differences in anti-JCV antibody prevalence were associated with MS disease characteristics, including duration and type of MS and number and duration of MS therapies. Overall seroprevalence of anti-JCV antibodies in MS patients from Europe, Canada and Australia was consistent with previous studies using the STRATIFY JCV assay. Anti-JCV prevalence differed significantly by age, gender and country, but no geographical pattern was evident. Disease and treatment type were not associated with differences in anti-JCV antibody status.

Unusual natalizumab-associated progressive multifocal leukoencephalopathy starting in the brainstem

we report on a 45-year-old German patient with relapsingremitting (RR) multiple sclerosis (MS) who was started on natalizumab (NAT) therapy in November 2007, because of ongoing disease activity despite interferon therapy. She had never been treated with immunosuppressants before. After she tested positive for anti-JCV (John Cunningham Virus)antibodies for the first time, she decided to discontinue NAT treatment in July 2011 (after 49 NAT infusions). At this time point, as well as during NAT therapy, she was clinically stable (EDSS 3.5). Six weeks later in August 2011, she developed new brainstem symptoms, with left facial and trigeminal nerve palsy, double vision and mild dysphagia. On magnetic resonance imaging (MRI), a large brainstem-midbrain lesion was seen (Fig. 1D). The symptoms were initially interpreted as MS relapse and treated with corticosteroids. After transient improvement, she deteriorated again and was seen for the first time at our hospital. Progressive multifocal leukoencephalopathy (PML) was diagnosed in September 2011 after detection of JCV DNA (31 c/ml in CSF, 5 c/ml in serum; EDSS 7.0). Subsequently, she developed severe immune reconstitution inflammatory syndrome (IRIS), deteriorated clinically (EDSS 9.5), and had to be transferred to the intensive care unit (ICU) for several weeks. Finally, she stabilized after repeated courses of high-dose iv glucocorticosteroids (GC) and iv immunoglobulins (IVIgG, 5 days a 0.4 g/kg body weight), as well as concomitant therapy with mefloquine and mirtazapine. Six months later, she had improved, but still showed severe ataxia and brainstem symptoms (EDSS 6.0). Retrospective analysis of all available MRI scans identified a small new-initially asymptomatic-T2 brainstem lesion as the first MRI manifestation of this patient’s PML in November 2010, which slowly progressed over 41 weeks until clinical PML presentation (Fig. 1A–D). Several aspects in this report are unusual: (1) brainstem PML is rare and has been reported in association with NAT therapy in MS patients only once so far [1]; (2) the longlasting pre-symptomatic phase of 41 weeks and clinical manifestation of PML only 6 weeks after NAT was discontinued; and (3) clinical improvement after combined therapy with GC and IVIgG. In this patient, a new, asymptomatic, non-contrast-enhancing T2 lesion appeared in the brainstem in November 2010 (Fig. 1B). Notably, before the MRI lesion was rated as important, the patient decided to stop NAT therapy in July 2011 due to fear of PML. At this time and during NAT treatment, the lesion was completely asymptomatic. The patient developed new brainstem symptoms only 6 weeks after discontinuation of NAT and showed a large brainstem-midbrain lesion on MRI at that time. Detailed retrospective MRI analysis identified that this large lesion had progressed over time from the small brainstem lesion 41 weeks before. NATassociated PML with a pre-symptomatic course up to 24 weeks has been reported, but not in the brainstem so far [2]. More recently, Yousry and colleagues [3] identified common MRI patterns of NAT-associated PML, which help in the early diagnosis of PML. Except for the unusual initial localization in the brainstem and size (\ 3 cm), all J. Havla (&) R. Hohlfeld T. Kumpfel Institute of Clinical Neuroimmunology, Ludwig-Maximilians-University, Medical Campus Grosshadern, Marchioninistr. 15, 81377 Munich, Germany e-mail: joachim.havla@med.lmu.de

JC-virus seroconversion in multiple sclerosis patients receiving natalizumab

Aim: The objectives of this study were to evaluate the rate of JC virus (JCV) seroconversion/seroreversion in a French cohort of multiple sclerosis (MS) patients receiving natalizumab (NTZ), describe the characteristics of this population, identify risk factors for JCV seropositivity and analyse the additional value of quantitative JCV serology results in this context. Methods: MS patients from two French MS centres, whose JCV serological status in 2011 while receiving NTZ was known (n=357; first-generation enzyme-linked immunosorbent assay (ELISA) test (Gen1)), were proposed for inclusion in this study. We evaluated the rate of JCV seroconversion over a period of one year with a second-generation ELISA test (Gen2; n=303) and analysed the quantitative results. Multivariate analysis was performed to identify risk factors for JCV seropositivity. Results: Among the patients with Gen2 JCV serology (n=303) that had been JCV-seronegative one year before (n=165), the rate of JCV seroconversion was 26.67% (44/165). We observed a higher proportion of anti-JCV antibody seroconverters (14.5%) than expected (≤3%) but also increasing index values of anti-JCV antibody over time. Conclusion: Our data suggest that JCV reactivation occurs during NTZ therapy and leads to an increase in the anti-JCV antibodies titre, thus making them more easily detectable by the second-generation ELISA test.

Anti-JCV Antibodies Detection and JCV DNA Levels in PBMC, Serum and Urine in a Cohort of Spanish Multiple Sclerosis Patients Treated with Natalizumab

One of the most effective multiple sclerosis (MS) treatment is natalizumab. Nevertheless, it has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV). Our main objective was to assess the utility of testing JCV-DNA, apart from anti-JCV antibodies, to determine which natalizumab-treated MS patients has been previously in contact with the virus. For this purpose, 138 MS natalizumab/non-natalizumab treated patients participated in several studies. Cross-sectional study (CS): association of several epidemiological variables with anti-JCV antibodies and JCV-DNA levels in PBMC/serum/urine. First longitudinal study (A): evaluation of JCV-DNA prevalence in urine throughout the treatment. Second longitudinal study (B): simultaneous assessment of antibodies and viral DNA levels in PBMC/serum/urine at two time points. CS: The seropositivity rate for anti-JCV antibodies (62.3%) and JCV prevalence in urine (59.4%) were similar; although 26% of our population was positive only using one of the two techniques. A: The viral prevalence in urine seemed to increase between the baseline visit and the others (Baseline-Visit/V18months, p = 0.006). B: Our rate of positive antibody seroconversion was 36%. Nearly all patients with detectable JCV-DNA levels in PBMC excreted the virus intermittently in urine; while our PML case, positive in PBMC and serum samples 2month before the PML, excreted JCV permanently. In conclusion, the determination of JCV DNA levels in urine could be complementary to anti-JCV antibodies for identifying MS patients who has been infected by the JCV. Further research would be necessary to understand the different JCV excretion profiles in urine.

Cerebrospinal fluid and serum JC virus antibody detection in multiple sclerosis patients treated with natalizumab

Progressive multifocal leukoencephalopathy (PML) is a complication of natalizumab treatment. In order to identify natalizumab-treated patients at risk of developing PML, we assayed for anti-JC virus (JCV) antibody levels in cerebrospinal fluid (CSF). Serial CSF antibody levels were obtained, with 4 patients showing increases in anti-JCV levels indicating possibly viral activation. In patients with both CSF and serum antibody levels, a comparison showed only a moderate Spearman Rank Correlation Coefficient of 0.38. Our data suggests that serum anti-JCV antibody testing alone may not suffice in identifying at-risk patients because of the lack of uniform correlation with CSF titers.

Changes to anti-JCV antibody levels in a Swedish national MS cohort

BackgroundThe anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML).ObjectiveTo assess the potential utility...

Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort

JC virus (JCV) is an opportunistic virus known to cause progressive multifocal leukoencephalopathy. Anti-JC virus (Anti-JCV) antibody prevalence in a large, geographically diverse, multi-national multiple sclerosis (MS) cohort was compared in a cross-sectional study. Overall, anti-JCV antibody prevalence was 57.6%. Anti-JCV antibody prevalence in MS patients ranged from approximately 47% to 68% across these countries: Norway, 47.4%; Denmark, 52.6%; Israel, 56.6%; France, 57.6%; Italy, 58.3%; Sweden, 59.0%; Germany, 59.1%; Austria, 66.7% and Turkey, 67.7%. Prevalence increased with age (from 49.5% in patients < 30 years of age to 66.5% in patients ≥ 60 years of age; p < 0.0001 comparing all age categories), was lower in females than in males (55.8% versus 61.9%; p < 0.0001) and was not affected by prior immunosuppressant or natalizumab use.

CPC-091 Natalizumab in Cypriot Patients with Relapsing Remitting Multiple Sclerosis: Three Year Data on Safety, Efficacy and Frequency of Anti-JC Virus Antibodies

BackgroundNatalizumab (NAT) is a recombinant humanised anti-α4-integrin antibody used in treating Relapsing Remitting (RR) Multiple Sclerosis (MS).Purpose To evaluate the long-term safety and efficacy of NAT in Cypriot patients, to...

Natalizumab in pediatric multiple sclerosis: results of a cohort of 55 cases

Background: Limited information is available on the use of natalizumab (NA) in pediatric multiple sclerosis (ped-MS) patients. Objective: The purpose of this study was to describe the long-term effects of NA in a large cohort of active ped-MS patients. Methods: Patients with definite ped-MS were treated with NA if in the previous year they had experienced at least two relapses or a severe relapse with incomplete recovery while on immunomodulating treatment, or at least two relapses and new magnetic resonance imaging (MRI) lesions regardless of any prior treatment. Results: The study included 55 patients (mean age: 14.4 years, mean number of relapses: 4.4, pre-treatment mean disease duration: 25.5 months). They received a median number of 26 infusions. Three relapses occurred during the follow-up, one female patient continued to deteriorate in cognitive functioning. Mean Expanded Disability Status Scale (EDSS) scores decreased from 2.7 to 1.9 at the last visit (p<0.001). During the follow-up the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Mild hematological abnormalities occurred in seven patients. Anti-JCV antibodies were detected in 20/51 tested patients. Conclusions: NA was well tolerated in all patients. A strong suppression of disease activity was observed in the majority of patients during the follow-up.

An assay to quantify species-specific anti-JC virus antibody levels in MS patients

Background: The StratifyJCV® test is a qualitative assay to classify MS patients as anti-JC virus (JCV) antibody positive or negative. Quantification of anti-JCV antibody levels in serum and cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients might add to the progressive multifocal leukoencephalopathy (PML) risk assessment. Objective: The objective of this study is to test sera of patients in a quantitative anti-JCV antibody assay, and to compare the results with preexisting data from the StratifyJCV® test. Methods: Sera of a total of 175 MS patients and matched non-MS-controls were tested for anti-JCV antibodies using glutathione S-transferase-tagged-VP1 as antigen. Antibody reactivity was quantified in arbitrary units using human immunoglobulin as standard. Results: The comparison of our assay with StratifyJCV® showed good inter-assay agreement (kappa 0.6), and strong correlation for antibody reactivity (r2 = 0.94). Discordant samples had low-reactive positivity, and a higher proportion (13% vs. 4%) tested positive in the StratifyJCV® test only. Conclusions: The method presented is a tool for the reliable quantification of anti-JCV antibodies, which demonstrates good agreement with results from StratifyJCV®. In contrast to StratifyJCV®, we pre-adsorbed all of the sera with BK virus (BKV) VP1 protein to reduce cross-reactivity. This step may account for a higher species-specificity of our assay. As such, our assay might be a promising additional tool for PML risk assessment.

T Cell Epitope Mapping of JC Polyoma Virus-Encoded Proteome Reveals Reduced T Cell Responses in HLA-DRB1*04:01+Donors

JC polyomavirus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. It is only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated multiple sclerosis patients, that JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells likely play an important role in controlling JCV infection, we here describe the T cell response to JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. We identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. We observed positive JCV-specific T cell responses in 28.6% to 77.6%, humoral immune response in 42.6% to 89.4%, and urinary viral shedding in 36.4% to 45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals. We show for the first time that JCV-specific T cell responses may be directed not only against JCV VP1 and large T antigen but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.

Best practice in the use of natalizumab in multiple sclerosis

Natalizumab is approved for the treatment of patients with relapsing-remitting multiple sclerosis who have failed first-line treatment with traditional disease-modifying therapies or who have highly active disease. The drug has proved highly effective, both in a clinical trial setting and in clinical practice, with marked reductions in the rate of clinical relapses and slowed disease progression. These clinical outcomes are mirrored by a marked reduction in disease activity as evidenced by magnetic resonance imaging of the brain. However, natalizumab treatment has been associated with a risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus (JCV) activation. When this condition was detected in a clinical trial shortly after approval, the drug was immediately and voluntarily withdrawn from the market. As a condition of its reinstatement, stringent pharmacovigilance measures and a risk management plan were enforced. The recent availability of a two-step enzyme-linked immunosorbent assay (ELISA) test for the presence of anti-JCV antibodies (free testing is available in a central laboratory for registered centers), along with an ever-improving understanding of other risk factors such as prior immunosuppressant use and duration of treatment, allow an increasingly refined stratification of the risk of PML. This improved stratification of risk can help guide decisions about treatment. This review will also deal with other topics of relevance to clinical practice such as the development of antinatalizumab antibodies and their negative implications in terms of hypersensitivity reactions and loss of efficacy, withdrawal of treatment, and compassionate pediatric use.

The effect of plasma exchange on serum anti-JC virus antibodies

Objective: Natalizumab, a highly effective treatment for multiple sclerosis (MS) and Crohn’s disease, is associated with progressive multifocal leukoencephalopathy (PML). Upon suspicion or diagnosis of PML, plasma exchange (PLEX) is performed to remove natalizumab from the circulation, allowing immune reconstitution of the central nervous system. Since PLEX may also remove other circulating antibodies, we examined the effects of PLEX on serum immunoglobulin (IgG) and anti–JC virus (JCV) antibody levels in MS patients with and without PML. Methods: Serum samples from 12 natalizumab-treated patients without PML collected before, during and after PLEX were tested for IgG isotypes using a commercial assay, and for anti-JCV antibodies using a two-step enzyme-linked immunosorbent assay. Five natalizumab-treated PML patients who underwent PLEX were also tested for anti-JCV antibodies. Results: PLEX produced a two- to three-fold reduction in all IgG isotypes. Among patients without PML, 42% (five of 12 patients) had detectable anti-JCV antibodies before PLEX; in these patients, anti-JCV antibodies were reduced approximately two- to five-fold, with levels returning to 50–100 percent of baseline two weeks after the final PLEX. The five PML patients, all of whom had detectable anti-JCV antibodies before PLEX, experienced similar reductions in anti-JCV antibody levels following PLEX. Conclusions: Our results indicate that PLEX effectively removes circulating antibodies; however, levels of endogenous anti-JCV antibody, unlike exogenously administered natalizumab, were replenished relatively quickly following PLEX. While interpretation of anti-JCV antibody levels during or within two weeks after PLEX may be problematic, humoral JCV immunity is not abolished by PLEX and antibody levels are rapidly restored.

Natalizumab Use in Patients With Crohnʼs Disease (CD) and Relapsing Multiple Sclerosis (MS): Updated Utilization and Safety Results

Natalizumab was approved by the FDA in 2008 for adult patients with moderately to severely active CD with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. The TYSABRI Outreach: Unified Commitment to Health (TOUCH®) Prescribing Program, Crohn's Disease: Investigating Natalizumab through Further Observational Research & Monitoring (CD INFORM), TYSABRI Global Observation Program In Safety (TYGRIS), and TYSABRI® Pregnancy Exposure Registry (TPER) are ongoing risk management activities designed to further evaluate the safety of natalizumab. This report summarizes recent data on natalizumab utilization and safety in patients with Crohn's disease (CD) and relapsing multiple sclerosis (MS). TOUCH® is a mandatory prescribing program for all patients, prescribers, pharmacies and infusion centers in the US using natalizumab. TOUCH® is designed to inform about the risk of progressive multifocal leukoencephalopathy (PML); warn against concurrent use with antineoplastic, immunosuppressant, or immunomodulating agents, and in patients who are immunocompromised; and promote early diagnosis of PML and timely discontinuation of natalizumab in the event of suspected PML. CD INFORM, a post-marketing commitment, collects patient history, efficacy as assessed by the Harvey Bradshaw Index (HBI), Health Related Quality of Life outcomes, and serious adverse events (SAE) in CD patients on natalizumab therapy. TYGRIS, also a post-marketing commitment, is evaluating the long-term safety of natalizumab in MS. Post-marketing surveillance data are also collected. TPER evaluates the outcomes of pregnancy in women with CD and MS exposed to natalizumab. As of 30 June 2012, ˜104,300 patients have been exposed to natalizumab in the post-marketing setting (103,259 MS; 1,041 CD),. As of 01 August 2012, 271 cases of PML have been confirmed (270 MS, 1 CD). Of the 271 natalizumabtreated patients who developed PML, 212 (78%) had survived, exhibiting varying levels of disability and there were 59 (22%) deaths. Presence of anti-JCV antibodies, prior treatment with immunosuppressants and longer treatment duration with natalizumab, especially beyond 2 years, are identified risk factors for potential development of PML. As of 07 August 2012, 163 patients were enrolled in CD INFORM with the number of natalizumab infusions ranging from 1-56, with a mean and median of 14.6 and 10, respectively. The average HBI at time of entry for these patients was 8.2 (range 0 to 28). Of the 99 CD patients with an HBI assessment after receiving 6 months of natalizumab therapy, the average total score was 4.8, a mean decrease of 2.8 points from baseline. Cumulatively, as of 07 August 2012, there were 93 SAEs occurring in 51 patients reported in CD INFORM, 4 patients experienced 8 SAEs that were considered treatment related. As of 23 May 2012, 375 women (7 with CD) were prospectively enrolled in the TPER with372 outcomes reported, including 8 twin pregnancies resulting in 2 outcomes for each pregnancy. Current exposure and safety data from patients receiving natalizumab in both indications will be presented. Cumulative data from both indications suggest a safety profile consistent with natalizumab product labeling.