anti-JC Virus Antibody Research Articles

Anti-JC Virus Serostatus Changes Before and During the COVID-19 Pandemic in US Patients with Multiple Sclerosis (MS) Treated with Natalizumab (P12-3.007)

<h3>Objective:</h3> To assess changes in the proportion of patients who converted to a positive anti-JC virus (JCV) antibody (Ab) serostatus before and during the COVID-19 pandemic. <h3>Background:</h3> Natalizumab, approved to treat relapsing MS, is associated with increased risk of progressive multifocal leukoencephalopathy, a rare opportunistic infection of the brain due to JCV. Masking and social distancing in the US during the COVID-19 pandemic profoundly attenuated the spread of seasonal influenza in 2020–2021. The mode of JCV transmission is not well defined, thus the pandemic offered a unique epidemiological opportunity to evaluate if isolation and masking during the COVID-19 pandemic affected JCV transmission. <h3>Design/Methods:</h3> Data from the TOUCH database for 22,375 patients treated with natalizumab in the US from 2017–2022 with available anti-JCV Ab record was assessed in annual epochs from April 1 to March 31. Anti-JCV Ab serostatus was determined by STRATIFY JCV^® DxSELECT. US regions examined (Northeast/South/Central/West) were determined using infusion site ZIP codes. <h3>Results:</h3> From April 1, 2017 to March 31, 2018, anti-JCV Ab serostatus change was observed for 7.7% of patients, with serostatus change of 7.4% and 7.4% of patients in the following 2 years (2018–2019 and 2019–2020). During the first and second years of the COVID-19 pandemic (2020–2021 and 2021–2022), 7.3% and 7.2% of patients’ serostatus changed, respectively. There were no differences in serostatus change by US region. Multivariate predictors of JC seroconversion will be shown when presented. <h3>Conclusions:</h3> The proportion of natalizumab patients with anti-JCV Ab serostatus change did not significantly differ during the first 2 years of the COVID-19 pandemic compared with the 3 prior years. These results suggest that, in contrast to seasonal influenza, masking and social distancing had no discernable effect on JCV serostatus changes. If not spread through social contact, further studies are needed to understand how JCV is transmitted. <b>Disclosure:</b> Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Krieger has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Krieger has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Expert Witness. The institution of Dr. Krieger has received research support from Novartis. The institution of Dr. Krieger has received research support from Bristol Myers Squibb. Mrs. Sinks has received personal compensation for serving as an employee of Biogen . Dr. Huang has nothing to disclose. Ms. Wen has a non-compensated relationship as a Statistician with Biogen that is relevant to AAN interests or activities. Mrs. Steverson has received personal compensation for serving as an employee of Biogen. Mrs. Steverson has stock in Biogen. An immediate family member of Dr. Piccinini has received personal compensation for serving as an employee of Biogen. Dr. Piccinini has received stock or an ownership interest from Biogen. Dr. Kalina has received personal compensation for serving as an employee of Biogen. Dr. White has stock in Biogen. Mrs. Avila has received personal compensation for serving as an employee of Biogen. Mrs. Avila has stock in Biogen.

Mutations in the John Cunningham virus VP1 gene could predispose to the development of progressive multifocal leukoencephalopathy in multiple sclerosis patients undergoing treatment with natalizumab

BackgroundPatients with Multiple Sclerosis (MS) undergoing treatment with natalizumab (NTZ) are at risk of developing progressive multifocal leukoencephalopathy (PML) due to the reactivation of John Cunningham (JC) virus. A relevant characteristic among PML cases is the development of single nucleotide mutations in the VP1 gene of the causal JC virus. The identification of such mutations in timely manner can provide valuable information for MS management. ObjectiveTo identify mutations along the JC virus VP1 gene in MS patients undergoing treatment with NTZ, and correlate them with anti-JC virus antibody index. MethodsEighty-eight MS patients, one hundred twenty controls, and six patients with diagnosis of Human Immunodeficiency Virus (HIV) with and without secondary PML were included. JC virus was identified in peripheral blood mononuclear cells and cerebrospinal fluid by PCR. Amplification and sequencing of the entire length of the VP1 gene were performed in all positive clinical samples. ResultsIn MS cases no mutations were observed in the JC virus VP1 gene, but it was positive in HIV controls with PML. Interestingly, the JC virus VP1 gene sequence derived from the HIV patients exhibited a non-silent substitution in position 186 (G → C), leading to an amino acid change (Lys → Asp). We did not find correlation between anti-JC virus antibody index and DNA viral detection. Conclusions. The identification of single nucleotide mutants in the JC virus VP1 gene might be an early predictive marker to PML for efficient patient treatment and follow-up.

Author response: Prospective validation of the PML risk biomarker l -selectin and influence of natalizumab extended intervals

On behalf of all authors, we would like to thank Mr. Tugemann for his interest in our article.1 It is correct that acute progressive multifocal leukoencephalopathy (PML) can, in some circumstances, lead to high(er) CD62L values. However, as the study was conducted prospectively and, more importantly, alongside treatment, we reported all results of samples shipped to us back to the treating physicians. At the time of measurement and reporting, we were not aware of the patients' disease state. Because this is the situation to be expected in postmarketing settings, we chose to report all measured values, even if the samples turned out to be less than 6 months before PML diagnosis. Although the exclusion of these samples would indeed have led to a perfect sensitivity with the threshold of 36.05, we believed that it would not accurately reflect the real-world situation. Similarly, we chose not to focus on other PML risk stratification factors such as previous immune suppression or anti-JC virus antibody serostatus because we could not rely on having this information for all samples shipped to us. We, therefore, decided to report on the feasibility of measuring one biomarker rather than presenting a holistic approach for risk stratification using all available markers, which was addressed before.2 As supported by this study, CD62L was proven to be a useful biomarker for PML risk stratification also in the real-world setting but could also help with monitoring immunologic changes because of natalizumab-extended interval dosing. Owing to its initial detection in a retrospective cohort, the validated methodology3 still requires a mandatory freeze/thaw cycle, thereby limiting its widespread use. However, we would be more than happy if methodological improvements could be achieved here.

Two susceptible HLA-DRB1 alleles for multiple sclerosis differentially regulate anti-JC virus antibody serostatus along with fingolimod

BackgroundProgressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod.MethodsWe enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped.ResultsHLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023).ConclusionsHLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

Natalizumab in patients with multiple sclerosis in Colombia: a case series

INTRODUCTION:Natalizumab is a humanized monoclonal antibody prescribed in the treatment of multiple sclerosis, the most prevalent chronic and inflammatory disease of the central nervous system (CNS). NEDA (no evidence of disease activity) status is the goal of multiple sclerosis treatment. METHODOLOGY:The clinical records of 22 patients with multiple sclerosis, followed for a mean of 9.2 years (range: 1.9 -18.3 years) between 2000 and 2018 were analyzed. These patients received treatment with natalizumab in a high-complexity neurological outpatient clinic in Bogotá, Colombia. RESULTS:Eighteen patients (82%) reached NEDA status within a median time of six months. Seven patients (32%) tested positive for anti-JC virus antibodies. However, none of them developed progressive multifocal leukoencephalopathy. During the evaluation period, five patients (23%) presented new lesions and 17 patients (77%) had relapses before reaching NEDA status. CONCLUSIONS:This study gave an exploratory analysis of the characteristics of a series of patients with MS in the Colombian context. In the retrospective analysis, it was observed that more than 80% of the studied sample that received treatment with natalizumab, reached NEDA status. Despite the methodological limitations inherent to this type of study and sample size, it suggests that natalizumab could be an appropriate medication for the management of multiple sclerosis in Colombia.

Application of "Mentzer's PML case definition" to natalizumab-treated patients in the setting of strict MRI-based pharmacovigilance.

To compare the available diagnostic criteria for progressive multifocal leukoencephalopathy (PML) diagnosis in a real-world cohort of patients with natalizumab-associated PML and to explore opportunities for improvement of such criteria in the context of pharmacovigilance of immunosuppressive therapies. We applied the "Mentzers PML case definition" to a dataset of 28 patients with natalizumab-associated PML (many of whom were identified through MRI screening in the context of pharmacovigilance), who were previously rated according to the American Academy of Neurology (AAN) PML diagnostic criteria, and compared the response to both sets of criteria. The "Mentzers case definition" resulted in a level of certainty 1-3 in patients with a positive JC virus PCR, termed 'definite' and 'probable' PML according to the AAN diagnostic criteria. Patients that tested negative for JC virus in CSF (29%) were classified level 4 by the "Mentzers case definition", neglecting the longitudinal clinical and radiological signs of PML available, while the AAN diagnostic criteria separated these patients in 'possible' and 'not PML'. Both the AAN PML diagnostic criteria and the "Mentzers case definition" require the positive detection of JC virus DNA in CSF to define patients at a higher degree of suspicion of PML. However, as sensitivity of JC virus PCR in CSF is limited and often returns negative in particular in early cases of PML with a mere MRI-based PML suspicion, both criteria have obvious limitations when frequent MRI is used for pharmacovigilance purposes. Thus, revision of PML diagnostic criteria is needed, including the incorporation of lesion evolution, and longitudinal CSF studies that also assess for the presences of intrathecally produced anti-JC virus antibodies.

Progression of a series of patients with relapsing-remitting multiple sclerosis treated for 7 years with natalizumab using the “no evidence of disease activity” parameter

IntroductionThe safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions. ObjectiveTo determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the “no evidence of disease activity” (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters. Patients and methodsWe performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions. ResultsThe study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti–JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy. ConclusionsNatalizumab is highly effective as measured by the NEDA long-term remission parameter.

Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: risk reduction, management and possibilities for subsequent immunoregulation

The risk of progressive multifocal leukoencephalopathy (PML) is one of the factors limiting the widespread use of natalizumab (NTZ). As a strategy for potentially reducing the frequency of the NTZ-associated PML, while maintaining the high therapy efficacy, in addition to the widely-used risk stratification strategy based on anti-JC virus antibody index and therapy duration, we propose the administration of NTZ with an extended dosing interval. Opinions vary on the effectiveness of plasmapharesis in confirmed cases of PML. The most challenging problem is how to manage patients, who develop PML, and what MS disease-modifying therapy should be considered for the subsequent use.

Prevalence of Anti-JC Virus (JCV) Antibodies in the Multiple Sclerosis (MS) Population in Cyprus: A Retrospective Study.

Background and Purpose Progressive multifocal leukoencephalopathy (PML) is a debilitating disease of the central nervous system caused by the ubiquitous polyomavirus JC (JCV) in immunocompromised hosts. In recent years, a new subpopulation of patients at risk for PML has emerged, due to the growing use of immunomodulatory or immunosuppressive therapies in autoimmune diseases such as multiple sclerosis (MS). The anti-JCV antibody index is used as a stratification tool in assessing the risk of developing PML. The objective of this study was to retrospectively describe the prevalence of anti-JCV antibodies in the MS population in Cyprus. Methods We retrospectively collected the demographics of 214 MS patients in Cyprus who were screened for anti-JCV antibodies using the STRATIFY JCV™ assay between September 2011 and June 2018. Logistic regression analysis was used to examine the effect of demographic variables on seropositivity, and bivariate tests were used to assess the association between demographic characteristics and JCV AI index. Results A total of 214 MS patients in Cyprus were tested. Overall anti-JCV antibody prevalence was 45.8% (95% confidence interval 37.2%–55.8%). We could not establish a significant association between seropositivity and increasing age or sex. In the subgroup analysis of natalizumab-treated patients, the annual seroconversion rate was 4.5%. Conclusions Overall seroprevalence of anti-JCV antibodies in MS patients in Cyprus using the STRATIFY JCV assay was lower than the worldwide reported mean. Although previously reported, in our study, the anti-JCV antibody seropositivity was not associated with increasing age or sex.

Real-world study of efficacy, risk management and reasons for discontinuation of natalizumab for treatment of multiple sclerosis in Russia.

BackgroundNTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far.ObjectiveTo characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia.MethodsWe analyzed data for 334 patients, who received at least one infusion of NTZ. Relapse rate, MRI activity, NEDA-3 status after 2 years were assessed. Anti-JC virus antibodies status and RMP implementation were evaluated. Drop-out rate and reasons for therapy discontinuation were analyzed.ResultsPatients switched to natalizumab in Russia are mainly female (63%), with median EDSS score of 3.5 and high disease activity: 93% had at least 1 relapse and 58% had both T1Gd+ and new T2 lesion a year before therapy initiation. Introduction of federal reimbursement allowed patients with less relapses to start therapy with natalizumab. The only predictor of 6-month progression was EDSS score at the baseline of therapy (HR = 2.1375, 95%CI 1.0026–4.5570, p = 0.0492). 82% patients reached NEDA-3 at 24 month of therapy. 25% of patients discontinued NTZ for reasons: tolerability (14.5%), JCV antibody status (61%), and patient’s decision (17%). RMP was implemented in only 36% patients.ConclusionNatalizumab appeared to have high efficacy in Russian clinical practice. Federal reimbursement allowed less active patients to start natalizumab. More efforts should be done to improve RMP implementation.

Prevalence of Anti-JC Virus Antibody Seropositivity in Patients with Multiple Sclerosis: A Systematic Review and Meta-Analysis

Background: The John Cunningham virus (JCV) is the causative agent of progressive multifocal leukoencephalopathy. Anti-JCV antibody seropositivity is an important consideration in patients with multiple sclerosis (MS). The reported prevalence of JCV in MS patients has been conflicting. Objective: We aimed to conduct a systematic review and meta-analysis to estimate the pooled prevalence of anti-JCV antibody seropositivity in cases with MS. Methods: We searched PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, ProQuest, Google Scholar, and gray literature including reference of included studies, and conference abstracts which were published up to April 2019. Two independent researchers independently assessed the articles. Results: The literature search found 181 articles. After eliminating duplicates, reviews, case reports, and trials, 15 articles remained. Finally, 8 articles were included for the final analysis (from Asia, Europe, the USA, and Canada). In total, 16,041 MS cases were analyzed. The prevalence of anti-JCV antibody seropositivity varied between 40 and 80%, and the pooled estimate was calculated as 60% (95% CI: 56–64%), though with significant heterogeneity (I² = 95%, p = 0.01). Conclusion: The prevalence of anti-JCV antibody seropositivity is variable among MS patients in different countries, and the pooled estimate showed that this is 60% overall.

Anti-JC virus antibody index changes in rituximab-treated multiple sclerosis patients.

Rituximab, a monoclonal antibody to CD20, is an effective treatment for relapsing remitting multiple sclerosis (MS) reducing relapse rate by at least 50% over time. Although the mechanism for this clinical benefit is unclear, rituximab depletes circulating B cells, which can perform antigen presentation and stimulation of T cells. Another anti-CD20 drug, ocrelizumab, has recently been FDA approved to treat both relapsing remitting and progressive forms of MS. While long-term effects of ocrelizumab use are essentially unknown, long-term use of rituximab has been associated with the development of progressive multifocal leukoencephalopathy (PML) at an incidence of approximately 1/25,000 in non-MS conditions. Serostatus for JC virus (JCV), the causative agent for PML, is an important risk stratification tool for natalizumab, but its utility in other MS treatments is uncertain. We found that rituximab use was associated with a reduction in JCV antibody index values in MS patients. Reductions in immunoglobulins, IgM in particular, are seen in concert with JCV antibody reductions. Physicians should exercise caution when using JCV antibody indices to assess any risk of PML for patients on rituximab.

Anti-JC virus antibody sera positivity and index value among patients with multiple sclerosis may be correlated with age, sex, and area of residence.

Anti-JC virus (JCV) antibody index is the predictive factor of progressive multifocal leukoencephalopathy (PML) for multiple sclerosis (MS) patients treating with natalizumab. The aim of this study is to evaluate the prevalence of anti-JCV antibody positivity and index among Iranian patients who are the candidate for natalizumab and its correlation with their demographic data and previous therapies. A cross-sectional design was assessed for receiving anti-JCV antibody test results between January 2014 and December 2016. Demographic data and disease characteristics were also obtained. Statistical analysis and logistic regression were done using SPSS. Among 803 MS patients that were observed, the prevalence of anti-JCV antibody positivity was 67.9% (mean of index = 2.23 ± 1.16) and 67.6% of positive patients had an index ≥ 1.5. Males were more antibody positive than females (81.7 and 64% respectively; significance (sig.) < 0.001, OR = 2.51, CI 1.65-3.81). The rate of positivity was lower in patients under the age of 18. Patients who lived in cold regions had significantly more prevalence of positivity (Num. = 403; sig. = 0.043 and OR = 1.86; CI 1.02-3.39) and with higher rate of index ≥ 1.5 (sig. = 0.017; OR = 3.99, CI 1.79-8.88). Disease onset age between 28 and 37years were more positive compared to 18-27years (N = 480; sig. = 0.02; OR = 1.85, CI 1.09-3.14). Age, male gender, onset age, and cold area of residency significantly influenced anti-JCV antibody sera positivity. Only age of onset and cold area of residency were related to the index. No significant difference was observed between type, dosage, and duration of previous immunosuppressant drugs and anti-JCV antibody positivity and index value.

Evolución de una serie de pacientes con esclerosis múltiple remitente-recurrente tratados con natalizumab durante 7 años mediante el parámetro no evidencia enfermedad activa

IntroductionThe safety and effectiveness of natalizumab in patients with relapsing-remitting multiple sclerosis (RRMS) has been demonstrated in clinical trials. However, due to the limitations of these trials, it is important to know how the condition behaves under long-term clinical practice conditions. ObjectiveTo determine the long-term effectiveness of natalizumab in patients with RRMS by means of annual evaluation of the “no evidence of disease activity” (NEDA) parameter, which includes number of relapses, disability (measured with the Expanded Disability Status Scale), and brain MRI parameters. Patients and methodsWe performed a retrospective study of patients with RRMS from 3 centres who were treated with one or more doses of natalizumab. Each year, we evaluated NEDA status and safety based on the percentage of patients who discontinued treatment with natalizumab and experienced adverse reactions. ResultsThe study included 89 patients, most of whom received treatment for 2 to 4 years, with a follow-up period of up to 7 years. Natalizumab significantly reduces the radiological and clinical progression of the disease, as well as the annual rate of relapses. The NEDA parameter demonstrates the effectiveness of the drug, with values of 75.28% for year one and 66.67% for year 7. Twenty-five patients (28.1%) dropped out after a median of 4 years. Fourteen of these patients (56%) dropped out due to the appearance of anti–JC virus antibodies, either in isolation or associated with another cause. Four dropouts (16%) were due to treatment ineffectiveness, with one patient dying due to progressive multifocal leukoencephalopathy. ConclusionsNatalizumab is highly effective as measured by the NEDA long-term remission parameter.

Safety and Efficacy of Natalizumab in Japanese Patients with Relapsing-Remitting Multiple Sclerosis: Open-Label Extension Study of a Phase 2 Trial.

IntroductionThe efficacy of natalizumab was evaluated in Japanese patients with relapsing-remitting multiple sclerosis (RRMS) in a 24-week, phase 2 bridging study. An open-label, 2-year extension study from this trial was conducted to assess the safety and efficacy of natalizumab treatment in Japanese patients.MethodsA total of 97 patients (43 previously on placebo; 54 previously on natalizumab) who had completed the bridging study were treated with 300 mg natalizumab every 4 weeks. Multiple sclerosis relapses, changes in Expanded Disability Status Scale (EDSS) scores, and adverse events were assessed at regular intervals. Anti-natalizumab and anti-JC virus (JCV) antibodies were measured.ResultsAfter 2 years of natalizumab treatment, the mean adjusted annualized relapse rate was 0.30 (95% confidence interval [CI]: 0.18–0.52) among previously-on-placebo patients and 0.13 (95% CI: 0.05–0.29) among previously-on-natalizumab patients. The mean change in EDSS score from baseline to week 120 was −0.03 among previously-on-placebo patients and −0.18 among previously-on-natalizumab patients. In both groups, >90% of patients experienced ≥1 adverse event. Two previously-on-placebo patients developed persistently positive anti-natalizumab antibodies. Approximately 65% of all patients tested positive for anti-JCV antibodies at open-label treatment initiation. No deaths or progressive multifocal leukoencephalopathy cases were reported.ConclusionsThe efficacy and safety findings from this 2-year open-label extension study are comparable to and confirm the results of other clinical trials of natalizumab conducted in non-Asian patient populations, and provide longer-term evidence of efficacy and safety in Japanese patients.Trial registrationClinicalTrials.gov identifier NCT01416155.FundingBiogen.

Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Several disease-modifying therapies have been shown to ameliorate the disease course; however, the individual treatment response and the occurrence of adverse events remain highly unpredictable. In the last 2 decades, a multitude of studies have aimed to identify biomarkers that enable treatment allocation in the individual patient or subgroup of patients with regard to treatment efficacy and safety profile. Following a PubMed database search, we provide an overview on what is presently known about body fluid markers for the prediction of response to the currently approved MS therapeutics. We also discuss the potential use of biomarkers with regard to drug-induced adverse events. To date, only a few molecules have been introduced in clinical routine: anti-drug antibodies against interferon (IFN)-β and natalizumab that are associated with abolished drug levels and treatment failure; anti-JC virus (JCV) antibody index that allows risk stratification for the development of progressive multifocal leukoencephalopathy (PML), a rare but severe adverse event during natalizumab treatment; and serostatus of varicella zoster virus as screening examination prior to fingolimod therapy to prevent the infection. A few candidate biomarkers still need closer examination, such as type I IFN signature and T-helper cell (Th)-17 reactivity for prediction of IFN-β treatment response, L-selectin expression for prediction of natalizumab-associated PML, interleukin (IL)-21 levels for prediction of secondary autoimmunity after exposure to alemtuzumab, lymphocyte count with regard to PML risk while receiving dimethyl fumarate or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) for monitoring of cardiac side effects during mitoxantrone therapy.

An Evaluation of the Longitudinal Stability of Anti-JC Virus (JCV) Antibody Levels in Patients with Multiple Sclerosis (MS) (P3.093)

An Evaluation of the Longitudinal Stability of Anti-JC Virus (JCV) Antibody Levels in Patients with Multiple Sclerosis (MS) (P3.093)

Anti-JC Virus Antibody Status and Use of Immunomodulatory Therapies in Patients with Multiple Sclerosis (P3.094)

Anti-JC Virus Antibody Status and Use of Immunomodulatory Therapies in Patients with Multiple Sclerosis (P3.094)

Longitudinal analyses of anti-JCV antibody index for risk assessment of progressive multifocal leukoencephalopathy.

Risk assessment for natalizumab-associated progressive multifocal leukoencephalopathy (Nat-PML) comprises the anti-JC virus (JCV) antibody index (AI). The anti-JCV AI was longitudinally determined in a natalizumab-treated MS cohort (Nat-MS, n = 468) and samples of Nat-PML patients (n = 15). In Nat-MS, the median AI was 0.8 (25th to 75th percentile, 0.2–2.8) with an intra-individual coefficient of variation (CV) of 9.8% (4.8–17.6). Patients with an AI ≤ 0.9 exhibited higher CV. The AI was higher (3.4 (3.1–3.6)) in samples before Nat-PML diagnosis than in seropositive Nat-MS (2.4 (1.0–3.4), n = 298, p = 0.010). AIs ≥ 3.0 were associated with a 14.5-fold (95% CI 2.3–90.4) increased PML risk (p = 0.002). Groups with an AI below 1.5 exhibit higher variability or even serostatus fluctuation. AI dynamics require further investigation.

Progressive Multifocal Leukoencephalopathy in a Multiple Sclerosis Patient Diagnosed after Switching from Natalizumab to Fingolimod.

Background. Natalizumab- (NTZ-) associated progressive multifocal leukoencephalopathy (PML) is a severe and often disabling infectious central nervous system disease that can become evident in multiple sclerosis (MS) patients after NTZ discontinuation. Recently, novel diagnostic biomarkers for the assessment of PML risk in NTZ treated MS patients such as the anti-JC virus antibody index have been reported, and the clinical relevance of milky-way lesions detectable by MRI has been discussed. Case Presentation and Conclusion. We report a MS patient in whom PML was highly suspected solely based on MRI findings after switching from NTZ to fingolimod despite repeatedly negative (ultrasensitive) polymerase chain reaction (PCR) testing for JC virus DNA in cerebrospinal fluid. The PML diagnosis was histopathologically confirmed by brain biopsy. The occurrence of an immune reconstitution inflammatory syndrome (IRIS) during fingolimod therapy, elevated measures of JCV antibody indices, and the relevance of milky-way-like lesions detectable by (7 T) MRI are discussed.