Risk Of PML Research Articles

Risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis treated with low‐dose natalizumab following fingolimod

AbstractObjectiveProgressive multifocal leukoencephalopathy (PML) may rarely develop in multiple sclerosis (MS) patients treated with certain disease‐modifying drugs. A female patient weighing 40 kg developed PML with 12 copies/mL of prototype JC virus (JCV) DNA in the cerebrospinal fluid after 11 y of 4 mg/kg every 6 wk with natalizumab (NTZ) and intermittent holidays of fingolimod (FTY). The aim of this study was to analyze the PML risk of this case.MethodsThe lymphocyte subsets of CD4+ CD62L+ (central memory) and CD8+ CD62L− (effector memory) were analyzed. Additionally, the total dosage per kg for 1 y before the onset of PML and the transition of the JCV index were assessed.ResultsIn PML‐naïve MS patients, both lymphocyte‐subset counts decreased during FTY therapy but recovered after FTY cessation. However, in this PML patient the recovery took more than 2 y. In the PML patient, the JCV index increased by 1.17 over 1 y until 10 mo before the onset of PML.ConclusionsAlthough each factor alone is not sufficient to pose a risk in our present PML patient, the presence of multiple factors may increase the risk of PML. Administering drugs such as NTZ, which carry a PML risk, to patients with a history of FTY treatment warrants caution. Dosage and interval adjustments of NTZ should be considered. Our study suggests the possibility that FTY may increase PML risk, highlighting the importance of considering the history of immunosuppressive drug therapy when administering NTZ in MS patients.

MS treatment de-escalation: review and commentary.

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.

Influence of physicians' risk perception on switching treatments between high- efficacy and non-high-efficacy disease‑modifying therapies in multiple sclerosis.

The decision of initiating treatment for multiple sclerosis (MS) with a high-efficacy DMT (HE DMT) or non-high-efficacy DMT (non-HE DMT) is influenced by several factors, including risk perception of patients and physicians. Investigate the influence of physicians' risk perception on decision-making when switching treatments for MS and the reasons for switching. Data were drawn from the Adelphi Real-World MS Disease-Specific Program (a retrospective survey) and analysis included people with RMS identified between 2017- 2021. Of 4129 patients with reasons for switch available, 3538 switched from non-HE DMT and 591 from HE DMT. Overall, 4.7% of patients were switched treatment by their physicians due to the risk of malignancies and infections including PML risk. The proportion of switches that were made due to the risk of PML were 23.9% in the HE DMT and 0.5% in the non-HE DMT groups. The top reasons for switching were relapse frequency (non-HE DMT vs HE-DMT: 26.8% vs 15.2%), lack of efficacy (20.9 vs 11.7) and increased number of MRI lesions (20.3% vs 12.4%). Physicians' risk perception of malignancies and infection excluding PML was not a leading factor when switching treatment. The risk of PML was a key factor, especially for switching patients from HE DMTs. In both groups, lack of efficacy was the key contributing factor for switching. Initiating the treatment with HE DMTs may potentially reduce the number of switches due to sub-optimal efficacy. These findings might help physicians to engage more in discussions with patients about the benefit/risk profile of DMTs.

Development of warm autoimmune hemolytic anemia after initiation of Ruxolitinib in a patient with STAT1 gain-of-function mutation

IntroductionSTAT1 gain-of-function (GOF) disease is associated with chronic mucocutaneous candidiasis (CMC) and a broad spectrum of infectious, inflammatory, and vascular manifestations. The Janus Kinase inhibitor ruxolitinib has been used successfully for CMC and autoimmune phenomena. We describe a case of warm autoimmune hemolytic anemia (WAIHA) in a patient with STAT1 GOF disease after initiating ruxolitinib. Case reportA 36-year-old man with STAT1 c.850G>A (p.Glu284Lys) mutation presented with CMC as well as recurrent viral and bacterial infections, lymphadenopathy, enteritis, nodular regenerative hyperplasia (NRH) and splenomegaly. Immune workup confirmed a combined immunodeficiency with hypogammaglobulinemia and T-cell lymphopenia. Ruxolitinib was initiated at 5 mg twice daily (due to pre-existing thrombocytopenia) with up titration over 3 months to 20 mg twice daily. He improved with weight gain, increased energy, resolution of chronic anemia, and improved lymphadenopathy and splenomegaly on imaging. Serum CXCL9 only minimally decreased from 4660 pg/ml to 3990 pg/ml. Soon after reaching ruxolitinib 20 mg twice daily, he developed JC viremia, prompting dose reduction to 15 mg BID. Within two weeks, he developed a non-COVID upper respiratory tract infection followed by fatigue, shortness of breath with ambulation, and dark urine. Emergency evaluation revealed warm antibody positive hemolytic anemia with a hemoglobin of 5 g/dL, and worsened thrombocytopenia. He was treated with blood transfusions, pulse steroids, and high-dose IVIG with stabilization but continued hemolysis. Due to the JC viremia, there was concern to give rituximab with increased PML risk. Bone marrow showed trilineage hematopoiesis, a mild increase in megakaryocytes and RBC precursors, and a loss of B-cell progenitors with retention of mature B cells. His B and T lymphocyte numbers had increased since prior to ruxolitinib, with a predominance of Tfh1-cells (58.7% of total Tfh-cells). He was started on sirolimus with a slow taper of prednisone with continued stable hemoglobin and platelets, and resolution of hemolysis after 3 months. ConclusionTo our knowledge, this is the first case of a STAT1 GOF patient developing WAIHA while receiving ruxolitinib therapy. Treatment choices were complicated by the risks of PML. Sirolimus combined with ruxolitinib allowed wean of corticosteroid and subsequent resolution of hemolysis.

Natalizumab continuation versus switching to ocrelizumab after PML risk stratification in RRMS patients: a natural experiment

BackgroundNatalizumab (NTZ) and ocrelizumab (OCR) can be used for the treatment of relapsing–remitting multiple sclerosis (RRMS). In patients treated with NTZ, screening for JC virus (JCV) is mandatory, and a positive serology usually requires a change in treatment after 2 years. In this study, JCV serology was used as a natural experiment to pseudo-randomize patients into NTZ continuation or OCR.MethodsAn observational analysis of patients who had received NTZ for at least 2 years and were either changed to OCR or maintained on NTZ, depending on JCV serology status, was performed. A stratification moment (STRm) was established when patients were pseudo-randomized to either arm (NTZ continuation if JCV negativity, or change to OCR if JCV positivity). Primary endpoints include time to first relapse and presence of relapses after STRm and OCR initiation. Secondary endpoints include clinical and radiological outcomes after 1 year.ResultsOf the 67 patients included, 40 continued on NTZ (60%) and 27 were changed to OCR (40%). Baseline characteristics were similar. Time to first relapse was not significantly different. Ten patients in the JCV + OCR arm presented a relapse after STRm (37%), four during the washout period, and 13 patients in the JCV-NTZ arm (32.5%, p = 0.701). No differences in secondary endpoints were detected in the first year after STRm.ConclusionsThe JCV status can be used as a natural experiment to compare treatment arms with a low selection bias. In our study, switching to OCR versus NTZ continuation led to similar disease activity outcomes.

Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies.

Progressive multifocal leukoencephalopathy (PML) is a rare and often lethal brain disorder caused by the common, typically benign polyomavirus 2, also known as JC virus (JCV). In a small percentage of immunosuppressed individuals, JCV is reactivated and infects the brain, causing devastating neurological defects. A wide range of immunosuppressed groups can develop PML, such as patients with: HIV/AIDS, hematological malignancies (e.g., leukemias, lymphomas, and multiple myeloma), autoimmune disorders (e.g., psoriasis, rheumatoid arthritis, and systemic lupus erythematosus), and organ transplants. In some patients, iatrogenic (i.e., drug-induced) PML occurs as a serious adverse event from exposure to immunosuppressant therapies used to treat their disease (e.g., hematological malignancies and multiple sclerosis). While JCV infection and immunosuppression are necessary, they are not sufficient to cause PML. We hypothesized that patients may also have a genetic susceptibility from the presence of rare deleterious genetic variants in immune-relevant genes (e.g., those that cause inborn errors of immunity). In our prior genetic study of 184 PML cases, we discovered 19 candidate PML risk variants. In the current study of another 152 cases, we validated 4 of 19 variants in both population controls (gnomAD 3.1) and matched controls (JCV+ multiple sclerosis patients on a PML-linked drug ≥ 2 years). The four variants, found in immune system genes with strong biological links, are: C8B, 1-57409459-C-A, rs139498867; LY9 (alias SLAMF3), 1-160769595-AG-A, rs763811636; FCN2, 9-137779251-G-A, rs76267164; STXBP2, 19-7712287-G-C, rs35490401. Carriers of any one of these variants are shown to be at high risk of PML when drug-exposed PML cases are compared to drug-exposed matched controls: P value = 3.50E-06, OR = 8.7 [3.7-20.6]. Measures of clinical validity and utility compare favorably to other genetic risk tests, such as BRCA1 and BRCA2 screening for breast cancer risk and HLA-B*15:02 pharmacogenetic screening for pharmacovigilance of carbamazepine to prevent Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. For the first time, a PML genetic risk test can be implemented for screening patients taking or considering treatment with a PML-linked drug in order to decrease the incidence of PML and enable safer use of highly effective therapies used to treat their underlying disease.

Effectiveness of Natalizumab in Achieving No Evidence of Disease Activity (NEDA-3)-Data From a Local Norwegian Cohort.

Objective: We aimed to determine the effectiveness of natalizumab (NTZ) by assessing overall No Evidence of Disease Activity 3 (NEDA-3) in a local Norwegian cohort.Background: NTZ is an immunomodulating drug used in the treatment of multiple sclerosis (MS). It has typically been used as a second-line treatment, but certain patients with high disease activity have started directly with NTZ.Methods: This retrospective cohort study includes all patients who received NTZ for relapsing–remitting MS at Nordland Hospital in the period 2008–2018. In June 2019, status for every patient was assessed, and a survival curve was used to show the cumulative probability of achieving NEDA-3 over time.Results: The cohort consisted of 66 patients, 49 women and 17 men with a mean age of 40.0 ± 10.8 years. Each patient received on average 45.8 ± 36.4 NTZ infusions. Mean age and Expanded Disability Status Scale (EDSS) at first infusion was 34.8 ± 10.5 and 3.2 ± 1.9, respectively. Prior to NTZ treatment, 83% had used other disease modulating drugs and 65% were anti-JC virus (JCV) seronegative. During the study period, seven patients converted to seropositive. In 2019, 40 patients had switched or stopped treatment: 19 due to positive JCV serostatus, 9 due to disease activity, 7 due to adverse effects or complications (1 progressive multifocal leukoencephalopathy), 2 due to pregnancy, and 3 due to autologous hematopoietic cell transplantation abroad. Three patients experienced rebound in the wake of discontinuation (7.5%). Of the patients receiving NTZ for more than 3 years (n = 33), 50% had achieved NEDA-3 after 3 years. Compared to those with evidence of disease activity (EDA), these NEDA-3 patients had significant lower EDSS score before first NTZ treatment (p = 0.04). They were also slightly, but not significantly, younger at debut of their MS, at the diagnosis and at first NTZ treatment. Of all the patients who ever started on NTZ, 23% had achieved NEDA-3 5 years later. The mean EDSS in 2019 was 3.6 ± 2.5.Conclusion: Despite the high rate of treatment switch, mainly due to the risk of PML, almost one in four who started on NTZ achieved NEDA-3 after 5 years, and the overall disease progression was low in the total cohort. Treating less advanced disease seems to predict better long-term stability.

Dimethyl fumarate: risk of PML associated with mild lymphopenia

Dimethyl fumarate: risk of PML associated with mild lymphopenia

Ofatumumab - a new drug for the treatment of multiple sclerosis

Recently anti-B-cell therapy has been increasingly integrated into the treatment of multiple sclerosis (MS). This review is devoted to ofatumumab, a new drug of this line. Ofatumumab, an all-human monoclonal antibody used to treat chronic leukemia, binds to a different region than the binding site of other CD20 antibodies, including both a small and large loop in the CD20 receptor structure. This monoclonal antibody provides favorable results for MS by reducing the frequency of exacerbations and the risk of disability progression, significantly more pronounced when compared with teriflunomide. The drug can be used in patients with active relapsing MS and SPMS with exacerbations, with the ineffectiveness of first-line drugs as one of the options for second-line therapy, in patients with highly active MS, especially with a high risk of PML (transfer from natalizumab), as well as if there are difficulties in organizing intravenous courses in day hospitals (produced as outpatient injections).

New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab.

Overview: We assessed the role of age and disease activity as new factors contributing to establish the risk of progressive multifocal leucoencephalopathy in multiple sclerosis patients treated with natalizumab in 36 University Hospitals in Europe. We performed the study in 1,307 multiple sclerosis patients (70.8% anti-John Cunninghan virus positive antibodies) treated with natalizumab for a median time of 3.28 years. Epidemiological, clinical, and laboratory variables were collected. Lipid-specific IgM oligoclonal band status was available in 277 patients. Factors associated with progressive multifocal leucoencephalopathy onset were explored by uni- and multivariate logistic regression.Results: Thirty-five patients developed progressive multifocal leucoencephalopathy. The multivariate analysis identified anti-John Cunninghan virus antibody indices and relapse rate as the best predictors for the onset of this serious opportunistic infection in the whole cohort. They allowed to stratify progressive multifocal leucoencephalopathy risk before natalizumab initiation in individual patients [area under the curve (AUC) = 0.85]. The risk ranged from <1/3,300 in patients with anti-John Cunninghan virus antibody indices <0.9 and relapse rate >0.5, to 1/50 in the opposite case. In patients with lipid-specific IgM oligoclonal bands assessment, age at natalizumab onset, anti-John Cunninghan virus antibody indices, and lipid-specific IgM oligoclonal band status predicted progressive multifocal leucoencephalopathy risk (AUC = 0.92). The absence of lipid-specific IgM oligoclonal bands was the best individual predictor (OR = 40.94). The individual risk ranged from <1/10,000 in patients younger than 45 years at natalizumab initiation, who showed anti John Cunningham virus antibody indices <0.9 and lipid-specific IgM oligoclonal bands to 1/33 in the opposite case.Conclusions: In a perspective of personalized medicine, disease activity, anti-lipid specific IgM oligoclonal bands, anti Jonh Cunninghan virus antibody levels, and age can help tailor natalizumab therapy in multiple sclerosis patients, as predictors of progressive multifocal leucoencephalopathy.

Editors' note: Prospective validation of the PML risk biomarker l -selectin and influence of natalizumab extended intervals

In “Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals,” Schwab et al. reported that natalizumab is associated with reduction in l-selectin (CD62L) values and an increase in risk of PML but that cessation of natalizumab or extension of treatment intervals leads to recovery of CD62L values, which could potentially decrease risk of PML. Tugemann commented that the sensitivity of this biomarker was affected by inclusion of samples from patients who developed PML—which could falsely increase results about the sensitivity of the marker—and patients who were JC virus (JCV)-negative, which could falsely decrease results about the sensitivity of the marker. Therefore, Tugemann believes that the analysis should have been restricted to patients who were JCV-positive without PML. Schwab et al. responded that (1) because this study was conducted prospectively, they were not aware of PML diagnosis when they processed the samples but that this mirrored a real-world scenario in which a clinician would send the biomarker without knowing a patient had PML, only to subsequently make the diagnosis and (2) they did not have JCV data for all patients. Despite these limitations, they emphasized the utility of CD62L values to stratify risk for PML and to assist with decision-making about the timing of natalizumab dosing, recognizing that the challenging methodology precludes widespread use. Thus, most clinicians will still have to resort to risk stratification for natalizumab use based on duration of treatment, exposure to other immunosuppression regimens, and JCV positivity. In “Prospective validation of the PML risk biomarker l-selectin and influence of natalizumab extended intervals,” Schwab et al. reported that natalizumab is associated with reduction in l-selectin (CD62L) values and an increase in risk of PML but that cessation of natalizumab or extension of treatment intervals leads to recovery of CD62L values, which could potentially decrease risk of PML. Tugemann commented that the sensitivity of this biomarker was affected by inclusion of samples from patients who developed PML—which could falsely increase results about the sensitivity of the marker—and patients who were JC virus (JCV)-negative, which could falsely decrease results about the sensitivity of the marker. Therefore, Tugemann believes that the analysis should have been restricted to patients who were JCV-positive without PML. Schwab et al. responded that (1) because this study was conducted prospectively, they were not aware of PML diagnosis when they processed the samples but that this mirrored a real-world scenario in which a clinician would send the biomarker without knowing a patient had PML, only to subsequently make the diagnosis and (2) they did not have JCV data for all patients. Despite these limitations, they emphasized the utility of CD62L values to stratify risk for PML and to assist with decision-making about the timing of natalizumab dosing, recognizing that the challenging methodology precludes widespread use. Thus, most clinicians will still have to resort to risk stratification for natalizumab use based on duration of treatment, exposure to other immunosuppression regimens, and JCV positivity.

High effector-memory CD8+ T-cell levels correlate with high PML risk in natalizumab-treated patients

BackgroundProgressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab (NTZ) treatment in multiple sclerosis (MS) patients. Based on the analysis of cryopreserved cells, several reports have showed that CD62L+ CD4+ T-cells percentage drops before PML onset. ObjectiveTo analyze CD62L and CD45RA expression on fresh-blood CD4+ and CD8+ T-cells from NTZ-treated patients, according to their estimated PML risk. MethodsWe prospectively enrolled 74 MS patients, including 62 NTZ-treated, and stratified them into low, intermediate and high PML risk groups. Circulating naïve and memory T-cell subsets were analyzed by flow cytometry. ResultsWe found no correlation between the percentage of CD62L+ CD4+ T-cells and PML risk. In contrast, the repartition of CD8+ T-cells subpopulations was altered in the high risk group: both the percentage and absolute count of CD8+ CD62L- CD45RA- effector memory T- cells (TEM) was significantly higher compared to patients at lower risk despite similar CD3+ and CD8+ T-cell counts. One high-risk patient with elevated CD8+ TEM and CD62L+ CD4+ T-cell levels developed PML six months after sampling. ConclusionOur results suggest that CD8+ TEM cells should be evaluated in larger studies as a potential surrogate marker of PML risk in NTZ-treated patients.

Progressive Multifocal Leukoencephalopathy: Current Insights.

Cases of PML should be evaluated according to predisposing factors, as these subgroups differ by incidence rate, clinical course, and prognosis. The three most significant groups at risk of PML are patients with hematological malignancies mostly previously treated with immunotherapies but also untreated, patients with HIV infection, and patients using monoclonal antibody (mAb) treatments. Epidemiological data is scarce and partly conflicting, but the distribution of the subgroups appears to have changed. While there is no specific anti-JCPyV treatment, restoration of the immune function is the most effective approach to PML treatment. Research is warranted to determine whether immune checkpoint inhibitors could benefit certain PML subgroups. There are no systematic national or international records of PML diagnoses or a risk stratification algorithm, except for MS patients receiving natalizumab (NTZ). These are needed to improve PML risk assessment and to tailor better prevention strategies.

1766. Osimertinib-Associated Progressive Multifocal Leucoencephalopathy

BackgroundProgressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of white matter in the central nervous system (CNS) caused by reactivation of John Cunningham (JC) virus. Drug-induced PML is increasingly reported with the widely used biological immunosuppressant drugs and molecular targeted antineoplastic agents. Monoclonal antibodies were the pioneer drugs to be associated with PML including the prototypical natalizumab.MethodsEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been rarely described in this context with few case reports of ibrutinib-associated PML. Osimertinib, a third-generation EGFR TKI, was recently FDA-approved for the first-line treatment of metastatic non-small-cell lung cancer (NSCLC), and to the best of our knowledge has never been associated with PML. We describe a case report of a rapidly progressive PML likely associated with osimertinib therapy.ResultsA 85-year-old female with history of NSCLC, on osimertinib, was admitted with progressively worsening left hemiparesis, facial palsy, unsteady gait, recurrent falls, and episodic confusion over a period of month. Brain magnetic resonance imaging revealed foci of non-enhancing increased T2 and fluid-attenuated inversion recovery (FLAIR) signal intensity in the periventricular and bilateral cerebral subcortical white matter. MRI cervical spine was unremarkable for acute enhancing lesions. Cerebrospinal fluid (CSF) was unremarkable for infectious etiology, oligoclonal bands, and cytology. The patient was readmitted 2 weeks later with worsening neurological deficits and new lesions in the bilateral middle cerebellar peduncles, pons, midbrain, and cerebral white matter. Positive CSF JC virus PCR lead to the final diagnosis of “probable” PML. Biopsy was deferred for high clinical suspicion of PML and procedural risks outweighing benefits. Osimertinib was likely contributing to PML in the absence of other immunosuppression.ConclusionInhibition of tyrosine kinase-dependent pathways can potentially aid in the replication of JC virus per previously reported ibrutinib-associated PML. Clinicians should be aware of PML risk in patients on osimertinib and TKI therapy, especially those with positive serum JC virus serology. Disclosures All authors: No reported disclosures.

Extended dosing interval reduces risk of natalizumab-related PML

Extended dosing interval reduces risk of natalizumab-related PML

PML Risk Perception in Patients Initiating Natalizumab for Multiple Sclerosis (P4.2-033)

PML Risk Perception in Patients Initiating Natalizumab for Multiple Sclerosis (P4.2-033)

Understanding risk of PML through multiple sclerosis

Understanding risk of PML through multiple sclerosis

Daclizumab, a Potential Exit Strategy in MS Patients at High Risk for Natalizumab-Associated PML? (P5.105)

Daclizumab, a Potential Exit Strategy in MS Patients at High Risk for Natalizumab-Associated PML? (P5.105)

Can Personalized Natalizumab Dosing Mitigate PML Risk and Minimize Disease Breakthrough? A Novel Assessment of Active Unbound Natalizumab (P5.346)

Can Personalized Natalizumab Dosing Mitigate PML Risk and Minimize Disease Breakthrough? A Novel Assessment of Active Unbound Natalizumab (P5.346)

Serum anti-JCV antibody indexes in Japanese patients with multiple sclerosis: elevations along with fingolimod treatment duration.

The risk of developing progressive multifocal leukoencephalopathy in natalizumab-treated multiple sclerosis (MS) patients is related to serum anti-JCV antibody (JCVAb) index. However, the correlation of JCVAb index with other disease-modifying treatments (DMTs) is not well understood. In this study, we investigated the JCVAb seropositivity rate/JCVAb indexes and its correlation with clinical profiles in Japanese MS patients, and the relationship between JCVAb indexes and DMTs. JCVAb indexes were measured in 149 serum samples from 105 patients with MS. JCVAb indexes and seropositivity, and their correlation with age, sex, disease duration, Kurtzke expanded disability status scale and the duration of the DMTs were evaluated in each patient. JCVAb was positive in 73 of 105 MS patients. Within 40 fingolimod-treated patients, 27 were positive for JCVAb and JCVAb indexes were positively correlated with the duration of fingolimod treatment. No significant relation was found between JCVAb indexes and the duration of treatment for the other disease-modifying drugs. JCVAb seropositivity was comparatively high in Japanese MS patients. Fingolimod treatment is likely to increase serum JCVAb index, possibly leading to the development of PML. Therefore, it is advised that JCVAb index should be serially monitored during fingolimod treatment to decrease PML risk.