Risk Of Progressive Multifocal Leukoencephalopathy Research Articles

Progressive multifocal leukoencephalopathy reports in rheumatoid arthritis concerning different treatment patterns-an exploratory assessment using the food and drug administration adverse event reporting system

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but potentially life-threatening brain infection caused by the John Cunningham virus. PML is a known adverse effect associated with molecular-targeted drugs and immunosuppressive agents. Recent concerns have emerged regarding the link between methotrexate (MTX) and PML. However, limited information exists on the influence of concomitant drug use in rheumatoid arthritis (RA) treatment, where various medications are often used together.Methods: To explore treatment patterns and patient background that affect PML reporting in RA, we analyzed data on RA cases from the Food and Drug Administration Adverse Event Reporting System (FAERS; JAPIC AERS) database between 1997 and 2019.Results and Discussion: Our analysis revealed significantly elevated crude and adjusted reporting odds ratios (aROR) for MTX, rituximab (RIT), azathioprine, and cyclophosphamide. When considering treatment patterns, the concomitant use of MTX and RIT showed a higher aROR than using MTX or RIT alone. Additional TNF-α inhibitors or glucocorticoids did not increase PML reports. Moreover, male sex and older age were associated with increased PML reports. While limitations are inherent in studies using spontaneous reporting data, our exploratory assessment suggests an association between PML and the combination of MTX and RIT and a higher risk in men and older patients. These findings help enhance our understanding of PML risk factors in the context of RA treatment.

Association of B-cell activating factor gene variants with serum anti-JCV antibody positivity in male patients with multiple sclerosis under natalizumab treatment: Implications for progressive multifocal leukoencephalopathy risk stratification

IntroductionProgressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. Methods162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. ResultsWhile type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (−) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. ConclusionsOur study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.

Absence of JC polyomavirus in stool samples of patients with multiple sclerosis despite high anti-JCV antibodies in serum

BackgroundNatalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal leukoencephalopathy (PML). So far, the relevant reservoir for PML-type JC polyomavirus (JCV) remains elusive. We here tested if the detection of JCV-DNA in stool of persons with MS treated with natalizumab could be a future tool for PML risk assessment. MethodsThe presence of JCV-DNA in stool, urine, and whole blood of MS patients treated with natalizumab and known serum anti-JCV antibodies index values (IV) was studied. Different DNA extraction methods, real-time (RT) and droplet digital (dd) PCR techniques were compared. JCV isolates were screened for PML-associated variants by sequencing. ResultsThirty MS patients treated with natalizumab were screened. For 21 patients, blood, stool, and urine samples were available. These patients were stratified according to their serum anti-JCV antibody IV (high (>1.5, n = 12); medium (1.5–0.9, n = 2); low (<0.9, n = 1); negative (n = 6)). JCV-DNA could not be detected in the whole blood or stool samples. Four urine samples had measurable JCV-DNA, ranging from 1.71×104–1.07×108 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×104–9.85×106 copies/mL measured by ddPCR. All JCV variants were wild-type and derived from patients with high antibody IV. ConclusionStool-specific DNA extraction methods provided the highest quality of DNA, while the sensitivity of ddPCR and RT- PCR was comparable. Our findings do not support assessing stool samples for PML risk stratification in persons with MS. Further studies are needed to explore where PML-associated viral variants arise.

Switching from natalizumab to an anti-CD20 monoclonal antibody in relapsing remitting multiple sclerosis: A systematic review

BackgroundUse of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established. MethodsIn accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included. ResultsThe overall incidence of clinical relapse during washout periods ranging from 4.4–10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02–0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %. ConclusionsThis systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.

Reduced Risk of Progressive Multifocal Leukoencephalopathy (PML) with Natalizumab Extended Interval Dosing (EID) Compared with Every-4-week (Q4W) Dosing: Updated Analysis of the TOUCH® Prescribing Program Database (P10-6.005)

Reduced Risk of Progressive Multifocal Leukoencephalopathy (PML) with Natalizumab Extended Interval Dosing (EID) Compared with Every-4-week (Q4W) Dosing: Updated Analysis of the TOUCH® Prescribing Program Database (P10-6.005)

Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis.

Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach. The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test. A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI -0.08 to 0.09; I2=20.4%; p=0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2=50%; p=0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ±20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID. A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.

Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation. Cladribine tablets act as a synthetic adenosine analog, disrupting DNA synthesis and repair, thereby reducing the number of lymphocytes. The generation of prospective, rigorous safety, and efficacy data in transitioning from natalizumab to cladribine is an unmet clinical need. To test the feasibility of transitioning patients with relapsing forms of MS natalizumab to cladribine tablets. Cladribine tablets after treatment with natalizumab (CLADRINA) is an open-label, single-arm, multicenter, collaborative phase IV, research study that will generate hypothesis regarding the safety, efficacy, and immunological impact of transition from natalizumab to cladribine tablets in patients with relapsing forms of MS. Participants will be recruited from three different sites. The primary endpoint is the absolute and percent change from baseline of lymphocytes and myeloid cell subsets, as well as blood neurofilament light levels. The secondary endpoint is the annualized relapse rate over the 12- and 24-month trial periods. Exploratory endpoints include the expanded disability status scale, and magnetic resonance imaging outcomes. The CLADRINA trial will generate data regarding the safety, efficacy, and immunological impact of the transition from natalizumab to cladribine. As the pace of immunological knowledge of MS continues, insight into disease modifying therapy transition strategies is needed.

Anxiety and Perception of Disease Control in Multiple Sclerosis Subjects Treated with Natalizumab.

Multiple sclerosis subjects treated with natalizumab face anxiety about developing progressive multifocal leukoencephalopathy (PML), besides the psychological distress caused by the disease. The aim of this study is to investigate whether increasing the frequency of neurological and nuclear magnetic resonance screening may affect anxiety and the perception of disease control in patients treated with natalizumab. A total of 62 relapsing-remitting multiple sclerosis patients were recruited from 2019 to 2020. All patients received conventional infusion treatments with natalizumab, along with a screening protocol for PML. Three clinical assessments were considered: at the beginning of the study (T0), after 3 months (T1) and after 6 months (T2). Patients were classified into three levels of risk, where level 1 represented a low risk of PML and level 3 a high risk. This classification determined treatment and screening protocol, i.e., the frequency of performing the Stratify test and the brain 3T NMR exam, as well as the frequency of infusion treatments. Anxiety and perception of disease control were assessed at T0, T1, and T2 by a skilled psychologist. The Friedman test and the Wilcoxon signed-rank test were used to compare outcomes at baseline with the two follow-ups. Statistical test results showed that the risk of PML (per 1000 patients) was significantly lower in women than in men (W = 198.5; p = 0.01). Moreover, significant differences between baseline and the two follow-ups were found, both for anxiety (F(2) = 122.6, p < 0.001) and for perception of disease control (F(2) = 123.5, p < 0.001). In both cases, there was significant improvement between baseline (T0) and the end of the study (T2) in any risk level (p < 0.001). An increase in the number of follow-ups, as well as an increase in instrumental investigations, might have a positive effect on both anxiety and the perception of disease control. However, there are many variables involved in the disease process that have an impact on patients' psychological well-being. Therefore, further and more extensive studies are necessary to evaluate how, and how much, each variable impacts the disease course.

Hydroxychloroquine can be resumed with close monitoring after retinopathy has developed, without major visual loss: Case Report.

To present a patient with systemic lupus erythematosus on longstanding hydroxychloroquine (HCQ) use for whom HCQ was stopped due to signs of toxicity, and then resumed four years later due to dire systemic need. Long term retrospective study. Humphrey visual fields (10-2 and 24-2), fundus autofluorescence imaging, and spectral domain OCT were used to follow progression over time. The patient was on HCQ for 26 years, with a cumulative dose over 3,000g. HCQ was stopped in 2011 due to macular toxicity. She remained off HCQ for four years, during which time she developed type 1 diabetes due to an immunologic attack on the pancreas, and then JC (John Cunningham) viremia after a period of treatment with mycophenolate, which put her at risk for progressive multifocal leukoencephalopathy. Mycophenolate was discontinued and HCQ was resumed with careful follow-up over the next 7 years. The toxic maculopathy showed only mild, slow progression since HCQ was resumed. Careful annual monitoring using HVF 10-2 and spectral domain OCT imaging remains the standard of care for patients on HCQ. However, it may be possible with close monitoring, when there is compelling systemic need, to resume HCQ after it has been stopped, with only slow progression of the retinopathy. This allowed the patient to have an improved quality of life and reduced the risk of severe morbidity and mortality.

Progressive Multifocal Leukoencephalopathy in Systemic Lupus Erythematosus: A Consequence of Patient-Intrinsic or -Extrinsic Factors?

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the central nervous system (CNS) caused by reactivation of the polyomavirus JC (JCV) typically in immunocompromised individuals. The risk of PML among rheumatic diseases may be higher for systemic lupus erythematosus (SLE), without, however, a clear association with the type and intensity of background therapy. We present the development and outcome of PML in a 32-year-old female lupus patient under mild immunosuppressive treatment, yet with marked B-cell lymphopenia in the peripheral blood and bone marrow (<1% of total lymphocytes). Despite treatment with the immune checkpoint inhibitor pembrolizumab, the patient showed progressive neurological and brain imaging deterioration and eventually died 15 months after PML diagnosis. To unveil possible underlying genetic liabilities, whole exome sequencing was performed which identified deleterious variants in GATA2 and CDH7 genes, which both have been linked to defective T- and/or B-lymphocyte production. These findings reiterate the possible role of disease-/patient-intrinsic factors, rather than that of drug-induced immunosuppression, in driving immune dysregulation and susceptibility to PML in certain patients with SLE.

Practical Clinical Guidelines for Natalizumab Treatment in Patients With Relapsing Multiple Sclerosis.

Natalizumab (TYSABRI®) was the first high-efficacy monoclonal antibody disease-modifying therapy (DMT) approved as a monotherapy for the treatment of adults with relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. Because natalizumab is administered by intravenous infusion, infusion nurses play a key role in the care of natalizumab-treated patients. In the 16 years since approval, substantial data have been gathered on the long-term, real-world effectiveness and safety of natalizumab. This article provides a synopsis of this data, as well as practical information for optimizing patient care. This includes information on strategies to mitigate the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients, natalizumab use during pregnancy, and use with vaccines. It also includes guidance on the preparation and administration of natalizumab and monitoring of natalizumab-treated patients.

Lessons learned after 20 years of real-world experience with natalizumab

BackgroundWhile natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002–2022) of experience with NTZ at our center, we observed no cases of PML. ObjectivesWe evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. MethodsFor this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. Results766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. ConclusionsThe utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.

Evaluating the efficacy and safety of transitioning patients with multiple sclerosis from natalizumab to ocrelizumab (OCTAVE)

Introduction: Natalizumab is associated with a risk of progressive multifocal leukoencephalopathy (PML) in multiple sclerosis (MS) patients infected with John Cunningham virus (JCV). Ocrelizumab has demonstrated efficacy to treat MS; however, its safety in patients previously treated with natalizumab is unclear. Objective: To evaluate the safety and efficacy of ocrelizumab in patients with relapsing MS (RMS) previously treated with natalizumab. Methods: Clinically and radiographically stable RMS patients, ages 18–65 treated with natalizumab for ⩾ 12 months, were enrolled in the study and initiated ocrelizumab 4–6 weeks after their final dose of natalizumab. Relapse assessment, expanded disability status scale, and brain magnetic resonance imaging (MRI) were performed prior to starting ocrelizumab and at months 3, 6, 9, and 12. Results: Forty-three patients were enrolled, and 41 (95%) completed the study. Two patients had a relapse while on ocrelizumab, one at month 9 and the other at month 12, without changes on brain MRI. Two additional patients had new brain MRI lesions detected at month 3, with no new symptoms. Thirteen serious adverse events (SAEs) were recorded, four of which were considered possibly related to ocrelizumab. Conclusion: Overall, our study indicates clinical and MRI stability for most patients transitioning from natalizumab to ocrelizumab. ClinicalTrials.gov Identifier: NCT03157830

Progressive multifocal leukoencephalopathy with natalizumab extended or standard interval dosing in the United States and the rest of the world

ABSTRACT Background Progressive multifocal leukoencephalopathy (PML), an important identified risk for natalizumab, has been described for standard interval dosing (SID; dosing interval every-4-weeks). Information on PML with natalizumab extended interval dosing (EID; dosing interval >every-4-weeks) in the US and the rest of the world (ROW) is limited. Research design and methods A retrospective analysis of patient demographics, risk factors, clinical characteristics, and clinical outcomes was conducted on confirmed natalizumab EID and SID PML cases evaluated from Biogen pharmacovigilance systems. Results Of 857 confirmed natalizumab PML cases, EID and SID accounted for 7.5% and 92.5%, respectively (US: 12.9% and 87.1%; ROW: 5.4% and 94.6%). PML risk factors included anti-JCV index > 1.5 (US: EID, 56.7% and SID, 12.8%; ROW: EID, 44.1% and SID, 21.0%), mean duration of natalizumab treatment (US: 90.0 and 70.2 months; ROW: 54.1 and 49.8 months), and prior immunosuppressive therapy (US: 20.0% and 21.7%; ROW:11.8% and 18.0%). In the EID and SID groups, 68.8% and 76.0% of patients, respectively, were alive at up to 2 years after diagnosis. Conclusions This analysis provides insights on PML in patients receiving natalizumab that extend current knowledge, particularly regarding PML in patients receiving natalizumab EID, which can be built upon in the future.

High levels of endothelial ICAM-1 prohibit natalizumab mediated abrogation of CD4+ T cell arrest on the inflamed BBB under flow in vitro

IntroductionThe humanized anti-α4 integrin blocking antibody natalizumab (NTZ) is an effective treatment for relapsing–remitting multiple sclerosis (RRMS) that is associated with the risk of progressive multifocal leukoencephalopathy (PML). While extended interval dosing (EID) of NTZ reduces the risk for PML, the minimal dose of NTZ required to maintain its therapeutic efficacy remains unknown.ObjectiveHere we aimed to identify the minimal NTZ concentration required to inhibit the arrest of human effector/memory CD4+ T cell subsets or of PBMCs to the blood–brain barrier (BBB) under physiological flow in vitro.ResultsMaking use of three different human in vitro BBB models and in vitro live-cell imaging we observed that NTZ mediated inhibition of α4-integrins failed to abrogate T cell arrest to the inflamed BBB under physiological flow. Complete inhibition of shear resistant T cell arrest required additional inhibition of β2-integrins, which correlated with a strong upregulation of endothelial intercellular adhesion molecule (ICAM)-1 on the respective BBB models investigated. Indeed, NTZ mediated inhibition of shear resistant T cell arrest to combinations of immobilized recombinant vascular cell adhesion molecule (VCAM)-1 and ICAM-1 was abrogated in the presence of tenfold higher molar concentrations of ICAM-1 over VCAM-1. Also, monovalent NTZ was less potent than bivalent NTZ in inhibiting T cell arrest to VCAM-1 under physiological flow. In accordance with our previous observations ICAM-1 but not VCAM-1 mediated T cell crawling against the direction of flow.ConclusionTaken together, our in vitro observations show that high levels of endothelial ICAM-1 abrogate NTZ mediated inhibition of T cell interaction with the BBB. EID of NTZ in MS patients may thus require consideration of the inflammatory status of the BBB as high levels of ICAM-1 may provide an alternative molecular cue allowing for pathogenic T cell entry into the CNS in the presence of NTZ.

Natalizumab Extended Interval Dosing (EID) is Associated with a Reduced Risk of Progressive Multifocal Leukoencephalopathy (PML) Compared with Every-4-Week (Q4W) Dosing: Updated Analysis of the TOUCH® Prescribing Program Database (P14-3.011)

Natalizumab Extended Interval Dosing (EID) is Associated with a Reduced Risk of Progressive Multifocal Leukoencephalopathy (PML) Compared with Every-4-Week (Q4W) Dosing: Updated Analysis of the TOUCH® Prescribing Program Database (P14-3.011)

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.

Progressive Multifocal Leukoencephalopathy (PML) With Anti-CD20 and Other Monoclonal Antibody (mAb) Therapies in Multiple Sclerosis (P8-3.016)

<h3>Objective:</h3> To review the incidence of progressive multifocal leukoencephalopathy (PML) associated with monoclonal antibody (mAb) therapies, specifically anti-CD20 medications used in multiple sclerosis (MS). <h3>Background:</h3> PML is an opportunistic and fatal inflammatory disease of the central nervous system, which occurs almost exclusively in immunocompromised hosts; therefore, patients receiving mAb immunotherapy become an at-risk population. B cell-depleting mAbs targeting CD20+ cells have become widely used in MS. Although their efficacy is well-known, their associated risk of PML, especially among those without previous disease-modifying therapy (DMT) exposure, has been insufficiently studied. <h3>Design/Methods:</h3> A systematic literature review of PubMed, Google Scholar, EMBASE, and Scopus was conducted by two independent researchers from June 1, 1997, to July 10, 2022. Further data was obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and individual pharmaceutical companies (Genentech, Novartis, and TG Therapeutics). Carryover cases from prior exposure to other immunosuppressants were excluded. <h3>Results:</h3> Between 2015 and 2017, 10 cases of PML were reported in the FAERS database among 334 MS patients taking rituximab; two had previously received natalizumab, leaving eight cases in total. Rituximab-associated PML was also seen in lymphoproliferative disorders (n=52), rheumatoid arthritis (n=9), and granulomatosis with polyangiitis (n=2). Two fatal PML cases were found in MS patients taking ocrelizumab. No cases of PML were reported with ofatumumab in MS; however, 5 cases were reported in chronic lymphocytic leukemia. PML has not been observed with ublituximab, which is currently under FDA review. Among other DMTs, PML was frequently reported with natalizumab (n=884), fingolimod (n=30), dimethyl fumarate (n=12), and alemtuzumab (n=1). <h3>Conclusions:</h3> Anti-CD20 therapies are a safe class of medications with a low infectious risk for PML, especially compared to other mAbs used in MS, such as natalizumab. Nonetheless, risk stratification in susceptible individuals, as done with natalizumab, could prove beneficial with all mAb treatments. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Dr. Srivastava has nothing to disclose. Dr. JENA has nothing to disclose. Dr. Kakara has nothing to disclose. Dr. Sriwastava has nothing to disclose. Maha Daimee has nothing to disclose. Dr. Xu has nothing to disclose.

Serum Natalizumab and Anti-Natalizumab Antibody Concentrations May Be Useful in Patient Management (P1-3.002)

<h3>Objective:</h3> Natalizumab (NTZ) and anti-natalizumab antibody concentrations in serum are used together to provide patient-specific pharmacokinetic and immunogenic assessment to aid in patient management. <h3>Background:</h3> NTZ is a monoclonal antibody directed against the a4-integrin subunit of a4b1 and a4b7 integrins. NTZ is used to treat relapsing and remitting forms of multiple sclerosis. Although a majority of patients on standard dosing (intravenous 300 mg, every 4 weeks) reach therapeutic drug concentrations, about 10% of patients will eventually fail NTZ therapy due to the development of anti-NTZ antibodies. <h3>Design/Methods:</h3> Serum measurements of NTZ and anti-NTZ antibody levels are performed by novel lab developed electro-chemiluminescent immunoassays. The natalizumab drug assay is validated to measure free drug (pharmacodynamically active) level in serum. The anti-natalizumab antibody assay is quantitative and drug-tolerant, meaning that circulating drug in patient serum does not interfere with anti-NTZ detection and quantitation. <h3>Results:</h3> Here, we report concomitant measurement of NTZ and anti-NTZ antibody in 160 patient serum samples. Positive anti-NTZ levels from 24 to 235 ng/mL were found in 7.5% (12/160) patients. Anti-NTZ-free samples (148/160) had NTZ drug levels ranging from undetectable (&lt;1.0) to 85 ug/mL. The mean and median drug level in 90 samples (results &gt;1.0) was 10.8 and 2.7, respectively. 61/90 samples had therapeutic drug concentrations (at least 2.0 ug/mL). In the presence of anti-NTZ, 67% (8/12) had undetectable drug level and (4/12) had mean and median drug levels of 1.2 and 1.3, respectively, which is 9- or 2-fold lower than the mean and median drug levels of the anti-NTZ Ab -free group. <h3>Conclusions:</h3> Low serum NTZ and high anti-NTZ are associated with loss of clinical efficacy, while elevated NTZ may increase progressive multifocal leukoencephalopathy risk. Assays to measure biologic drugs and their anti-drug antibodies in patient serum may be useful tools in dose optimization and patient management. <b>Disclosure:</b> Dr. Yang has received personal compensation for serving as an employee of Labcorp. Dr. Chun has nothing to disclose.

Concomitant diagnosis of multiple sclerosis and human immunodeficiency virus (HIV) infection: case report and thereview of literature.

To date, few cases of multiple sclerosis (MS) patients with concomitant Human Immunodeficiency Virus (HIV) infection have been described. However, none of the previously described cases has been treated with Natalizumab, probably due to the increasing risk of progressive multifocal leukoencephalopathy (PML). We report the case of a patient concomitantly diagnosed for HIV infection and MS treated with combined antiretroviral therapy (cART) and Natalizumab for 19 months, without clinical or radiological MS activity. Our case might suggest considering Natalizumab in patients with concomitant HIV infection, especially for those with significant disease activity requiring a high efficacy disease modifying treatment.