Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS.

BACKGROUND: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. METHODS: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. RESULTS: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39-0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33-0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34-0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23-0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. CONCLUSION: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings.ClinicalTrials.gov: NCT02201108.

Glial Activity Load on PET Reveals Persistent "Smoldering" Inflammation in MS Despite Disease-Modifying Treatment: 18F-PBR06 Study.

PURPOSE OF THE REPORT: 18F-PBR06-PET targeting 18-kDa translocator protein can detect abnormal microglial activation (MA) in multiple sclerosis (MS). The objectives of this study are to develop individualized mapping of MA using 18F-PBR06, to determine the effect of disease-modifying treatment (DMT) efficacy on reducing MA, and to determine its clinical, radiological, and serological correlates in MS patients. PATIENTS AND METHODS: Thirty 18F-PBR06-PET scans were performed in 22 MS patients (mean age, 46 ± 13 years; 16 females) and 8 healthy controls (HCs). Logarithmically transformed "glial activity load on PET" scores (calculated as the sum of voxel-by-voxel z-scores ≥4), "lnGALP," were compared between MS and HC and between MS subjects on high-efficacy DMTs (H-DMT, n = 13) and those on no or lower-efficacy treatment, and correlated with clinical measures, serum biomarkers, and cortical thickness. RESULTS: Cortical gray matter (CoGM) and white matter (WM) lnGALP scores were higher in MS versus HC (+33% and +48%, P < 0.001). In H-DMT group, CoGM and WM lnGALP scores were significantly lower than lower-efficacy treatment (P < 0.01) but remained abnormally higher than in HC group (P = 0.006). Within H-DMT patients, CoGM lnGALP scores correlated positively with physical disability, fatigue and serum glial fibrillary acid protein levels (r = 0.65-0.79, all P's < 0.05), and inversely with cortical thickness (r = -0.66, P < 0.05). CONCLUSIONS: High-efficacy DMTs decrease, but do not normalize, CoGM and WM MA in MS patients. Such "residual" MA in CoGM is associated with clinical disability, serum biomarkers, and cortical degeneration. Individualized mapping of translocator protein PET using 18F-PBR06 is clinically feasible and can potentially serve as an imaging biomarker for evaluating "smoldering" inflammation in MS patients.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis.

Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of therapeutics in multiple sclerosis (MS). BTK is expressed in B-cells and myeloid cells, key progenitors of which include dendritic cells, microglia and macrophages, integral effectors of MS pathogenesis, along with mast cells, establishing the relevance of BTK inhibitors to diverse autoimmune conditions. First-generation BTK inhibitors are currently utilized in the treatment of B-cell malignancies and show efficacy in B-cell modulation. B-cell depleting therapies have shown success as disease-modifying treatments (DMTs) in MS, highlighting the potential of BTK inhibitors for this indication; however, first-generation BTK inhibitors exhibit a challenging safety profile that is unsuitable for chronic use, as required for MS DMTs. A second generation of highly selective BTK inhibitors has shown efficacy in modulating MS-relevant mechanisms of pathogenesis in preclinical as well as clinical studies. Six of these BTK inhibitors are undergoing clinical development for MS, three of which are also under investigation for chronic spontaneous urticaria (CSU), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase II trials of selected BTK inhibitors for MS showed reductions in new gadolinium-enhancing lesions on magnetic resonance imaging scans; however, the safety profile is yet to be ascertained in chronic use. Understanding of the safety profile is developing by combining safety insights from the ongoing phase II and III trials of second-generation BTK inhibitors for MS, CSU, RA and SLE. This narrative review investigates the potential of BTK inhibitors as an MS DMT, the improved selectivity of second-generation inhibitors, comparative safety insights established thus far through clinical development programmes and proposed implications in female reproductive health and in long-term administration.

A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis Why was this study done? This study was done to find out about current knowledge on a type of drug, called Bruton's tyrosine kinase inhibitors, or BTK inhibitors. There are currently six BTK inhibitors being studied as a possible new drug for treating multiple sclerosis (MS). Some of these six drugs are also being studied as a possible new drug for chronic spontaneous urticaria, rheumatoid arthritis and systemic lupus erythematosus. These are all autoimmune conditions, where the immune system mistakenly attacks parts of the body. Clinician scientists wanted to understand what is currently known about BTK inhibitors, how they work in the laboratory and how safe they could be for treating autoimmune conditions. This could help us understand more about BTK inhibitors in MS.What did the scientists do? The scientists assessed existing research on these six BTK inhibitors, through a process known as a literature review. These were results from ongoing clinical trials, and information collected through studying BTK inhibitors in laboratories. The researchers pieced together all these findings, to produce this paper that summarizes the results.What did the scientists find? The scientists found that most studies of BTK inhibitors for MS are still ongoing. So far, BTK inhibitors seem to show reasonable safety in most studies, but it is too early to know. The researchers also found out about how BTK inhibitors work in the lab, about what could happen if the drugs are taken for a long time and how they could impact female reproductive health.What do these findings mean? These findings will help other scientists learn more about BTK inhibitors in MS. Trials with BTK inhibitors for MS are still ongoing, but piecing together all the current findings gives a picture of what we know and what still needs to be done.

Predictors of relapsing disease course following index event in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune disease that can present as a monophasic or relapsing disease course. Here, we investigate the predictors of developing relapsing disease with a focus on the index event. METHODS: MOGAD patients followed at Massachusetts General Hospital and Brigham and Women's Hospital were included. Data on demographic, clinical, and laboratory features were collected. Time-to-event survival analysis was performed using a Cox proportional hazards model. Univariate and multivariate regression analyses were performed. RESULTS: We included 124 patients with a diagnosis of MOGAD of which 62.1% (n = 77) were female. The median (IQR) onset age and follow-up time were 31 (16, 45), and 4.08 (2.2, 7.9) years respectively. In total, 40.3% (n = 50) of patients remained monophasic and, 59.7% (n = 74) developed a relapsing course. The median (IQR) time between the index event and the second attack was 3(2, 13.7) months. Starting maintenance therapy following the index event was associated with decreased risk of relapsing disease (HR:0.26; 95%CI: 0.12, 0.54; P < 0.001). Maintenance therapy with intravenous immunoglobulin (HR:0.1; 95% CI:0.01, 0.78, P = 0.02), rituximab (HR: 0.21; 95%CI: 0.08, 0.55; P = 0.001), and mycophenolate mofetil (HR: 0.27; 95%CI: 0.09, 0.77; P = 0.01) was associated with a decreased risk of relapsing disease course. A polyphasic first attack (HR:2.4; 95%CI:1.31, 4.4; P = 0.004) and high CSF protein (HR:2.06; 95%CI: 1.01, 4.16; P = 0.04) were associated with a relapsing course. CONCLUSIONS: In MOGAD patients, starting maintenance therapy following the index event reduces the risk of relapsing disease regardless of age, sex, and onset phenotype, while polyphasic first attack, and elevated CSF protein predict relapsing disease course.

Effectiveness of immunotherapies in relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can cause optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis (ADEM). Immunotherapy is often used for relapsing disease, but there is variability in treatment decisions. OBJECTIVE: The objective was to determine the annualized relapse rates (ARRs) and incidence rate ratios (IRRs) compared to pre-treatment and relapse-freedom probabilities among patients receiving steroids, B-cell depletion (BCD), intravenous immunoglobulin (IVIG), and mycophenolate mofetil (MMF). METHODS: Retrospective cohort study of patients with relapsing MOGAD treated at Mass General Brigham. ARRs and IRRs compared to pre-treatment, and relapse-freedom probability and odds ratio for relapse-freedom compared to prednisone were calculated. RESULTS: A total of 88 patients met the inclusion criteria. The ARR on IVIG was 0.13 (95% confidence interval (CI) = 0.06-0.27) and the relapse-freedom probability after at least 6 months of therapy was 72%. The ARR on BCD was 0.51 (95% CI = 0.34-0.77), and the relapse-freedom probability was 33%. The ARR on MMF was 0.32 (95% CI = 0.19-0.53) and the relapse-freedom probability was 49%. In pediatric-onset disease, MMF had the lowest ARRs (0.15, 95% CI = 0.07-0.33). CONCLUSION: IVIG had the lowest ARRs and IRRs compared to pre-treatment and the highest relapse-freedom odds ratio compared to prednisone, while BCD had the lowest. In pediatric-onset MOGAD, MMF had the lowest ARRs.

Gene-environment interactions: Epstein-Barr virus infection and risk of pediatric-onset multiple sclerosis.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.

OBJECTIVES: Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50-100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. METHODS: A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. RESULTS: The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre-post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. CONCLUSIONS: The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites.

Assessing Needs and Perceptions of Research Participation in Pediatric-Onset Multiple Sclerosis: A Multistakeholder Survey.

BACKGROUND: Patient-powered research networks (PPRNs) for autoimmune disease are widely used in the adult population to recruit patients and drive patient-centered research, but few have included pediatric patients. We aimed to characterize viewpoints regarding research needs and participation in pediatric-onset multiple sclerosis (POMS) via a PPRN-disseminated survey. METHODS: This is an exploratory, cross-sectional study. The study period was February 1, 2022, to February 9, 2023. Three questionnaires were disseminated to (1) patients with POMS (PwPOMS), (2) caregivers of PwPOMS (C-PwPOMS), and (3) health care providers/researchers in POMS (HR-POMS). RESULTS: A total of 88 participants were included for analysis; 44% (n = 39) were PwPOMS, 42% (n = 37) were C-PwPOMS, and 14% (n = 12) were HR-POMS. Some PwPOMS (18%) and C-PwPOMS (9%) expressed research hesitancy, but more, 69% of PwPOMS and 68% of C-PwPOMS, were interested in research participation. Nevertheless, less than half of PwPOMS (38%) and C-PwPOMS (38%) reported previous research involvement. HR-POMS reported difficulties in funding (100%) and recruiting participants (58%). PwPOMS (67%), C-PwPOMS (62%), and HR-POMS (67%) were open to future involvement in PPRNs. CONCLUSIONS: Participants with POMS in this study expressed strong interest in research involvement but also expressed participation hesitancy, which may contribute to recruiting challenges expressed by researchers. Although the exploratory design limits generalizability to the larger POMS population, this study shows PPRNs are well-suited to soliciting attitudes and opinions of key stakeholders in POMS. Future studies utilizing PPRNs for POMS should prioritize diverse, representative cohorts and focus on understanding and mitigating issues hindering research participation.

Gene-environment interactions and risk of pediatric-onset multiple sclerosis associated with time spent outdoors.

BACKGROUND: Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS: In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS: In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS: The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.

Progression independent of relapses in aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and multiple sclerosis.

OBJECTIVES: To determine whether progression independent of relapse activity (PIRA) is present in Aquaporin4-IgG-seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD), Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and relapsing remitting Multiple sclerosis (RRMS). METHODS: We retrospectively studied the change in EDSS, confirmed disability worsening (CDW) (i.e., PIRA), and new MRI lesions in AQP4+NMOSD, and MOGAD and MS patients. Linear mixed-effect regression model was used to compare the longitudinal changes in EDSS, and Cox regression was used to compare changes in MRI. RESULTS: The estimated mean ΔEDSS in the AQP4+NMOSD and matched MS group were +0.06 (95%CI: -0.40, +0.52, p = 0.76), and +0.02 (95%CI: -0.05, +0.08, p = 0.6) respectively. The same estimate was -0.08 (95%CI: -0.18, +0.02, p = 0.12) in MOGAD and +0.05 (95%CI: -0.05, +0.15, p = 0.35) in matched MS group. Comparing groups for the presence of CDW (i.e., PIRA) showed that PIRA is more associated with MS compared to AQP4+NMOSD (p = 0.02) and MOGAD (p<0.001). Compared to their matched MS groups, the annualized rate of PIRA was significantly lower in AQP4 (0.08 vs 0.44; p<0.0001), and MOG groups (0.04 vs 0.13; p<0.0001). New T2 or enhancing lesions on brain MRI were higher in MS compared to AQP4+NMOSD and MOGAD patients. CONCLUSION: Relapse-independent changes in the EDSS, CDW, and MRI activity are not common in AQP4+NMOSD and MOGAD, especially when compared with MS. Since our patients were on relapse prevention therapies at the time of EDSS measurements, our study supports the importance of preventing relapses in AQP4+NMOSD and MOGAD and suggests different pathologic mechanisms of relapse-free neurological damage between MS and AQP4+NMOSD/MOGAD.

Identification and management of subclinical disease activity in early multiple sclerosis: a review.

IMPORTANCE: Early treatment initiation in multiple sclerosis (MS) is crucial in preventing irreversible neurological damage and disability progression. The current assessment of disease activity relies on relapse rates and magnetic resonance imaging (MRI) lesion activity, but inclusion of other early, often "hidden," indicators of disease activity may describe a more comprehensive picture of MS. OBSERVATIONS: Early indicators of MS disease activity other than relapses and MRI activity, such as cognitive impairment, brain atrophy, and fatigue, are not typically captured by routine disease monitoring. Furthermore, silent progression (neurological decline not clearly captured by standard methods) may occur undetected by relapse and MRI lesion activity monitoring. Consequently, patients considered to have no disease activity actually may have worsening disease, suggesting a need to revise MS management strategies with respect to timely initiation and escalation of disease-modifying therapy (DMT). Traditionally, first-line MS treatment starts with low- or moderate-efficacy therapies, before escalating to high-efficacy therapies (HETs) after evidence of breakthrough disease activity. However, multiple observational studies have shown that early initiation of HETs can prevent or reduce disability progression. Ongoing randomized clinical trials are comparing escalation and early HET approaches. CONCLUSIONS AND RELEVANCE: There is an urgent need to reassess how MS disease activity and worsening are measured. A greater awareness of "hidden" indicators, potentially combined with biomarkers to reveal silent disease activity and neurodegeneration underlying MS, would provide a more complete picture of MS and allow for timely therapeutic intervention with HET or switching DMTs to address suboptimal treatment responses.

Increasing Neurofilament and Glial Fibrillary Acidic Protein After Treatment Discontinuation Predicts Multiple Sclerosis Disease Activity.

BACKGROUND AND OBJECTIVES: Stable patients with multiple sclerosis (MS) may discontinue treatment, but the risk of disease activity is unknown. Serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are biomarkers of subclinical disease activity and may help risk stratification. In this study, sNfL and sGFAP levels in stable patients were evaluated before and after treatment discontinuation to determine association with disease activity. METHODS: This observational study included patients enrolled in the Comprehensive Longitudinal Investigation in MS at the Brigham and Women's Hospital who discontinued treatment after >2 years disease activity-free. Two serum samples within 2 years, before and after treatment stop, were sent for sNfL and sGFAP measurements by single-molecule array. Biannual neurologic examinations and yearly MRI scans determined disease activity by 3 time-to-event outcomes: 6-month confirmed disability worsening (CDW), clinical attacks, and MRI activity (new T2 or contrast-enhancing lesions). Associations between each outcome and log-transformed sNfL and sGFAP levels pretreatment stop and posttreatment stop and the percent change were estimated using multivariable Cox regression analysis adjusting for age, disability, disease duration, and duration from attack before treatment stop. RESULTS: Seventy-eight patients (92% female) discontinued treatment at a median (interquartile range) age of 48.5 years (39.0-55.7) and disease duration of 12.3 years (7.5-18.8) and were followed up for 6.3 years (4.2-8.5). CDW occurred in 27 patients (35%), new attacks in 19 (24%), and new MRI activity in 26 (33%). Higher posttreatment stop sNfL level was associated with CDW (adjusted hazard ratio (aHR) 2.80, 95% CI 1.36-5.76, p = 0.005) and new MRI activity (aHR 3.09, 95% CI 1.42-6.70, p = 0.004). Patients who had >100% increase in sNfL level from pretreatment stop to posttreatment stop had greater risk of CDW (HR 3.87, 95% CI 1.4-10.7, p = 0.009) and developing new MRI activity (HR 4.02, 95% CI 1.51-10.7, p = 0.005). Patients who had >50% increase in sGFAP level also had greater risk of CDW (HR 5.34, 95% CI 1.4-19.9, p = 0.012) and developing new MRI activity (HR 5.16, 95% CI 1.71-15.6, p = 0.004). DISCUSSION: Stable patients who discontinue treatment may be risk stratified by sNfL and sGFAP levels measured before and after discontinuing treatment. Further studies are needed to validate findings and determine whether resuming treatment in patients with increasing biomarker levels reduces risk of subsequent disease activity.

A 28-Year-Old Woman With Left-Sided Weakness and Atypical MRI Lesions: From the National Multiple Sclerosis Society Case Conference Proceedings.

A 28-year-old woman presented with subacute relapsing left-sided weakness. MRI demonstrated both enhancing C3-C6 and nonenhancing T2-T4 lesions. Initial provisional diagnosis was inflammatory/autoimmune. Her left-sided weakness progressed despite immunosuppressive therapies. We reassessed our original suspected diagnosis because of an atypical clinicoradiologic course, leading to biopsy and a definitive diagnosis.

Accuracy of serum neurofilament light to identify contrast-enhancing lesions in multiple sclerosis.

BACKGROUND: Contrast-enhancing magnetic resonance imaging (MRI) lesions (CELs) indicate acute multiple sclerosis inflammation. Serum biomarkers, neurofilament light (sNfL), and glial fibrillary acidic protein (sGFAP) may increase in the presence of CELs, and indicate a need to perform MRI. OBJECTIVE: We assessed the accuracy of biomarkers to detect CELs. METHODS: Patients with two gadolinium-enhanced MRIs and serum biomarkers tested within 3 months were included (N = 557, 66% female). Optimal cut-points from Bland-Altman analysis for spot biomarker level and Youden's index for delta-change from remission were evaluated. RESULTS: A total of 116 patients (21%) had CELs. A spot sNfL measurement >23.0 pg/mL corresponded to 7.0 times higher odds of CEL presence (95% CI: 3.8, 12.8), with 25.9% sensitivity, 95.2% specificity, operating characteristic curve (AUC) 0.61; while sNfL delta-change >30.8% from remission corresponded to 5.0 times higher odds (95% CI: 3.2, 7.8), 52.6% sensitivity, 81.9% specificity, AUC 0.67. sGFAP had poor CEL detection. In patients > 50 years, neither cut-point remained significant. sNfL delta-change outperformed spot levels at identifying asymptomatic CELs (AUC 0.67 vs 0.59) and in patients without treatment escalation between samples (AUC 0.67 vs 0.57). CONCLUSION: Spot sNfL >23.0 pg/mL or a 30.8% increase from remission provides modest prediction of CELs in patients <50 years; however, low sNfL does not obviate the need for MRI.

NF-κB and STAT3 activation in CD4 T cells in pediatric MOG antibody-associated disease.

In this study, we examined CD4 T cell activation using various stimuli in pediatric MOGAD patients (n = 4, untreated remission samples) and healthy controls (n = 5), to understand how both antigen-specific and bystander mechanisms contribute to CD4 T cell activation in MOGAD. TNFα, IL6, and MOG peptide pool were found to activate NF-κB or STAT3 pathways by measuring the expression of regulators (A20, IκBα) and phosphorylated subunits (phospho-p65 and phospho-STAT3) using immunolabeling. Prednisolone reversed activation of both NF-κB and STAT3 and increased the expression of A20 and IκBα. TNFR blocking partially reversed NF-κB activation in certain CD4 T cell subsets, but did not effect STAT3 activation. We observed that activation of NF-κB and STAT3 in response to various stimuli behaves mostly same in MOGAD (remission) and HC. IL6 stimulation resulted in higher STAT3 phosphorylation in MOGAD patients at 75 min, specifically in central and effector memory CD4 T cells (with unadjusted p-values). These findings suggest the potential therapeutic targeting of NF-κB and STAT3 pathways in MOGAD. Further investigation is needed to validate the significance of extended STAT3 phosphorylation and its correlation with IL6 receptor blocker treatment response.

Association between PROMIS10, SF-36 and NeuroQoL in persons with multiple sclerosis.

BACKGROUND: Patient reported outcome measures (PROs) are considered promising tools for use in clinical settings to measure the impact of disease on physical, mental and social well-being from the patient's perspective. The Patient Reported Outcome Measurement Information System Scale v1.1-Global Health (PROMIS-10) is a measure that is well-suited to clinical practice, but the relationships between this measure and longer PRO measures used in multiple sclerosis (MS) research are unknown. METHODS: Subjects enrolled in SysteMS: A Systems Biology Study of Clinical, Radiological, and Molecular Markers in Subjects with MS at the Brigham and Women's Hospital were eligible to contribute to the study. 349 subjects completed three PRO measures at study entry: PROMIS-10, Medical Outcomes Study Short-Form 36 (SF-36), and Quality of Life in Neurological Disorders (Neuro-QoL™). All questions and global scores from PROMIS-10 were correlated with all domain and summary component scores for SF-36 and all domain scores for Neuro-QoL using Pearson's correlation coefficient. Further, the global scores from PROMIS-10 were correlated with the expanded disability status scale (EDSS) and compared between disease categories (relapsing vs progressive MS). RESULTS: Strong correlations were observed between PROMIS-10 questions and SF-36 domains aimed at measuring the same construct. Further, the PROMIS-10 Global Physical Health score was correlated with the Physical Component Score from the SF-36 (r = 0.798), and the PROMIS Global Mental Health score was correlated with the Mental Component Score from the SF-36 (r = 0.726). Strong correlations between PROMIS-10 questions and two Neuro-QoL domains (fatigue and lower extremity function) were observed, but other Neuro-QoL domains were not strongly correlated with PROMIS-10 questions. PROMIS-10 Global Physical Health had stronger relationship to EDSS and disease category compared to the Global Mental Health. CONCLUSIONS: PROMIS-10 questions and global scores are highly correlated with the corresponding domains of SF-36 in PwMS. Neuro-QoL provides different information regarding HRQOL since different domains are being measured.

Multiple sclerosis lesions that impair memory map to a connected memory circuit.

BACKGROUND: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30-50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. METHODS: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. RESULTS: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. CONCLUSIONS: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS.

Inflammatory and neurodegenerative serum protein biomarkers increase sensitivity to detect disease activity in multiple sclerosis.

Background/Objectives: Serum proteomic analysis of deeply-phenotyped samples, biological pathway modeling and network analysis were performed to elucidate the inflammatory and neurodegenerative processes of multiple sclerosis (MS) and identify sensitive biomarkers of MS disease activity (DA). Methods: Over 1100 serum proteins were evaluated in >600 samples from three MS cohorts to identify biomarkers of clinical and radiographic (gadolinium-enhancing lesions) new MS DA. Protein levels were analyzed and associated with presence of gadolinium-enhancing lesions, clinical relapse status (CRS), and annualized relapse rate (ARR) to create a custom assay panel. Results: Twenty proteins were associated with increased clinical and radiographic MS DA. Serum neurofilament light chain (NfL) showed the strongest univariate correlation with radiographic and clinical DA measures. Multivariate modeling significantly outperformed univariate NfL to predict gadolinium lesion activity, CRS and ARR. Discussion: These findings provide insight regarding correlations between inflammatory and neurodegenerative biomarkers and clinical and radiographic MS DA. Funding: Octave Bioscience, Inc (Menlo Park, CA).

Clinical validation of a multi-protein, serum-based assay for disease activity assessments in multiple sclerosis.

An 18-protein multiple sclerosis (MS) disease activity (DA) test was validated based on associations between algorithm scores and clinical/radiographic assessments (N = 614 serum samples; Train [n = 426; algorithm development] and Test [n = 188; evaluation] subsets). The multi-protein model was trained based on presence/absence of gadolinium-positive (Gd+) lesions and was also strongly associated with new/enlarging T2 lesions, and active versus stable disease (composite of radiographic and clinical evidence of DA) with improved performance (p < 0.05) compared to the neurofilament light single protein model. The odds of having ≥1 Gd+ lesions with a moderate/high DA score were 4.49 times that of a low DA score, and the odds of having ≥2 Gd+ lesions with a high DA score were 20.99 times that of a low/moderate DA score. The MSDA Test was clinically validated with improved performance compared to the top-performing single-protein model and can serve as a quantitative tool to enhance the care of MS patients.