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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. [ABSTRACT FROM AUTHOR]

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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population. [ABSTRACT FROM AUTHOR]

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown. Objective: To test whether genes harboring rare variants associated with adult-onset MS risk (PRF1, PRKRA, NLRP8, and HDAC7) and 52 major histocompatibility complex (MHC) genes are associated with POMS. Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk. Results: After correction for multiple comparisons, one adult-onset MS gene (PRF1, p = 2.70 × 10−3) and two MHC genes (BRD2, p = 5.89 × 10−5 and AGER, p = 7.96 × 10−5) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501. Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER. These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases. [ABSTRACT FROM AUTHOR]

Background: Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. Objective: Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). Methods: POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. Results: Six hundred and sixty-nine patients were surveyed between March 2020 and August 2021. There were 73 confirmed COVID-19 infections. Eight of nine hospitalized patients (89%), and all patients admitted to the ICU were treated with B cell depleting therapy. The unadjusted odds ratio of hospitalization among those who tested positive of having had COVID-19 was 15.27 among those on B-cell-depleting therapy (p = 0.016). Conclusions: B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders. [ABSTRACT FROM AUTHOR]

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls. Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores. Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores (p s > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p = 0.83); Cogstate Brief Battery (26% vs. 32%, p = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite (p = 0.03), Symbol Digit Modalities Test (p = 0.02), Rey Auditory Verbal Learning Test (p = 0.01), and Cogstate choice reaction time (p < 0.001). Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS. [ABSTRACT FROM AUTHOR]

Objective: To identify features of the gut microbiome associated with multiple sclerosis activity over time. Methods: We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric‐onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice‐Williams‐Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium‐enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease‐modifying therapies. Results: Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co‐occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium‐enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. Interpretation: Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity. [ABSTRACT FROM AUTHOR]