The majority of patients with relapsing-remitting multiple sclerosis (RRMS) eventually advance to a progressive stage of disease, characterized by gradual, relentless accumulation of neurological disability. Individuals with progressive MS (pMS) are less likely to respond to disease modifying therapies used in the treatment of RRMS, particularly if a significant amount of time has elapsed since they last experienced a clinical relapse or developed an acutely inflamed white matter lesion. The molecular and cellular basis underlying the transition to pMS is poorly understood. While some pathological hallmarks of pMS overlap with those of RRMS, there are also distinctive features, including slowly expanding(“smoldering”) white matter lesions and diffuse microglial activation in the normal appearing white matter. Chronological age is the strongest predictor of whether an individual with MS has a progressive as opposed to a relapsing remitting course. This suggests that pathological changes associated with secondary pMS arise from an interaction between CNS autoimmunity and normal age-related changes in immune function (immunosenesence and “inflammaging”). Here we discuss potential mechanisms by which the aging immune system might reshape the CNS autoimmune response in individuals with MS to foster the pathological and clinical signatures of progressive disease. A deeper understanding of the role of inflammaging and immunosenesence in autoimmune demyelinating disease could elucidate novel biomarkers and therapeutic targets for the management of pMS.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.

Background Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. Objective To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. Methods The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). Results We included 271 cases (mean age at disease onset of 15.7 years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p = 0.01). Conclusions While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

Objective:We utilized Mendelian randomization to estimate the causal relationship between increasing body mass index (BMI) and pediatric MS susceptibility using a weighted BMI genetic risk score (BMI GRS). Background:Childhood and adolescent obesity are associated with a two-fold increased risk of pediatric and adult-onset MS. However, the relationship between obesity and MS may be confounded by lifestyle and/or socioeconomic factors that have not been appropriately adjusted for in previous studies. Methods:The BMI GRS incorporates the cumulative effect of 97 variants associated with BMI identified from the largest genome-wide association study (GWAS), to date (Locke et al, 2015). A split-sample instrumental variable (IV) analysis was used by summing all risk alleles multiplied by the estimated effect of each risk allele on the phenotype derived from the GWAS. Participants included non-Hispanic white pediatric MS cases and controls from over 15 sites across the U.S. (total sample size: 394 MS cases, 10,875 controls). Results:A significant association between BMI GRS and pediatric MS was demonstrated (causal odds ratio [OR] = 1.20, 95[percnt] CI 1.06, 1.36; p=0.004) after adjusting for sex, ancestry, HLA-DRB1*15:01 (the strongest genetic predictor of MS) and a weighted genetic risk score comprised of 110 non-HLA MS risk variants. Evidence of interaction between BMI GRS and HLA-DRB1*15:01 was also present (p-interaction=0.04); individuals carrying 1-2 DRB1* 15:01 risk alleles demonstrated a stronger association (OR=1.39, 95[percnt] CI 1.16, 1.37) compared to non-carriers (OR=1.05, 95[percnt] CI 0.88, 1.26). Conclusions:For the first time, we provide evidence supporting increased BMI is causally associated with pediatric MS and interacts with HLA-DRB1*15:01 status. Further, pediatric MS risk conferred by obesity may involve predisposing genetic factors for increased BMI, suggesting that specific inflammatory mechanisms involved in the obesity pathway may mediate disease onset.

BACKGROUND: Disease modifying therapies (DMT) are used widely in pediatric multiple sclerosis (POMS), but up to half of children with MS have poor medication adherence. Social and medical consequences may result, including increased relapse rate and missed school. Reasons for poor medication adherence in pediatric MS are unknown, but elucidation of these reasons may improve outcomes in this population. OBJECTIVE: To identify factors influencing medication adherence in POMS. DESIGN/METHODS: Children with MS from 9 North American centers were enrolled in a randomized-control trial of medication adherence including electronic monitoring paired with motivational interviewing (MI) vs. attention control. Children with a diagnosis of MS on DMT for at least 6 months were included in the study. Interviews followed MI theory, and were used to evoke reasons and methods for behavioral change in participants. Qualitative thematic analysis of 14 baseline interviews with participants randomized to the MI arm of the study (9 female, 15±2 yrs.) captured emergent themes. RESULTS: Themes included: (1) Importance of medication adherence: participants referred to symptoms at diagnosis (“numbness”, “tingling”, “no vision in right eye”) as motivators. (2) Strategies for remembering to take medication: parental reminders, alarms, routines. (3) Obstacles to adherence: distractions, going out with friends, ability to self-inject. (4) Reactions to using electronic monitoring: participants described tracking daily patterns of medication adherence as helpful. CONCLUSIONS: Through MI, children with MS identified barriers and facilitators to medication adherence. Facilitators included use of the tracking device, the identification of specific strategies related to routinization, and recall of neurological symptoms. Barriers included challenges with self-injection as well as those related to changes in daily routine. Surprisingly, pain and fear did not emerge as barriers to medication use. Future studies will evaluate whether thematic changes occurred through the course of the study, and whether changes in adherence accompanied thematic changes. Disclosure: Dr. Grover has nothing to disclose. Dr. Edwards has nothing to disclose. Dr. Alper has nothing to disclose. Dr. Banwell has received personal compensation for activities with Novartis. Dr. Banwell has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders. Dr. Breiner has nothing to disclose. Dr. Gorman has nothing to disclose. Dr. Graves has nothing to disclose. Dr. Hart has nothing to disclose. Dr. Lotze has nothing to disclose. Dr. Mar has nothing to disclose. Dr. Mednick has nothing to disclose. Dr. Ness has nothing to disclose. Dr. Noguera has nothing to disclose. Dr. Quon has nothing to disclose. Dr. Schreiner has received personal compensation for activities with Biogen Idec and MSAA as a consultant. Dr. Schwartz has nothing to disclose. Dr. Waldman has received royalty payments from UpToDate. Dr. Waubant has received personal compensation for activities with Roche Diagnostics Corporation, Genzyme Corporation, and Novartis. Dr. Waubant has received research support from Roche Diagnostics Corporation, Biogen Idec, and Novartis. Dr. Slater has nothing to disclose. Dr. Yeh has nothing to disclose.

BACKGROUND/OBJECTIVE:Alterations in the gut microbiome may be influential in neurological disease. We explored gut microbiome profiles in early pediatric MS and age and sex matched controls. DESIGN/METHODS:Children ≤18 years old attending a University of California, San Francisco pediatric clinic were invited to participate in a genetic and environmental risk factors study (NS071463,PI:Waubant). MS cases were within 2 years of onset. Controls were free from autoimmune disorders (asthma and eczema allowed). Stools were shipped on ice and stored at -80C. The 16S rRNA gene was amplified from extracted DNA and bacterial profiles were generated using the PhyloChip G3 microarray (Second Genome, Inc., CA). Associations between the pediatric characteristics and variation in the bacterial community composition were assessed using nonmetric multidimensional scaling and permutational multivariate analysis of variance with distance matrices. RESULTS:Between Nov/2011-Nov/2013, 20 MS (10 girls, 10 boys) and 16 controls (9 girls, 7 boys) aged 13.2 years (mean; SD=3.84; range 4-18) provided stool samples. Within two months pre-stool collection, 3 children (2 cases, 1 control) were exposed to an antibiotic, 10 (8 cases, 2 controls) to a corticosteroid and 12 to an immuno-modulatory or -suppressant drug (10 cases, 2 controls). All cases met McDonald criteria, had relapsing-remitting MS and a short disease duration (mean=11 months; range 2-24 at stool collection). The median EDSS at enrolment was 2.0 (range 0-4.0). Preliminary microbiome results indicated significant differences in specific bacterial taxa between cases and controls, with enriched tax predominated by Proteobacteria (e.g. Shigella, Escherichia), p<0.001, false discovery rates, q<0.192. Depleted taxa displayed greater heterogeneity, and included Firmicutes (Eubacterium rectale) and Actinobacteria (Corynebacterium) but also higher false discovery rates (all q<0.372 and p<0.044). CONCLUSIONS:Specific taxa were significantly altered in relative abundance in very early onset pediatric MS, with enrichment for microbiota known to be associated with gastrointestinal infectious processes. Study Supported by:NIH(NS071463);NMSS(RG4861A3/1);PI:Waubant