Faculty Bibliography

Introduction: Treatment of pediatric MS is challenging as most disease-modifying therapies (DMT) lack efficacy data in children, and there are no comparative effectiveness studies to guide initial DMT choice.
Objective(s): We aim to assess the real-world effectiveness of initial treatment with newer compared to injectable DMTs on disease activity in MS and CIS treated before 18 years.
Method(s): This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon beta or glatiramer acetate) DMT. Propensity scores (PS) were computed with logistic regression to predict newer DMT use, including pre-identified confounders (sex, race, ethnicity, site, age at onset and first DMT, first event characteristics, height, weight, diagnosis, number of relapses in prior 6 months, new T2 hyperintense or gadolinium enhancing lesions in prior 6 months, baseline EDSS). Relapse rate was modeled with negative binomial regression for number of events on initial DMT, adjusted for PS quintile. Time to new/enlarging T2 and gadolinium enhancing lesions on MRI brain were modeled with midpoint survival analyses, adjusted for PS quintile.
Result(s): 741 children (66% female, 15% CIS) began initial therapy, 197 with a newer and 544 with an injectable DMT. Those started on newer DMT were older at onset (14.3 vs injectable 13.4 years), less likely to have a monofocal first event (37% vs injectable 55%), and more likely to have MS (87% vs injectable 79%). Number of relapses in the prior 6 months was slightly lower in those started on newer DMT (0.8 vs injectable 1.0), while first event severity and EDSS were similar between groups. Balance in confounders was acceptable within PS quintiles. In PS quintile adjusted analysis, those started on newer DMT had significantly lower relapse rate than those started on injectable DMT (rate ratio 0.45, 95% CI 0.29-0.70, p< 0.001). Those started on newer DMT also had lower rate of new/enlarging T2 (HR 0.52, 95% CI 0.37-0.73) and gadolinium enhancing lesions (HR 0.38, 95% CI 0.23-0.62) than those on injectable DMT.
Conclusion(s): Initial treatment of children with MS/CIS with newer DMTs led to better disease activity control compared to initial therapy with injectables, supporting greater effectiveness of newer therapies. Data on long-term safety of newer DMTs is required

INTRODUCTION/BACKGROUND:In the clinic, the assessment of patients with multiple sclerosis (MS) is typically qualitative and non-standardized. OBJECTIVES/OBJECTIVE:2 (Apple, Cupertino, CA, USA)-based neurological assessment platform allowing patients to input relevant information without the aid of a medical technician, creating a longitudinal, clinically meaningful, digital medical record. To report results from human factor (HF) and usability studies, and the initial large-scale implementation in a practice setting. METHODS:The HF study examined use-error patterns in small groups of MS patients and healthy controls (n = 14), the usability study assessed the effectiveness of patient interaction with the tool by patients with a range of MS disability (n = 60) in a clinical setting, and the implementation study deployed the MSPT across a diverse population of patients (n = 1000) in a large MS center for routine clinical care. RESULTS:MSPT assessments were completed by all users in the HF study; minor changes to design were recommended. In the usability study, 73% of patients with MS completed the MSPT, with an average administration time of 32 min; 85% described their experience with the tool as satisfactory. In the initial implementation for routine care, 84% of patients with MS completed the MSPT, with an average administration time of 28 min. CONCLUSION/CONCLUSIONS:Patients with MS with varying disability levels completed the MSPT with minimal or no supervision, resulting in comprehensive, efficient, standardized, quantitative, clinically meaningful data collection as part of routine medical care, thus allowing for large-scale, real-world evidence generation. FUNDING/BACKGROUND:Biogen. TRIAL REGISTRATION/BACKGROUND:NCT02664324.

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

OBJECTIVE:The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety. METHODS:The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population. RESULTS:In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed. Are studies needed for efficacy or should safety be the primary goal? Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials. Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible. CONCLUSIONS:A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.

OBJECTIVE/UNASSIGNED:The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children. METHODS/UNASSIGNED:DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard. RESULTS/UNASSIGNED:Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively. CONCLUSION/UNASSIGNED:The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Background: Adult MS research has identified an increased prevalence of various autoimmune conditions among family members of diagnosed patients. There has not been comparable studies of pediatric MS populations, while this cohort may represent a unique population from a risk factors perspective.
Objective(s): This study was undertaken to quantify the incidence of autoimmune conditions among first and second degree relatives of pediatric MS patients as compared to controls. The study sought to quantify both the rate, type and patterns of diagnoses seen throughout family members of pediatric MS patients.
Method(s): A multi center case-control study of risk factors for pediatric MS has been ongoing for since 2011. Pediatric patients with a diagnosis of MS and pediatric controls were recruited to provide data and biologic specimens for a number of research projects. Included in this effort was the acquisition of family history questionnaires. The medical data from these questionnaires were analyzed for the presence of certain medical diagnoses among first and second degree relatives. Logistic regression models were used to test for differences between cases and controls in reporting a family history of autoimmune diseases, when adjusting for sex, race, age, ethnicity, and mother's education level. Odds ratios and 95% confidence intervals were calculated based on the logistic regression models.
Result(s): Several conditions were found to have statistically significant differences in prevalence among first and second degree family members of MS patients as compared to controls. Diabetes, thyroid disorders and rheumatoid arthritis has the most notable differences between patients and controls while eczema and psoriasis were not different. The odds ratio of any family history of autoimmune disease was 2.27 among cases compared to controls. The odds ratio of an autoimmune disease among family members was significantly higher among paternal relatives as compared to maternal relatives (eg OR of 6.37 compared to 2.64).
Conclusion(s): This study has identified an increased prevalence of certain autoimmune disorders among first and second degree family members of pediatric MS patients. This aligns with prior findings among adult populations that found higher rates of autoimmune disorders among family members of adult onset MS patients. Novel to this study was the difference in relative risk of autoimmune conditions occurring in paternal versus maternal family members

Introduction: Dans PARADIGMS, premiere etude phase III en double aveugle dans la SEP pediatrique, le fingolimod a diminue significativement le taux annualise de poussees (TAP) de 82 % versus l'interferon (IFN) beta-1a. Objectifs: Effectuer des analyses dans des sous-groupes (anticorps neutralisants anti-IFN, naifs de traitement); evaluer l'effet chez les patients plus jeunes et prepuberes, la progression du handicap, la qualite de vie. Patients et Methodes: Les analyses de sous-groupes des criteres principal (TAP) et secondaire principal (nouvelles lesions T2, NT2) et post-hoc sur la progression confirmee du handicap ont ete realisees. La qualite de vie (QdV) liee a la sante a ete evaluee par les patients ou les parents a l'aide du questionnaire PedsQL (Quality of Life) avant et a la fin de l'etude (jusqu'a 2 ans): changements du score total et des scores sante physique et sante psychosociale. Resultats: Dans toutes les analyses de sous-groupes, le fingolimod a diminue significativement le TAP (81,5-85,8 %) et NT2 (47,6-53,4 %) versus l'IFNbeta-1a. Le risque de progression du handicap confirmee a 3 mois etait reduit de 77,2 % ([HR] = 0,23, p = 0,007). L'analyse post-hoc a confirme son effet positif sur les scores totaux et de sante physique de QdV rapportes par les patients et les parents, et de sante psychosociale rapporte par les patients versus l'IFN beta-1a (tous p < 0,05). Discussion(s): Le fingolimod dans la SEP pediatrique a ete associe a un controle de l'activite de la maladie dans toutes les analyses complementaires, chez les patients traites precedemment ou non, et ce de maniere plus marquee chez les patients plus jeunes. Des benefices sur la progression du handicap ont ete observes sur une duree de traitement allant jusqu'a 2 ans. Conclusion(s): Le fingolimod versus IFN beta-1a a ete associe a une amelioration significative du controle de l'activite de la maladie et de la qualite de vie liee a la sante.

BACKGROUND:Fatigue is one of the most commonly experienced symptoms in multiple sclerosis (MS). The neural correlates of fatigue in MS, in general and specifically in early onset, remain poorly understood. This study employed resting-state fMRI (rsfMRI) to investigate the functional connectivity of fatigue in MS patients with early age onset. METHODS:Twenty-seven relapsing-remitting MS patients (20 ± 7yo at the age of diagnosis and 26.0 ± 5.5yo at the time of study) were recruited and 22 patients were studied. Structural and rsfMRI sequences were performed on a 3-Tesla Seimens MRI scanner. Seed-based analysis was performed using CONN Functional Connectivity Toolbox for Statistic Parametric Mapping. The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact scale (MFIS) as well as EDSS, Beck Depression Inventory, and symptomatology were measured. Non-fatigued (N = 12) and fatigued patients (N = 10) were separated based on FSS scores, with a score of 5 or greater being classified as fatigued. Group differences in rsfMRI between non-fatigued and fatigued patients were analyzed. Correlations between these functional connectivity differences and behavioral fatigue scores were also analyzed. RESULTS: = 0.402, p = 0.006). Correlations remained significant after accounting for depression scores. CONCLUSIONS:rsfMRI identified Alterations in two distinct connections (the connectivity between insula and posterior cingulate gyrus and between the right thalamus and right precentral gyrus) that differed between fatigued and non-fatigued patients, as well as correlated with cognitive fatigue severity. These findings suggest that disruption of sensorimotor, high-order motor, and non-motor executive function likely contributes to the neural mechanism of fatigue in MS. Knowledge of the neural mechanisms of underlying MS fatigue could inform more effective treatment strategies.

Introduction: MS is a neurodegenerative, autoimmune disease associated with significant symptom burden such as fatigue, cognitive impairment, motor dysfunction, and depression. Thus, there is a need for therapeutic options for accessible symptom management. tDCS is an emerging neuromodulation treatment that delivers low amperage direct current (=2 mA) to targeted brain regions through scalp electrodes. tDCS is thought to lower the neuronal threshold required for action potentials and is often used to augment the benefit achieved through repetitive stimulation. Recent studies have demonstrated that at-home, remotely supervised tDCS (RS-tDCS) sessions can are successful in reducing fatigue in MS, studies have yet to elucidate the longevity of symptom benefit. Method(s): Participants with MS (N = 26) were recruited to complete a 20 sessions of RS-tDCS over a four-week period (5 sessions per week). We utilized a left anodal dorsolateral prefrontal cortex (DLPFC) montage as the target point for the treatment. The tDCS stimulation was at 2.0 mA. Surveys were completed at least one month following completion of the last RS-tDCS session asking whether any treatment benefit was achieved and whether it was sustained. Half the participants (N =13) received a sham/placebo stimulation, while the other half of the participants (N = 13) received the active stimulation. Both lab technicians and participants were blinded to the participant's conditions. Result(s): 65% of all participants reported treatment benefit. 92% (N =12) among the active participants and 38% (N = 5) among sham participants experienced benefit. The active group experienced a greater rate of benefit compared to the sham group (p<0.001). Furthermore, half of the participants assigned to the active condition that reported experiencing benefit also indicated that the benefit persisted (50%) and only a single participant who experienced benefit in the sham condition indicated that benefit persisted (20%). Conclusion(s): RS-tDCS results in symptom improvement in an MS cohort both immediately after the treatment finishes as well as, for many participants, after one month after treatment finishes. More clinical research should be done to elucidate the mechanism of long-lasting neural change due to tDCS that may help to improve MS symptoms. Longer studies should be done to examine whether self-reported benefit increases with number of sessions.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles.