Faculty Bibliography

Background/UNASSIGNED:. Methods/UNASSIGNED:Patients with PoMS (N=215; aged 10-<18 years) were randomised to once-daily oral fingolimod (N=107) or once-weekly intramuscular IFN β-1a (N=108). HRQoL outcomes were assessed using the 23-item Pediatric Quality of Life (PedsQL) scale that comprises Physical and Psychosocial Health Summary Scores (including Emotional, Social and School Functioning). A post hoc inferential analysis evaluated changes in self-reported or parent-reported PedsQL scores from baseline up to 2 years between treatment groups using an analysis of covariance model. Results/UNASSIGNED:Treatment with fingolimod showed improvements versus IFN β-1a on the PedsQL scale in both the self-reported and parent-reported Total Scale Scores (4.66 vs -1.16, p≤0.001 and 2.71 vs -1.02, p≤0.05, respectively). The proportion of patients achieving a clinically meaningful improvement in the PedsQL Total Scale Score was two times higher with fingolimod versus IFN β-1a per the self-reported scores (47.5% vs 24.2%, p=0.001), and fingolimod was favoured versus IFN β-1a per the parent-reported scores (37.8% vs 24.7%, p=non-significant). Group differences in self-reported Total Scale Scores in favour of fingolimod were most pronounced among patients who had ≥2 relapses in the year prior to study entry or who showed improving or stable Expanded Disability Status Scale scores during the study. Conclusion/UNASSIGNED:Fingolimod improved HRQoL compared with IFN β-1a in patients with PoMS as evidenced by the self-reported and parent-reported PedsQL scores.

BACKGROUND:Multiple sclerosis (MS) patients with stable disease course might view continued treatment as unnecessary. However, guidelines regarding treatment discontinuation are currently lacking. OBJECTIVE:To assess the clinical course after treatment discontinuation in MS patients with long disease duration. METHODS:Patients who discontinued disease-modifying treatments (DMTs) and not resume treatment (n = 216) were extracted from New York State MS Consortium (NYSMSC) and followed across three time points (average 4.6 years). Stable course was defined as no change in Expanded Disability Status Scale (EDSS) scores (<1.0 increase if EDSS<6.0 or <0.5-point increase if EDSS≥6.0) from baseline (time 1) to DMT discontinuation (time 2). Both stable and worsening MS patients were later assessed again after the DMT discontinuation (time 3). Additional analyses were performed based on disease subtype, type of medication, age cut-off of 55 and EDSS of 6.0. RESULTS:From the cohort of 216 MS patients who discontinued DMT, 161 (72.5%) were classified as stable before DMT discontinuation. After DMT discontinuation, 53 previously stable MS patients (32.9%) experienced disability worsening/progression (DWP). 29.2 and 40% of previously stable RRMS and SPMS respectively had DWP after DMT discontinuation. Over two years after DMT discontinuation, the rate of DWP was similar between patients younger or older than 55 years (31.1% vs 25.9%, respectively). MS patients with EDSS≥6.0 had greater DWP when compared to less disabled patients while remaining on therapy as well as after discontinuation (40.7% vs 15.4%, p < 0.001 and 39.6% vs 15.2%, p < 0.001, respectively). CONCLUSION/CONCLUSIONS:MS patients with stable disease course experience DWP after treatment discontinuation, with no clear relation to age and disease subtype. Patients with EDSS≥6.0 are at higher risk for DWP.

Introduction: 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. Data regarding the demographic features and clinical outcomes of POMS patients treated with these DMTs could help guide future treatment algorithms in this population. Objective/Aims: To describe the demographic features and clinical and radiologic course of POMS patients on the commonly used newer DMTs within the US Network of Pediatric MS Centers.
Method(s): This is an analysis of prospectively collected data from patients seen at 11 regional pediatric MS referral centers participating in the US Network of Pediatric MS Centers. POMS patients who initiated treatment between 10- & lt;18 years with dimethyl fumarate, fingolimod, natalizumab, rituximab or ocrelizumab were included and analyzed as individual cohorts.
Result(s): 168 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 15.2-16.5 years (median EDSS from 1.0-2.0), with 96-100% of patients at or above Tanner Stage 2. Disease duration at time of initiation of index DMT ranged from 1.1-1.6 years, while treatment duration with the index DMT ranged from 1.1-2.2 years. Mean number of relapses in the year prior to initiating index DMT ranged from 0.4-1.0. Mean number of relapses while on index DMT ranged from 0.1-0.4. New T2 and enhancing lesions occurred in 77-88% 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 7-52% and 11-35% patients, respectively.
Conclusion(s): Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit in a large number of POMS patients, which can be used to guide future studies in this population

Introduction: Patients (pts) with paediatric multiple sclerosis (PedMS) have higher relapse rates and radiological activity, accumulating disability at a younger age vs adult-onset MS. There are challenges in conducting clinical trials for PedMS due to the low number of available pts and competing trials. Moreover, testing a new drug vs placebo or low efficacy control poses ethical concerns due to the high disease activity. Few Phase 3 studies have assessed the efficacy/safety of disease-modifying therapies (DMTs) in PedMS; PARADIGMS demonstrated a significant reduction in annualised relapse rate (ARR) for fingolimod vs interferon (IFN)beta-1a in PedMS. A large unmet need for new studied treatment options for PedMS remains.
Objective(s): To present the innovative Bayesian design of the Phase 3 NEOS study aimed to assess the efficacy and safety of ofatumumab and siponimod in PedMS.
Method(s): NEOS is a 2-year, randomised, 3-arm, double-blind, triple-dummy, parallel-group, multicentre, active-comparator, controlled global study comparing ofatumumab and siponimod vs fingolimod in the core part, followed by 2-5 years of an openlabel extension part. Eligibility criteria include pts aged 10 to <18 years, with Expanded Disability Status Scale score 0-5.5 who had experienced >=1 relapse in the last year or >=2 relapses in last 2 years or evidence of >=1 gadolinium-enhancing lesions on MRI within 12 months before randomisation. The primary objective is to demonstrate the non-inferiority (NI) of ofatumumab and siponimod vs fingolimod, assessed by ARR up to 2 years, and will be analysed using a Bayesian negative binomial regression model. This model incorporates information from historical studies on all 3 treatments to reduce the required sample size. The key secondary objective is to demonstrate superiority of ofatumumab and siponimod vs historical IFNbeta-1a data, assessed by ARR. Other endpoints include number of new/newly enlarging T2 lesions on MRI per year, serum neurofilament light chain and safety/tolerability. Randomisation of ~180 pts (n=60 per arm) will provide >80% power for the demonstration of NI (margin of 2.0) for each test treatment vs fingolimod.
Result(s): Study design will be presented at the congress.
Conclusion(s): The innovative NEOS study design does not include placebo or low efficacy controls and thus offers PedMS pts a DMT already shown to be highly effective in adults. NEOS has the potential to bring 2 new future treatment options-ofatumumab and siponimod for PedMS

BACKGROUND:Only recently has the first disease-modifying therapy been approved for children with multiple sclerosis (MS) and practice patterns including substantial off-label use have evolved. Understanding attitudes towards treatment of paediatric MS and whether this has changed due to the ongoing COVID-19 pandemic is vital to guide future therapeutic trials and for developing guidelines that reflect practice. METHODS:We performed an online survey within the International Paediatric Multiple Sclerosis Study Group between July and September 2020. The survey was sent to 130 members from 25 countries and consisted of five sections: demographic data, treatment, disease modifying therapies and COVID-19, outcome and three patient cases. RESULTS:The survey was completed by 66 members (51%), both paediatric neurologists and adult neurologists. Fingolimod and β-interferons were the most frequently used disease-modifying therapies, especially among paediatric neurologists. Almost a third (31%) of respondents had altered their prescribing practice due to COVID-19, in particular at the beginning of the pandemic. CONCLUSIONS:The survey results indicate a tendency of moving from the traditional escalation therapy starting with injectables towards an early start with newer, highly effective disease modifying therapies. The COVID-19 pandemic only slightly affected prescribing patterns and treatment choices in paediatric MS.

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/CONCLUSIONS: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.

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.

Slowed information processing speed is among the earliest markers of cognitive impairment in multiple sclerosis (MS) and has been associated with white matter (WM) structural integrity. Localization of WM tracts associated with slowing, but not significant impairment, on specific cognitive tasks in pediatric and young age onset MS can facilitate early and effective therapeutic intervention. Diffusion tensor imaging data were collected on 25 MS patients and 24 controls who also underwent the Symbol Digit Modalities Test (SDMT) and the computer-based Cogstate simple and choice reaction time tests. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivities were correlated voxel-wise with processing speed measures. All DTI metrics of several white matter tracts were significantly different between groups (p < 0.05). Notably, higher MD, RD, and AD, but not FA, in the corpus callosum correlated with lower scores on both SDMT and simple reaction time. Additionally, all diffusivity metrics in the left corticospinal tract correlated negatively with SDMT scores, whereas only MD in the right superior fronto-occipital fasciculus correlated with simple reaction time. In conclusion, subtle slowing of processing speed is correlated with WM damage in the visual-motor processing pathways in patients with young age of MS onset.