Long-Term Treatment Strategies of Pediatric Multiple Sclerosis, Including the use of Disease Modifying Therapies.
ABSTRACT: Multiple sclerosis (MS) presenting in the pediatric years can lead to landmark disability levels younger in life than adult onset MS and so therefore early and effective treatment remains paramount for long-term outcomes. The goals of MS therapeutics in adults have widened to address multiple mechanisms: anti-inflammatory, neuroprotective, and myelin repair, yet the optimal paradigm for MS therapies in the pediatric population is not known. Pediatric onset MS add complexities due to the ongoing development of the central nervous system and the immune system. Clinical trials have led to an increasing number of pharmaceutical therapies for adult onset MS (AOMS), one POMS randomized controlled trial is completed and other trials are ongoing, yet due to the low prevalence of POMS, the dynamic landscape and risk management of the MS disease modifying therapies (DMT) it remains more difficult to complete trials in POMS. There is consensus that controlled clinical trials leading to appropriate and safe therapies for POMS are important for a multitude of reasons that include unique pediatric pharmacokinetics, short and long-term safety, developmental issues, clinical benefits, and regulatory approval. This review will focus on new treatment goals, paradigm, strategies, monitoring, compliance, and products in the long-term treatment of POMS. The discussion will focus on these new concepts and the published data related to DMT use in POMS. This review provides significant insight into new concepts of treatment goals and current approaches to enhance the lives of the POMS patients now and in the future.
Project description:<h4>Objective</h4>To determine whether pediatric-onset multiple sclerosis (POMS) and adults-onset multiple sclerosis (AOMS) patients are different in initial disease severity and recovery and to investigate the associations with peripheral blood mononuclear cells (PBMCs) transcriptional profiles.<h4>Methods</h4>Clinical and radiological severity of first and second relapses and 6-month recovery were analyzed in 2153 multiple sclerosis (MS) patients and compared between POMS (onset at 8-18years old) and AOMS (onset at 19-40 years old) patients. PBMCs transcriptomes of 15 POMS and 15 gender-matched AOMS patients were analyzed 6 months after the first relapse and compared to 55 age-matched healthy controls. Differentially Expressed Genes (DEGs) with a false discovery rate ? 10% were evaluated using the Partek software.<h4>Results</h4>POMS had increased Expanded Disability Status Scale (EDSS) score at first and second relapses, higher brain gadolinium-enhancing T1-lesions volume at first relapse, and more complete recovery after both relapses compared to AOMS. POMS patients, who recovered completely from the first relapse, were characterized by 19 DEGs that were mainly related to suppression of antigen presentation. Six upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls. POMS patients, who showed no recovery from the first relapse, were characterized by 28 DEGs that were mainly associated with B-cell activation. Five upstream regulators of these genes were differentially expressed between pediatric and adult healthy controls.<h4>Interpretation</h4>POMS patients may have more severe first and second relapses than AOMS. However, most often, POMS have better recovery that may be attributed to PBMCs age-related transcriptional profiles associated with antigen presentation and B-cell activation.
Project description:Pediatric-onset multiple sclerosis (POMS) may represent a model of vulnerability to damage occurring during a period of active maturation of the human brain. Whereas adaptive mechanisms seem to take place in the POMS brain in the short-medium term, natural history studies have shown that these patients reach irreversible disability, despite slower progression, at a significantly younger age than adult-onset MS (AOMS) patients. We tested for the first time whether significant brain alterations already occurred in POMS patients in their early adulthood and with no or minimal disability (n?=?15) in comparison with age- and disability-matched AOMS patients (n?=?14) and to normal controls (NC, n?=?20). We used a multimodal MRI approach by modeling, using FSL, voxelwise measures of microstructural integrity of white matter tracts and gray matter volumes with those of intra- and internetwork functional connectivity (FC) (analysis of variance, p???0.01, corrected for multiple comparisons across space). POMS patients showed, when compared with both NC and AOMS patients, altered measures of diffusion tensor imaging (reduced fractional anisotropy and/or increased diffusivities) and higher probability of lesion occurrence in a clinically eloquent region for physical disability such as the posterior corona radiata. In addition, POMS patients showed, compared with the other two groups, reduced long-range FC, assessed from resting functional MRI, between default mode network and secondary visual network, whose interaction subserves important cognitive functions such as spatial attention and visual learning. Overall, this pattern of structural damage and brain connectivity disruption in early adult POMS patients with no or minimal clinical disability might explain their unfavorable clinical outcome in the long term.
Project description:Pediatric-onset multiple sclerosis (POMS) is rarer than adult-onset disease, and represents a different diagnostic and treatment challenge to clinicians. We review POMS clinical and radiographic presentations, and explore important differences between POMS and adult-onset MS natural histories and long-term outcomes. Despite having more active disease, current treatment guidelines for patients with POMS endorse the off-label use of lower-efficacy disease-modifying therapies (DMTs) as first line. We review the available MS DMTs, their evidence for use in POMS, and the contrasting treatment strategies of high-efficacy early treatment and escalation therapy. We introduce a new treatment approach, the "high-efficacy early treatment", or HEET strategy, based on using directly observed, high-efficacy intravenously infused DMTs as first-line therapies. Like other proposed POMS treatment strategies, HEET will need to be prospectively studied, and all treatment decisions should be determined by an experienced neurologist, the patient, and his/her parents.
Project description:OBJECTIVE:To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age. METHODS:This is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005. RESULTS:As of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ?12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults. CONCLUSION:Newer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.
Project description:Multiple sclerosis (MS) is an autoimmune inflammatory disease affecting the central nervous system leading to demyelination. MS in the pediatric population is rare, but has been shown to lead to significant disability over the duration of the disease. As we have learned more about pediatric MS, there has been a development of improved diagnostic criteria leading to earlier diagnosis, earlier initiation of disease-modifying therapies (DMT), and an increasing number of DMT used in the treatment of pediatric MS. Over time, treatment with DMT has trended towards the initiation of higher efficacy treatment at time of diagnosis to help prevent further disease progression and accrual of disability over time, and there is evidence in current literature that supports this change in treatment patterns. In this review, we discuss the current knowledge in diagnosis, treatment, and clinical outcomes in pediatric MS.
Project description:In the past decades, multiple sclerosis (MS) treatment has experienced vast changes resulting from major advances in disease-modifying therapies (DMT). Looking at the overall number of studies, investigations with therapeutic advantages and encouraging results are exceeded by studies of promising compounds that failed due to either negative or inconclusive results or have been interrupted for other reasons. Importantly, these failed clinical trials are informative experiments that can help us to understand the pathophysiological mechanisms underlying MS. In several trials, concepts taken from experimental models were not translatable to humans, although they did not lack a well-considered pathophysiological rationale. The lessons learned from these discrepancies may benefit future studies and reduce the risks for patients. This review summarizes trials on MS since 2015 that have either failed or have been interrupted for various reasons. We identify potential causes of failure or inconclusiveness, looking at the path from basic animal experiments to clinical trials, and discuss the implications for our current view on MS pathogenesis, clinical practice, and future study designs. We focus on anti-inflammatory treatment strategies, without including studies on already approved and effective DMT. Clinical trials addressing neuroprotective and alternative treatment strategies are presented in a separate article.
Project description:BACKGROUND:Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology. OBJECTIVE:We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS. METHODS:Cases with onset <18?years (n?=?569) and controls (n?=?16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases (n?=?7588). RESULTS:HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR)meta?=?2.95, p?<?2.0?×?10-16). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated (p?<?0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (ORavg?=?1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta?=?2.77, 95% confidence interval: 2.33, 3.32, p?<?2.0?×?10-16) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02. CONCLUSION:Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.
Project description:We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ?50 years at symptom onset) versus adult-onset (AOMS, 18-<50 years) MS and (2) the association between interferon-beta (IFN?) and disability progression in older relapsing-onset MS adults (?50 years).This retrospective study (1980-2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFN?-treated relapsing-onset MS patients aged ?50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFN? eligibility were examined using survival analyses.LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFN?. Among older relapsing-onset MS adults, no significant association between IFN? exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18-1.22) or historical controls (HR: 0.54; 95% CI: 0.20-1.42) were considered.LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFN? exposure was not significantly associated with reduced disability in older MS patients.
Project description:Knowledge of the effect of modifiable lifestyle factors in the pediatric multiple sclerosis (MS) population is limited. We therefore conducted a scoping review, following the framework provided by Arksey and O'Malley. Four databases were searched for pediatric MS and modifiable lifestyle factors using index terms and keywords, from inception to May 2018. All quantitative and qualitative primary articles were included and limited to English and full text. Of the 7202 articles identified and screened, 25 full-text articles were relevant to our objective and were included. These articles focused on diet obesity, physical activity, and sleep. In cross-sectional analyses, these lifestyle factors were associated with increased risk of pediatric onset MS (POMS), and increased disease activity. Diet, particularly vitamin D and vegetable intake, was associated with reduced relapse rate. Obesity was linked to increased risk of POMS, and physical activity was associated with reduced relapse rate and sleep/rest fatigue. Thus, available studies of lifestyle related outcomes in pediatric MS suggest specific lifestyle related factors, including obesity, higher vitamin D levels, and higher physical activity may associate with lower disease burden in POMS. Studies reviewed are limited by their observational designs. Future studies with longitudinal and experimental designs may further clarify the role of modifiable lifestyle factors in this population.
Project description:MicroRNAs (miRNAs) and transcription factors (TFs) play key roles in complex multifactorial diseases like multiple sclerosis (MS). Starting from the miRNomic profile previously associated with a cohort of pediatric MS (PedMS) patients, we applied a combined molecular and computational approach in order to verify published data in patients with adult-onset MS (AOMS). Six out of the 13 selected miRNAs (miR-320a, miR-125a-5p, miR-652-3p, miR-185-5p, miR-942-5p, miR-25-3p) were significantly upregulated in PedMS and AOMS patients, suggesting that they may be considered circulating biomarkers distinctive of the disease independently from age. A computational and unbiased miRNA-based screening of target genes not necessarily associated to MS was then performed in order to provide an extensive view of the genetic mechanisms underlying the disease. A comprehensive MS-specific miRNA-TF co-regulatory network was hypothesized; among others, SP1, RELA, NF-?B, TP53, AR, MYC, HDAC1, and STAT3 regulated the transcription of 61 targets. Interestingly, NF-?B and STAT3 cooperatively regulate the expression of immune response genes and control the cross-talk between inflammatory and immune cells. Further functional analysis will be performed on the identified critical hubs. Above all, in our view, this approach supports the need of multidisciplinary strategies for shedding light into the pathogenesis of MS.