Equity of Access to Disease-Modifying Therapy for Pediatric Multiple Sclerosis: A Survey of Canadian Prescribers.

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: A prospective Danish cohort study

Cognitive impairment in multiple sclerosis (MS) can lead to reduced quality of life, social functioning, and employment. Few studies have investigated cognitive outcomes among patients with pediatric-onset MS (POMS) over the long term. To compare long-term information-processing efficiency between patients with POMS and adult-onset MS (AOMS). This population-based longitudinal cohort study accessed the Swedish MS Registry (SMSreg), which collates information from all 64 neurology clinics in Sweden. Registered cases with definite MS in the SMSreg with an onset before April 15, 2018, and at least 2 Symbol Digit Modalities Test (SDMT) scores recorded were included. Only persons aged 18 to 55 years and with duration of disease of less than 30 years at the time of SDMT administration were included, to ensure comparable ranges between patients with POMS and AOMS. Of 8247 persons with an SDMT recorded in the SMSreg, 5704 met inclusion criteria, 300 (5.3%) of whom had POMS. Data were collected from April 1, 2006, through April 15, 2018 and analyzed from April through August 2018. Pediatric-onset MS (onset <18 years of age) vs AOMS (onset ≥18 years of age). Information-processing efficiency measured every 6 or 12 months by the SDMT. Linear mixed-effects models were used to compare all available SDMT scores between patients with POMS and those with AOMS. Persons with cognitive impairment (ever vs never) were identified using regression-based norms and compared between POMS and AOMS groups using logistic regression. Of the 5704 participants, 4015 were female (70.4%), and 5569 had a relapsing-onset disease course (97.6%). Most participants were exposed to a disease-modifying therapy (DMT) during follow-up (98.8%). Median age at baseline for the POMS group was 25.6 years (interquartile range, 21.0-31.7 years) and for the AOMS group, 38.3 years (interquartile range, 31.4-45.2 years). A total of 46 429 unique SDMT scores were analyzed. After adjustment for sex, age, disease duration, disease course, total number of SDMTs completed, oral or visual SDMT form, and DMT exposure, the SDMT score for patients with POMS was significantly lower than that of patients with AOMS (β coefficient, -3.59 [95% CI, -5.56 to -1.54]). The SDMT score for patients with POMS declined faster than that of patients with AOMS (β coefficient, -0.30 [95% CI, -0.42 tp -0.17]). The odds of cognitive impairment were also significantly elevated in the POMS group (odds ratio, 1.44; 95% CI, 1.06-1.98). In adulthood, patients with POMS demonstrated a more rapid reduction in information-processing efficiency over time and were more likely to experience cognitive impairment than patients with AOMS, independent of age or disease duration. Further investigation is required to understand the mechanisms by which early MS onset influences cognitive outcomes.

Shared Decision Making and Disease Modifying Therapy in Families of Children and Adolescents with Pediatric Onset Multiple Sclerosis

Efficacy and safety of disease-modifying therapies in pediatric-onset multiple sclerosis: A systematic review of clinical trials and observational studies.

Pediatric-onset multiple sclerosis may contrast with adult-onset multiple sclerosis, in terms of disease activity. We aimed to determine differentiating features between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis, at diagnosis and after one year under disease modifying therapies, and analyse the attainment of the status of "No Evidence of Disease Activity" between groups. We analyzed demographical, laboratory, clinical and imaging features of patients with relapsing-remitting multiple sclerosis diagnosed at our center, according to the McDonald's 2010 criteria, with ≥ 1 year under disease modifying therapies and with available magnetic resonance imaging scans at diagnosis and one year after disease modifying therapies initiation. Patients were paired according to gender and disease modifying therapies in use. "No Evidence of Disease Activity" status was assessed, and differences were studied. Fifteen pediatric-onset multiple sclerosis (aged ≥ 8 and < 18 years) and 15 adult-onset multiple sclerosis (≥ 18 and < 55 years) patients were recruited. We found a statistically significant difference in the number of T2 weighted image diffuse lesions/with poorly defined borders (p = 0.015). The mean expanded disability status scale score after one year under disease modifying therapies was lower in the pediatric-onset multiple sclerosis group (1.6 ± 0.8) compared to the adult-onset multiple sclerosis group (2.3 ± 0.8; p = 0.032). Nevertheless, no differences were found regarding the percentage of cases achieving "No Evidence of Disease Activity" in either group. Although there is an empirical impression about the difference in inflammatory activity between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis, it was not possible to corroborate it in our study. Nevertheless, this was an exploratory and retrospective analysis of a small sample of patients, identifying variables in which such differences appear to be most important. Extensive studies of children, adolescents and adults with multiple sclerosis will be needed to categorize the clinical and radiological differences that allow the identification of drug response biomarkers in the early stages of the disease.

A number of new disease-modifying therapies have recently been developed and approved for use in adult-onset multiple sclerosis. However, few treatment options are approved for patients with paediatric-onset multiple sclerosis. There are an increasing number of clinical trials evaluating the efficacy and safety of disease-modifying therapies in children and teens living with multiple sclerosis. Clinical trials are difficult to complete in rare diseases like paediatric-onset multiple sclerosis; however, it is critical to assess safety and monitoring in this vulnerable population by applying robust research methodology to randomized controlled clinical trials. Longer-term extension analyses are also needed to better evaluate the efficacy, dosing and long-term safety of adult disease-modifying therapy for use in paediatric-onset multiple sclerosis. Future research should focus on defining optimal first-line disease-modifying therapy in paediatric-onset multiple sclerosis as related to both efficacy and safety, improving recruitment and completion rates of clinical trials, identifying relevant biomarkers of disease activity, analysing outcome measures related to treatment response and assessing long-term safety for this unique population living with a chronic disease.

Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register. The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Pediatric-onset multiple sclerosis (POMS) is a rare neuroinflammatory and neurodegenerative disease that has a significant impact on long-term physical and cognitive patient outcomes. A small percentage of multiple sclerosis (MS) diagnoses occur before the age of 18 years. Before treatment initiation, a careful differential diagnosis and exclusion of other similar acquired demyelinating syndromes such as anti-aquaporin-4-associated neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein antibody spectrum disorder (MOGSD) is warranted. The recent 2017 changes to the McDonald criteria can successfully predict up to 71% of MS diagnoses and have good specificity of 95% and sensitivity of 71%. Additional measures such as the presence of T1-weighted hypointense lesions and/or contrast-enhancing lesions significantly increase the accuracy of diagnosis. In adults, early use of disease-modifying therapies (DMTs) is instrumental to a better long-term prognosis, including lower rates of relapse and disability worsening, and numerous FDA-approved therapies for adult-onset MS are available. However, unlike their adult counterparts, the development, testing, and regulatory approval of POMS treatments have been significantly slower and hindered by logistic and/or ethical considerations. Currently, only two MS DMTs (fingolimod and teriflunomide) have been tested in large phase III trials and approved by regulatory agencies for use in POMS. First-line therapies not approved by the FDA for use in children (interferon-β and glatiramer acetate) are also commonly used and result in a significant reduction in inflammatory activity when compared with non-treated POMS patients. An increasing number of POMS patients are now treated with moderate efficacy therapies such as dimethyl fumarate and high-efficacy therapies such as natalizumab, anti-CD20 monoclonal antibodies, anti-CD52 monoclonal antibodies, and/or autologous hematopoietic stem cell transplantation. These high-efficacy DMTs generally provide additional reduction in inflammatory activity when compared with the first-line medications (up to 62% of relapse-rate reduction). Therefore, a number of phase II and III trials are currently investigating their efficacy and safety in POMS patients. In this review, we discuss potential changes in the regulatory approval process for POMS patients that are recommended for DMTs already approved for the adult MS population, including smaller sample size for pharmacokinetic/pharmacodynamic studies, MRI-centered primary outcomes, and/or inclusion of teenagers in the adult trials.

Accumulating evidence points to worse clinical outcomes among adults with multiple sclerosis (MS) belonging to minority or poverty-affected groups. By contrast, little is known about the outcomes of these populations with pediatric-onset MS (POMS). Individuals with POMS represent 5% of the MS population and are more racially diverse yet have been understudied regarding socioeconomic environment or characteristics. In this study, we investigated the association between childhood social determinants of health (SDOH) and brain MRI outcomes in patients with POMS. This is a retrospective single-site cohort study of patients with POMS with brain MRI quantitatively analyzed using icobrain software to yield total white matter lesion, black hole, whole brain, white matter, and gray matter volumes. All patients with POMS evaluated at New York University Langone MS Center and who underwent high-quality volumetric MRI scans were included in this study. SDOH indicators of race, ethnicity, health insurance type, parental education, and childhood neighborhood social vulnerability index (SVI) were examined for association with MRI outcomes using linear least absolute shrinkage selection operator penalized regression modeling. Disease-modifying therapy (DMT) timing and DMT efficacy were compared for each SDOH category. A total of 138 patients with POMS (70% female) were included with a mean age of 19.86 years and median disease duration of 4 years at time of scan. Public health insurance, Black race, Hispanic ethnicity, low parental education, and high SVI (greater neighborhood disadvantage) were each associated with white matter lesion and black hole volume. SVI was the strongest individual predictor of total white matter lesion (β = 4.63, p = 0.002) and black hole volume (β = 2.91, p = 0.003). In models incorporating all SDOH variables, public health insurance was the strongest predictor of total lesion (β = 2.48, p = 0.01) and black hole volume (β = 1.50, p = 0.02), attenuating the effect of SVI (β = 1.66, p = 0.33 and β = 1.00, p = 0.39). There were no differences in DMT timing or efficacy between categories of social disadvantage. Individual-level and neighborhood-level indicators of social disadvantage are associated with worse brain MRI outcomes in POMS. Further investigation of race, ethnicity, and childhood disadvantage as risk factors of MS susceptibility and severity is needed to reduce MS health disparities.

Availability of new disease-modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear whether this improvement also involves patients with pediatric-onset MS (POMS), whose early management is more challenging. To evaluate changes in the prognosis of POMS over time in association with changes in therapeutic and managing standards. Retrospective, multicenter, observational study. Data were extracted and collected in May 2019 from the Italian MS Registry, a digital database including more than 59 000 patients. Inclusion criteria were MS onset before age 18 years, diagnosis before January 2014, and disease duration of at least 3 years. Exclusion criteria were primary progressive MS, Expanded Disability Status Scale (EDSS) score of at least 8 one year after onset, unavailability of diagnosis date, and less than 2 EDSS score evaluations. Eligible patients were 4704 patients with POMS. According to these criteria, we enrolled 3198 patients, excluding 1506. We compared time to reach disability milestones by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006, and 2007-2013), adjusting for possible confounders linked to EDSS evaluations and clinical disease activity. We then analyzed the difference among the 4 diagnosis epochs regarding demographic characteristics, clinical disease activity at onset, and DMTs management. Disability milestones were EDSS score 4.0 and 6.0, confirmed in the following clinical evaluation and in the last available visit. We enrolled 3198 patients with POMS (mean age at onset, 15.2 years; 69% female; median time to diagnosis, 3.2 years; annualized relapse rate in first 1 and 3 years, 1.3 and 0.6, respectively), with a mean (SD) follow-up of 21.8 (11.7) years. Median survival times to reach EDSS score of 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS score of 4.0 (hazard ratio [HR], 0.70; 95% CI, 0.58-0.83 in 1993-1999; HR, 0.48; 95% CI, 0.38-0.60 in 2000-2006; and HR, 0.44; 95% CI, 0.32-0.59 in 2007-2013) and 6.0 (HR, 0.72; 95% CI, 0.57-0.90; HR, 0.44; 95% CI, 0.33-0.60; and HR, 0.30; 0.20-0.46). In later diagnosis epochs, a greater number of patients with POMS were treated with DMTs, especially high-potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. In POMS, the risk of persistent disability has been reduced by 50% to 70% in recent diagnosis epochs, probably owing to improvement in therapeutic and managing standards.

Pediatric Multiple Sclerosis

<h3>Objective:</h3> The aim of this study was to evaluate the efficacy and safety of ocrelizumab treatment for pediatric-onset Multiple Sclerosis (POMS) in a real-world clinical setting. <h3>Background:</h3> There is a growing consensus favouring earlier use of highly effective disease modifying therapies (DMTs) in POMS. <h3>Design/Methods:</h3> We conducted a prospective study including consecutive POMS (&lt;18 years) from three UK tertiary paediatric neurosciences centers who received ocrelizumab. <h3>Results:</h3> We included a total of 60 POMS patients; 49 female (81.7%), 41 non-white (68.3%), median age 14.6 yrs (IQR 13.3, 15.5). Median follow-up period was 1.0 yr (range, 0.1–2.6). Forty-three patients (71.7%) had ocrelizumab as their first DMT. The median number of relapses per patient pre-treatment was 2 (range 1–5). Two patients relapsed within one month of starting ocrelizumab and 1 patient had an optic neuritis 6-months post ocrelizumab initiation. During the follow-up period, a median of 2 (range 1–5) repeated MRI scans were performed (total scans, n=140). Forty out of 43 (93.0%) patients achieved no evidence of disease activity (NEDA-3) at 12-months follow-up; two patients had one new brain lesion each at 6-months and a different patient had a relapse (optic neuritis) without new brain lesions at 6-months post treatment. Median EDSS score remained stable during follow-up; 1.0 at baseline and follow-up (p=0.21). In addition, there was no change in cognitive measures at follow-up; baseline SDMT mean score 46 vs follow-up SDMT mean score 48 (p=0.39). The most common adverse events reported were infusion-related-reactions (33/60, 55%), all of which were grade 1 or 2. Serious adverse events were recorded in one patient with enterovirus meningitis, who made a full recovery. <h3>Conclusions:</h3> This study confirms that ocrelizumab, which is proven efficacious for adults with MS, is also effective in POMS with a comparable safety profile. Assessment for long-term efficacy and safety is ongoing. <b>Disclosure:</b> Dr. Abdel-Mannan has nothing to disclose. Arman Eshaghi has nothing to disclose. Dr. Champsas has nothing to disclose. Kshitij Mankad has nothing to disclose. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage. Dr. Rossor has nothing to disclose. Sukhvir Wright has nothing to disclose. Dr. Wassmer has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Wassmer has received research support from Birmingham Children’s Hospital Charity Research Foundation. The institution of Cheryl Hemingway has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. The institution of Cheryl Hemingway has received personal compensation in the range of $0-$499 for serving as a Consultant for Novartis. The institution of Cheryl Hemingway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Cheryl Hemingway has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of Cheryl Hemingway has received research support from Medical research Committee. Ming Lim has nothing to disclose. Prof. Ciccarelli has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Prof. Ciccarelli has received personal compensation in the range of $0-$499 for serving on a Speakers Bureau for Merck. Prof. Ciccarelli has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for NEUROLOGY Journal. Dr. Hacohen has nothing to disclose.

ObjectiveTo evaluate quality of life (QoL), measured by the EQ-5D, in adults with pediatric-onset multiple sclerosis (POMS) or adult-onset multiple sclerosis (AOMS) and explore determinants of QoL in both groups.MethodsData were collected from the nationwide Swedish multiple sclerosis (MS) registry. Demographic characteristics, EQ-5D-3 level, Multiple Sclerosis Impact Scale (MSIS-29) score, Expanded Disability Status Scale (EDSS) score, Symbol Digit Modalities Test score, relapses, and disease-modifying therapy (DMT) exposure were collected on an approximately annual basis (2011–2019). Patients with definite MS with ≥2 EQ-5D measurements collected between ages 18 and 50 were included. The principal outcome was the EQ-5D visual analogue scale (EQ-VAS) score. Linear mixed models compared all available EQ-VAS scores between patients with POMS and patients with AOMS and determinants of EQ-VAS among patients with POMS and patients with AOMS (assessed separately).ResultsA total of 5,094 persons met inclusion criteria: 354 (6.9%) had POMS. A total of 21,357 unique EQ-5D scores were recorded. Most participants were female (70.0%) with a relapsing-onset disease course (98.1%). There was no difference in EQ-VAS scores between patients with POMS and patients with AOMS following adjustment for confounders (β-coefficient for patients with POMS vs patients with AOMS [reference]: 0.99; 95% confidence interval −0.89 to 2.87). Experiencing a relapse, severe neurologic disability (EDSS ≥6.0 vs <3.0), and higher MSIS-29 psychological score were consistently associated with lower QoL, while higher information processing efficiency and exposure to first-line DMTs were associated with higher QoL scores in both groups.ConclusionsThere were no differences in QoL between patients with POMS and patients with AOMS in adulthood. Findings provide support for a focus on reducing neurologic disability and improving psychological status as approaches to potentially improve the QoL of persons with MS.