Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis

Baroncini, Damiano; Simone, Marta; Iaffaldano, Pietro; Morra, Vincenzo Brescia; Lanzillo, Roberta; Filippi, Massimo; Romeo, Marzia; Patti, Francesco; Chisari, Clara Grazia; Cocco, Eleonora; Fenu, Giuseppe; Salemi, Giuseppe; Ragonese, Paolo; Inglese, Matilde; Cellerino, Maria; Margari, Lucia; Comi, Giancarlo; Zaffaroni, Mauro; Ghezzi, Angelo; registry, Italian Ms

doi:10.1001/jamaneurol.2021.1008

Cited by 36 publications

(32 citation statements)

References 68 publications

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Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

“…Over the last several years, multiple large observational studies have reported on long-term outcomes in patients with POMS [ 7 , 25 ]. A recent Italian registry study included a total of 3198 patients with POMS who were followed for an average of 21.8 years [ 7 ]. The time to reach different disability levels was significantly decreased with each diagnosis epoch (up to 50–70% when compared with the natural history), which can be attributed mainly to the initiation of highly efficacious drugs during the pediatric age and continued use of DMT for a longer period of time when compared with prior epochs [ 7 ].…”

Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

“…A recent Italian registry study included a total of 3198 patients with POMS who were followed for an average of 21.8 years [ 7 ]. The time to reach different disability levels was significantly decreased with each diagnosis epoch (up to 50–70% when compared with the natural history), which can be attributed mainly to the initiation of highly efficacious drugs during the pediatric age and continued use of DMT for a longer period of time when compared with prior epochs [ 7 ]. In a similar fashion, 549 POMS patients from the Swedish MS registry also took significantly longer time to reach certain EDSS milestones, but still were younger when compared with the AOMS cohort [ 25 ].…”

Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

“…These impairments can have long-term consequences, including a lower likelihood of pursuing higher education, lower annual earning, frequent sick days during work life, and early enrollment into disability pension programs [ 6 ]. Therefore, efforts towards early diagnosis, discovery of early predictors of long-term outcomes, and appropriate early drug intervention are highly warranted [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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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.

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Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

Section: Disability Outcomes Predictors and Importance Of Treatment In Pomsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

et al. 2021

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“…Then, we stratified this subgroup into 4 consecutive epochs of diagnosis, as defined by Baroncini and colleagues: before 1993, from 1993 to 1999, from 2000 to 2006, and from 2007 to 2013 (corresponding to the time of approval of pivotal DMTs in Italy). 26 Then, we reran the analysis as described above.…”

Section: Discussionmentioning

confidence: 99%

Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis

Meo

Filippi

Trojano

et al. 2022

Annals of Neurology

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This study was undertaken to describe and compare disease course and prognosis of early (ie, disease onset before age 11 years) and late (ie, disease onset after age 11 years) onset pediatric multiple sclerosis. Methods: Prospectively collected clinical information from Italian Multiple Sclerosis Register of 1993 pediatric multiple sclerosis patients, of whom 172 had early onset, was analyzed. Cox models adjusted for sex, baseline Expanded Disability Status Scale score, and disease-modifying treatments and stratified for diagnostic criteria adopted (Poser vs McDonald) were used to assess the risk of reaching irreversible Expanded Disability Status Scale scores of 3, 4, and 6, and conversion to secondary progressive phenotype in early versus late onset pediatric patients. Prognostic factors were also evaluated. Results: A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode were observed in early versus late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer from disease onset to convert to secondary progressive phenotype and to reach all

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Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis

Benallegue,

Rollot,

Wiertlewski

et al. 2024

JAMA Neurol

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ImportanceModerately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.ObjectiveTo assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, Setting, and ParticipantsThis was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.ExposureHET or MET at treatment initiation.Main Outcomes and MeasuresThe primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.ResultsOf the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P &lt; .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and RelevanceResults of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.

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Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis

Cited by 36 publications

References 68 publications

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Multiple Sclerosis in Children: Differential Diagnosis, Prognosis, and Disease-Modifying Treatment

Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis

Highly Effective Therapies as First-Line Treatment for Pediatric-Onset Multiple Sclerosis

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