Lotze, Timothy E.

Background: Age is the strongest factor determining disease expression in multiple sclerosis (MS). We previously demonstrated biological age acceleration in pediatric-onset MS (POMS) compared to controls with both epigenetic clocks (DNAm) and telomere length (TL). It is unknown whether these markers report overlapping or distinct aging-related processes. Objectives: To determine the correlation between DNAm and TL aging markers. Methods: We conducted a cross-sectional case–control study within the US Network of Pediatric MS Centers. We calculated age acceleration residuals for the Horvath, Hannum, PhenoAge, and GrimAge epigenetic clocks and measured TL from whole blood samples to estimate telomere to somatic DNA ratios (T/S ratio). We employed multivariable analysis of covariance to assess the correlation between DNAm estimates and TL. Results: We analyzed biological ages in 270 participants (125 POMS, mean 15.7 years; 145 controls, mean 15.3 years). There were moderate correlations among the different DNAm clocks, but no correlations between DNAm clocks and TL in pooled analyses. In a stratified analysis, only the control group showed a modest correlation between TL and PhenoAge clock ( r = 0.2, p = 0.06). Conclusions: DNAm did not correlate with TL in this sample of POMS and controls, suggesting that these biomarkers may capture complementary and non-overlapping elements of aging-related biology.

Objective To assess real‐world effectiveness of switching disease‐modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity. Methods Of 2615 pediatric‐onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders. Results A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety‐three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52–1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20–0.57; rate ratio: 0.38, 95% CI = 0.21–0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09–0.37; rate ratio: 0.21, 95% CI = 0.10–0.44) ( p < 0.001). Adjusted number needed to treat in person‐years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03–8.69) and infusion over injectable 1.43 (95% CI = 1.00–3.88). Interpretation Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long‐term safety data are required. ANN NEUROL 2026;99:715–729

This study evaluated the efficacy of the multiple sclerosis disease-modifying therapies, intramuscular interferon beta-1a (Avonex) and subcutaneous peginterferon beta-1a (Plegridy), using data from the United States Network of Pediatric Multiple Sclerosis Centers. In this retrospective analysis, 154 patients with multiple sclerosis were included who were treated with Avonex (n = 130), Plegridy (n = 23), or both treatments (n = 1) before the age of 18 years. After 3 months’ sustained use acclimation (“wash-in”), the probability of being relapse-free during the first year was 68.3% for Avonex-treated patients and 69.9% for Plegridy-treated patients; annualized relapse rates were 0.50 and 0.59, respectively. Both disease-modifying therapies demonstrated efficacy similar to that reported in adult populations. Despite the lack of formal approval for pediatric multiple sclerosis, these outcomes indicate that patients may benefit from treatment with Avonex or Plegridy. Understanding efficacy of specific disease-modifying therapies in pediatric multiple sclerosis is essential to making informed treatment decisions.