Paediatric-onset multiple sclerosis : epidemiology and treatment with a special focus on rituximab

<p dir="ltr"><b>Background:</b> Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, affecting almost 3 million people worldwide. Approximately 5% experience disease onset during childhood or adolescence, yet data on its occurrence in this age remain limited. Paediatric-onset MS (PoMS) is typically associated with higher inflammatory activity than Adult-onset MS, which calls for early and effective treatment to prevent long-term disability. Despite this, comparative data on PoMS treatment are scarce. Of the more than 20 disease-modifying therapies (DMTs) approved for adult MS, only fingolimod, teriflunomide, and dimethyl fumarate are approved for paediatric use in Europe, and only fingolimod is approved in the United States. None of the highly effective DMTs are approved for children, highlighting the need for better evidence to guide treatment decisions.</p><p dir="ltr">This thesis further characterises the epidemiology of PoMS and provides real- world evidence on treatment patterns and outcomes, with particular emphasis on rituximab-a highly effective B-cell depleting therapy (BCDT) widely used in Sweden over the past decade.</p><p dir="ltr"><b>Methods:</b> The thesis comprises five studies. First, it validates the Swedish Multiple Sclerosis registry for use in PoMS by comparing registry data against medical records. Second, it characterises the occurrence of PoMS in Sweden using data from two complementary national population-based registers: the Swedish Multiple Sclerosis Registry and the Swedish Patient Register. Third, it examines international treatment patterns based on a cross-sectional survey. Finally, it investigates real-world outcomes of DMT use in PoMS through both an international multicentre case series of rituximab and a Swedish population- based cohort design, allowing for comparison across DMTs.</p><p dir="ltr"><b>Results:</b> In the validation study, MS registry data from 122 individuals with PoMS demonstrated an overall concordance exceeding 90% when compared with medical records. However, more than 30% of the data were missing for rituximab infusions, magnetic resonance imaging (MRI) examinations, and relapses.</p><p dir="ltr">The incidence rate of PoMS in Sweden was 1.12 per 100,000 person-years (95% Confidence Interval [CI]: 0.98-1.27), and the prevalence was 2.82 per 100,000 children and adolescents (95% CI: 2.60-3.06), with slightly lower age- and sex- standardised estimates. Estimates increased with age and showed a female predominance from age 12, remaining stable over time.</p><p dir="ltr">In the survey conducted within the International Paediatric Multiple Sclerosis Study Group, 66 respondents from 25 countries reported that interferons and fingolimod, which are moderately effective DMTs, were the most commonly used DMTs. However, a trend toward earlier use of highly effective DMTs was observed.</p><p dir="ltr">In the rituximab case series, which included 61 individuals with PoMS treated over a median of 20.9 months (range 1.1-151.1), rituximab was associated with an annualised relapse rate of 0.02 (95% CI: 0.01-0.05) and an annualised rate of new MRI lesions of 0.08 (95% CI: 0.03-0.25), representing a highly significant decrease compared to before therapy was initiated. Adverse events occurred in 67% of cases, mostly mild to moderate, and treatment persistence was 90%.</p><p dir="ltr">In the treatment persistence study, which included 383 individuals with PoMS and 934 treatment episodes, all other DMTs were associated with significantly higher risks of discontinuation compared to rituximab, with adjusted hazard ratios of 4.33 (95% CI: 3.26-5.76) for natalizumab, 4.57 (95% CI: 3.23-6.46) for fingolimod, 5.51 (95% CI: 3.81-7.96) for dimethyl fumarate, and 11.23 (95% CI: 8.30-15.20) for injectables. Results remained robust throughout sensitivity analyses.</p><p dir="ltr"><b>Conclusion:</b> In PoMS, moderately effective DMTs remain widely used internationally, although there is a growing trend toward initiating highly effective therapies earlier. In our real-world studies, rituximab appeared as a promising option, demonstrating strong effectiveness and a favourable safety profile. Treatment persistence was significantly higher, not only compared to the moderately effective DMTs approved for paediatric use but also compared to the highly effective DMT natalizumab. These findings support a more proactive, evidence-informed approach to managing PoMS, with rituximab and other BCDTs as promising candidates for early intervention.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Sandesjö F,</b> Alping P, Fink K, Wickström R, Piehl F, Frisell T, Mckay KA. Validation of the Swedish Multiple Sclerosis registry for pediatric-onset multiple sclerosis. Multiple Sclerosis Journal - Experimental, Translational and Clinical. 2025;11(1):20552173251314118. <a href="https://doi.org/10.1177/20552173251314118" rel="noreferrer" target="_blank">https://doi.org/10.1177/20552173251314118</a></p><p dir="ltr">Il. <b>Sandesjö F,</b> Tremlett H, Fink K, Marrie RA, Zhu F, Wickström R, Mckay KA. Incidence rate and prevalence of pediatric-onset multiple sclerosis in Sweden: A population-based register study. European Journal of Neurology. 2024;31(5):e16253. <a href="https://doi.org/10.1111/ene.16253" rel="noreferrer" target="_blank">https://doi.org/10.1111/ene.16253</a></p><p dir="ltr">III. <b>Sandesjö F,</b> Wassmer E, Deiva K, Amato MP, Chitnis T, Hemingway C, Krupp L, Pohl D, Rostasy K, Waubant E, Banwell B, Wickström R. Current international trends in the treatment of multiple sclerosis in children - Impact of the COVID-19 pandemic. Multiple Sclerosis and Related Disorders. 2021;56:103277. <a href="https://doi.org/10.1016/j.msard.2021.103277" rel="noreferrer" target="_blank">https://doi.org/10.1016/j.msard.2021.103277</a></p><p dir="ltr">IV. Breu M*, <b>Sandesjö F*</b>, Milos RI, Svoboda J, Salzer J, Schneider L, Reichelt JB, Bertolini A, Blaschek A, Fink K, Höftberger R, Lycke J, Rostásy K, Seidl R, Siegert S, Wickström R ** , Kornek B **. Rituximab treatment in pediatric-onset multiple sclerosis. European Journal of Neurology. 2024;31(5):e16228. *Shared first authorship. ** Shared last authorship. <a href="https://doi.org/10.1111/ene.16228" rel="noreferrer" target="_blank">https://doi.org/10.1111/ene.16228</a></p><p dir="ltr">V. <b>Sandesjö F,</b> Mckay KA, Fink K, Piehl F, Wickstrom R. Treatment Persistence in Pediatric-onset Multiple Sclerosis - A Swedish nationwide registry study. [Submitted]</p>