Multiple Sclerosis Progression and Relapse Activity in Children
Authors: Iaffaldano Pietro , Portaccio Emilio , Lucisano Giuseppe , Simone Marta , Manni Alessia , Guerra Tommaso , Paolicelli Damiano , Betti Matteo , De Meo Ermelinda , Pastò Luisa , Razzolini Lorenzo , Rocca Maria A. , Ferrè Laura , Brescia Morra Vincenzo , Patti Francesco , Zaffaroni Mauro , Gasperini Claudio , De Luca Giovanna , Ferraro Diana , Granella Franco , Pozzilli Carlo , Romano Silvia , Gallo Paolo , Bergamaschi Roberto , Coniglio Maria Gabriella , Lus Giacomo , Vianello Marika , Banfi Paola , Lugaresi Alessandra , Totaro Rocco , Spitaleri Daniele , Cocco Eleonora , Di Palma Franco , Maimone Davide , Valentino Paola , Torri Clerici Valentina , Protti Alessandra , Maniscalco Giorgia Teresa , Salemi Giuseppe , Pesci Ilaria , Aguglia Umberto , Lepore Vito , Filippi Massimo , Trojano Maria , Amato Maria Pia ,   Italian Multiple Sclerosis Register, Ferraro Elisabetta , Logullo Francesco O. , Marfia Girolama A. , Bombardi Roberto , Nasuelli Davide , Bellantonio Paolo , De Riz Milena , Gazzola Paola , Cavaletti Guido , Inglese Matilde , Conte Antonella , Tedeschi Gioacchino , Di Sapio Alessia , Leone Alessandro , Montepietra Sara , Marini Bruno , Gatto Maurizia , Sessa Maria , Ferrò Maria T. , Rini Augusto , Cargnelutti Daniela , Mirabella Massimiliano , Burlina Alessandro , Avolio Carlo , Cavalla Paola , Rovaris Marco , Ardito Bonaventura , Piantadosi Carlo , Confalonieri Paolo A. , Clerici Raffaella , Strumia Silvia , De Robertis Francesca , Quatrale Rocco , Sinisi Leonardo , Fioretti Cristina , Di Lazzaro Vincenzo , Bucello Sebastiano , Mancinelli Luca , Ribizzi Giuseppe , Zarbo Roberto , Grimaldi Luigi M. E. , Corea Francesco , Sidoti Vincenzo , Massacesi Luca , Balgera Roberto , Romano Marcello C. , D'Andrea Francesco , Ancona Anna Luisa , Pizzorno Matteo , Rinalduzzi Steno , Passantino Francesco , Capone Lorenzo , Bianchi Marta , Venturi Simonetta , Trivelli Giuseppe , Brichetto Giampaolo , Fermi Silvia , Bramanti Placido , Iodice Rosa , Piras Maria Luisa , Celani Maria Grazia , Barone Paolo , Tassinari Tiziana , Marson Annamaria , Clerico Marinella , Banfi Paola , Solaro Claudio 
Published: November 2023

ImportanceAlthough 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.ObjectiveTo 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).Design, Setting, and ParticipantsThis 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.Main Outcomes and MeasuresThe main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors.ExposuresClinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT.ResultsAfter 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 &amp;lt; .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 &amp;lt; .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P &amp;lt; .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P &amp;lt; .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).Conclusions and RelevancePIRA 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.