Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan 1;81(1):50-58.
doi: 10.1001/jamaneurol.2023.4455.

Multiple Sclerosis Progression and Relapse Activity in Children

Pietro Iaffaldano  1 , Emilio Portaccio  2 , Giuseppe Lucisano  1   3 , Marta Simone  4 , Alessia Manni  1 , Tommaso Guerra  1 , Damiano Paolicelli  1 , Matteo Betti  2 , Ermelinda De Meo  2 , Luisa Pastò  2 , Lorenzo Razzolini  2 , Maria A Rocca  5   6 , Laura Ferrè  5 , Vincenzo Brescia Morra  7 , Francesco Patti  8 , Mauro Zaffaroni  9 , Claudio Gasperini  10 , Giovanna De Luca  11 , Diana Ferraro  12 , Franco Granella  13 , Carlo Pozzilli  14 , Silvia Romano  15 , Paolo Gallo  16 , Roberto Bergamaschi  17 , Maria Gabriella Coniglio  18 , Giacomo Lus  19 , Marika Vianello  20 , Paola Banfi  21 , Alessandra Lugaresi  22   23 , Rocco Totaro  24 , Daniele Spitaleri  25 , Eleonora Cocco  26 , Franco Di Palma  27 , Davide Maimone  28 , Paola Valentino  29 , Valentina Torri Clerici  30 , Alessandra Protti  31 , Giorgia Teresa Maniscalco  32 , Giuseppe Salemi  33 , Ilaria Pesci  34 , Umberto Aguglia  35 , Vito Lepore  36 , Massimo Filippi  5   6 , Maria Trojano  1 , Maria Pia Amato  2   37 ; Italian Multiple Sclerosis Register
Collaborators, Affiliations

Multiple Sclerosis Progression and Relapse Activity in Children

Pietro Iaffaldano et al. JAMA Neurol. .

Erratum in

  • Error in Table 4.
    [No authors listed] [No authors listed] JAMA Neurol. 2024 Jan 1;81(1):88. doi: 10.1001/jamaneurol.2023.5461. JAMA Neurol. 2024. PMID: 38189820 Free PMC article. No abstract available.

Abstract

Importance: 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.

Objective: 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).

Design, setting, and participants: 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.

Main outcomes and measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors.

Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT.

Results: 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).

Conclusions and relevance: 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.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Iaffaldano reported receiving personal fees from Merck, Novartis, BMS, Biogen, Roche, Alexion, and Genzyme outside the submitted work. Dr Portaccio reported receiving personal fees from Biogen, Celgene, Genzyme, Merck, Novartis, Sanofi, and Roche outside the submitted work. Dr Manni reported receiving travel support and advisory board or speakers’ honoraria from Biogen, Sanofi Genzyme, Roche, Merck, Novartis, and Bristol-Myers Squibb outside the submitted work. Dr Paolicelli reported receiving personal fees from Sanofi, Merck, Biogen, and Janssen outside the submitted work. Dr Razzolini reported receiving personal fees from Merck, Sanofi Genzyme, Novartis, Roche, Biogen, and Janssen outside the submitted work. Dr Rocca reported receiving personal fees from Biogen, Bristol-Myers Squibb, Eli Lilly, Janssen, Roche, AstraZeneca, Biogen, Bristol-Myers Squibb, Bromatech, Celgene, Genzyme, Horizon Therapeutics Italy, Merck Serono SpA, Novartis, Roche, Sanofi, and Teva outside the submitted work. Dr Ferrè reported receiving personal fees from Novartis and nonfinancial support from Sanofi, Merck, and Roche outside the submitted work. Dr Granella reported receiving grants from Roche and personal fees from Biogen, Sanofi, Roche, Novartis, Merck Serono, Bristol-Myers Squibb, and Pfizer outside the submitted work. Dr Pozzilli reported receiving grants from Roche and Novartis and personal fees from Bristol, Alexion, and Merck outside the submitted work. Dr Bergamaschi reported receiving grants from Biogen, Merck Serono, Roche, Novartis, and Sanofi Genzyme and personal fees from Biogen, Merck Serono, Roche, Novartis, Celgene, Janssen, and Sanofi Genzyme outside the submitted work. Dr Lugaresi reported receiving personal fees from Biogen, Bristol-Myers Squibb, Alexion, Merck Serono, Novartis, and Sanofi Genzyme and grants from Novartis and Sanofi/Genzyme outside the submitted work. Dr Maimone reported receiving personal fees from Biogen, Merck, Novartis, Roche, Sanofi, and Bristol-Myers Squibb outside the submitted work. Dr Lepore reported receiving personal fees from Istituto di Ricerche Farmacologiche Mario Negri IRCCS outside the submitted work. Dr Filippi reported receiving personal fees from Alexion, Almirall, Biogen, Merck, Novartis, Roche, Sanofi, Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, Teva, Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, and Sanofi-Genzyme and grants from Biogen Idec, Merck-Serono, Novartis, and Roche outside the submitted work. Dr Trojano reported receiving personal fees from Biogen, Novartis, Roche, Merck, Bristol Meyer Squibb, and Genzyme and grants from Biogen, Novartis, and Roche outside the submitted work. Dr Amato reported receiving grants from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme and personal fees from Biogen, Merck, Novartis, Roche, Sanofi Genzyme, Celgene BMS, Janssen, Horizon, Teva, and Bayer outside the submitted work. No other disclosures were reported.

Figures

Figure.
Figure.. Kaplan-Meier Estimate of the Cumulative Incidence of the First Confirmed Disability Accrual (CDA), Progression Independent of Relapse Activity (PIRA), and Relapse-Associated Worsening (RAW) Events and Contribution of First PIRA and RAW Events to CDA in Different Decades of Age
See this image and copyright information in PMC

References

    1. Kappos L, Butzkueven H, Wiendl H, et al. ; Tysabri® Observational Program (TOP) Investigators . Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study. Mult Scler. 2018;24(7):963-973. doi:10.1177/1352458517709619 - DOI - PMC - PubMed
    1. Cree BAC, Hollenbach JA, Bove R, et al. ; University of California, San Francisco MS-EPIC Team . Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666. doi:10.1002/ana.25463 - DOI - PMC - PubMed
    1. Kappos L, Wolinsky JS, Giovannoni G, et al. . Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77(9):1132-1140. doi:10.1001/jamaneurol.2020.1568 - DOI - PMC - PubMed
    1. Lublin FD, Häring DA, Ganjgahi H, et al. . How patients with multiple sclerosis acquire disability. Brain. 2022;145(9):3147-3161. doi:10.1093/brain/awac016 - DOI - PMC - PubMed
    1. Portaccio E, Bellinvia A, Fonderico M, et al. . Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain. 2022;145(8):2796-2805. doi:10.1093/brain/awac111 - DOI - PubMed

Publication types