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. 2024 Mar 1;81(3):273-282.
doi: 10.1001/jamaneurol.2023.5566.

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

Nail Benallegue  1   2 , Fabien Rollot  3   4   5   6 , Sandrine Wiertlewski  2   7 , Romain Casey  3   4   5   6 , Marc Debouverie  8 , Anne Kerbrat  9 , Jérôme De Seze  10 , Jonathan Ciron  11   12 , Aurelie Ruet  13   14 , Pierre Labauge  15 , Elisabeth Maillart  16 , Helene Zephir  17 , Caroline Papeix  18 , Gilles Defer  19 , Christine Lebrun-Frenay  20 , Thibault Moreau  21 , Eric Berger  22 , Bruno Stankoff  23 , Pierre Clavelou  24 , Olivier Heinzlef  25 , Jean Pelletier  26 , Eric Thouvenot  27   28 , Abdullatif Al Khedr  29 , Bertrand Bourre  30 , Olivier Casez  31 , Philippe Cabre  32 , Abir Wahab  33 , Laurent Magy  34 , Sandra Vukusic  3   4   5   6 , David-Axel Laplaud  2   7 ; OFSEP (Observatoire Français de la Sclérose en Plaques) Investigators
Collaborators, Affiliations

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

Nail Benallegue et al. JAMA Neurol. .

Abstract

Importance: Moderately 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.

Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity.

Design, setting, and participants: This 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.

Exposure: HET or MET at treatment initiation.

Main outcomes and measures: The 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.

Results: Of 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 < .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 relevance: Results 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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Benallegue reported compensation for travel from Roche outside the submitted work. Dr Wiertlewski reported receiving personal fees from Biogen, Novartis, Alexion, Merck, Roche, and Janssen outside the submitted work. Dr de Seze reported receiving personal fees from Biogen, Alexion, Horizon, Roche, Merck, Sanofi, Novartis, Janssen, Sandoz, UCB Pharma, and LFB Pharma outside the submitted work. Dr Ciron reported receiving advisory board fees from Biogen, Novartis, Merck, Roche, Sanofi, Alexion, and Horizon Therapeutics outside the submitted work. Dr Ruet reported receiving personal fees and nonfinancial support from Biogen, Novartis, and Merck; grants from Roche and BMS; and grants and personal fees from Sanofi-Genzyme outside the submitted work. Dr Maillart reported receiving grants from Biogen and ARSEP and personal fees from Biogen, Merck, Novartis, Sanofi-Genzyme, Janssen, Roche, and Teva outside the submitted work. Dr Zéphir reported receiving advisory board, consulting, and/or personal fees from Biogen, Alexion, Horizon Therapeutics, Novartis, Merck, and Janssen and grants from Roche outside the submitted work. Dr Papeix reported receiving conference and personal fees from Alexion and Horizon outside the submitted work. Dr Defer reported receiving personal fees from Biogen, Novartis, BMS, Merck Serono, Roche, and Genzyme outside the submitted work. Dr Moreau reported receiving travel grants and advisory board fees from Biogen, Novartis, Sanofi, and Roche outside the submitted work. Dr Berger reported receiving personal fees from Novartis, Biogen Idec, and Merck outside the submitted work. Dr Stankoff reported receiving grants from Roche, Merck Serono, and Novartis and lecture fees from Novartis, Merck, and Janssen outside the submitted work. Dr Thouvenot reported receiving personal fees from Janssen, Roche, Sanofi, and BMS and personal fees and grants from Merck, Novartis, and Biogen outside the submitted work. Dr Casez reported receiving personal fees from Biogen, Roche, Novartis, and Merck during the conduct of the study. Dr Wahab reported receiving personal fees from Novartis, Merck, and Janssen outside the submitted work. Dr Magy reported receiving personal fees from Biogen, Roche, and Novartis outside the submitted work. Dr Vukusic reported receiving grants from Biogen, BMS, Merck, Novartis, Janssen, Roche, and Sanofi and personal fees from Biogen, BMS, Merck, Novartis, Janssen, Roche, Sanofi, and Sandoz (all to institution) outside the submitted work. Dr Laplaud reported receiving personal fees from Biogen, Alexion, Novartis, Merck, Sanofi, MSD, and Janssen and grants from Roche, Fondation EDMUS, Fondation ARSEP, and Agence Nationale de la Recherche (ANR), outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow Diagram
DMT indicates disease-modifying therapy; HET, highly effective therapy; MET, moderately effective therapy; MS, multiple sclerosis.
Figure 2.
Figure 2.. Relapse Rate According to Index Treatment Strategy
A, First relapse rate. B, Cumulative probabilities of a first relapse occurrence after treatment initiation according to index disease-modifying therapy. C, Relapse rate on a 3-month interval basis, 12 months before and 24 months after disease-modifying therapy initiation according to first treatment strategy (95% CI). HET indicates highly effective therapy; MET, moderately effective therapy.
Figure 3.
Figure 3.. Treatment Discontinuation According to Index Treatment Strategy Group
A, Treatment discontinuation hazard rates. B, Cumulative probabilities according to time since treatment initiation. C, Treatment-switching events depicted as a sunburst chart. Each ring symbolizes a treatment line. The inner ring contains the distribution of the initial group, with subthemes radiating out (ie, an outer ring illustrates a treatment switch from its corresponding inner ring). The size of each segment reflects the number of occurrences, and hence the relative importance of switches. Embedded numbers correspond to the number of patients in each subgroup. HET indicates highly effective therapy; MET, moderately effective therapy.
See this image and copyright information in PMC

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