Assessing early clinical and MRI predictors of treatment response in pediatric multiple sclerosis patients.

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Background and aims
Pediatric multiple sclerosis (MS), with disease onset before 18 years of age, represents 3-10% of all MS cases.1 During the last decade, pediatric MS has been increasingly recognized, thus making necessary to identify specific features related to disease onset during childhood and adolescence.
More than 98% of children and adolescents diagnosed with MS follows a relapsing-remitting (RR) course.2 It is characterized by both clinical and MRI evidence of highly active inflammation and remyelination,3 with frequent but highly recoverable relapses early in the disease.4 Among pediatric MS population significant differences in clinical, MRI, and immunological features were observed between early (i.e., by convention, before age 11 years) and late onset pediatric MS patients.
Considering these points, it appeared necessary as first to further characterize this population by analyzing data from a large real-life cohort of pediatric onset MS patients collected in the Italian MS Registry.
In details, we aimed to describe and the natural history of early and late onset pediatric MS and to identify clinical and MRI features at disease onset able to predict a more severe disease course. Then, we aimed to identify early clinical and MRI predictors of three-years treatment response in order to optimize treatment strategies to a better risk-benefit ratio from new highly active drugs. Moreover, we aimed to combine clinical and MRI features recorded over the first year of treatment to identify a score of treatment response specific for pediatric patients.

Results
For the first part of our project, from 3332 pediatric onset MS patients, a cohort of 1993 pediatric onset MS patients was selected from the Italian MS Register.5 Of 1993 pediatric MS cases selected for the final analysis, 172 (9%) were classified as early onset pediatric MS.
A greater proportion of males, isolated brainstem involvement, and longer time interval between first and second clinical episode was observed in early vs late onset pediatric patients. Compared to late onset, early onset pediatric patients took longer time from disease onset to convert to secondary progressive phenotype and to reach three distinct disability milestones (Expanded Disability Status Scale scores of 3, 4, and 6). Recovery from first demyelinating event, time to first relapse, annualized relapse rate during the first 3 years of disease and disease-modifying treatments exposure were independent predictors for long-term disability in early onset pediatric patients. In late onset pediatric patients, isolated optic neuritis, multifocal symptoms or progressive course at disease onset were additional predictors for long-term disability.
To the second aim of our project, we identified the presence of at least three new T2 or Gd+ lesions detected on 1-year MRI scan and the occurrence of at least 2 relapses during the first year of treatment as independent predictors of treatment failure after 3 years. According to these findings, we grouped risk levels into three classes:
- Group 0: <2 relapses during the first year of treatment and <3 new T2 or Gd+ lesions at 1-year MRI scan;
- Group 1: 2 relapses during the first year of treatment or 3 new T2 or Gd+ lesions at 1-year MRI scan;
- Group 2: 2 relapses during the first year of treatment and 3 new T2 or Gd+ lesions at 1-year MRI scan.
According to this features the 79 % of pediatric MS patients resulted in group 0, 19% in group 1 and 2% in group 2. Given the small number of patients in the highest risk category, group 1 and 2 were also considered together, to define the highest risk group.
High risk vs low risk category had a positive predictive value of 75% and a negative predictive value of 73%, a sensitivity of 44%, a specificity of 91%, and a global accuracy of 68% for identifying patients developing treatment failure over 3 years. Furthermore, pediatric MS patients in low risk category showed a probability of EDSS worsening over 3 years following the first year of therapy of 11% while pediatric MS patients in high risk category of 26%.

Conclusions
Comparing the natural history of early and late onset pediatric MS in a large, real-life cohort of patients, our study identified several specific features of early onset pediatric MS.
Moreover, this study also points to the critical importance of early treatment in this population, and it adds relevant prognostic information to improve the clinical management of pediatric MS patients.
The combination of clinical relapses with substantial MRI activity appeared as the best predictor of short-term treatment failure and disease progression in pediatric MS patients. The adoption of this simple and pediatric MS-specific score in the clinical practice could help clinician in evaluating treatment failure and in optimizing treatment strategies.



Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
• De Meo E, Filippi M, Trojano M, Comi G, Patti F, Brescia Morra V, Salemi G, Onofrj M, Lus G, Cocco E, Fonderico M, Torri Clerici V, Maniscalco GT, Valentino P, Bertolotto A, Lugaresi A, Bergamaschi R, Rovaris M, Sola P, Tedeschi G, Pesci I, Aguglia U, Cavalla P, Maimone D, Granella F, Vianello M, Simone M, Portaccio E, Amato MP. Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis. Ann Neurol. 2022 Apr;91(4):483-495. doi: 10.1002/ana.26322. Epub 2022 Feb 28. PMID: 35150168.

Abstracts:
• De Meo E, Fonderico M, Filippi M, Patti F, Brescia Morra V, Salemi G, Lus G, Onofrji M, Cocco E, Maniscalco G, Bertolotto A, Confalonieri P, Bergamaschi R, Lugaresi A, Valentino P, Sola P, Cavalla P, Maimone D, Granella F, Pesci I, Rovaris M, Simone M, Trojano M, Amato MP. Long term disability progression in early and late onset pediatric multiple sclerosis patients. Eur J Neurol 2021; 28 (Suppl 1): 464 (EAN Congress 2021)
• E. De Meo, M. Filippi, V. Brescia Morra, F. Patti, G.T. Maniscalco, P.A. Confalonieri, G. Salemi, M. Onofrj, G. Lus, M. Simone, M. Trojano, M.P. Amato. Assessing treatment response in pediatric multiple sclerosis patients. Multiple Sclerosis Journal. 2021;27(2_suppl):134-740. doi:10.1177/13524585211044667 (ECTRIMS 2021)
• De Meo E, Fonderico M, Filippi M, Patti F, Brescia Morra V, Salemi G, Lus G, Onofrji M, Cocco E, Maniscalco G, Bertolotto A, Confalonieri P, Bergamaschi R, Lugaresi A, Valentino P, Sola P, Cavalla P, Maimone D, Granella F, Pesci I, Rovaris M, Simone M, Trojano M, Amato MP.Natural history of multiple sclerosis with childhood and adolescence onset. Multiple Sclerosis Journal. 2021;27(2_suppl):134-740. doi:10.1177/13524585211044667 (ECTRIMS 2021)
• Ermelinda De Meo, Massimo Filippi, Vincenzo Brescia Morra, Francesco Patti, Giorgia Teresa Maniscalco, Valentina Torri Clerici, Giuseppe Salemi, Marco Onofrj, Giacomo Lus, Marta Simone, Maria Trojano, Maria Pia Amato. Assessing treatment response in pediatric multiple sclerosis patients (P16-4.003), Neurology May 2022, 98 (18 Supplement) 3251 (AAN 2022).

De Meo E, Filippi M, Trojano M, Comi G, Patti F, Brescia Morra V, Salemi G, Onofrj M, Lus G, Cocco E, Fonderico M, Torri Clerici V, Maniscalco GT, Valentino P, Bertolotto A, Lugaresi A, Bergamaschi R, Rovaris M, Sola P, Tedeschi G, Pesci I, Aguglia U, Cavalla P, Maimone D, Granella F, Vianello M, Simone M, Portaccio E, Amato MP. Comparing Natural History of Early and Late Onset Pediatric Multiple Sclerosis. Ann Neurol. 2022 Apr;91(4):483-495. doi: 10.1002/ana.26322. Epub 2022 Feb 28. PMID: 35150168