Assessing the clinical course of pediatric onset multiple sclerosis in different treatment eras: are we really modifying the disease?
SYNOPSIS AND RESULTS
Availability of new disease modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear if this improvement also involves pediatric-onset MS (POMS) patients, whose early management is limited by a low number of approved DMTs and, possibly, other factors, such as cognitive impairment, involvement of the family in therapeutic decisions and risk of low adherence to therapies. Our aim was to evaluate if prognosis of POMS was getting better over time, in relation to changes in therapeutic and managing standards. Inclusion criteria were: MS onset before 18 years of age, confirmed MS diagnosis before January 2014 and disease duration ≥3 years at last observation. Exclusion criteria were having primary progressive or undefined MS course, crucial errors in data entry, EDSS score ≥8 one year after the onset of disease, missing diagnosis date and less than two EDSS score evaluations. We compared time to reach persistent disability milestones (EDSS 4.0 and 6.0) by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006 and 2007-2013), adjusting for possible confounders linked to EDSS evaluations (EDSS score evaluations per year, period of EDSS assessment and disease duration at first EDSS evaluation) and clinical disease activity (age at onset, sex, ARR in the first three years, type of clinical onset, time from onset to diagnosis). We then analysed the difference among the four diagnosis epochs regarding demographic characteristics, clinical disease activity at onset and DMTs management.
Data start
Data end
2019-06-10
2020-06-15
PARTICIPATING CENTERS
Marta Simone, Lucia Margari, Unità di Neuropsichiatria Infantile, Dipartimento di Scienze Biomediche e Oncologia, Università di Bari, Bari Pietro Iaffaldano, Centro SM, Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso Università di Bari, Bari Vincenzo Brescia Morra, Roberta Lanzillo, Centro di Cura e Ricerca Clinica sulla SM, Dipartimento di Neuroscienze, Scienze della Riproduzione e Odontostomatologia, Università di Napoli Federico II, Napoli Massimo Filippi, Dipartimento di Neurologia e Neurofisiologia, Centro SM, Neuroimaging Research Unit, Istituto Scientifico San Raffaele, Milano Marzia Romeo, Dipartimento di Neurologia and Neuriabilitazione, IRCCS Istituto Scientifico San Raffaele, Milano Francesco Patti, Clara Grazia Chisari, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania Eleonora Cocco, Giuseppe Fenu, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma Giuseppe Salemi, Paolo Ragonese Dipartimento di Biomedicina, Neuroscienze e Diagnostica avanzata, Università degli Studi di Palermo, Palermo, Matilde Inglese, Maria Cellerino, Dipartimento di Neuroscienze, Riabilitazione Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Ospedale Policlinico San Martino-IRCCS, Genova Giancarlo Comi, INSPE e Centro Sclerosi Multipla IRCCS, Ospedale San Raffaele Milano
OUTCOME
Introduction and aims Availability of new disease modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear if this improvement also involves pediatric-onset MS (POMS) patients, whose early management is limited by a low number of approved DMTs and, possibly, other factors, such as cognitive impairment, involvement of the family in therapeutic decisions and risk of low adherence to therapies. Our aim was to evaluate if prognosis of POMS was getting better over time, in relation to changes in therapeutic and managing standards. Inclusion criteria were: MS onset before 18 years of age, confirmed MS diagnosis before January 2014 and disease duration ≥3 years at last observation. Exclusion criteria were having primary progressive or undefined MS course, crucial errors in data entry, EDSS score ≥8 one year after the onset of disease, missing diagnosis date and less than two EDSS score evaluations. We compared time to reach persistent disability milestones (EDSS 4.0 and 6.0) by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006 and 2007-2013), adjusting for possible confounders linked to EDSS evaluations (EDSS score evaluations per year, period of EDSS assessment and disease duration at first EDSS evaluation) and clinical disease activity (age at onset, sex, ARR in the first three years, type of clinical onset, time from onset to diagnosis). We then analysed the difference among the four diagnosis epochs regarding demographic characteristics, clinical disease activity at onset and DMTs management.
Results At May 2019, the Italian MS Registry included 59,278 patients, of which 4,704 (7.9%) had MS onset before 18 years of age. According to our inclusion and exclusion criteria, we enrolled 3,198 POMS patients, coming from 82 different MS centers in Italy. Distribution of patients among diagnosis epochs was 619 (19%) in <1993, 785 (25%) in 1993-1999, 934 (29%) in 2000-2006 and 860 (27%) in 2007-2013. Mean age of onset was 15.2 years, 69% were female, median time to diagnosis was 3.2 years, annualized relapse rate in first one/three years was 1.3/0.6, the mean follow-up was 21.811.7 years. The majority of patients were treated with DMTs (88%), of these 40% with high potency drugs (e.g. natalizumab, fingolimod). Considering the whole cohort, only 22% started DMTs in pediatric age, but this percentage increases to 53% in the subgroup with pediatric-diagnosis (1300 patients). Median survival times to reach EDSS 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS 4.0 (HR 0.70 in 1993-1999, 0.48 in 2000-2006 and 0.44 in 2007-2013) and 6.0 (HR 0.72, 0.44 and 0.30). In recent diagnosis epochs, a greater number of POMS patients were treated with DMTs, especially high potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. Analyses of the subgroup of patients with pediatric-diagnosis gave similar results.
Conclusions In POMS the risk of persistent disability has been reduced by 50-70% in recent diagnosis epochs, probably due to improvement in therapeutic and managing standards. In the coming years, an increase of approved DMTs before 18 years of age and upgrades in drug safety will probably lead to a further improvement of prognosis in this population.
Pubblicazioni e Comunicazioni a Congressi Publications and Congress Presentations
Baroncini D, Iaffaldano P, Simone M., Brescia Morra V, Lanzillo R, Filippi M, Romeo M, Patti F, Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Comi G., Zaffaroni M. and Ghezzi A. Changes in management of pediatric-onset multiple sclerosis: are we really modifying the disease course? Data from the Italian MS registry. Accepted as oral presentation (abstract number: 3938) at 2020 American Academy of Neurology (Congress canceled due to COVID-19 pandemic) Baroncini D., Simone M., Iaffaldano P., Brescia Morra V., Lanzillo R., Filippi M., Romeo M., Patti F., Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Margari L., Comi G., Zaffaroni M. and Ghezzi A. The risk of persistent disability is decreasing over time in pediatric-onset multiple sclerosis patients. Accepted for publication in JAMA neurology in March 2021.
PUBLICATIONS
Baroncini D, Iaffaldano P, Simone M., Brescia Morra V, Lanzillo R, Filippi M, Romeo M, Patti F, Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Comi G., Zaffaroni M. and Ghezzi A. Changes in management of pediatric-onset multiple sclerosis: are we really modifying the disease course? Data from the Italian MS registry. Accettato come presentazione orale (abstract numero: 3938) al 2020 American Academy of Neurology (Congresso cancellato a causa della pandemia da Covid-19).
Baroncini D., Simone M., Iaffaldano P., Brescia Morra V., Lanzillo R., Filippi M., Romeo M., Patti F., Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Margari L., Comi G., Zaffaroni M. and Ghezzi A. The risk of persistent disability is decreasing over time in pediatric-onset multiple sclerosis patients. JAMA Neurology 2021;78(6):726-735.
Fondazione Italiana Sclerosi Multipla – FISM – Ente del Terzo Settore/ETS e, in forma abbreviata, FISM ETS. Iscrizione al RUNTS Rep. N° 89695 - Fondazione con Riconoscimento di Personalità Giuridica - C.F. 95051730109
Assessing the clinical course of pediatric onset multiple sclerosis in different treatment eras: are we really modifying the disease?
Availability of new disease modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear if this improvement also involves pediatric-onset MS (POMS) patients, whose early management is limited by a low number of approved DMTs and, possibly, other factors, such as cognitive impairment, involvement of the family in therapeutic decisions and risk of low adherence to therapies.
Our aim was to evaluate if prognosis of POMS was getting better over time, in relation to changes in therapeutic and managing standards.
Inclusion criteria were: MS onset before 18 years of age, confirmed MS diagnosis before January 2014 and disease duration ≥3 years at last observation. Exclusion criteria were having primary progressive or undefined MS course, crucial errors in data entry, EDSS score ≥8 one year after the onset of disease, missing diagnosis date and less than two EDSS score evaluations. We compared time to reach persistent disability milestones (EDSS 4.0 and 6.0) by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006 and 2007-2013), adjusting for possible confounders linked to EDSS evaluations (EDSS score evaluations per year, period of EDSS assessment and disease duration at first EDSS evaluation) and clinical disease activity (age at onset, sex, ARR in the first three years, type of clinical onset, time from onset to diagnosis). We then analysed the difference among the four diagnosis epochs regarding demographic characteristics, clinical disease activity at onset and DMTs management.
Marta Simone, Lucia Margari, Unità di Neuropsichiatria Infantile, Dipartimento di Scienze Biomediche e Oncologia, Università di Bari, Bari
Pietro Iaffaldano, Centro SM, Dipartimento di Scienze Mediche di Base, Neuroscienze ed Organi di Senso Università di Bari, Bari
Vincenzo Brescia Morra, Roberta Lanzillo, Centro di Cura e Ricerca Clinica sulla SM, Dipartimento di Neuroscienze, Scienze della Riproduzione e Odontostomatologia, Università di Napoli Federico II, Napoli
Massimo Filippi, Dipartimento di Neurologia e Neurofisiologia, Centro SM, Neuroimaging Research Unit, Istituto Scientifico San Raffaele, Milano
Marzia Romeo, Dipartimento di Neurologia and Neuriabilitazione, IRCCS Istituto Scientifico San Raffaele, Milano
Francesco Patti, Clara Grazia Chisari, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania
Eleonora Cocco, Giuseppe Fenu, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari
Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma
Giuseppe Salemi, Paolo Ragonese Dipartimento di Biomedicina, Neuroscienze e Diagnostica avanzata, Università degli Studi di Palermo, Palermo,
Matilde Inglese, Maria Cellerino, Dipartimento di Neuroscienze, Riabilitazione Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), Ospedale Policlinico San Martino-IRCCS, Genova
Giancarlo Comi, INSPE e Centro Sclerosi Multipla IRCCS, Ospedale San Raffaele Milano
Introduction and aims
Availability of new disease modifying therapies (DMTs) and changes of therapeutic paradigms have led to a general improvement of multiple sclerosis (MS) prognosis in adults. It is still unclear if this improvement also involves pediatric-onset MS (POMS) patients, whose early management is limited by a low number of approved DMTs and, possibly, other factors, such as cognitive impairment, involvement of the family in therapeutic decisions and risk of low adherence to therapies.
Our aim was to evaluate if prognosis of POMS was getting better over time, in relation to changes in therapeutic and managing standards.
Inclusion criteria were: MS onset before 18 years of age, confirmed MS diagnosis before January 2014 and disease duration ≥3 years at last observation. Exclusion criteria were having primary progressive or undefined MS course, crucial errors in data entry, EDSS score ≥8 one year after the onset of disease, missing diagnosis date and less than two EDSS score evaluations. We compared time to reach persistent disability milestones (EDSS 4.0 and 6.0) by epoch of MS diagnosis (<1993, 1993-1999, 2000-2006 and 2007-2013), adjusting for possible confounders linked to EDSS evaluations (EDSS score evaluations per year, period of EDSS assessment and disease duration at first EDSS evaluation) and clinical disease activity (age at onset, sex, ARR in the first three years, type of clinical onset, time from onset to diagnosis). We then analysed the difference among the four diagnosis epochs regarding demographic characteristics, clinical disease activity at onset and DMTs management.
Results
At May 2019, the Italian MS Registry included 59,278 patients, of which 4,704 (7.9%) had MS onset before 18 years of age. According to our inclusion and exclusion criteria, we enrolled 3,198 POMS patients, coming from 82 different MS centers in Italy. Distribution of patients among diagnosis epochs was 619 (19%) in <1993, 785 (25%) in 1993-1999, 934 (29%) in 2000-2006 and 860 (27%) in 2007-2013. Mean age of onset was 15.2 years, 69% were female, median time to diagnosis was 3.2 years, annualized relapse rate in first one/three years was 1.3/0.6, the mean follow-up was 21.811.7 years. The majority of patients were treated with DMTs (88%), of these 40% with high potency drugs (e.g. natalizumab, fingolimod). Considering the whole cohort, only 22% started DMTs in pediatric age, but this percentage increases to 53% in the subgroup with pediatric-diagnosis (1300 patients).
Median survival times to reach EDSS 4.0 and 6.0 were 31.7 and 40.5 years. The cumulative risk of reaching disability milestones gradually decreased over time, both for EDSS 4.0 (HR 0.70 in 1993-1999, 0.48 in 2000-2006 and 0.44 in 2007-2013) and 6.0 (HR 0.72, 0.44 and 0.30). In recent diagnosis epochs, a greater number of POMS patients were treated with DMTs, especially high potency drugs, that were given earlier and for a longer period. Demographic characteristics and clinical disease activity at onset did not change significantly over time. Analyses of the subgroup of patients with pediatric-diagnosis gave similar results.
Conclusions
In POMS the risk of persistent disability has been reduced by 50-70% in recent diagnosis epochs, probably due to improvement in therapeutic and managing standards. In the coming years, an increase of approved DMTs before 18 years of age and upgrades in drug safety will probably lead to a further improvement of prognosis in this population.
Pubblicazioni e Comunicazioni a Congressi
Publications and Congress Presentations
Baroncini D, Iaffaldano P, Simone M., Brescia Morra V, Lanzillo R, Filippi M, Romeo M, Patti F, Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Comi G., Zaffaroni M. and Ghezzi A. Changes in management of pediatric-onset multiple sclerosis: are we really modifying the disease course? Data from the Italian MS registry. Accepted as oral presentation (abstract number: 3938) at 2020 American Academy of Neurology (Congress canceled due to COVID-19 pandemic)
Baroncini D., Simone M., Iaffaldano P., Brescia Morra V., Lanzillo R., Filippi M., Romeo M., Patti F., Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Margari L., Comi G., Zaffaroni M. and Ghezzi A. The risk of persistent disability is decreasing over time in pediatric-onset multiple sclerosis patients. Accepted for publication in JAMA neurology in March 2021.
Baroncini D, Iaffaldano P, Simone M., Brescia Morra V, Lanzillo R, Filippi M, Romeo M, Patti F, Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Comi G., Zaffaroni M. and Ghezzi A. Changes in management of pediatric-onset multiple sclerosis: are we really modifying the disease course? Data from the Italian MS registry. Accettato come presentazione orale (abstract numero: 3938) al 2020 American Academy of Neurology (Congresso cancellato a causa della pandemia da Covid-19).
Baroncini D., Simone M., Iaffaldano P., Brescia Morra V., Lanzillo R., Filippi M., Romeo M., Patti F., Chisari C.G., Cocco E., Fenu G., Salemi G., Ragonese P., Inglese M., Cellerino M., Margari L., Comi G., Zaffaroni M. and Ghezzi A. The risk of persistent disability is decreasing over time in pediatric-onset multiple sclerosis patients. JAMA Neurology 2021;78(6):726-735.
https://doi.org/10.1001/jamaneurol.2021.1008
https://pubmed.ncbi.nlm.nih.gov/33938921/