Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination, and degenerative changes. Most individuals are diagnosed with MS at age 20–40 years. Pediatric-onset MS (POMS), before the age of 18, represents 3-10% of the whole MS population, while late-onset MS (LOMS), after the age of 50, now accounts for 3-5% of all MS diagnosis. Age at onset plays an important prognostic role, not fully understood, and may impact disease course and treatment response. Clinic- and population- based studies suggested that the onset of the progressive phase and time to Expanded Disability Status Scale (EDSS) milestones is an age-dependent phenomenon, independent of the initial course of MS. Nevertheless, predicting disability accumulation just upon chronologic age would be an oversimplification. In both POMS and Adult-Onset MS (AOMS), the strongest predictor for reaching the EDSS milestones is age at clinical onset: the earlier the onset of disease, the younger the age at which the main disability milestones are reached. Additionally, age at onset influences the response to disease-modifying therapy (DMT). A recent meta-analysis of the main Randomized Clinical Trials (RCTs) demonstrated that the efficacy of DMTs on disability worsening has an inverse correlation with increasing age. As the prevalence of LOMS is increasing, data regarding DMT effectiveness in this group of patients are warranted. This is even more relevant due to comorbidity and possibly higher risks of treatment-related adverse events in this age group. As for the pediatric counterpart, clinical trials in POMS subjects are extremely limited, also due to ethical considerations on the use of placebo owing to highly active disease in this population. Although most of the DMTs are not licensed for POMS, their off-label prescription is increasing in this sub-population. Therefore, benefit to risk balance and treatment decision-making in these extreme age populations present unique age- and disease-related challenges. Since a sizeable proportion of pediatric and older patients are treated in the real-world setting, registry-based cohort studies represent a major source of data to elucidate the above issues. The research question, addressed in this multicenter study based on the Italian MS register, was whether and how treatment response differs in three cohorts of RRMS patients defined by age at onset: POMS (≤ 18 years), AOMS (18 - 49 years) and LOMS (≥ 50 years).
Data start
Data end
2019-02-27
2020-10-15
PARTICIPATING CENTERS
Pietro Iaffaldano, Maria Trojano, Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari Giuseppe Lucisano, CORESEARCH Srl, Pescara; Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari
OUTCOME
Introduction and aims Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination, and degenerative changes. Most individuals are diagnosed with MS at age 20–40 years. Pediatric-onset MS (POMS), before the age of 18, represents 3-10% of the whole MS population, while late-onset MS (LOMS), after the age of 50, now accounts for 3-5% of all MS diagnosis. Age at onset plays an important prognostic role, not fully understood, and may impact disease course and treatment response. Clinic- and population- based studies suggested that the onset of the progressive phase and time to Expanded Disability Status Scale (EDSS) milestones is an age-dependent phenomenon, independent of the initial course of MS. Nevertheless, predicting disability accumulation just upon chronologic age would be an oversimplification. In both POMS and Adult-Onset MS (AOMS), the strongest predictor for reaching the EDSS milestones is age at clinical onset: the earlier the onset of disease, the younger the age at which the main disability milestones are reached. Additionally, age at onset influences the response to disease-modifying therapy (DMT). A recent meta-analysis of the main Randomized Clinical Trials (RCTs) demonstrated that the efficacy of DMTs on disability worsening has an inverse correlation with increasing age. As the prevalence of LOMS is increasing, data regarding DMT effectiveness in this group of patients are warranted. This is even more relevant due to comorbidity and possibly higher risks of treatment-related adverse events in this age group. As for the pediatric counterpart, clinical trials in POMS subjects are extremely limited, also due to ethical considerations on the use of placebo owing to highly active disease in this population. Although most of the DMTs are not licensed for POMS, their off-label prescription is increasing in this sub-population. Therefore, benefit to risk balance and treatment decision-making in these extreme age populations present unique age- and disease-related challenges. Since a sizeable proportion of pediatric and older patients are treated in the real-world setting, registry-based cohort studies represent a major source of data to elucidate the above issues. The research question, addressed in this multicenter study based on the Italian MS register, was whether and how treatment response differs in three cohorts of RRMS patients defined by age at onset: POMS (≤ 18 years), AOMS (18 - 49 years) and LOMS (≥ 50 years).
Results We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained Expanded Disability Status Scale of 4.0. The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in pediatric-onset and adult-onset patients [adjusted Hazard Ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for pediatric-onset and 6.3 (4.9-8.0) for adult-onset, p< 0.0001] showing a trend in late-onset patients [adjusted Hazard Ratio = 1.9 (0.9-1.4), p= 0.07]. These results were confirmed for a sustained Expanded Disability Status Scale score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all the three cohorts and female sex exerted a protective role in the late-onset cohort.
Conclusions This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
Pubblicazioni e comunicazioni a congressi/ Publications and congress presentations
Publications Amato MP, Fonderico M, Portaccio E, Pastò L, Razzolini L, Prestipino E, Bellinvia A, Tudisco L, Fratangelo R, Comi G, Patti F, De Luca G, Brescia Morra V, Cocco E, Pozzilli C, Sola P, Bergamaschi R, Salemi G, Inglese M, Millefiorini E, Galgani S, Zaffaroni M, Ghezzi A, Salvetti M, Lus G, Florio C, Totaro R, Granella F, Vianello M, Gatto M, Di Battista G, Aguglia U, Logullo FO, Simone M, Lucisano G, Iaffaldano P, Trojano M. Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis. Brain. 2020 Oct 1;143(10):3013-3024
Oral presentations Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). 50° National Congress of Italian Society of Neurology, Bologna 12-15 October 2019
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). Ectrims 2019, Stockholm, Sweden, 11-13 September 2019.
PUBLICATIONS
Amato MP, Fonderico M, Portaccio E, Pastò L, Razzolini L, Prestipino E, Bellinvia A, Tudisco L, Fratangelo R, Comi G, Patti F, De Luca G, Brescia Morra V, Cocco E, Pozzilli C, Sola P, Bergamaschi R, Salemi G, Inglese M, Millefiorini E, Galgani S, Zaffaroni M, Ghezzi A, Salvetti M, Lus G, Florio C, Totaro R, Granella F, Vianello M, Gatto M, Di Battista G, Aguglia U, Logullo FO, Simone M, Lucisano G, Iaffaldano P, Trojano M. Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis. Brain. 2020 Oct 1;143(10):3013-3024
Presentazioni orali: Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). 50° National Congress of Italian Society of Neurology, Bologna 12-15 October 2019
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). Ectrims 2019, Stockholm, Sweden, 11-13 September 2019.
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
E-MUSIC: Early MUltiple Sclerosis Italian Cohort
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination, and degenerative changes. Most individuals are diagnosed with MS at age 20–40 years. Pediatric-onset MS (POMS), before the age of 18, represents 3-10% of the whole MS population, while late-onset MS (LOMS), after the age of 50, now accounts for 3-5% of all MS diagnosis. Age at onset plays an important prognostic role, not fully understood, and may impact disease course and treatment response. Clinic- and population- based studies suggested that the onset of the progressive phase and time to Expanded Disability Status Scale (EDSS) milestones is an age-dependent phenomenon, independent of the initial course of MS. Nevertheless, predicting disability accumulation just upon chronologic age would be an oversimplification. In both POMS and Adult-Onset MS (AOMS), the strongest predictor for reaching the EDSS milestones is age at clinical onset: the earlier the onset of disease, the younger the age at which the main disability milestones are reached.
Additionally, age at onset influences the response to disease-modifying therapy (DMT). A recent meta-analysis of the main Randomized Clinical Trials (RCTs) demonstrated that the efficacy of DMTs on disability worsening has an inverse correlation with increasing age. As the prevalence of LOMS is increasing, data regarding DMT effectiveness in this group of patients are warranted. This is even more relevant due to comorbidity and possibly higher risks of treatment-related adverse events in this age group. As for the pediatric counterpart, clinical trials in POMS subjects are extremely limited, also due to ethical considerations on the use of placebo owing to highly active disease in this population. Although most of the DMTs are not licensed for POMS, their off-label prescription is increasing in this sub-population. Therefore, benefit to risk balance and treatment decision-making in these extreme age populations present unique age- and disease-related challenges.
Since a sizeable proportion of pediatric and older patients are treated in the real-world setting, registry-based cohort studies represent a major source of data to elucidate the above issues.
The research question, addressed in this multicenter study based on the Italian MS register, was whether and how treatment response differs in three cohorts of RRMS patients defined by age at onset: POMS (≤ 18 years), AOMS (18 - 49 years) and LOMS (≥ 50 years).
Pietro Iaffaldano, Maria Trojano, Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari
Giuseppe Lucisano, CORESEARCH Srl, Pescara; Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari
Introduction and aims
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination, and degenerative changes. Most individuals are diagnosed with MS at age 20–40 years. Pediatric-onset MS (POMS), before the age of 18, represents 3-10% of the whole MS population, while late-onset MS (LOMS), after the age of 50, now accounts for 3-5% of all MS diagnosis. Age at onset plays an important prognostic role, not fully understood, and may impact disease course and treatment response. Clinic- and population- based studies suggested that the onset of the progressive phase and time to Expanded Disability Status Scale (EDSS) milestones is an age-dependent phenomenon, independent of the initial course of MS. Nevertheless, predicting disability accumulation just upon chronologic age would be an oversimplification. In both POMS and Adult-Onset MS (AOMS), the strongest predictor for reaching the EDSS milestones is age at clinical onset: the earlier the onset of disease, the younger the age at which the main disability milestones are reached.
Additionally, age at onset influences the response to disease-modifying therapy (DMT). A recent meta-analysis of the main Randomized Clinical Trials (RCTs) demonstrated that the efficacy of DMTs on disability worsening has an inverse correlation with increasing age. As the prevalence of LOMS is increasing, data regarding DMT effectiveness in this group of patients are warranted. This is even more relevant due to comorbidity and possibly higher risks of treatment-related adverse events in this age group. As for the pediatric counterpart, clinical trials in POMS subjects are extremely limited, also due to ethical considerations on the use of placebo owing to highly active disease in this population. Although most of the DMTs are not licensed for POMS, their off-label prescription is increasing in this sub-population. Therefore, benefit to risk balance and treatment decision-making in these extreme age populations present unique age- and disease-related challenges.
Since a sizeable proportion of pediatric and older patients are treated in the real-world setting, registry-based cohort studies represent a major source of data to elucidate the above issues.
The research question, addressed in this multicenter study based on the Italian MS register, was whether and how treatment response differs in three cohorts of RRMS patients defined by age at onset: POMS (≤ 18 years), AOMS (18 - 49 years) and LOMS (≥ 50 years).
Results
We included patients with a relapsing-remitting phenotype, ≥5 years follow-up, ≥3 Expanded Disability Status Scale evaluations and a first neurological evaluation within 3 years from the first demyelinating event. Multivariate Cox regression models (adjusted hazard ratio with 95% confidence intervals) were used to assess the risk of reaching a first 12-month confirmed disability worsening and the risk of reaching a sustained Expanded Disability Status Scale of 4.0.
The effect of disease-modifying drugs was assessed as quartiles of time exposure. We found that disease-modifying drugs reduced the risk of 12-month confirmed disability worsening, with a progressive risk reduction in different quartiles of exposure in pediatric-onset and adult-onset patients [adjusted Hazard Ratios in non-exposed versus exposed >62% of the follow-up time: 8.0 (3.5-17.9) for pediatric-onset and 6.3 (4.9-8.0) for adult-onset, p< 0.0001] showing a trend in late-onset patients [adjusted Hazard Ratio = 1.9 (0.9-1.4), p= 0.07]. These results were confirmed for a sustained Expanded Disability Status Scale score of 4.0. We also found that relapses were a risk factor for 12-month confirmed disability worsening in all the three cohorts and female sex exerted a protective role in the late-onset cohort.
Conclusions
This study provides evidence that sustained exposure to disease-modifying drugs decreases the risk of disability accumulation, seemingly in a dose-dependent manner. It confirms that the effectiveness of disease-modifying drugs is lower in late-onset patients, although still detectable.
Pubblicazioni e comunicazioni a congressi/ Publications and congress presentations
Publications
Amato MP, Fonderico M, Portaccio E, Pastò L, Razzolini L, Prestipino E, Bellinvia A, Tudisco L, Fratangelo R, Comi G, Patti F, De Luca G, Brescia Morra V, Cocco E, Pozzilli C, Sola P, Bergamaschi R, Salemi G, Inglese M, Millefiorini E, Galgani S, Zaffaroni M, Ghezzi A, Salvetti M, Lus G, Florio C, Totaro R, Granella F, Vianello M, Gatto M, Di Battista G, Aguglia U, Logullo FO, Simone M, Lucisano G, Iaffaldano P, Trojano M.
Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.
Brain. 2020 Oct 1;143(10):3013-3024
Oral presentations
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). 50° National Congress of Italian Society of Neurology, Bologna 12-15 October 2019
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). Ectrims 2019, Stockholm, Sweden, 11-13 September 2019.
Amato MP, Fonderico M, Portaccio E, Pastò L, Razzolini L, Prestipino E, Bellinvia A, Tudisco L, Fratangelo R, Comi G, Patti F, De Luca G, Brescia Morra V, Cocco E, Pozzilli C, Sola P, Bergamaschi R, Salemi G, Inglese M, Millefiorini E, Galgani S, Zaffaroni M, Ghezzi A, Salvetti M, Lus G, Florio C, Totaro R, Granella F, Vianello M, Gatto M, Di Battista G, Aguglia U, Logullo FO, Simone M, Lucisano G, Iaffaldano P, Trojano M.
Disease-modifying drugs can reduce disability progression in relapsing multiple sclerosis.
Brain. 2020 Oct 1;143(10):3013-3024
https://doi: 10.1093/brain/awaa251
Presentazioni orali:
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). 50° National Congress of Italian Society of Neurology, Bologna 12-15 October 2019
Fonderico M. Exposure to disease modifying drugs reduces disability progression in pediatric-, adult- and late-onset relapsing multiple sclerosis: real world data from the early multiple sclerosis italian cohort (E-MUSIC). Ectrims 2019, Stockholm, Sweden, 11-13 September 2019.