INSPIRA - Italian analysis of the National multiple sclerosis registry Studying the concept of Progression Independent from Relapse Activity
SYNOPSIS AND RESULTS
To date, secondary-progressive multiple sclerosis (SPMS) is diagnosed retrospectively by neurologists, according to the Lublin’ definition: a history of a gradual disability progression, independent of relapses, after an initial relapsing course. No biological nor clinical markers are available to make more sensitive and reliable the identification of the SP conversion. Thus, it is difficult to establish the exact date of conversion from one course to the other one, mainly because, on a clinical standpoint, the relapsing-remitting (RR) and the SP forms are a continuum of disease with the boundary between them being somewhat indistinct. Recently, objective definitions of SPMS have been proposed. The data driven definitions are based on the application of algorithms to the EDSS score evaluations longitudinally recorded in disease registry or clinical databases. The majority of the studies so far performed to assess the risk factors for SPMS transition have been conducted on clinical cohorts in which the SPMS definition was based on the subjective judgement of the neurologists. The way the conversion to SPMS is defined might affect the evaluation of risk factors, including the effect of disease modifying therapies (DMTs), potentially associated with the disease course transition. In this study we compared the risk factors for the transition from RR to SP course in a large cohort of relapsing onset MS prospectively followed-up in the Italian MS Registry, using two different SPMS definitions: the first was based on the subjective decision made by the treating neurologist, and the second was based on a more recently proposed data-driven algorithm. Risk factors for reaching an irreversible EDSS score 6.0 after the SP transition were also evaluated.
Data start
Data end
2018-09-20
2019-06-15
PARTICIPATING CENTERS
Giuseppe Lucisano, Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara; Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari Francesco Patti, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania Vincenzo Brescia Morra, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti. Alessandra Lugaresi, Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna; Dipartimento di Scienze Biomediche e Neuromotorie, Università degli Studi di Bologna, Bologna Mauro Zaffaroni, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA) Matilde Inglese, Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica E Scienze Materno - Infantili (DINOGMI), Università degli Studi di Genova, Ospedale Policlinico San Martino, IRCCS, Genova Giuseppe Salemi, Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università degli Studi di Palermo, Palermo Eleonora Cocco, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli Diana Ferraro, Dipartimento d Neuroscienze, Unità di Neurologia, Università degli Studi di Modena e Reggio Emilia; Nuovo Ospedale Civile Sant’Agostino Estense in Baggiovara, Modena Simonetta Galgani, Centro SM, Azienda Ospedaliera S. Camillo Forlanini, Roma Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli Marco Rovaris, Fondazione Don Carlo Gnocchi, Milano Giorgia Teresa Maniscalco, Neurologia, Ospedale Cardarelli, Centro Regionale per la Sclerosi Multipla, Napoli Francesco Ottavio Logullo, UOC Neurologia Macerata, Area Vasta 3, ASUR Marche, Macerata Giuseppina Marrazzo, Valeria Lovato, Roche S.p.A., Monza Giancarlo Comi, Massimo Filippi, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano Maria Pia Amato, Dipartimento NEUROFARBA, Università degli Studi di Firenze, Firenze
OUTCOME
Introduction and aims To date, secondary-progressive multiple sclerosis (SPMS) is diagnosed retrospectively by neurologists, according to the Lublin’ definition: a history of a gradual disability progression, independent of relapses, after an initial relapsing course. No biological nor clinical markers are available to make more sensitive and reliable the identification of the SP conversion. Thus, it is difficult to establish the exact date of conversion from one course to the other one, mainly because, on a clinical standpoint, the relapsing-remitting (RR) and the SP forms are a continuum of disease with the boundary between them being somewhat indistinct. Recently, objective definitions of SPMS have been proposed. The data driven definitions are based on the application of algorithms to the EDSS score evaluations longitudinally recorded in disease registry or clinical databases. The majority of the studies so far performed to assess the risk factors for SPMS transition have been conducted on clinical cohorts in which the SPMS definition was based on the subjective judgement of the neurologists. The way the conversion to SPMS is defined might affect the evaluation of risk factors, including the effect of disease modifying therapies (DMTs), potentially associated with the disease course transition. In this study we compared the risk factors for the transition from RR to SP course in a large cohort of relapsing onset MS prospectively followed-up in the Italian MS Registry, using two different SPMS definitions: the first was based on the subjective decision made by the treating neurologist, and the second was based on a more recently proposed data-driven algorithm. Risk factors for reaching an irreversible EDSS score 6.0 after the SP transition were also evaluated.
Results On 20th September 2018 the Scientific Committee of the Italian MS Registry granted the approval to this project and the approval of data use. After receiving all the approval needed, we performed the data extraction using the global Italian dataset updated at 31st May 2018. Relapsing onset MS patients (n=19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible EDSS 6.0, after SP transition, were estimated by using multivariable Cox regression models. Two SPMS definitions were used: 1. Neurologist Definition (ND). A definition based on the subjective decision made by the neurologists according to the Lublin criteria for SP. For this definition the date of SP conversion, entered by the neurologists in the (iMed®) software, was used. 2. Data-Driven Algorithm (DDA). An algorithm based on a previous published definition with some modifications: a 3-strata progression magnitude (1.5-point increase if the baseline EDSS was 0, 1.0-point increase if the baseline EDSS was 1.0-5.5, 0.5-point increase if the baseline EDSS was > 5.5 ) with a minimum EDSS score of 4.0 and a minimal pyramidal FS score of 2.0 at the time of conversion to SPMS confirmed at 3 months and at the end of follow-up (last EDSS score ≥ 4.0; last pyramidal FS score ≥ 2.0). In order to reduce the impact of transient EDSS modifications due to relapses, all the EDSS scores collected during a relapse (± 30 days) were excluded. SPMS identified by the DDA (n=2,343, 12.1%) were older, more disabled and with a faster progression to severe disability (p<0.0001), than those identified by the ND (n=3,868, 20.0%). In both groups, the most consistent risk factors (p<0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the DMT exposure. DMT exposure during SP, the did not impact the risk of reaching irreversible EDSS 6.0.
Conclusions Our study suggests that a more objective definition of SPMS based on a DDA is more reliable to identify patients with a more aggressive SP course in comparison to a retrospective subjective judgment of the treating neurologist. These findings can help to select more homogeneous population of SPMS patients to be included in future clinical trials or observational studies to evaluate the effect of DMTs during the SP phase of the disease. Moreover, our results provide further insights on the most robust prognostic factors associated to the SPMS transition confirmed by using different criteria of SPMS. It is noteworthy that the results also confirm the role of DMT exposure in reducing this risk, but not in preventing the disability accumulation after the transition to SPMS. National MS registries, such as the Italian MS Registry, represent formidable tools to provide important information on the disease course and the effect of DMTs in the different phases of the disease.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations Pupbications: The full paper which present the complete results of this study has published by Multiple Sclerosis Journal and an Editorial has been dedicated to our work: Iaffaldano P, Lucisano G, Patti F, Brescia Morra V, De Luca G, Lugaresi A, Zaffaroni M, Inglese M, Salemi G, Cocco E, Conte A, Ferraro D, Galgani S, Bergamaschi R, Pozzilli C, Salvetti M, Lus G, Rovaris M, Maniscalco GT, Logullo FO, Paolicelli D, Achille M, Marrazzo G, Lovato V, Comi G, Filippi M, Amato MP, Trojano M; Italian MS Register. Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors. Mult Scler. 2021 Mar;27(3):430-438. doi: 10.1177/1352458520974366. Lorscheider J. When does a heap become a heap? Mult Scler. 2021 Mar;27(3):329-330. doi: 10.1177/1352458520988459. Congress: Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 35th ECTRIMS Congress, Stockholm, Sweden 11-13 September 2019. This presentaion has been selected for the congress highlights. Evaluating the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 50°congresso SIN Bologna 2019
PUBLICATIONS
Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 35th ECTRIMS Congress, Stockholm, Sweden 11-13 September 2019. This presentaion has been selected for the congress highlights.
Evaluating the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 50°congresso SIN Bologna 2019
Un articolo sui risultati di questo studio è stato pubblicato da Multiple Sclerosis Journal e un editoriale è stato dedicato a questo lavoro: Iaffaldano P, Lucisano G, Patti F, Brescia Morra V, De Luca G, Lugaresi A, Zaffaroni M, Inglese M, Salemi G, Cocco E, Conte A, Ferraro D, Galgani S, Bergamaschi R, Pozzilli C, Salvetti M, Lus G, Rovaris M, Maniscalco GT, Logullo FO, Paolicelli D, Achille M, Marrazzo G, Lovato V, Comi G, Filippi M, Amato MP, Trojano M; Italian MS Register. Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors. Mult Scler. 2021 Mar;27(3):430-438.
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
INSPIRA - Italian analysis of the National multiple sclerosis registry Studying the concept of Progression Independent from Relapse Activity
To date, secondary-progressive multiple sclerosis (SPMS) is diagnosed retrospectively by neurologists, according to the Lublin’ definition: a history of a gradual disability progression, independent of relapses, after an initial relapsing course. No biological nor clinical markers are available to make more sensitive and reliable the identification of the SP conversion. Thus, it is difficult to establish the exact date of conversion from one course to the other one, mainly because, on a clinical standpoint, the relapsing-remitting (RR) and the SP forms are a continuum of disease with the boundary between them being somewhat indistinct. Recently, objective definitions of SPMS have been proposed. The data driven definitions are based on the application of algorithms to the EDSS score evaluations longitudinally recorded in disease registry or clinical databases.
The majority of the studies so far performed to assess the risk factors for SPMS transition have been conducted on clinical cohorts in which the SPMS definition was based on the subjective judgement of the neurologists. The way the conversion to SPMS is defined might affect the evaluation of risk factors, including the effect of disease modifying therapies (DMTs), potentially associated with the disease course transition.
In this study we compared the risk factors for the transition from RR to SP course in a large cohort of relapsing onset MS prospectively followed-up in the Italian MS Registry, using two different SPMS definitions: the first was based on the subjective decision made by the treating neurologist, and the second was based on a more recently proposed data-driven algorithm. Risk factors for reaching an irreversible EDSS score 6.0 after the SP transition were also evaluated.
Giuseppe Lucisano, Center for Outcomes Research and Clinical Epidemiology (CORESEARCH), Pescara; Dipartimento di scienze mediche di base, Neuroscienze ed organi di senso, Università degli Studi di Bari, Bari
Francesco Patti, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania
Vincenzo Brescia Morra, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli
Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti.
Alessandra Lugaresi, Riabilitazione Sclerosi Multipla, IRCCS Istituto delle Scienze Neurologiche di Bologna; Dipartimento di Scienze Biomediche e Neuromotorie, Università degli Studi di Bologna, Bologna
Mauro Zaffaroni, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA)
Matilde Inglese, Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica E Scienze Materno - Infantili (DINOGMI), Università degli Studi di Genova, Ospedale Policlinico San Martino, IRCCS, Genova
Giuseppe Salemi, Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università degli Studi di Palermo, Palermo
Eleonora Cocco, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari
Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli
Diana Ferraro, Dipartimento d Neuroscienze, Unità di Neurologia, Università degli Studi di Modena e Reggio Emilia; Nuovo Ospedale Civile Sant’Agostino Estense in Baggiovara, Modena
Simonetta Galgani, Centro SM, Azienda Ospedaliera S. Camillo Forlanini, Roma
Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia
Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma
Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli
Marco Rovaris, Fondazione Don Carlo Gnocchi, Milano
Giorgia Teresa Maniscalco, Neurologia, Ospedale Cardarelli, Centro Regionale per la Sclerosi Multipla, Napoli
Francesco Ottavio Logullo, UOC Neurologia Macerata, Area Vasta 3, ASUR Marche, Macerata
Giuseppina Marrazzo, Valeria Lovato, Roche S.p.A., Monza
Giancarlo Comi, Massimo Filippi, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano
Maria Pia Amato, Dipartimento NEUROFARBA, Università degli Studi di Firenze, Firenze
Introduction and aims
To date, secondary-progressive multiple sclerosis (SPMS) is diagnosed retrospectively by neurologists, according to the Lublin’ definition: a history of a gradual disability progression, independent of relapses, after an initial relapsing course. No biological nor clinical markers are available to make more sensitive and reliable the identification of the SP conversion. Thus, it is difficult to establish the exact date of conversion from one course to the other one, mainly because, on a clinical standpoint, the relapsing-remitting (RR) and the SP forms are a continuum of disease with the boundary between them being somewhat indistinct. Recently, objective definitions of SPMS have been proposed. The data driven definitions are based on the application of algorithms to the EDSS score evaluations longitudinally recorded in disease registry or clinical databases.
The majority of the studies so far performed to assess the risk factors for SPMS transition have been conducted on clinical cohorts in which the SPMS definition was based on the subjective judgement of the neurologists. The way the conversion to SPMS is defined might affect the evaluation of risk factors, including the effect of disease modifying therapies (DMTs), potentially associated with the disease course transition.
In this study we compared the risk factors for the transition from RR to SP course in a large cohort of relapsing onset MS prospectively followed-up in the Italian MS Registry, using two different SPMS definitions: the first was based on the subjective decision made by the treating neurologist, and the second was based on a more recently proposed data-driven algorithm. Risk factors for reaching an irreversible EDSS score 6.0 after the SP transition were also evaluated.
Results
On 20th September 2018 the Scientific Committee of the Italian MS Registry granted the approval to this project and the approval of data use. After receiving all the approval needed, we performed the data extraction using the global Italian dataset updated at 31st May 2018. Relapsing onset MS patients (n=19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible EDSS 6.0, after SP transition, were estimated by using multivariable Cox regression models.
Two SPMS definitions were used:
1. Neurologist Definition (ND). A definition based on the subjective decision made by the neurologists according to the Lublin criteria for SP. For this definition the date of SP conversion, entered by the neurologists in the (iMed®) software, was used.
2. Data-Driven Algorithm (DDA). An algorithm based on a previous published definition with some modifications: a 3-strata progression magnitude (1.5-point increase if the baseline EDSS was 0, 1.0-point increase if the baseline EDSS was 1.0-5.5, 0.5-point increase if the baseline EDSS was > 5.5 ) with a minimum EDSS score of 4.0 and a minimal pyramidal FS score of 2.0 at the time of conversion to SPMS confirmed at 3 months and at the end of follow-up (last EDSS score ≥ 4.0; last pyramidal FS score ≥ 2.0). In order to reduce the impact of transient EDSS modifications due to relapses, all the EDSS scores collected during a relapse (± 30 days) were excluded.
SPMS identified by the DDA (n=2,343, 12.1%) were older, more disabled and with a faster progression to severe disability (p<0.0001), than those identified by the ND (n=3,868, 20.0%). In both groups, the most consistent risk factors (p<0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the DMT exposure. DMT exposure during SP, the did not impact the risk of reaching irreversible EDSS 6.0.
Conclusions
Our study suggests that a more objective definition of SPMS based on a DDA is more reliable to identify patients with a more aggressive SP course in comparison to a retrospective subjective judgment of the treating neurologist. These findings can help to select more homogeneous population of SPMS patients to be included in future clinical trials or observational studies to evaluate the effect of DMTs during the SP phase of the disease. Moreover, our results provide further insights on the most robust prognostic factors associated to the SPMS transition confirmed by using different criteria of SPMS. It is noteworthy that the results also confirm the role of DMT exposure in reducing this risk, but not in preventing the disability accumulation after the transition to SPMS.
National MS registries, such as the Italian MS Registry, represent formidable tools to provide important information on the disease course and the effect of DMTs in the different phases of the disease.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Pupbications:
The full paper which present the complete results of this study has published by Multiple Sclerosis Journal and an Editorial has been dedicated to our work:
Iaffaldano P, Lucisano G, Patti F, Brescia Morra V, De Luca G, Lugaresi A, Zaffaroni M, Inglese M, Salemi G, Cocco E, Conte A, Ferraro D, Galgani S, Bergamaschi R, Pozzilli C, Salvetti M, Lus G, Rovaris M, Maniscalco GT, Logullo FO, Paolicelli D, Achille M, Marrazzo G, Lovato V, Comi G, Filippi M, Amato MP, Trojano M; Italian MS Register. Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors. Mult Scler. 2021 Mar;27(3):430-438. doi: 10.1177/1352458520974366.
Lorscheider J. When does a heap become a heap? Mult Scler. 2021 Mar;27(3):329-330. doi: 10.1177/1352458520988459.
Congress:
Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 35th ECTRIMS Congress, Stockholm, Sweden 11-13 September 2019. This presentaion has been selected for the congress highlights.
Evaluating the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 50°congresso SIN Bologna 2019
Defining the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 35th ECTRIMS Congress, Stockholm, Sweden 11-13 September 2019. This presentaion has been selected for the congress highlights.
Evaluating the risk factors for the conversion to secondary progressive multiple sclerosis: a retrospective cohort study of the Italian MS Register. 50°congresso SIN Bologna 2019
Un articolo sui risultati di questo studio è stato pubblicato da Multiple Sclerosis Journal e un editoriale è stato dedicato a questo lavoro:
Iaffaldano P, Lucisano G, Patti F, Brescia Morra V, De Luca G, Lugaresi A, Zaffaroni M, Inglese M, Salemi G, Cocco E, Conte A, Ferraro D, Galgani S, Bergamaschi R, Pozzilli C, Salvetti M, Lus G, Rovaris M, Maniscalco GT, Logullo FO, Paolicelli D, Achille M, Marrazzo G, Lovato V, Comi G, Filippi M, Amato MP, Trojano M; Italian MS Register. Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors. Mult Scler. 2021 Mar;27(3):430-438.
https://doi.org/10.1177/1352458520974366
Lorscheider J. When does a heap become a heap? Mult Scler. 2021 Mar;27(3):329-330.
https://doi.10.1177/1352458520988459