INTEREST. Italian Multiple Sclerosis Registry non interventional retrospective analysis in secondary progressive multiple sclerosis
SYNOPSIS AND RESULTS
The distinction between relapsing-remitting (RR) MS and progressive phenotypes remains a critical challenge for the neurologist in real clinical practice: currently there are not specific parameters or validated biomarkers to address the diagnostic doubt, which remains entrusted to clinical experience. In fact, in clinical practice secondary progressive (SP) MS is typically confirmed retrospectively, following an history of gradual EDSS worsening, after an initial relapsing course, according to the Lublin definition (Lublin F et al. 1996, 2014). The lack of a single universally accepted definition and the difficulty in distinguishing RRMS and SPMS as a separate entity complicate the management of an already complex pathology. Recently, some studies have proposed an objective definition of SPMS (Lorscheider J et al. Brain 2016). The EXPAND trial, a multicenter study aimed to investigate the efficacy and safety of Siponimod in patient with SPMS, delineated a different definition of SP. The primary objective of this study is to compare, in terms of diagnostic performances, two data-driven definitions, the one based on a modified version of the Lorscheider algorithm (Iaffaldano P et al. MSJ 2020) (DDA) and the one based on the EXPAND inclusion criteria, with the “neurologist’s definition” (ND), currently considered the gold standard in clinical practice. The aim of the study is also to better outline the epidemiological and clinical characteristics of progressive forms: annual incidence and prevalence, treatment strategies, outcome and natural history.
Data start
Data end
2019-08-02
2020-07-15
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 Massimo Filippi, Giancarlo Comi, Francesca Sangalli, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano Marco Onofrj, Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti. Francesco Patti, Clara Grazia Chisari, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania Vincenzo Brescia Morra, Antonio Carotenuto, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli Mauro Zaffaroni, Damiano Baroncini, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA) Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma Eleonora Cocco, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari Patrizia Sola, Dipartimento di Neuroscienze, Unità di Neurologia Università degli Studi di Modena e Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Modena Giuseppe Salemi, Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università degli Studi di Palermo, Palermo Matilde Inglese, Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica E Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Ospedale Policlinico San Martino, IRCCS, Genova Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia Simonetta Galgani, Centro SM, Azienda Ospedaliera S. Camillo Forlanini, Roma Maria Pia Amato, Dipartimento NEUROFARBA, Università degli Studi di Firenze, Firenze Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli Marco Salvetti, CENTERS Centro Neurologico Terapie Sperimentali - Sapienza Università Di Roma, Azienda Ospedaliera S. Andrea, Roma Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli Ciro Florio, Centro regionale SM, Ospedale A. Cardarelli, Napoli Rocco Totaro, Centro Malattie Demielinizzanti - Clinica Neurologica, Ospedale San Salvatore - L'Aquila Marika Vianello, O.U. Neurologia, Ospedale "Ca' Foncello", Unità SM, Treviso Franco Granella, Unità di Neuroscienze, Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma Elisabetta Ferraro, Centro SM, PO San Filippo Neri, ASL Roma 1, Roma Umberto Aguglia, Ambulatorio Sclerosi Multipla - Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria Maurizia Gatto, Centro Malattie Demielinizzanti, Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti (BARI) Delia Colombo, Mihaela Nica, Novartis Italia
OUTCOME
Introduction and aims The distinction between relapsing-remitting (RR) MS and progressive phenotypes remains a critical challenge for the neurologist in real clinical practice: currently there are not specific parameters or validated biomarkers to address the diagnostic doubt, which remains entrusted to clinical experience. In fact, in clinical practice secondary progressive (SP) MS is typically confirmed retrospectively, following an history of gradual EDSS worsening, after an initial relapsing course, according to the Lublin definition (Lublin F et al. 1996, 2014). The lack of a single universally accepted definition and the difficulty in distinguishing RRMS and SPMS as a separate entity complicate the management of an already complex pathology. Recently, some studies have proposed an objective definition of SPMS (Lorscheider J et al. Brain 2016). The EXPAND trial, a multicenter study aimed to investigate the efficacy and safety of Siponimod in patient with SPMS, delineated a different definition of SP. The primary objective of this study is to compare, in terms of diagnostic performances, two data-driven definitions, the one based on a modified version of the Lorscheider algorithm (Iaffaldano P et al. MSJ 2020) (DDA) and the one based on the EXPAND inclusion criteria, with the “neurologist’s definition” (ND), currently considered the gold standard in clinical practice. The aim of the study is also to better outline the epidemiological and clinical characteristics of progressive forms: annual incidence and prevalence, treatment strategies, outcome and natural history.
Results The study has been conducted using longitudinal, retrospectively acquired clinical data extracted from the Italian MS register. Patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria were validated, using the ND as gold standard, in terms of calibration, discrimination and goodness of fit by calculating sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test. The final cohort was composed of 10,240 RRMS patients. According the ND 880 (8.59%) patients were classified as SPMS. Applying the DDA definition of SP transition 1,806 (17.64%) patients were classified as SP, whereas 1,134 (11.07%) patients were classified as SPMS by using the EXPAND definition. The annual rate of conversion to SPMS during the follow-up was 0.74 every 100 patients/year based on the ND, 1.57 every 100 patients/year using the DDA and 0.94 every 100 patients/year applying the EXPAND definition. In our cohort, the median time for conversion to the SP form is 10 years, according to all three definitions. The EXPAND definition identifies SPMS patients with the highest conversion age, with fewer relapses in the pre-conversion period, and with low disease activity post-conversion to SP, leading to a later diagnosis of the progressive phase of the disease in comparison to the ND and the DDA definition. This is also evidenced by the percentage of patients treated with DMT, which is lower in this subgroup of patients identified by the EXPAND definition in comparison to the subgroups identified by the ND and the DDA definition. The total number of patients identified as SP by both the data-driven definition and the neurologist’s judgement was 1,569, whereas 604 patients were identified as SP both by applying the EXPAND trial inclusion criteria and by the neurologist’s decision. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (DDA=0.55; EXPAND definition=0.57). The AIC (DDA=4301; EXPAND definition=5510) and the R-Square (DDA=0.15 vs EXPAND definition=0.05), were in favour of the DDA, which showed a greater discrimination power (AUC: 0.83 vs 0.65) and was associated with a higher sensibility (77.1% vs 38.0%). Both the definition showed a similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the DDA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively). Compared to the gold standard (ND), the data-driven definition based on the EXPAND criteria shows a low sensitivity (38%), because of the exclusion of EDSS worsening events related to relapses. However, these restrictive criteria allow to reach high levels of specificity, with a low risk of identifying as SP patients who are still in the RR phase of the disease. Both criteria are not able to reach levels of sensitivity and specificity that can led to consider them a valid replacement to the judgment of the neurologist: we have not found a method that can be identified as a possible new gold standard. However, between the two algorithms, the one that is closer to the definition of SP judged by the clinician is that of the DDA, with a sensitivity of 77.1%.
Conclusions In conclusion, an accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SPMS transition than neurologist’s definition. Moreover, our results indicate that the global accuracy of the DDA seems to be higher than that of a definition based on the EXPAND trial inclusion criteria.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations How to define Secondary Progressive Multiple Sclerosis using different data driven definitions: A validation study from the Italian MS Register. Oral presentation at 51° SIN Congress, Milano 2020 Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register. Poster presentation at the 8th JOINT ACTRIMS-ECTRIMS Congress, September 2020
PUBLICATIONS
How to define Secondary Progressive Multiple Sclerosis using different data driven definitions: A validation study from the Italian MS Register. Oral presentation at 51° SIN Congress, Milano 2020 Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register. Poster presentation at the 8th JOINT ACTRIMS-ECTRIMS Congress, September 2020
Iaffaldano P, Lucisano G, Guerra T, Patti F, Onofrj M, Brescia Morra V, Zaffaroni M, Pozzilli C, Cocco E, Sola P, Salemi G, Inglese M, Bergamaschi R, Gasperini C, Conte A, Salvetti M, Lus G, Maniscalco GT, Totaro R, Vianello M, Granella F, Ferraro E, Aguglia U, Gatto M, Sangalli F, Chisari CG, De Luca G, Carotenuto A, Baroncini D, Colombo D, Nica M, Paolicelli D, Comi G, Filippi M, Amato MP, Trojano M. Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.Mult Scler. 2022 Dec;28(14):2243-2252. doi: 10.1177/13524585221114007. Epub 2022 Aug 15.PMID: 35971322
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
INTEREST. Italian Multiple Sclerosis Registry non interventional retrospective analysis in secondary progressive multiple sclerosis
The distinction between relapsing-remitting (RR) MS and progressive phenotypes remains a critical challenge for the neurologist in real clinical practice: currently there are not specific parameters or validated biomarkers to address the diagnostic doubt, which remains entrusted to clinical experience. In fact, in clinical practice secondary progressive (SP) MS is typically confirmed retrospectively, following an history of gradual EDSS worsening, after an initial relapsing course, according to the Lublin definition (Lublin F et al. 1996, 2014).
The lack of a single universally accepted definition and the difficulty in distinguishing RRMS and SPMS as a separate entity complicate the management of an already complex pathology. Recently, some studies have proposed an objective definition of SPMS (Lorscheider J et al. Brain 2016). The EXPAND trial, a multicenter study aimed to investigate the efficacy and safety of Siponimod in patient with SPMS, delineated a different definition of SP.
The primary objective of this study is to compare, in terms of diagnostic performances, two data-driven definitions, the one based on a modified version of the Lorscheider algorithm (Iaffaldano P et al. MSJ 2020) (DDA) and the one based on the EXPAND inclusion criteria, with the “neurologist’s definition” (ND), currently considered the gold standard in clinical practice. The aim of the study is also to better outline the epidemiological and clinical characteristics of progressive forms: annual incidence and prevalence, treatment strategies, outcome and natural history.
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
Massimo Filippi, Giancarlo Comi, Francesca Sangalli, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano
Marco Onofrj, Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti.
Francesco Patti, Clara Grazia Chisari, Centro SM, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania
Vincenzo Brescia Morra, Antonio Carotenuto, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli
Mauro Zaffaroni, Damiano Baroncini, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA)
Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma
Eleonora Cocco, Dipartimento di Scienze Mediche e Salute Pubblica, Università di Cagliari, Centro SM, Cagliari
Patrizia Sola, Dipartimento di Neuroscienze, Unità di Neurologia Università degli Studi di Modena e Reggio Emilia, Nuovo Ospedale Civile S. Agostino/Estense, Modena
Giuseppe Salemi, Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata, Università degli Studi di Palermo, Palermo
Matilde Inglese, Dipartimento Di Neuroscienze, Riabilitazione, Oftalmologia, Genetica E Scienze Materno-Infantili (DINOGMI), Università degli Studi di Genova, Ospedale Policlinico San Martino, IRCCS, Genova
Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia
Simonetta Galgani, Centro SM, Azienda Ospedaliera S. Camillo Forlanini, Roma
Maria Pia Amato, Dipartimento NEUROFARBA, Università degli Studi di Firenze, Firenze
Antonella Conte, Dipartimento di Neuroscienze Umane, Sapienza Università di Roma, Roma; IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, Pozzilli
Marco Salvetti, CENTERS Centro Neurologico Terapie Sperimentali - Sapienza Università Di Roma, Azienda Ospedaliera S. Andrea, Roma
Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli
Ciro Florio, Centro regionale SM, Ospedale A. Cardarelli, Napoli
Rocco Totaro, Centro Malattie Demielinizzanti - Clinica Neurologica, Ospedale San Salvatore - L'Aquila
Marika Vianello, O.U. Neurologia, Ospedale "Ca' Foncello", Unità SM, Treviso
Franco Granella, Unità di Neuroscienze, Dipartimento di Medicina e Chirurgia, Università degli Studi di Parma, Parma
Elisabetta Ferraro, Centro SM, PO San Filippo Neri, ASL Roma 1, Roma
Umberto Aguglia, Ambulatorio Sclerosi Multipla - Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria
Maurizia Gatto, Centro Malattie Demielinizzanti, Ospedale Generale Regionale F. Miulli, Acquaviva delle Fonti (BARI)
Delia Colombo, Mihaela Nica, Novartis Italia
Introduction and aims
The distinction between relapsing-remitting (RR) MS and progressive phenotypes remains a critical challenge for the neurologist in real clinical practice: currently there are not specific parameters or validated biomarkers to address the diagnostic doubt, which remains entrusted to clinical experience. In fact, in clinical practice secondary progressive (SP) MS is typically confirmed retrospectively, following an history of gradual EDSS worsening, after an initial relapsing course, according to the Lublin definition (Lublin F et al. 1996, 2014).
The lack of a single universally accepted definition and the difficulty in distinguishing RRMS and SPMS as a separate entity complicate the management of an already complex pathology. Recently, some studies have proposed an objective definition of SPMS (Lorscheider J et al. Brain 2016). The EXPAND trial, a multicenter study aimed to investigate the efficacy and safety of Siponimod in patient with SPMS, delineated a different definition of SP.
The primary objective of this study is to compare, in terms of diagnostic performances, two data-driven definitions, the one based on a modified version of the Lorscheider algorithm (Iaffaldano P et al. MSJ 2020) (DDA) and the one based on the EXPAND inclusion criteria, with the “neurologist’s definition” (ND), currently considered the gold standard in clinical practice. The aim of the study is also to better outline the epidemiological and clinical characteristics of progressive forms: annual incidence and prevalence, treatment strategies, outcome and natural history.
Results
The study has been conducted using longitudinal, retrospectively acquired clinical data extracted from the Italian MS register. Patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria were validated, using the ND as gold standard, in terms of calibration, discrimination and goodness of fit by calculating sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.
The final cohort was composed of 10,240 RRMS patients. According the ND 880 (8.59%) patients were classified as SPMS. Applying the DDA definition of SP transition 1,806 (17.64%) patients were classified as SP, whereas 1,134 (11.07%) patients were classified as SPMS by using the EXPAND definition. The annual rate of conversion to SPMS during the follow-up was 0.74 every 100 patients/year based on the ND, 1.57 every 100 patients/year using the DDA and 0.94 every 100 patients/year applying the EXPAND definition.
In our cohort, the median time for conversion to the SP form is 10 years, according to all three definitions. The EXPAND definition identifies SPMS patients with the highest conversion age, with fewer relapses in the pre-conversion period, and with low disease activity post-conversion to SP, leading to a later diagnosis of the progressive phase of the disease in comparison to the ND and the DDA definition. This is also evidenced by the percentage of patients treated with DMT, which is lower in this subgroup of patients identified by the EXPAND definition in comparison to the subgroups identified by the ND and the DDA definition. The total number of patients identified as SP by both the data-driven definition and the neurologist’s judgement was 1,569, whereas 604 patients were identified as SP both by applying the EXPAND trial inclusion criteria and by the neurologist’s decision. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (DDA=0.55; EXPAND definition=0.57). The AIC (DDA=4301; EXPAND definition=5510) and the R-Square (DDA=0.15 vs EXPAND definition=0.05), were in favour of the DDA, which showed a greater discrimination power (AUC: 0.83 vs 0.65) and was associated with a higher sensibility (77.1% vs 38.0%). Both the definition showed a similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the DDA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively). Compared to the gold standard (ND), the data-driven definition based on the EXPAND criteria shows a low sensitivity (38%), because of the exclusion of EDSS worsening events related to relapses. However, these restrictive criteria allow to reach high levels of specificity, with a low risk of identifying as SP patients who are still in the RR phase of the disease. Both criteria are not able to reach levels of sensitivity and specificity that can led to consider them a valid replacement to the judgment of the neurologist: we have not found a method that can be identified as a possible new gold standard. However, between the two algorithms, the one that is closer to the definition of SP judged by the clinician is that of the DDA, with a sensitivity of 77.1%.
Conclusions
In conclusion, an accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SPMS transition than neurologist’s definition. Moreover, our results indicate that the global accuracy of the DDA seems to be higher than that of a definition based on the EXPAND trial inclusion criteria.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
How to define Secondary Progressive Multiple Sclerosis using different data driven definitions: A validation study from the Italian MS Register. Oral presentation at 51° SIN Congress, Milano 2020
Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register. Poster presentation at the 8th JOINT ACTRIMS-ECTRIMS Congress, September 2020
How to define Secondary Progressive Multiple Sclerosis using different data driven definitions: A validation study from the Italian MS Register. Oral presentation at 51° SIN Congress, Milano 2020
Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register. Poster presentation at the 8th JOINT ACTRIMS-ECTRIMS Congress, September 2020
Iaffaldano P, Lucisano G, Guerra T, Patti F, Onofrj M, Brescia Morra V, Zaffaroni M, Pozzilli C, Cocco E, Sola P, Salemi G, Inglese M, Bergamaschi R, Gasperini C, Conte A, Salvetti M, Lus G, Maniscalco GT, Totaro R, Vianello M, Granella F, Ferraro E, Aguglia U, Gatto M, Sangalli F, Chisari CG, De Luca G, Carotenuto A, Baroncini D, Colombo D, Nica M, Paolicelli D, Comi G, Filippi M, Amato MP, Trojano M. Towards a validated definition of the clinical transition to secondary progressive multiple sclerosis: A study from the Italian MS Register.Mult Scler. 2022 Dec;28(14):2243-2252. doi: 10.1177/13524585221114007. Epub 2022 Aug 15.PMID: 35971322