Early-aggressive treatment algorithm versus classical escalation therapy in relapsing Multiple Sclerosis
SYNOPSIS AND RESULTS
The most important goal of multiple sclerosis (MS) therapy is the prevention of long-term disability accumulation. The therapeutic scenario for relapsing–remitting MS (RRMS) has widely expanded during the past 20 years. Choosing the MS therapy has become increasingly complex, due to the difficulties in weighing the risk/benefit ratio of several different available disease modifying therapies (DMTs). To date, except for individuals expressing poor clinical and radiological features at baseline, the most applied treatment algorithm for early naïve MS is based on an escalation strategy. According to this approach, patients start with safe moderate-efficacy DMTs and switch to high-efficacy immunotherapies with a more complex safety profiles in case of first treatment failure. The superiority of high-efficacy DMTs, such as natalizumab, alemtuzumab, ocrelizumab, cladribrine, mitoxantrone or fingolimod, in reducing measures of clinical and MRI disease activity in comparison to the traditional first-line MS therapies, such as interferon (IFN) ß, glatiramer acetate (GA), teriflunomide or dimethylfumarate have been consistently proven by different randomized clinical trials (RCTs) and/or observational studies. Moreover, indirect comparisons from extension arms and subgroup analyses of randomized trials suggest that high-efficacy therapies are associated with improved control of relapse activity when initiated earlier after MS onset. Whether patients initiating therapy with high-efficacy DMTs derive a greater long-term benefit on disability accumulation than those who start with moderate-efficacy agents, remains a matter of debate. Recent observational studies showed evidence that early initiation of highly effective therapy in RRMS may provide more benefit that an escalation approach in decreasing the risk of developing secondary progression and disability accrual, at least in a medium-term of 5-6 years of follow-up. In this study, we compared the long-term effect of an early versus a late start (escalation approach) of high-efficacy DMTs on disability trajectories in a large population of naïve RRMS who started the first treatment within the first year from the disease onset and longitudinally followed up to 10 years.
Data start
Data end
2018-02-20
2020-06-15
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 Sclerosi Multipla, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania Mauro Zaffaroni, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA) Vincenzo Brescia Morra, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti 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 Giorgia Teresa Maniscalco, Neurologia, Ospedale Cardarelli, Centro Regionale per la Sclerosi Multipla, Napoli 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 Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli Valentina Torri Clerici, U.O. Neuroimmunologia e Malattie Neuromuscolari, Fondazione IRCCS Istituto Neurologico C. Besta, Milano Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia Davide Maimone, Centro Sclerosi Multipla - UOC di Neurologia - ARNAS Garibaldi, Catania Elio Scarpini, Centro Sclerosi Multipla, UOSD Malattie Neurodegenerative, IRCCS Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano Marco Capobianco, Centro Regionale di riferimento per la SM, Unità Neurologica, Ospedale Universitario San Luigi, Orbassano, TO Giancarlo Comi, Massimo Filippi, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano
OUTCOME
Introduction and aims The most important goal of multiple sclerosis (MS) therapy is the prevention of long-term disability accumulation. The therapeutic scenario for relapsing–remitting MS (RRMS) has widely expanded during the past 20 years. Choosing the MS therapy has become increasingly complex, due to the difficulties in weighing the risk/benefit ratio of several different available disease modifying therapies (DMTs). To date, except for individuals expressing poor clinical and radiological features at baseline, the most applied treatment algorithm for early naïve MS is based on an escalation strategy. According to this approach, patients start with safe moderate-efficacy DMTs and switch to high-efficacy immunotherapies with a more complex safety profiles in case of first treatment failure. The superiority of high-efficacy DMTs, such as natalizumab, alemtuzumab, ocrelizumab, cladribrine, mitoxantrone or fingolimod, in reducing measures of clinical and MRI disease activity in comparison to the traditional first-line MS therapies, such as interferon (IFN) ß, glatiramer acetate (GA), teriflunomide or dimethylfumarate have been consistently proven by different randomized clinical trials (RCTs) and/or observational studies. Moreover, indirect comparisons from extension arms and subgroup analyses of randomized trials suggest that high-efficacy therapies are associated with improved control of relapse activity when initiated earlier after MS onset. Whether patients initiating therapy with high-efficacy DMTs derive a greater long-term benefit on disability accumulation than those who start with moderate-efficacy agents, remains a matter of debate. Recent observational studies showed evidence that early initiation of highly effective therapy in RRMS may provide more benefit that an escalation approach in decreasing the risk of developing secondary progression and disability accrual, at least in a medium-term of 5-6 years of follow-up. In this study, we compared the long-term effect of an early versus a late start (escalation approach) of high-efficacy DMTs on disability trajectories in a large population of naïve RRMS who started the first treatment within the first year from the disease onset and longitudinally followed up to 10 years.
Results According to the Registry rules, on February 5th 2018, the Scientific Committee of the Italian MS Registry granted the approval to conduct this project and extract and use the registry data. Patients with relapsing onset MS, with a follow-up duration of at least 5 years, a first visit within 3 years from disease onset and at least 3 Expanded Disability Status Scale (EDSS) score evaluations after the first DMT start were extracted from the Italian MS Registry database. Patients meeting the eligibility criteria were divided in two groups: the early intensive treatment (EIT) group if their first treatment was one of the six high-efficacy DMTs (natalizumab, alemtuzumab, mitoxantrone, fingolimod, cladribine or ocrelizumab) and the escalation treatment (ESC) group if their first therapy was a moderate-efficacy DMT (IFN ß, GA, teriflunomide, dimethylfumarate or azathioprine) followed by escalation to a high-efficacy DMT, due to a lack of efficacy, after at least one year of treatment. Patients were 1:1 propensity score (PS)-matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups. Longitudinal clinical data of 53,010 patients from 89 MS centers were available in the Italian MS Registry at the time of data extraction (November 2019). After applying the inclusion and the exclusion criteria we retrieved 2,702 RRMS patients from 62 Italian MS centers. In this cohort, 365 patients received a treatment classifiable as EIT approach, while a larger sample of 2,337 patients was treated according to the ESC strategy. The PS matching procedure produced 363 pairs of patients. Mean annual delta-EDSS were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean estimated delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year, to 0.30 (0.07-0.53, p=0.009) and to 0.64 (0.35-0.93, p<0.001) at 5 and 8 years respectively, while at 10 years (the last year of study observation) it was 0.67 (0.31-1.03, p=0.0003). The maximum mean delta-EDSS difference was 0.72 (0.40-1.04, p<0.001) measured at 9 years.
Conclusions The results of our real-world study indicate that the long-term disability trajectories are more favorable with an EIT strategy than with moderate-efficacy DMTs followed by escalation to high-efficacy DMTs. Although further studies are necessary, especially to establish the long-term safety risks of the EIT approach, these findings may drive the treatment decisions of physicians, in particular in the cases of naïve patients with poor prognosis factors at the onset of disease.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. MSVIRTUAL2020: 8th joint ACTRIMS-ECTRIMS Meeting. Virtual Meeting 11-13 September 2020 Comparing disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. 51° Congresso della Società Italiana di Neurologia. Congresso virtuale.28-30 novembre 2020
PUBLICATIONS
Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. MSVIRTUAL 2020: 8th joint ACTRIMS-ECTRIMS Meeting. Virtual Meeting 11-13 September 2020. Comparing disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. 51° Congresso della Società Italiana di Neurologia. Congresso virtuale. 28-30 novembre 2020.
Iaffaldano P, Lucisano G, Caputo F, Paolicelli D, Patti F, Zaffaroni M, Brescia Morra V, Pozzilli C, De Luca G, Inglese M, Salemi G, Maniscalco GT, Cocco E, Sola P, Lus G, Conte A, Amato MP, Granella F, Gasperini C, Bellantonio P, Totaro R, Rovaris M, Salvetti M, Torri Clerici VLA, Bergamaschi R, Maimone D, Scarpini E, Capobianco M, Comi G, Filippi M, Trojano M; Italian MS Register.Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies.Ther Adv Neurol Disord. 2021 May 31;14:17562864211019574. doi: 10.1177/17562864211019574. eCollection 2021. PMID: 34104220
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
Early-aggressive treatment algorithm versus classical escalation therapy in relapsing Multiple Sclerosis
The most important goal of multiple sclerosis (MS) therapy is the prevention of long-term disability accumulation. The therapeutic scenario for relapsing–remitting MS (RRMS) has widely expanded during the past 20 years. Choosing the MS therapy has become increasingly complex, due to the difficulties in weighing the risk/benefit ratio of several different available disease modifying therapies (DMTs). To date, except for individuals expressing poor clinical and radiological features at baseline, the most applied treatment algorithm for early naïve MS is based on an escalation strategy. According to this approach, patients start with safe moderate-efficacy DMTs and switch to high-efficacy immunotherapies with a more complex safety profiles in case of first treatment failure. The superiority of high-efficacy DMTs, such as natalizumab, alemtuzumab, ocrelizumab, cladribrine, mitoxantrone or fingolimod, in reducing measures of clinical and MRI disease activity in comparison to the traditional first-line MS therapies, such as interferon (IFN) ß, glatiramer acetate (GA), teriflunomide or dimethylfumarate have been consistently proven by different randomized clinical trials (RCTs) and/or observational studies. Moreover, indirect comparisons from extension arms and subgroup analyses of randomized trials suggest that high-efficacy therapies are associated with improved control of relapse activity when initiated earlier after MS onset. Whether patients initiating therapy with high-efficacy DMTs derive a greater long-term benefit on disability accumulation than those who start with moderate-efficacy agents, remains a matter of debate. Recent observational studies showed evidence that early initiation of highly effective therapy in RRMS may provide more benefit that an escalation approach in decreasing the risk of developing secondary progression and disability accrual, at least in a medium-term of 5-6 years of follow-up.
In this study, we compared the long-term effect of an early versus a late start (escalation approach) of high-efficacy DMTs on disability trajectories in a large population of naïve RRMS who started the first treatment within the first year from the disease onset and longitudinally followed up to 10 years.
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 Sclerosi Multipla, Azienda Ospedaliera-Universitaria, Policlinico Vittorio Emanuele, Università degli Studi di Catania, Catania
Mauro Zaffaroni, Centro SM di Gallarate, ASST della Valle Olona, Gallarate (VA)
Vincenzo Brescia Morra, Centro di Cura e Ricerca Clinica per la SM; Dipartimento di Neuroscienze (NSRO), Università Federico II, Napoli
Carlo Pozzilli, Centro SM, Ospedale S. Andrea, Sapienza Università di Roma, Roma
Giovanna De Luca, Clinica Neurologica, Università G. D'Annunzio, Policlinico SS Annunziata Chieti
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
Giorgia Teresa Maniscalco, Neurologia, Ospedale Cardarelli, Centro Regionale per la Sclerosi Multipla, Napoli
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
Giacomo Lus, Centro SM, II Divisione di Neurologia, Dipartimento di Medicina Clinica e Sperimentale, Seconda Università di Napoli, Napoli
Valentina Torri Clerici, U.O. Neuroimmunologia e Malattie Neuromuscolari, Fondazione IRCCS Istituto Neurologico C. Besta, Milano
Roberto Bergamaschi, IRCCS Fondazione Mondino, Pavia
Davide Maimone, Centro Sclerosi Multipla - UOC di Neurologia - ARNAS Garibaldi, Catania
Elio Scarpini, Centro Sclerosi Multipla, UOSD Malattie Neurodegenerative, IRCCS Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano
Marco Capobianco, Centro Regionale di riferimento per la SM, Unità Neurologica, Ospedale Universitario San Luigi, Orbassano, TO
Giancarlo Comi, Massimo Filippi, Dipartimento di Neurologia, Centro SM, Istituto Scientifico San Raffaele, Milano
Introduction and aims
The most important goal of multiple sclerosis (MS) therapy is the prevention of long-term disability accumulation. The therapeutic scenario for relapsing–remitting MS (RRMS) has widely expanded during the past 20 years. Choosing the MS therapy has become increasingly complex, due to the difficulties in weighing the risk/benefit ratio of several different available disease modifying therapies (DMTs). To date, except for individuals expressing poor clinical and radiological features at baseline, the most applied treatment algorithm for early naïve MS is based on an escalation strategy. According to this approach, patients start with safe moderate-efficacy DMTs and switch to high-efficacy immunotherapies with a more complex safety profiles in case of first treatment failure. The superiority of high-efficacy DMTs, such as natalizumab, alemtuzumab, ocrelizumab, cladribrine, mitoxantrone or fingolimod, in reducing measures of clinical and MRI disease activity in comparison to the traditional first-line MS therapies, such as interferon (IFN) ß, glatiramer acetate (GA), teriflunomide or dimethylfumarate have been consistently proven by different randomized clinical trials (RCTs) and/or observational studies. Moreover, indirect comparisons from extension arms and subgroup analyses of randomized trials suggest that high-efficacy therapies are associated with improved control of relapse activity when initiated earlier after MS onset. Whether patients initiating therapy with high-efficacy DMTs derive a greater long-term benefit on disability accumulation than those who start with moderate-efficacy agents, remains a matter of debate. Recent observational studies showed evidence that early initiation of highly effective therapy in RRMS may provide more benefit that an escalation approach in decreasing the risk of developing secondary progression and disability accrual, at least in a medium-term of 5-6 years of follow-up.
In this study, we compared the long-term effect of an early versus a late start (escalation approach) of high-efficacy DMTs on disability trajectories in a large population of naïve RRMS who started the first treatment within the first year from the disease onset and longitudinally followed up to 10 years.
Results
According to the Registry rules, on February 5th 2018, the Scientific Committee of the Italian MS Registry granted the approval to conduct this project and extract and use the registry data. Patients with relapsing onset MS, with a follow-up duration of at least 5 years, a first visit within 3 years from disease onset and at least 3 Expanded Disability Status Scale (EDSS) score evaluations after the first DMT start were extracted from the Italian MS Registry database. Patients meeting the eligibility criteria were divided in two groups: the early intensive treatment
(EIT) group if their first treatment was one of the six high-efficacy DMTs (natalizumab, alemtuzumab, mitoxantrone, fingolimod, cladribine or ocrelizumab) and the escalation treatment (ESC) group if their first therapy was a moderate-efficacy DMT (IFN ß, GA, teriflunomide, dimethylfumarate or azathioprine) followed by escalation to a high-efficacy DMT, due to a lack of efficacy, after at least one year of treatment.
Patients were 1:1 propensity score (PS)-matched for characteristics at the first DMT. The disability trajectories were evaluated by applying a longitudinal model for repeated measures. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.
Longitudinal clinical data of 53,010 patients from 89 MS centers were available in the Italian MS Registry at the time of data extraction (November 2019). After applying the inclusion and the exclusion criteria we retrieved 2,702 RRMS patients from 62 Italian MS centers. In this cohort, 365 patients received a treatment classifiable as EIT approach, while a larger sample of 2,337 patients was treated according to the ESC strategy. The PS matching procedure produced 363 pairs of patients. Mean annual delta-EDSS were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean estimated delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year, to 0.30 (0.07-0.53, p=0.009) and to 0.64 (0.35-0.93, p<0.001) at 5 and 8 years respectively, while at 10 years (the last year of study observation) it was 0.67 (0.31-1.03, p=0.0003). The maximum mean delta-EDSS difference was 0.72 (0.40-1.04, p<0.001) measured at 9 years.
Conclusions
The results of our real-world study indicate that the long-term disability trajectories are more favorable with an EIT strategy than with moderate-efficacy DMTs followed by escalation to high-efficacy DMTs. Although further studies are necessary, especially to establish the long-term safety risks of the EIT approach, these findings may drive the treatment decisions of physicians, in particular in the cases of naïve patients with poor prognosis factors at the onset of disease.
Pubblicazioni e Comunicazioni a Congressi/ Publications and Congress Presentations
Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. MSVIRTUAL2020: 8th joint ACTRIMS-ECTRIMS Meeting. Virtual Meeting 11-13 September 2020
Comparing disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. 51° Congresso della Società Italiana di Neurologia. Congresso virtuale.28-30 novembre 2020
Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. MSVIRTUAL 2020: 8th joint ACTRIMS-ECTRIMS Meeting. Virtual Meeting 11-13 September 2020.
Comparing disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies. 51° Congresso della Società Italiana di Neurologia. Congresso virtuale. 28-30 novembre 2020.
Iaffaldano P, Lucisano G, Caputo F, Paolicelli D, Patti F, Zaffaroni M, Brescia Morra V, Pozzilli C, De Luca G, Inglese M, Salemi G, Maniscalco GT, Cocco E, Sola P, Lus G, Conte A, Amato MP, Granella F, Gasperini C, Bellantonio P, Totaro R, Rovaris M, Salvetti M, Torri Clerici VLA, Bergamaschi R, Maimone D, Scarpini E, Capobianco M, Comi G, Filippi M, Trojano M; Italian MS Register.Long-term disability trajectories in relapsing multiple sclerosis patients treated with early intensive or escalation treatment strategies.Ther Adv Neurol Disord. 2021 May 31;14:17562864211019574. doi: 10.1177/17562864211019574. eCollection 2021. PMID: 34104220