Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression

Emilio Portaccio^#¹, Matteo Betti^#², Ermelinda De Meo^{2

3}, Ilaria Addazio², Luisa Pastò², Lorenzo Razzolini², Rocco Totaro⁴, Daniele Spitaleri⁵, Alessandra Lugaresi^{6

7}, Eleonora Cocco⁸, Marco Onofrj⁹, Franco Di Palma¹⁰, Francesco Patti^{11

12}, Davide Maimone¹³, Paola Valentino¹⁴, Valentina Torri Clerici¹⁵, Alessandra Protti¹⁶, Diana Ferraro¹⁷, Giacomo Lus¹⁸, Giorgia Teresa Maniscalco¹⁹, Vincenzo Brescia Morra²⁰, Giuseppe Salemi²¹, Franco Granella²², Ilaria Pesci²³, Roberto Bergamaschi²⁴, Umberto Aguglia²⁵, Marika Vianello²⁶, Marta Simone²⁷, Vito Lepore²⁸, Pietro Iaffaldano²⁹, Giancarlo Comi³⁰, Massimo Filippi^{31

32}, Maria Trojano²⁹, Maria Pia Amato^{2

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33}; Italian Multiple Sclerosis Register

Affiliations

¹ Department of NEUROFARBA, University of Florence, Careggi University Hospital, Florence, Italy. emilio.portaccio@unifi.it.
² Department of NEUROFARBA, University of Florence, Careggi University Hospital, Florence, Italy.
³ NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁴ San Salvatore Hospital, L'Aquila, Italy.
⁵ AORN San G. Moscati, Avellino, Italy.
⁶ IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Bologna, Italy.
⁷ Dipartimento Di Scienze Biomediche E Neuromotorie, Università Di Bologna, Bologna, Italy.
⁸ University of Cagliari, Cagliari, Italy.
⁹ University G. d'Annunzio Di Chieti-Pescara, Chieti, Italy.
¹⁰ ASST Lariana Ospedale S. Anna, Como, Italy.
¹¹ University of Catania, Catania, Italy.
¹² UOS Sclerosi Multipla, Policlinico G Rodolico-San Marco, University of Catania, Catania, Italy.
¹³ Centro Sclerosi Multipla, Azienda Ospedaliera Cannizzaro, Catania, Italy.
¹⁴ Institute of Neurology, University Magna Graecia, Catanzaro, Italy.
¹⁵ Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
¹⁶ Niguarda Hospital, Milan, Italy.
¹⁷ Department of Neurosciences, Ospedale Civile Di Baggiovara, Azienda Ospedaliero-Universitaria Di Modena, Modena, Italy.
¹⁸ University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁹ A Cardarelli Hospital, Naples, Italy.
²⁰ Federico II University, Naples, Italy.
²¹ Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy.
²² University of Parma, Parma, Italy.
²³ Ospedale VAIO Di Fidenza AUSL PR, Fidenza (PR), Italy.
²⁴ IRCCS Fondazione Mondino, Pavia, Italy.
²⁵ Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
²⁶ Ca' Fancello Hospital, AULSS2, Treviso, Italy.
²⁷ Pediatric MS Center, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy.
²⁸ Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
²⁹ Department of Translational Biomedicine and Neurosciences, University of Bari Aldo Moro, DiBraiN, Bari, Italy.
³⁰ Casa Di Cura del Policlinico, Vita-Salute San Raffaele University, Milan, Italy.
³¹ Vita-Salute San Raffaele University, Milan, Italy.
³² IRCCS San Raffaele Scientific Institute, Milan, Italy.
³³ IRCCS Don Carlo Gnocchi Foundation, Florence, Italy.

^# Contributed equally.

PMID: 38805052
PMCID: PMC11319422
DOI: 10.1007/s00415-024-12448-4

Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression

Emilio Portaccio et al. J Neurol. 2024 Aug.

. 2024 Aug;271(8):5074-5082.

doi: 10.1007/s00415-024-12448-4. Epub 2024 May 28.

Authors

Affiliations

¹ Department of NEUROFARBA, University of Florence, Careggi University Hospital, Florence, Italy. emilio.portaccio@unifi.it.
² Department of NEUROFARBA, University of Florence, Careggi University Hospital, Florence, Italy.
³ NMR Research Unit, Queen Square Multiple Sclerosis Centre, UCL Queen Square Institute of Neurology, University College London, London, UK.
⁴ San Salvatore Hospital, L'Aquila, Italy.
⁵ AORN San G. Moscati, Avellino, Italy.
⁶ IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Bologna, Italy.
⁷ Dipartimento Di Scienze Biomediche E Neuromotorie, Università Di Bologna, Bologna, Italy.
⁸ University of Cagliari, Cagliari, Italy.
⁹ University G. d'Annunzio Di Chieti-Pescara, Chieti, Italy.
¹⁰ ASST Lariana Ospedale S. Anna, Como, Italy.
¹¹ University of Catania, Catania, Italy.
¹² UOS Sclerosi Multipla, Policlinico G Rodolico-San Marco, University of Catania, Catania, Italy.
¹³ Centro Sclerosi Multipla, Azienda Ospedaliera Cannizzaro, Catania, Italy.
¹⁴ Institute of Neurology, University Magna Graecia, Catanzaro, Italy.
¹⁵ Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
¹⁶ Niguarda Hospital, Milan, Italy.
¹⁷ Department of Neurosciences, Ospedale Civile Di Baggiovara, Azienda Ospedaliero-Universitaria Di Modena, Modena, Italy.
¹⁸ University of Campania Luigi Vanvitelli, Naples, Italy.
¹⁹ A Cardarelli Hospital, Naples, Italy.
²⁰ Federico II University, Naples, Italy.
²¹ Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Palermo, Italy.
²² University of Parma, Parma, Italy.
²³ Ospedale VAIO Di Fidenza AUSL PR, Fidenza (PR), Italy.
²⁴ IRCCS Fondazione Mondino, Pavia, Italy.
²⁵ Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy.
²⁶ Ca' Fancello Hospital, AULSS2, Treviso, Italy.
²⁷ Pediatric MS Center, Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy.
²⁸ Istituto Di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
²⁹ Department of Translational Biomedicine and Neurosciences, University of Bari Aldo Moro, DiBraiN, Bari, Italy.
³⁰ Casa Di Cura del Policlinico, Vita-Salute San Raffaele University, Milan, Italy.
³¹ Vita-Salute San Raffaele University, Milan, Italy.
³² IRCCS San Raffaele Scientific Institute, Milan, Italy.
³³ IRCCS Don Carlo Gnocchi Foundation, Florence, Italy.

^# Contributed equally.

PMID: 38805052
PMCID: PMC11319422
DOI: 10.1007/s00415-024-12448-4

Erratum in

Correction to: Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression.
Portaccio E, Betti M, De Meo E, Addazio I, Pastò L, Razzolini L, Totaro R, Spitaleri D, Lugaresi A, Cocco E, Onofrj M, Di Palma F, Patti F, Maimone D, Valentino P, Clerici VT, Protti A, Ferraro D, Lus G, Maniscalco GT, Morra VB, Salemi G, Granella F, Pesci I, Bergamaschi R, Aguglia U, Vianello M, Simone M, Lepore V, Iaffaldano P, Comi G, Filippi M, Trojano M, Amato MP; Italian Multiple Sclerosis Register. Portaccio E, et al. J Neurol. 2024 Oct;271(10):7066-7068. doi: 10.1007/s00415-024-12627-3. J Neurol. 2024. PMID: 39231861 Free PMC article. No abstract available.

Abstract

Objectives: We investigated the occurrence and relative contribution of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) to confirmed disability accrual (CDA) and transition to secondary progression (SP) in relapsing multiple sclerosis (MS).

Methods: Relapsing-onset MS patients with follow-up > / = 5 years (16,130) were extracted from the Italian MS Registry. CDA was a 6-month confirmed increase in Expanded Disability Status Scale (EDSS) score. Sustained disability accumulation (SDA) was a CDA with no EDSS improvement in all subsequent visits. Predictors of PIRA and RAW and the association between final EDSS score and type of CDA were assessed using logistic multivariable regression and multivariable ordinal regression models, respectively.

Results: Over 11.8 ± 5.4 years, 16,731 CDA events occurred in 8998 (55.8%) patients. PIRA (12,175) accounted for 72.3% of CDA. SDA occurred in 8912 (73.2%) PIRA and 2583 (56.7%) RAW (p < 0.001). 4453 (27.6%) patients transitioned to SPMS, 4010 (73.2%) out of 5476 patients with sustained PIRA and 443 (24.8%) out of 1790 patients with non-sustained PIRA. In the multivariable ordinal regression analysis, higher final EDSS score was associated with PIRA (estimated coefficient 0.349, 95% CI 0.120-0.577, p = 0.003).

Discussion: In this real-world relapsing-onset MS cohort, PIRA was the main driver of disability accumulation and was associated with higher disability in the long term. Sustained PIRA was linked to transition to SP and could represent a more accurate PIRA definition and a criterion to mark the putative onset of the progressive phase.

Keywords: Multiple sclerosis; Progression independent of relapse activity; Relapse-associated worsening; Secondary progression.

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Conflict of interest statement

E. Portaccio received compensation for travel grants, participation in advisory board and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, Roche, BMS Cellgene, Janssen and Novartis; serves on the editorial board of Frontiers in Neurology and Brain Sciences. M. Betti reports no disclosures. E. De Meo reports no disclosures. I. Addazio reports no disclosures. L. Pastò received research support from Novartis, Biogen and speaker honoraria from Teva. L. Razzolini received research support from Novartis. R. Totaro received funding for travel or speaker honoraria from Alfa Wasserman, Bayer, Biogen, CLS Bering, Merck Serono, Novartis, Sanofi Aventis, Roche, and Teva. D. Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer Schering, Novartis and Sanofi Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. A. Lugaresi served as a Biogen, Merck, Mylan, Novartis, Roche, Sanofi/Genzyme and Teva Advisory Board Member. She received congress and travel/accommodation expense compensations or speaker honoraria from Biogen, Merck, Mylan, Novartis, Sanofi/Genzyme, Teva and Fondazione Italiana Sclerosi Multipla (FISM). Her institutions received research grants from Novartis. E. Cocco received research grants and honoraria as a speaker and member of advisory boards by: Almirall, Bayer, Biogen Idec, Merck Serono, Novartis, Sanofi–Genzyme, Teva, Roche. M. Onofrj reports no disclosures. F. Di Palma reports no disclosures. F. Patti received honoraria for speaking activities by Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi–Genzyme, and Teva; he also served as advisory board member the following companies: Alexion, Almirall, BMS Cellgene, Janssen, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi–Genzyme, and Teva; he was also funded by Biogen, Merck, Novartis, Reload Association, Italian Health Minister, Italian University Minister University of Catania and FISM for epidemiological studies; he received grants for congress participation from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi–Genzyme, and Teva. D. Maimone received compensations for congress and travel expenses and participation in advisory boards by Bayer, Biogen, Bristo Myers Squibb, Merck, Novartis, Roche, Sanofi. P. Valentino received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, and Roche. V. Torri Clerici received honoraria for speaking or writing from Novartis, Sanofi–Genzyme, Almirall, Bristol Meyer Squibb and Horizon; she acted as an Advisory Board member for Biogen, Lundbeck, Novartis, Sanofi–Genzyme, Bristol Meyer Squibb, Roche, Almirall and Merck Serono. She is involved as principal investigator in clinical trials for Sanofi–Genzyme, FISM, Bristol Meyer Squibb, Roche and Merck Serono; she has received support for research projects from Almirall. A. Protti reports no disclosures. D. Ferraro has received travel grants and/or fees for speaking and/or advisory boards from Alexion, Biogen, Bristol-Myers Squibb, Celgene, Merck, Novartis, Roche, Sanofi. G. Lus reports no disclosures. G.T. Maniscalco received personal compensation from Serono, Biogen, Novartis, Roche and Teva for public speaking and advisory boards. V. Brescia Morra received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva. G. Salemi received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, Teva. Alexion, BMS Cellgene, and Horizon. F. Granella received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva. I. Pesci reports no disclosures. R. Bergamaschi has served on scientific advisory boards for Biogen, Merck Serono, Novartis, Sanofi–Genzyme; received research support from Almirall, Bayer, Biogen, Merck Serono, Novartis, Sanofi–Genzyme; received support for travel and congress from Biogen, Roche, Merck Serono, Sanofi–Genzyme, Teva; received honoraria for speaking engagement from Biogen, Merck Serono, Novartis, Sanofi–Genzyme. U. Aguglia received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva. M. Vianello received compensation for travel grants or speaking activities from Biogen, Merck Serono, Roche, BMS Cellgene, Janssen and Novartis. M. Simone reports no disclosures. V. Lepore reports no disclosures. P. Iaffaldano received grants to attend scientific congresses or speaker honoraria from Biogen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, and Teva. G. Comi received consulting fees from Actelion, Bayer Schering, Merck Serono, Novartis, Sanofi, and Teva, and lecture fees from Bayer Schering, Biogen Dompé, Merck Serono, Novartis, Sanofi, Serono, Symposia International Foundation, and Teva. M. Filippi is Editor-in-Chief of the Journal of Neurology; received compensation for consulting services and/or speaking activities from Bayer, Biogen Idec, Merck Serono, Novartis, Roche, Sanofi–Genzyme, Takeda, and Teva Pharmaceutical Industries; and still receives research support from Biogen Idec, Merck Serono, Novartis, Roche, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, and ARiSLA (Fondazione Italiana di Ricerca per la SLA). M. Trojano received travel and/or Speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck, Serono and Novartis reported receiving speaker honoraria and research grants to her institution from and serving on advisory boards of Biogen, Merck Serono, and Novartis. M.P. Amato served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis, and serves on the editorial board of Multiple Sclerosis Journal and BMC Neurology.

Figures

**Fig. 1**
Flow chart of the study population. MS Multiple sclerorsis, CIS Clinically isolated syndrome, RR Relapsing remitting, EDSS Expanded disability status scale

See this image and copyright information in PMC

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Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression

Affiliations

Progression independent of relapse activity in relapsing multiple sclerosis: impact and relationship with secondary progression

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

MeSH terms

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