Characterization of non-active secondary progressive multiple sclerosis: diagnosis challenge ad assessment of progression independent from relapse activity phenomena
SYNOPSIS AND RESULTS
The clinical course of multiple sclerosis (MS) is currently described as a continuum of neuroinflammation and neurodegeneration, which challenges the classic distinction in clinical phenotype. (1-4) Relapse-associated worsening (RAW) combined with progression independent of relapse activity (PIRA) are detectable throughout the disease course. (5-9) Regulatory agencies still retain this subdivision in phenotypes for prescriptive purposes of disease-modifying treatments (DMTs). (10, 11) In this field, precise diagnostic criteria of secondary disease progression are not yet clarified and patients with inactive secondary progressive MS (SPMS) currently cannot benefit from any specific treatment, unlike active forms with siponimod. Moreover, the algorithms used to define PIRA and data-driven definitions of SPMS may overlap. (12) Real-world data from the Italian MS and Related Disorders Register (RISM) proved to address unanswered research questions in the field of progressive MS. A previous study of our group (13), using data from RISM, compared data-driven SPMS definitions based on a modified version of Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria, using the neurologist’s definition (ND) as gold standard, in terms of sensitivity, specificity, positive and negative predictive value, Akaike information criterion and area under the curve. (14-16) We found that data-driven definitions demonstrated a greater ability to capture SP transition than the neurologist’s definition and the global accuracy of DDA seems to be higher than the EXPAND definition. Therefore, in continuity with the results of this study, this project aims to expand the comparison, in terms of diagnostic performances, of the neurologist's definition (ND) and different data-driven SPMS definitions, including the DDA, the EXPAND and the HERCULES (a Phase III trial for non-active SPMS patients) trials inclusion criteria. We will then assess the risk of PIRA events before and after SP conversion (including the effect of DMT exposure), evaluating how this can affect the irreversible accumulation of disability over time.
Data start
Data end
2024-02-26
2026-05-31
PARTICIPATING CENTERS
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OUTCOME
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PUBLICATIONS
Guerra T, Lucisano G, Rocca MA, Cocco E, Patti F, De Luca G, Portaccio E, Foschi M, Ferraro D, Pozzilli C, Romano S, Annovazzi P, Brescia Morra V, Tortorella C, Fantozzi R, Perini P, Coniglio MG, Salemi G, Inglese M, Maniscalco GT, Torri Clerici VLAM, Lugaresi A, Lus G, Colombo E, Granella F, Cavalla P, Di Sapio A, Conte A, Cerqua R, Totaro R, Caputo F, Paolicelli D, Farina A, Mondino MM, Todaro DS, Olivieri N, Amato MP, Filippi M, Trojano M, Iaffaldano P; Italian Multiple Sclerosis and Related Disorders Register (RISM). HerMeS: a registry-based evaluation of the HERCULES criteria for identifying nonrelapsing SPMS. J Neurol. 2026 Mar 9;273(3):193. doi: 10.1007/s00415-026-13716-1. PMID: 41803454.
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
Characterization of non-active secondary progressive multiple sclerosis: diagnosis challenge ad assessment of progression independent from relapse activity phenomena
The clinical course of multiple sclerosis (MS) is currently described as a continuum of neuroinflammation and neurodegeneration, which challenges the classic distinction in clinical phenotype. (1-4) Relapse-associated worsening (RAW) combined with progression independent of relapse activity (PIRA) are detectable throughout the disease course. (5-9) Regulatory agencies still retain this subdivision in phenotypes for prescriptive purposes of disease-modifying treatments (DMTs). (10, 11) In this field, precise diagnostic criteria of secondary disease progression are not yet clarified and patients with inactive secondary progressive MS (SPMS) currently cannot benefit from any specific treatment, unlike active forms with siponimod. Moreover, the algorithms used to define PIRA and data-driven definitions of SPMS may overlap. (12)
Real-world data from the Italian MS and Related Disorders Register (RISM) proved to address unanswered research questions in the field of progressive MS. A previous study of our group (13), using data from RISM, compared data-driven SPMS definitions based on a modified version of Lorscheider’s algorithm (DDA) and on the EXPAND trial inclusion criteria, using the neurologist’s definition (ND) as gold standard, in terms of sensitivity, specificity, positive and negative predictive value, Akaike information criterion and area under the curve. (14-16) We found that data-driven definitions demonstrated a greater ability to capture SP transition than the neurologist’s definition and the global accuracy of DDA seems to be higher than the EXPAND definition.
Therefore, in continuity with the results of this study, this project aims to expand the comparison, in terms of diagnostic performances, of the neurologist's definition (ND) and different data-driven SPMS definitions, including the DDA, the EXPAND and the HERCULES (a Phase III trial for non-active SPMS patients) trials inclusion criteria.
We will then assess the risk of PIRA events before and after SP conversion (including the effect of DMT exposure), evaluating how this can affect the irreversible accumulation of disability over time.
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Guerra T, Lucisano G, Rocca MA, Cocco E, Patti F, De Luca G, Portaccio E, Foschi M, Ferraro D, Pozzilli C, Romano S, Annovazzi P, Brescia Morra V, Tortorella C, Fantozzi R, Perini P, Coniglio MG, Salemi G, Inglese M, Maniscalco GT, Torri Clerici VLAM, Lugaresi A, Lus G, Colombo E, Granella F, Cavalla P, Di Sapio A, Conte A, Cerqua R, Totaro R, Caputo F, Paolicelli D, Farina A, Mondino MM, Todaro DS, Olivieri N, Amato MP, Filippi M, Trojano M, Iaffaldano P; Italian Multiple Sclerosis and Related Disorders Register (RISM). HerMeS: a registry-based evaluation of the HERCULES criteria for identifying nonrelapsing SPMS. J Neurol. 2026 Mar 9;273(3):193. doi: 10.1007/s00415-026-13716-1. PMID: 41803454.