Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study)

Damiano Paolicelli; Giuseppe Lucisano; Alessia Manni; Pietro Iaffaldano; Marta Simone; Antonio Iaffaldano; Tommaso Guerra; Vincenzo Mangialardi; Francesco Patti; Eleonora Cocco; Giovanna De Luca; Pietro Annovazzi; Paolo Ragonese; Carlo Pozzilli; Matilde Inglese; Paola Perini; Claudio Gasperini; Carla Tortorella; Girolama Alessandra Marfia; Diana Ferraro; Giacomo Lus; Marika Vianello; Maria Assunta Rocca; Antonella Conte; Silvia Romano; Vincenzo Brescia Morra; Alessandra Lugaresi; Alessia Di Sapio; Clara Grazia Chisari; Raffaella Cerqua; Umberto Aguglia; Ilaria Pesci; Carlo Avolio; Emanuele D'Amico; Roberto Bergamaschi; Rocco Totaro; Marco Rovaris; Sebastiano Crisafulli; Massimiliano Mirabella; Paola Cavalla; Roberta Fantozzi; Antonio Gallo; Maria Pia Amato; Massimo Filippi; Maria Trojano

doi:10.1177/13524585261457317

Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study)

Damiano Paolicelli
, Giuseppe Lucisano
, Alessia Manni
, Pietro Iaffaldano
, Marta Simone
, Antonio Iaffaldano
, Tommaso Guerra
, Vincenzo Mangialardi
, Francesco Patti
, Eleonora Cocco
, Giovanna De Luca
, Pietro Annovazzi
, Paolo Ragonese
, Carlo Pozzilli
, Matilde Inglese
, Paola Perini
, Claudio Gasperini
, Carla Tortorella
, Girolama Alessandra Marfia
, Diana Ferraro

Giacomo Lus, Marika Vianello, Maria Assunta Rocca, Antonella Conte, Silvia Romano, Vincenzo Brescia Morra, Alessandra Lugaresi, Alessia Di Sapio, Clara Grazia Chisari, Raffaella Cerqua, Umberto Aguglia, Ilaria Pesci, Carlo Avolio, Emanuele D'Amico, Roberto Bergamaschi, Rocco Totaro, Marco Rovaris, Sebastiano Crisafulli, Massimiliano Mirabella, Paola Cavalla, Roberta Fantozzi, Antonio Gallo, Maria Pia Amato, Massimo Filippi, Maria Trojano

Research output: Contribution to journal › Article › peer-review

Abstract

Background: In multiple sclerosis (MS), real-world evidence supports early intensive treatment (EIT) with high-efficacy therapies (HET) over escalation (ESC), although comparative data on long-term safety across sequences remain limited. Objective: To compare the incidence of infections and neoplasms in patients treated with different treatment sequences. Methods: Data were extracted from the Italian MS and Related Disorders Register. DMTs were classified as moderate-efficacy treatment (MET), continuous HET (C-HET) or pulsed HET (P-HET). Six therapeutic sequences were reconstructed: MET-only, C-HET-only, P-HET-only, MET→C-HET, MET→P-HET and P-HET→MET. Incidence rates (IRs; per 1000 person-years) and incidence rate ratios (IRRs) were estimated using multivariable Poisson regression, adjusting for age, sex, Expanded Disability Status Scale (EDSS), disease duration, MS phenotype and prior relapse activity. Results: A total of 37,375 patients were included in the analysis, with a median duration of treatment exposure of 8.8 years. Infection risk was significantly higher with C-HET-only (IR, 24.82; IRR, 3.12), P-HET-only (IR, 13.43; IRR, 1.69), MET→C-HET (IR, 10.46; IRR, 1.32) and MET→P-HET (IR, 12.30; IRR, 1.55) versus MET-only (IR, 7.94), while P-HET→MET showed no significant difference from MET-only (IR, 7.67; IRR, 0.97). Regarding neoplasm incidence, P-HET-only showed the lowest rates (IR, 0.18; IRR, 0.24), whereas it was significantly higher in C-HET-only (IR, 1.33; IRR, 1.79) and MET→C-HET (IR, 1.01; IRR, 1.36) versus MET-only (IR, 0.74). Conclusions: This is the first real-world study to compare the safety of different sequences in a national registry. ESC strategies did not confer a long-term safety advantage over EIT. Among HET regimens, C-HET was associated with the greatest risk of both serious infections and neoplasms, whereas P-HET showed the lowest neoplasm incidence.

Original language	English
Pages (from-to)	N/A-N/A
Journal	Multiple Sclerosis
Issue number	Jul4
DOIs	https://doi.org/10.1177/13524585261457317
Publication status	Published - 2026

Keywords

Multiple sclerosis
combination
drug therapy
drug-related side effects and adverse reactions
immunomodulatory agents
monoclonal antibodies
real-world evidence

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10.1177/13524585261457317

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Paolicelli, D., Lucisano, G., Manni, A., Iaffaldano, P., Simone, M., Iaffaldano, A., Guerra, T., Mangialardi, V., Patti, F., Cocco, E., De Luca, G., Annovazzi, P., Ragonese, P., Pozzilli, C., Inglese, M., Perini, P., Gasperini, C., Tortorella, C., Marfia, G. A., ... Trojano, M. (2026). Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study). Multiple Sclerosis, (Jul4), N/A-N/A. https://doi.org/10.1177/13524585261457317

@article{0784685b115542d89f5de9c7f3ddd846,

title = "Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS\&RD) (ProSA study)",

abstract = "Background: In multiple sclerosis (MS), real-world evidence supports early intensive treatment (EIT) with high-efficacy therapies (HET) over escalation (ESC), although comparative data on long-term safety across sequences remain limited. Objective: To compare the incidence of infections and neoplasms in patients treated with different treatment sequences. Methods: Data were extracted from the Italian MS and Related Disorders Register. DMTs were classified as moderate-efficacy treatment (MET), continuous HET (C-HET) or pulsed HET (P-HET). Six therapeutic sequences were reconstructed: MET-only, C-HET-only, P-HET-only, MET→C-HET, MET→P-HET and P-HET→MET. Incidence rates (IRs; per 1000 person-years) and incidence rate ratios (IRRs) were estimated using multivariable Poisson regression, adjusting for age, sex, Expanded Disability Status Scale (EDSS), disease duration, MS phenotype and prior relapse activity. Results: A total of 37,375 patients were included in the analysis, with a median duration of treatment exposure of 8.8 years. Infection risk was significantly higher with C-HET-only (IR, 24.82; IRR, 3.12), P-HET-only (IR, 13.43; IRR, 1.69), MET→C-HET (IR, 10.46; IRR, 1.32) and MET→P-HET (IR, 12.30; IRR, 1.55) versus MET-only (IR, 7.94), while P-HET→MET showed no significant difference from MET-only (IR, 7.67; IRR, 0.97). Regarding neoplasm incidence, P-HET-only showed the lowest rates (IR, 0.18; IRR, 0.24), whereas it was significantly higher in C-HET-only (IR, 1.33; IRR, 1.79) and MET→C-HET (IR, 1.01; IRR, 1.36) versus MET-only (IR, 0.74). Conclusions: This is the first real-world study to compare the safety of different sequences in a national registry. ESC strategies did not confer a long-term safety advantage over EIT. Among HET regimens, C-HET was associated with the greatest risk of both serious infections and neoplasms, whereas P-HET showed the lowest neoplasm incidence.",

keywords = "Multiple sclerosis, combination, drug therapy, drug-related side effects and adverse reactions, immunomodulatory agents, monoclonal antibodies, real-world evidence, Multiple sclerosis, combination, drug therapy, drug-related side effects and adverse reactions, immunomodulatory agents, monoclonal antibodies, real-world evidence",

author = "Damiano Paolicelli and Giuseppe Lucisano and Alessia Manni and Pietro Iaffaldano and Marta Simone and Antonio Iaffaldano and Tommaso Guerra and Vincenzo Mangialardi and Francesco Patti and Eleonora Cocco and \{De Luca\}, Giovanna and Pietro Annovazzi and Paolo Ragonese and Carlo Pozzilli and Matilde Inglese and Paola Perini and Claudio Gasperini and Carla Tortorella and Marfia, \{Girolama Alessandra\} and Diana Ferraro and Giacomo Lus and Marika Vianello and Rocca, \{Maria Assunta\} and Antonella Conte and Silvia Romano and \{Brescia Morra\}, Vincenzo and Alessandra Lugaresi and \{Di Sapio\}, Alessia and Chisari, \{Clara Grazia\} and Raffaella Cerqua and Umberto Aguglia and Ilaria Pesci and Carlo Avolio and Emanuele D'Amico and Roberto Bergamaschi and Rocco Totaro and Marco Rovaris and Sebastiano Crisafulli and Massimiliano Mirabella and Paola Cavalla and Roberta Fantozzi and Antonio Gallo and Amato, \{Maria Pia\} and Massimo Filippi and Maria Trojano",

year = "2026",

doi = "10.1177/13524585261457317",

language = "English",

pages = "N/A--N/A",

journal = "Multiple Sclerosis",

issn = "1352-4585",

publisher = "SAGE Publications Ltd",

number = "Jul4",

}

Paolicelli, D, Lucisano, G, Manni, A, Iaffaldano, P, Simone, M, Iaffaldano, A, Guerra, T, Mangialardi, V, Patti, F, Cocco, E, De Luca, G, Annovazzi, P, Ragonese, P, Pozzilli, C, Inglese, M, Perini, P, Gasperini, C, Tortorella, C, Marfia, GA, Ferraro, D, Lus, G, Vianello, M, Rocca, MA, Conte, A, Romano, S, Brescia Morra, V, Lugaresi, A, Di Sapio, A, Chisari, CG, Cerqua, R, Aguglia, U, Pesci, I, Avolio, C, D'Amico, E, Bergamaschi, R, Totaro, R, Rovaris, M, Crisafulli, S, Mirabella, M, Cavalla, P, Fantozzi, R, Gallo, A, Amato, MP, Filippi, M & Trojano, M 2026, 'Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study)', Multiple Sclerosis, no. Jul4, pp. N/A-N/A. https://doi.org/10.1177/13524585261457317

Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study). / Paolicelli, Damiano; Lucisano, Giuseppe; Manni, Alessia et al.
In: Multiple Sclerosis, No. Jul4, 2026, p. N/A-N/A.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study)

AU - Paolicelli, Damiano

AU - Lucisano, Giuseppe

AU - Manni, Alessia

AU - Iaffaldano, Pietro

AU - Simone, Marta

AU - Iaffaldano, Antonio

AU - Guerra, Tommaso

AU - Mangialardi, Vincenzo

AU - Patti, Francesco

AU - Cocco, Eleonora

AU - De Luca, Giovanna

AU - Annovazzi, Pietro

AU - Ragonese, Paolo

AU - Pozzilli, Carlo

AU - Inglese, Matilde

AU - Perini, Paola

AU - Gasperini, Claudio

AU - Tortorella, Carla

AU - Marfia, Girolama Alessandra

AU - Ferraro, Diana

AU - Lus, Giacomo

AU - Vianello, Marika

AU - Rocca, Maria Assunta

AU - Conte, Antonella

AU - Romano, Silvia

AU - Brescia Morra, Vincenzo

AU - Lugaresi, Alessandra

AU - Di Sapio, Alessia

AU - Chisari, Clara Grazia

AU - Cerqua, Raffaella

AU - Aguglia, Umberto

AU - Pesci, Ilaria

AU - Avolio, Carlo

AU - D'Amico, Emanuele

AU - Bergamaschi, Roberto

AU - Totaro, Rocco

AU - Rovaris, Marco

AU - Crisafulli, Sebastiano

AU - Mirabella, Massimiliano

AU - Cavalla, Paola

AU - Fantozzi, Roberta

AU - Gallo, Antonio

AU - Amato, Maria Pia

AU - Filippi, Massimo

AU - Trojano, Maria

PY - 2026

Y1 - 2026

N2 - Background: In multiple sclerosis (MS), real-world evidence supports early intensive treatment (EIT) with high-efficacy therapies (HET) over escalation (ESC), although comparative data on long-term safety across sequences remain limited. Objective: To compare the incidence of infections and neoplasms in patients treated with different treatment sequences. Methods: Data were extracted from the Italian MS and Related Disorders Register. DMTs were classified as moderate-efficacy treatment (MET), continuous HET (C-HET) or pulsed HET (P-HET). Six therapeutic sequences were reconstructed: MET-only, C-HET-only, P-HET-only, MET→C-HET, MET→P-HET and P-HET→MET. Incidence rates (IRs; per 1000 person-years) and incidence rate ratios (IRRs) were estimated using multivariable Poisson regression, adjusting for age, sex, Expanded Disability Status Scale (EDSS), disease duration, MS phenotype and prior relapse activity. Results: A total of 37,375 patients were included in the analysis, with a median duration of treatment exposure of 8.8 years. Infection risk was significantly higher with C-HET-only (IR, 24.82; IRR, 3.12), P-HET-only (IR, 13.43; IRR, 1.69), MET→C-HET (IR, 10.46; IRR, 1.32) and MET→P-HET (IR, 12.30; IRR, 1.55) versus MET-only (IR, 7.94), while P-HET→MET showed no significant difference from MET-only (IR, 7.67; IRR, 0.97). Regarding neoplasm incidence, P-HET-only showed the lowest rates (IR, 0.18; IRR, 0.24), whereas it was significantly higher in C-HET-only (IR, 1.33; IRR, 1.79) and MET→C-HET (IR, 1.01; IRR, 1.36) versus MET-only (IR, 0.74). Conclusions: This is the first real-world study to compare the safety of different sequences in a national registry. ESC strategies did not confer a long-term safety advantage over EIT. Among HET regimens, C-HET was associated with the greatest risk of both serious infections and neoplasms, whereas P-HET showed the lowest neoplasm incidence.

AB - Background: In multiple sclerosis (MS), real-world evidence supports early intensive treatment (EIT) with high-efficacy therapies (HET) over escalation (ESC), although comparative data on long-term safety across sequences remain limited. Objective: To compare the incidence of infections and neoplasms in patients treated with different treatment sequences. Methods: Data were extracted from the Italian MS and Related Disorders Register. DMTs were classified as moderate-efficacy treatment (MET), continuous HET (C-HET) or pulsed HET (P-HET). Six therapeutic sequences were reconstructed: MET-only, C-HET-only, P-HET-only, MET→C-HET, MET→P-HET and P-HET→MET. Incidence rates (IRs; per 1000 person-years) and incidence rate ratios (IRRs) were estimated using multivariable Poisson regression, adjusting for age, sex, Expanded Disability Status Scale (EDSS), disease duration, MS phenotype and prior relapse activity. Results: A total of 37,375 patients were included in the analysis, with a median duration of treatment exposure of 8.8 years. Infection risk was significantly higher with C-HET-only (IR, 24.82; IRR, 3.12), P-HET-only (IR, 13.43; IRR, 1.69), MET→C-HET (IR, 10.46; IRR, 1.32) and MET→P-HET (IR, 12.30; IRR, 1.55) versus MET-only (IR, 7.94), while P-HET→MET showed no significant difference from MET-only (IR, 7.67; IRR, 0.97). Regarding neoplasm incidence, P-HET-only showed the lowest rates (IR, 0.18; IRR, 0.24), whereas it was significantly higher in C-HET-only (IR, 1.33; IRR, 1.79) and MET→C-HET (IR, 1.01; IRR, 1.36) versus MET-only (IR, 0.74). Conclusions: This is the first real-world study to compare the safety of different sequences in a national registry. ESC strategies did not confer a long-term safety advantage over EIT. Among HET regimens, C-HET was associated with the greatest risk of both serious infections and neoplasms, whereas P-HET showed the lowest neoplasm incidence.

KW - Multiple sclerosis

KW - combination

KW - drug therapy

KW - drug-related side effects and adverse reactions

KW - immunomodulatory agents

KW - monoclonal antibodies

KW - real-world evidence

KW - Multiple sclerosis

KW - combination

KW - drug therapy

KW - drug-related side effects and adverse reactions

KW - immunomodulatory agents

KW - monoclonal antibodies

KW - real-world evidence

UR - https://publicatt.unicatt.it/handle/10807/342436

U2 - 10.1177/13524585261457317

DO - 10.1177/13524585261457317

M3 - Article

SN - 1352-4585

SP - N/A-N/A

JO - Multiple Sclerosis

JF - Multiple Sclerosis

IS - Jul4

ER -

Paolicelli D, Lucisano G, Manni A, Iaffaldano P, Simone M, Iaffaldano A et al. Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study). Multiple Sclerosis. 2026;(Jul4):N/A-N/A. doi: 10.1177/13524585261457317

Profiling the long-term risk of severe adverse events in a cohort of multiple sclerosis patients treated with different treatment sequences: Results from the Italian Multiple Sclerosis and Related Disorders Registry (I-MS&RD) (ProSA study)

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