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 -