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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Multiple sclerosis (Houndmills, Basingstoke, England) Pub Date : 2026-10-01 Epub Date: 2026-07-04 DOI:10.1177/13524585261457317

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

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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.

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意大利多发性硬化症和相关疾病登记处（I-MS&RD）（ProSA研究）的结果：对接受不同治疗顺序的多发性硬化症患者进行严重不良事件的长期风险分析。

背景：在多发性硬化症（MS）中，现实世界的证据支持早期强化治疗（EIT）与高效疗法（HET）而不是升级疗法（ESC），尽管跨序列的长期安全性比较数据仍然有限。目的：比较不同治疗顺序患者感染和肿瘤的发生率。方法：数据取自意大利多发性硬化症和相关疾病登记册。dmt分为中等疗效治疗（MET）、连续HET （C-HET）或脉冲HET （P-HET）。重建了6个治疗序列：MET-only、C-HET-only、P-HET-only、MET→C-HET、MET→P-HET和P-HET→MET。发病率（IRs；每1000人年）和发病率比（IRRs）使用多变量泊松回归估计，调整年龄、性别、扩展残疾状态量表（EDSS）、疾病持续时间、MS表型和既往复发活动。结果：共有37375名患者被纳入分析，治疗暴露的中位持续时间为8.8年。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）和MET→P-HET （IR, 12.30； IRR, 1.55）与MET-only （IR, 7.94）相比，感染风险显著增加，而P-HET→MET与MET-only （IR, 7.67； IRR, 0.97）无显著差异。关于肿瘤发病率，P-HET-only的发生率最低（IR, 0.18； IRR, 0.24），而C-HET-only （IR, 1.33； IRR, 1.79）和MET→c - heet （IR, 1.01； IRR, 1.36）的发生率明显高于MET-only （IR, 0.74）。结论：这是第一个在国家注册中比较不同序列安全性的真实研究。与EIT相比，ESC策略并不具有长期的安全性优势。在HET方案中，C-HET与最大的严重感染和肿瘤风险相关，而P-HET显示最低的肿瘤发生率。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Multiple sclerosis (Houndmills, Basingstoke, England)

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