Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS.
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Haggiag Shalom, Prosperini Luca, Filippi Massimo, Rocca Maria A, Iaffaldano Pietro, Patti Francesco, Inglese Matilde, Borriello Giovanna, Totaro Rocco, Lus Giacomo, Fantozzi Roberta, Brescia Morra Vincenzo, Romano Silvia, Frau Jessica, Marfia Girolama Alessandra, Maniscalco Giorgia Teresa, Amato Maria Pia, Di Sapio Alessia, De Luca Giovanna, Crisafulli Sebastiano Giuseppe, Curti Erica, Foschi Matteo, Cavalla Paola, Salemi Giuseppe, Conte Antonella, Valentino Paola, Ferraro Diana, Lugaresi Alessandra, Realmuto Sabrina, Perini Paola, Ferraro Elisabetta, Montepietra Sara, Avolio Carlo, Vianello Marika, Gazzola Paola, Marinelli Fabiana, Pasquali Livia, Bucello Sebastiano, Vecchio Domizia, Protti Alessandra, Sangalli Francesca, Rovaris Marco, Grimaldi Luigi, De Riz Milena, Barone Paolo, Scarano Valentina, Ardito Bonaventura, Sinisi Leonardo, Immovilli Paolo, Pesci Ilaria, Colombo Elena, Capobianco Marco Alfonso, Fioretti Cristina, Coniglio Maria Gabriella, Giordano Antonello, Tassinari Tiziana, Cargnelutti Daniela, Matta Francesca, Falcini Mario, Gatto Maurizia, Mascoli Nerina, Balgera Roberto, Sessa Edoardo, Iodice Rosa, Solaro Claudio, Plewnia Katrin, Santangelo Mario, Barcella Valeria, Ferrò Maria Teresa, Sica Francesco, Cerqua Raffaella, Santuccio Giuseppe, Corea Francesco, Leone Alessandro, Nasuelli Davide, Rini Augusto Maria, Brichetto Giampaolo, Cottone Salvatore, Ulivelli Monica, Pizzorno Matteo, Rossi Patrizia, Milano Eva, Zuliani Luigi, Ruggieri Serena, Gasperini Claudio, Trojano Maria, Tortorella Carla
Аннотация
OBJECTIVE: To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS.
DESIGN, SETTING, AND PARTICIPANTS: This comparative effectiveness research study used data from 108 Italian multiple sclerosis (MS) centers affiliated with the Italian Multiple Sclerosis and Related Disorders Register. All treatment-naive patients with RRMS who initiated cladribine or an S1PRM (fingolimod, ozanimod, or ponesimod) between January 2011 and October 2021 and had at least 12 months of follow-up were included. Propensity score matching and pairwise censoring were used to balance baseline differences and follow-up duration. Patient data were extracted from the register in September 2024.
EXPOSURE: Initiation of cladribine or an S1PRM, with duration reflecting clinical practice.
MAIN OUTCOMES AND MEASURES: The primary outcome was no evidence of disease activity (NEDA-3) and its subcomponents. Secondary analyses evaluated disability accrual subdivided into progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW), plus variables associated with treatment response. Cox proportional hazards models, adjusted for visit and magnetic resonance imaging (MRI) frequency, were used to compare outcomes.
RESULTS: Of the 1587 patients (485 taking cladribine and 1102 taking S1PRMs), matching yielded 475 pairs (950 individuals; mean [SD] age, 34.7 [10.7] years; 686 female [72.2%]), with a median (IQR) follow-up period of 25 (12-60) months. For the cladribine vs S1PRM groups, no significant differences were observed in relapse rates (72 patients [15.2%] vs 76 patients [16.0%]), MRI activity (137 patients [31.3%] vs 145 patients [34.8%]), or NEDA-3 loss (194 patients [44.4% vs 219 patients [52.2%]). Cladribine was associated with a lower risk of disability worsening vs S1PRM (54 patients [11.4%] vs 70 patients [14.7%]; hazard ratio [HR], 0.64; 95% CI, 0.42-0.96; P = .03), a finding that was confirmed in sensitivity analyses for patients younger than 40 years, those whose diagnoses were made according to the 2017 McDonald Criteria, and those with Expanded Disability Status Scale score less than or equal to 3.0. This was mainly driven by reduced PIRA risk with cladribine (HR, 0.40; 95% CI, 0.20-0.79; P = .009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P = .04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P = .01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15; P = .58).
CONCLUSIONS AND RELEVANCE: These findings suggest cladribine was associated with superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control.