Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS

QuestionHow does cladribine compare with sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with relapsing-remitting multiple sclerosis?FindingsIn this comparative effectiveness research study of 950 propensity score-matched treatment-naive patients with at least 12 months (median, 25 months) of follow-up, cladribine and S1PRMs demonstrated comparable relapse rates, magnetic resonance imaging activity, and no evidence of disease activity with 3 components loss, with cladribine associated with a significantly lower risk of confirmed disability worsening, likely driven by a reduction in progression independent of relapse activity events, and with indications of reduced clinical activity control beyond 36 months.MeaningThese findings suggest cladribine may provide greater short-term protection against disability progression, with a possible need for redosing or treatment switch to sustain disease control beyond 3 years.This comparative effectiveness research study investigates the clinical effectiveness of cladribine vs sphingosine-1-phosphate (S1P) receptor modulators in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS).ImportanceEarly treatment choice in relapsing-remitting multiple sclerosis (RRMS) is prognostically crucial, yet robust comparative data on cladribine vs sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive patients with RRMS are limited.ObjectiveTo compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS.Design, Setting, and ParticipantsThis 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.ExposureInitiation of cladribine or an S1PRM, with duration reflecting clinical practice.Main Outcomes and MeasuresThe 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.ResultsOf 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 RelevanceThese 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.