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Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS
Shalom Haggiag1, Luca Prosperini1, Massimo Filippi2
1Centro Sclerosi Multipla, Dipartimento di Neuroscienze, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy.
JAMA Network Open
|November 3, 2025
Summary
Cladribine showed superior effectiveness in reducing disability progression in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients over 25 months compared to S1PRMs. However, its relapse prevention benefits diminished after 36 months, necessitating potential retreatment.
Area of Science:
- Neurology
- Immunology
- Pharmacology
Background:
- Early treatment selection is critical for managing relapsing-remitting multiple sclerosis (RRMS).
- Comparative data on cladribine versus sphingosine-1-phosphate receptor modulators (S1PRMs) in treatment-naive RRMS patients are limited.
- Understanding treatment effectiveness is crucial for optimizing patient outcomes.
Purpose of the Study:
- To compare the clinical effectiveness of cladribine versus S1PRMs in treatment-naive RRMS patients.
- To evaluate differences in disease activity, disability accrual, and treatment response.
- To inform early treatment decisions for RRMS management.
Main Methods:
- A comparative effectiveness research study utilizing data from 108 Italian MS centers.
- Inclusion of treatment-naive RRMS patients initiating cladribine or S1PRMs (fingolimod, ozanimod, ponesimod) between 2011-2021 with ≥12 months follow-up.
- Propensity score matching and pairwise censoring were employed to balance baseline characteristics and follow-up duration; Cox proportional hazards models were used for outcome comparison.
Main Results:
- No significant differences were observed in relapse rates, MRI activity, or NEDA-3 loss between cladribine and S1PRM groups in the initial 25-month follow-up.
- Cladribine demonstrated a lower risk of disability worsening, primarily driven by reduced progression independent of relapse activity (PIRA).
- After 36 months, cladribine was associated with a higher risk of relapse and increased NEDA-3 loss, while discontinuation rates were similar.
Conclusions:
- Cladribine showed superior effectiveness in reducing disability progression over 25 months, likely due to reduced PIRA, despite comparable short-term NEDA-3 outcomes.
- The relapse prevention benefit of cladribine diminished after 36 months, suggesting a need for retreatment or therapy modification for sustained long-term disease control.
- These findings highlight the importance of considering the time-dependent efficacy of early RRMS treatments.
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