JAMA Netw Open

Cladribine may offer early protection against disability in treatment-naïve RRMS

November 5, 2025

Study details: This comparative effectiveness study analyzed 950 treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) from 108 Italian MS centers. Patients initiating cladribine or a sphingosine-1-phosphate receptor modulator (S1PRM: fingolimod, ozanimod, or ponesimod) between 2011 and 2021 were propensity score–matched and followed for a median of 25 months. Primary outcomes: relapse rate, MRI activity, and no evidence of disease activity (NEDA-3). Secondary outcomes: disability progression, including progression independent of relapse activity (PIRA).

Results: Relapse rates, MRI activity, and NEDA-3 loss were comparable between groups. However, cladribine was associated with a significantly lower risk of confirmed disability worsening (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.42–0.96; P=0.03), primarily due to reduced PIRA events (HR, 0.40; 95% CI, 0.20–0.79; P=0.009). After 36 months, cladribine-treated patients showed increased relapse risk (HR, 1.81; 95% CI, 1.02-3.20; P=0.04) and NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67; P=0.01), suggesting waning efficacy.

Clinical impact: Cladribine may offer superior short-term protection against disability progression in treatment-naive RRMS, supporting its use as an early high-efficacy option. However, long-term disease control may require re-dosing or switching therapy beyond three years.

Source:

Haggiag S, et al. (2025, November 3). JAMA Netw Open. Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS. https://pubmed.ncbi.nlm.nih.gov/41182765/