Fingolimod was the first sphingosine-1-phosphate receptor modulator and in Europe is used second line after failure of a previous drug, siponimod is licenced in Europe for secondary progressive MS, ozanimod (not really used in UK) and ponseimod can be used first line for relapsing MS. They all target S1P1 receptor and in other countries are used for the same indications, but not in Europe…Bonkers as it has nothing to do with science. Cladribine in Europe and other parts is also second-line but not in the UK where it has been approved for first line treatment for ages. This means it can be used in treatment naive people. As cladribine is only treated over 1 year in 4 years as opposed to daily dosing there was more cases of disease breakthrough….and here they suggest a retreatment at 3 rather than 4 years. When cladribine was developed lymphopenia (low lymphocyte counts) was considered an adverse side effect and so stategies were put in place to avoid this…however, it is actually a mechanism of action and one wonders if some people are underdosed as a consequence of this.
Haggiag S et al. ,Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS. JAMA Netw Open. 2025;8(11):e2541025. doi: 10.1001/jamanetworkopen.2025.41025. PMID: 41182765.
Importance: Early 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.
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…. 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…. However, relapse prevention declined after 36 months, suggesting retreatment or therapy modification within 3 years may be needed to maintain long-term disease control.
Source: multiple-sclerosis-research.org