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Comparative Study
. 2025 Nov 3;8(11):e2541025.
doi: 10.1001/jamanetworkopen.2025.41025.

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

Shalom Haggiag  1 , Luca Prosperini  1 , Massimo Filippi  2 , Maria A Rocca  2 , Pietro Iaffaldano  3 , Francesco Patti  4 , Matilde Inglese  5 , Giovanna Borriello  6 , Rocco Totaro  7 , Giacomo Lus  8 , Roberta Fantozzi  9 , Vincenzo Brescia Morra  10 , Silvia Romano  11 , Jessica Frau  12 , Girolama Alessandra Marfia  13 , Giorgia Teresa Maniscalco  14 , Maria Pia Amato  15 , Alessia Di Sapio  16 , Giovanna De Luca  17 , Sebastiano Giuseppe Crisafulli  18 , Erica Curti  19 , Matteo Foschi  20   21 , Paola Cavalla  22 , Giuseppe Salemi  23 , Antonella Conte  24   25 , Paola Valentino  26 , Diana Ferraro  27 , Alessandra Lugaresi  28   29 , Sabrina Realmuto  30 , Paola Perini  31 , Elisabetta Ferraro  32 , Sara Montepietra  33 , Carlo Avolio  34 , Marika Vianello  35 , Paola Gazzola  36 , Fabiana Marinelli  37 , Livia Pasquali  38 , Sebastiano Bucello  39 , Domizia Vecchio  40 , Alessandra Protti  41 , Francesca Sangalli  42 , Marco Rovaris  43 , Luigi Grimaldi  44   45 , Milena De Riz  46 , Paolo Barone  47 , Valentina Scarano  48 , Bonaventura Ardito  49 , Leonardo Sinisi  50 , Paolo Immovilli  51 , Ilaria Pesci  52 , Elena Colombo  53 , Marco Alfonso Capobianco  54 , Cristina Fioretti  55 , Maria Gabriella Coniglio  56 , Antonello Giordano  57 , Tiziana Tassinari  58 , Daniela Cargnelutti  59 , Francesca Matta  60 , Mario Falcini  61 , Maurizia Gatto  62 , Nerina Mascoli  63 , Roberto Balgera  64 , Edoardo Sessa  65 , Rosa Iodice  66 , Claudio Solaro  67 , Katrin Plewnia  68 , Mario Santangelo  69 , Valeria Barcella  70 , Maria Teresa Ferrò  71 , Francesco Sica  72 , Raffaella Cerqua  73 , Giuseppe Santuccio  74 , Francesco Corea  75 , Alessandro Leone  76 , Davide Nasuelli  77 , Augusto Maria Rini  78 , Giampaolo Brichetto  79 , Salvatore Cottone  80 , Monica Ulivelli  81 , Matteo Pizzorno  82 , Patrizia Rossi  83 , Eva Milano  84 , Luigi Zuliani  85 , Serena Ruggieri  1 , Claudio Gasperini  1 , Maria Trojano  3 , Carla Tortorella  1
Affiliations
Comparative Study

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

Shalom Haggiag et al. JAMA Netw Open. .

Abstract

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. 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Haggiag reported receiving personal fees from Novartis, Merck Serono, Roche, Sanofi, BMS, and Alexion. Dr Prosperini reported receiving personal fees and nonfinancial support from Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, and Viatris. Dr Filippi reported receiving personal fees and/or research support from Alexion, Almirall, Bayer, Biogen, Celgene, Chiesi Italia SpA, Eli Lilly, Genzyme, the Italian Ministry of Health, the Italian Ministry of University and Research, Janssen, Merck-Serono, Neopharmed Gentili, Novartis, Novo Nordisk, Roche, Sanofi, Takeda, and Teva; and participating in advisory boards for Alexion, Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi, Sanofi-Aventis, Sanofi-Genzyme, and Takeda, as well as scientific direction of educational events for Biogen, Merck, Roche, Celgene, Bristol-Myers Squibb, Lilly, Novartis, Sanofi-Genzyme. Dr Rocca reported receiving personal fees from AstraZaneca, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Eli Lilly, Genzyme, Horizon Therapeutics Italy, Janssen, Merck Serono SpA, Novartis, Roche, Sanofi, and Teva and research support from the Multiple Sclerosis Society of Canada, the Italian Ministry of Health, the Italian Ministry of University and Research; Dr Rocca is also Associate Editor for Multiple Sclerosis and Related Disorders and Associate Co-Editor for Europe and Africa for Multiple Sclerosis Journal. Dr Iaffaldano reported receiving personal fees from Alexion, Biogen Idec, Bayer, Teva, Roche, BMS, Merck Serono, Novartis and Genzyme. Dr Patti reported receiving personal fees from Alexion, Almirall, Amgen, Biogen, Bristol-Myers and Squibb, Janssen, Merck, Novartis, Roche, Sandoz, Sanofi and grant research support from Biogen, Merck, Novartis, Roche, Sanosi, MIUR, Italian Ministry of Health, and Reload Onlus Association. Dr Inglese reported receiving personal fees from Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, Sanofi, and Janssen. Dr Borriello reported receiving personal fees from Alexion, Biogen, Merck, Sanofi, Novartis, Roche, Teva, and Bristol Myers Squibb. Dr Totaro reported receiving personal fees from and/or serving on advisory boards for Alexion, Almirall, Amgen, Biogen, Lundbeck, Merck Serono, Novartis, Roche, and Sanofi-Genzyme. Dr Lus reported receiving grants and personal fees from Alexion, Amgen, Biogen Idec, Bristol, Merck Serono, Novartis, Sanofi Genzyme, and Roche. Dr Fantozzi reported receiving personal fees from Novartis, Merk-Serono, BMS, Biogen, and Roche. Dr Brescia Morra reported receiving funding and personal fees from Novartis, Roche, Biogen, Teva, Almirall, Sanofi-Genzyme, Merck, Bayer, Mylan, and Bristol Myers Squibb. Dr Romano reported receiving travel support from Biogen and Roche. Dr Frau reported receiving personal fees from Merck Serono, Genzyme, Biogen and Teva and serving on scientific advisory boards for Biogen and Genzyme. Dr Marfia reported receiving fees and grant support from Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, F. Hoffmann–La Roche, Mylan, Alexion, Janssen Cilag, and Bristol Myers Squibb, and serving as an advisory board member for Biogen Idec, Sanofi Genzyme, Merck-Serono, Neurapharm, Novartis, and F. Hoffmann–La Roche; Dr Marfia is also the principal investigator in clinical trials for Biogen Idec, Merck Serono, Novartis, F. Hoffmann–La Roche, Sanofi-Genzyme, Merck Serono, and Bristol Myers Squibb. Dr Maniscalco reported receiving personal fees from Biogen, Merck Serono, Novartis, Roche, Sanofi, Alexion, and Amgen. Dr Amato reported receiving grants from the National Multiple Sclerosis Society, the Canadian Multiple Sclerosis Society, the Italian Health Ministry, Regione Toscana, Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Teva, Almirall, and Roche, and personal fees for serving as a speaker and member of advisory boards for Bayer, Biogen, Merck, Novartis, Sanofi Genzyme, Teva, Almirall, Roche, Celgene BMS, and Sandoz. Dr Di Sapio reported receiving personal fees from Biogen, Novartis, Roche, Sanofi, Merck Serono, Bristol Meyer Squibb, Janssen, Alexion, Alnylam, and Amgen. Dr De Luca reported receiving personal fees from Merck, Roche, Biogen, and Novartis and serving on the advisory boards for Merck, Roche, and Lundbeck. Dr Grisafulli reported receiving support for congress participation from Mylan, Merck-Serono, Novartis, and Roche, and serving on the advisory boards for Novartis and Roche. Dr Foschi reported receiving personal fees from Roche, Novartis, Biogen, Sanofi, Merck, and Bristol-Myers, and serving as a consultant for Roche and Novartis. Dr Cavalla reported receiving person fees from Biogen, Merck-Serono, Novartis, Roche, Sanofi/Genzyme, and Teva and serving as an advisory board member for Almirall, Biogen, Merck-Serono, Sanofi-Genzyme, Roche, and Teva. Dr Conte reported receiving personal fees from Roche, Biogen, Novartis, BMS, Allmiral, Merck, and Lundbeck and research support from Biogen. Dr Valentino reported receiving personal fees from Roche, Merck, and Novartis. Dr Ferraro reported receiving personal fees from Alexion. Dr Lugaresi reported receiving personal fees from Alexion, Amgen/Horizon, Biogen, Bristol-Myers Squibb/Celgene, Janssen/Johnson&Johnson, Merck Serono, Novartis, Roche, and Sanofi/Genzyme. Dr Perini reported receiving personal fees from Merck, Biogen, Sanofi-Aventis, Novartis-Pharma, Teva, Roche, Almirall, and Alexion, and serving as a consultant and member of advisory boards for Biogen, Genzyme, Merck, Almirall, Merck, Roche, and Novartis. Dr Ferraro reported receiving personal fees from Bristol-Myers Squibb, Merck Serono, Novartis, Roche, and Sanofi. Dr Avolio reported receiving personal fees and grants from Roche, Novartis, Sanofi, Bristol-Myers Squibb, Biogen, Merck, Alexion, and Amgen, and serving as an advisory board member of Roche, Novartis, Sanofi, Bristol-Myers Squibb, Biogen, Merck, Alexion, and Amgen. Dr Vianello reported receiving personal fees from Biogen, Genzyme, Bristol-Myers Squibb, Serono, Merck, Novartis, Roche, and Janssen. Dr Marinelli reported receiving personal fees from Merck Serono, Bristol-Myers Squibb, Novartis, and Roche. Dr Pasquali reported receiving fees and grants from Biogen, Sanofi-Genzyme, Novartis, Alexion, Roche, and Merck Serono, and participating in advisory boards from Merck and Sanofi-Genzyme, Dr Bucello reported receiving personal fees from Roche and Novartis; serving as a consultant for Biogen, Sanofi, Merck Serono, and Novartis; and participating in speakers’ bureaus for Biogen, Bristol-Myers Squibb, Novartis, Merck, Sanofi, and Roche. Dr Vecchio reported receiving fees from Novartis, Sanofi, Roche and Merck. and research support from Fondazione Italiana Sclerosi Multipla paid to their institution. Dr Sangalli reported receiving fees from Alexion, Biogen, Bristol-Myers Squibb, Janssen, Merck Serono, Novartis, Roche, and Sanofi. Dr Rovaris reported receiving fees from Merck, Bristol-Myers Squibb, and Roche. Dr De Riz reported receiving personal fees from Merck-Serono, Novartis, Roche, Sanofi, Biogen, Teva, Almirall, Bristol-Myers Squibb, and Horizon Therapeutics. Dr Grimaldi reported receiving personal fees from Merck, Biogen Idec, Sanofi-Aventis, Teva, Roche, Novartis, Alexion and Bayer. Dr Ardito reported receiving personal fees from Bristol-Myers Squibb, Novartis, Sanofi Aventis, Alexion, Genzyme, and Lusofarmaco, and serving as a consultant for Biogen and Novartis. Dr Sinisi reported receiving personal fees from Merck Serono, Bristol-Myers Squibb, and Johnson&Johnson, and participating in advisory boards with Novartis and Merck Serono. Dr Immovilli reported receiving personal fees from Roche, Novartis, Bristol-Myers Squibb, Jansen, Sanofi, Merck, and Alexion. Dr Pesci reported receiving fees from Merck, Biogen, Roche, Novartis, and Bristol. Dr Colombo reported receiving personal fees from Sanofi, Biogen, Novartis, Merck, Roche, Bristol-Myers Squibb, Janssen, and Alexion. Dr Coniglio reported receiving personal fees from Biogen, Bristol-Myers Squibb, Merck Serono, Novartis, Roche, and Sanofi Genzyme. Dr Cargnelutti reported receiving personal fees from Roche, Novartis, Merck, Sanofi Genzyme, and Biogen. Dr Matta reported receiving honoraria from Novartis, Merck, Sanofi, Genzyme, and Roche. Dr Falcini reported receiving travel grants from Novartis, Biogen, Roche, and Alexion. Dr Mascoli reported receiving personal fees from Novartis and Biogen. Dr Solaro reported receiving personal fees from Merck, Biogen, Novartis, Roche, and Almirall. Dr Sica reported serving as an advisory board member of Novartis, Biogen, Bristol-Myers Squibb, and Merck Serono. Dr Cerqua reported receiving personal fees from Roche, Novartis, Sanofi Genzyme, Alexion, Jansenn, and Merck Serono. Dr Rini reported receiving personal fees from Novartis, BIAL, Abbvie, and Sanofi. Dr Zuliani reported receiving personal fees from Alexion, Almirall, Biogen, Genzyme, Merck-Serono, Mylan, Novartis, and Roche. Dr Ruggieri reported receiving personal fees from Biogen, Bristol-Myers Squibb, Merck, Novartis, Alexion and Roche. Dr Gasperini reported receiving personal fees from Biogen, Merck-Serono, Teva, Sanofi, Novartis, Genzyme, and Alexion. Dr Trojano reported receiving personal fees from Biogen, Novartis, Roche, Merck, Sanofi, and Bristol-Myers Squibb. Dr Tortorella reported receiving honoraria from Biogen, Bristol-Myers Squibb, Merck, Novartis, Alexion, Amgen and Roche for consulting services, speaking and/or travel support. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Patient Inclusion Flowchart for Analysis of Treatment-Naive Patients With Relapsing-Remitting Multiple Sclerosis Treated With Cladribine or Sphingosine-1-Phosphate Receptor Modulators (S1PRMs) With ≥12 Months of Follow-Up
Figure 2.
Figure 2.. Kaplan-Meier Curves Comparing Patients Taking Cladribine vs Sphingosine-1-Phosphate Receptor Modulators (S1PRMs)
Graphs show probability of relapse-free survival (A), disability progression–free survival (B), magnetic resonance imaging (MRI) activity (C), and (D) no evidence of disease activity with 3 components (NEDA-3) loss. HR indicates hazard ratio.
See this image and copyright information in PMC

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