{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T06:31:05Z","timestamp":1781332265970,"version":"3.54.1"},"reference-count":48,"publisher":"American Medical Association (AMA)","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"<jats:sec id=\"ab-zoi251124-4\">\n                    <jats:title>Importance<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-5\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To compare the clinical effectiveness of cladribine vs S1PRMs in treatment-naive individuals with RRMS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-6\">\n                    <jats:title>Design, Setting, and Participants<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-7\">\n                    <jats:title>Exposure<\/jats:title>\n                    <jats:p>Initiation of cladribine or an S1PRM, with duration reflecting clinical practice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-8\">\n                    <jats:title>Main Outcomes and Measures<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-9\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.03), 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;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.009), with no RAW difference. After 36 months, patients treated with cladribine showed higher relapse risk (HR, 1.81; 95% CI, 1.02-3.20;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.04) and increased NEDA-3 loss (HR, 2.08; 95% CI, 1.18-3.67;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.01). Discontinuation rates were similar (HR, 0.92; 95% CI, 0.67-1.15;\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      \u2009=\u2009.58).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"ab-zoi251124-10\">\n                    <jats:title>Conclusions and Relevance<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.41025","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T16:01:56Z","timestamp":1762185716000},"page":"e2541025","source":"Crossref","is-referenced-by-count":5,"title":["Comparative Effectiveness of Cladribine and S1P Receptor Modulators in Treatment-Naive Relapsing-Remitting MS"],"prefix":"10.1001","volume":"8","author":[{"given":"Shalom","family":"Haggiag","sequence":"first","affiliation":[{"name":"Centro Sclerosi Multipla, Dipartimento di Neuroscienze, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Prosperini","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla, Dipartimento di Neuroscienze, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Filippi","sequence":"additional","affiliation":[{"name":"Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)  San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Rocca","sequence":"additional","affiliation":[{"name":"Neurology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS)  San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Iaffaldano","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla,  DiBraiN: Dipartimento di Biomedicina Traslazionale e Neuroscienze, Universit\u00e0 di Bari, Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Patti","sequence":"additional","affiliation":[{"name":"Dipartimento G.F. Ingrassia, Scienze Mediche e Chirurgiche e Tecnologie Avanzate, Universit\u00e0 Catania; Unita Operativa Semplice Sclerosi Multipla, Azienda Ospedaliero Universitaria Policlinico G. Rodolico, San Marco, Universit\u00e0 Catania Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matilde","family":"Inglese","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale Policlinico San Martino, Genoa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Borriello","sequence":"additional","affiliation":[{"name":"Centro Clinico Sclerosi Multipla, Ospedale Fatebenefratelli San Pietro, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocco","family":"Totaro","sequence":"additional","affiliation":[{"name":"Centro Malattie Demielinizzanti, Clinica Neurologica Ospedale San Salvatore, L\u2019Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomo","family":"Lus","sequence":"additional","affiliation":[{"name":"Centro Clinico per la Sclerosi Multipla, II Clinica Neurologica, II Universit\u00e0 di Napoli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Fantozzi","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Brescia Morra","sequence":"additional","affiliation":[{"name":"Centro Regionale Sclerosi Multipla, Unit\u00e0 Operativa Semplice, Azienda Ospedaliero Universitaria,  Policlinico Federico II, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs, Sapienza University of Rome, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Frau","sequence":"additional","affiliation":[{"name":"Multiple Sclerosis Center, Azienda Sanitaria Locale di Cagliari Department of Medical Science and Public Health, University of Cagliari, Cagliari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girolama Alessandra","family":"Marfia","sequence":"additional","affiliation":[{"name":"Unita Operativa Semplice Dipartimentale Sclerosi Multipla, Dipartimento Medicina dei Sistemi, Universit\u00e0 Tor Vergata, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia Teresa","family":"Maniscalco","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera di Rilievo Nazionale Antonio Cardarelli, Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Pia","family":"Amato","sequence":"additional","affiliation":[{"name":"Dipartimento NEUROFARBA, Sezione Neuroscienze, Universit\u00e0 degli Studi di Firenze, Centro Sclerosi Multipla SODc Riabilitazione Neurologica, Azienda Ospedaliero Universitaria Careggi, Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Di Sapio","sequence":"additional","affiliation":[{"name":"Regional Referral Multiple Sclerosis Centre, Department of Neurology,  University Hospital San Luigi Gonzaga, Orbassano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"De Luca","sequence":"additional","affiliation":[{"name":"Centro Sclerosi Multipla, Clinica Neurologica Policlinico SS. 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