{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T17:53:41Z","timestamp":1790963621568,"version":"4.1.0"},"reference-count":23,"publisher":"American Medical Association (AMA)","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2025,7,1]]},"abstract":"\n Importance<\/jats:title>\n Chronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n The Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H\n 1<\/jats:sub>\n -antihistamine treatment.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Patients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg\/d), twice per day (800 mg\/d), 3 times per day (1200 mg\/d), or matching placebo.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes<\/jats:title>\n The primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg\/d, vs placebo from baseline in ISS7 (least squares [LS] mean, \u22129.21 vs \u22125.77; difference, \u22123.44 [95% CI, \u22126.25 to \u22120.62];\n P<\/jats:italic>\n \u2009=\u2009.02) and UAS7 (LS mean, \u221216.89 vs \u221210.14; difference, \u22126.75 [95% CI, \u221212.23 to \u22121.26];\n P<\/jats:italic>\n \u2009=\u2009.02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein\u2013coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-\u03b5 receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg\/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H\n 1<\/jats:sub>\n -antihistamines. Further research is needed to determine long-term efficacy and potential harms.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT05107115<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamadermatol.2025.0733","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T11:30:54Z","timestamp":1745407854000},"page":"679","source":"Crossref","is-referenced-by-count":37,"title":["Rilzabrutinib in Antihistamine-Refractory Chronic Spontaneous Urticaria"],"prefix":"10.1001","volume":"161","author":[{"given":"Ana","family":"Gim\u00e9nez-Arnau","sequence":"first","affiliation":[{"name":"Hospital del Mar Research Institute, Universitat Pompeu Fabra, Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Ferrucci","sequence":"additional","affiliation":[{"name":"SC Dermatologia, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moshe","family":"Ben-Shoshan","sequence":"additional","affiliation":[{"name":"Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Centre, Montr\u00e9al, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Mikol","sequence":"additional","affiliation":[{"name":"Sanofi, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Lucats","sequence":"additional","affiliation":[{"name":"Sanofi, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris","family":"Sun","sequence":"additional","affiliation":[{"name":"Sanofi, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leda","family":"Mannent","sequence":"additional","affiliation":[{"name":"Sanofi, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Gereige","sequence":"additional","affiliation":[{"name":"Sanofi, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"2","key":"doi250013r1","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/all.15603","article-title":"Chronic spontaneous urticaria: focus on pathophysiology to unlock treatment advances.","volume":"78","author":"Kaplan","year":"2023","journal-title":"Allergy"},{"issue":"8","key":"doi250013r2","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.1007\/s13555-023-00955-7","article-title":"Chronic spontaneous urticaria: how to measure it and the need to define treatment success.","volume":"13","author":"Armstrong","year":"2023","journal-title":"Dermatol Ther (Heidelb)"},{"issue":"1","key":"doi250013r3","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s41572-022-00389-z","article-title":"Urticaria.","volume":"8","author":"Kolkhir","year":"2022","journal-title":"Nat Rev Dis Primers"},{"issue":"3","key":"doi250013r4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.2500\/aap.2023.44.230011","article-title":"Common but neglected problem in chronic spontaneous urticaria: sleep disturbance.","volume":"44","author":"Can","year":"2023","journal-title":"Allergy Asthma Proc"},{"issue":"1","key":"doi250013r5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s40360-023-00665-y","article-title":"The efficacy and safety of high-dose nonsedating antihistamines in chronic spontaneous urticaria: a systematic review and meta-analysis of randomized clinical trials.","volume":"24","author":"Xiao","year":"2023","journal-title":"BMC Pharmacol Toxicol"},{"issue":"3","key":"doi250013r6","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1111\/all.15090","article-title":"The international EAACI\/GA2LEN\/EuroGuiDerm\/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.","volume":"77","author":"Zuberbier","year":"2022","journal-title":"Allergy"},{"issue":"8","key":"doi250013r7","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1111\/all.15261","article-title":"Bruton\u2019s tyrosine kinase inhibition\u2014an emerging therapeutic strategy in immune-mediated dermatological conditions.","volume":"77","author":"Mendes-Bastos","year":"2022","journal-title":"Allergy"},{"issue":"5","key":"doi250013r8","doi-asserted-by":"publisher","first-page":"2400","DOI":"10.3390\/molecules28052400","article-title":"Bruton\u2019s tyrosine kinase inhibitors (BTKIs): review of preclinical studies and evaluation of clinical trials.","volume":"28","author":"Rozkiewicz","year":"2023","journal-title":"Molecules"},{"issue":"6","key":"doi250013r9","doi-asserted-by":"publisher","first-page":"1498","DOI":"10.1016\/j.jaci.2022.08.027","article-title":"Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria.","volume":"150","author":"Maurer","year":"2022","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"doi250013r10","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1007\/s40521-021-00286-y","article-title":"The use of Bruton\u2019s tyrosine kinase inhibitors to treat allergic disorders.","volume":"8","author":"Dispenza","year":"2021","journal-title":"Curr Treat Options Allergy"},{"issue":"1","key":"doi250013r11","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.anai.2024.03.002","article-title":"Bruton\u2019s tyrosine kinase inhibition for the treatment of allergic disorders.","volume":"133","author":"Lin","year":"2024","journal-title":"Ann Allergy Asthma Immunol"},{"issue":"2","key":"doi250013r12","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/j.jaci.2023.10.007","article-title":"Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks.","volume":"153","author":"Jain","year":"2024","journal-title":"J Allergy Clin Immunol"},{"issue":"7","key":"doi250013r13","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1111\/cts.13524","article-title":"Rilzabrutinib, a reversible covalent Bruton\u2019s tyrosine kinase inhibitor: absorption, metabolism, excretion, and absolute bioavailability in healthy participants.","volume":"16","author":"Ucpinar","year":"2023","journal-title":"Clin Transl Sci"},{"issue":"7","key":"doi250013r14","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.4049\/jimmunol.2001130","article-title":"Preclinical efficacy and anti-inflammatory mechanisms of action of the Bruton tyrosine kinase inhibitor rilzabrutinib for immune-mediated disease.","volume":"206","author":"Langrish","year":"2021","journal-title":"J Immunol"},{"issue":"11","key":"doi250013r15","doi-asserted-by":"publisher","first-page":"1961","DOI":"10.1038\/s41591-021-01537-w","article-title":"Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial.","volume":"27","author":"Metz","year":"2021","journal-title":"Nat Med"},{"issue":"3","key":"doi250013r16","doi-asserted-by":"publisher","first-page":"498","DOI":"10.4168\/aair.2021.13.3.498","article-title":"Elevated MRGPRX2 levels related to disease severity in patients with chronic spontaneous urticaria.","volume":"13","author":"Cao","year":"2021","journal-title":"Allergy Asthma Immunol Res"},{"issue":"18","key":"doi250013r17","doi-asserted-by":"publisher","first-page":"5957","DOI":"10.3390\/jcm12185957","article-title":"IL-31-pruritus interleukin: serum values and clinical impact in chronic spontaneous urticaria\u2014a Romanian retrospective study.","volume":"12","author":"Dobrican-Baru?a","year":"2023","journal-title":"J Clin Med"},{"key":"doi250013r18","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2021.639097","article-title":"Interleukin-31 signaling bridges the gap between immune cells, the nervous system and epithelial tissues.","volume":"8","author":"Nemmer","year":"2021","journal-title":"Front Med (Lausanne)"},{"issue":"4","key":"doi250013r19","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1111\/bjd.20431","article-title":"Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.","volume":"185","author":"Murrell","year":"2021","journal-title":"Br J Dermatol"},{"issue":"15","key":"doi250013r20","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1056\/NEJMoa2110297","article-title":"Rilzabrutinib, an oral BTK inhibitor, in immune thrombocytopenia.","volume":"386","author":"Kuter","year":"2022","journal-title":"N Engl J Med"},{"issue":"20","key":"doi250013r21","doi-asserted-by":"publisher","first-page":"6139","DOI":"10.3390\/jcm11206139","article-title":"Bruton\u2019s tyrosine kinase inhibitors: the next frontier of B-cell-targeted therapies for cancer, autoimmune disorders, and multiple sclerosis.","volume":"11","author":"Garg","year":"2022","journal-title":"J Clin Med"},{"issue":"5","key":"doi250013r22","doi-asserted-by":"publisher","first-page":"S230","DOI":"10.1016\/j.anai.2023.10.019","article-title":"Fast symptom improvement and favorable safety profile with remibrutinib in chronic spontaneous urticaria: REMIX-1\/-2 studies.","volume":"131","author":"Saini","year":"2023","journal-title":"Ann Allergy Asthma Immunol"},{"issue":"2","key":"doi250013r23","doi-asserted-by":"publisher","first-page":"AB366","DOI":"10.1016\/j.jaci.2023.11.873","article-title":"Barzolvolimab significantly decreases chronic spontaneous urticaria disease activity and is well tolerated: top line results from a phase 2 trial.","volume":"153","author":"Maurer","year":"2024","journal-title":"J Allergy Clin Immunol"}],"container-title":["JAMA Dermatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/articlepdf\/2833141\/jamadermatology_gimnezarnau_2025_oi_250013_1752181147.17467.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,16]],"date-time":"2025-07-16T15:00:39Z","timestamp":1752678039000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamadermatology\/fullarticle\/2833141"}},"subtitle":["The RILECSU Phase 2 Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,7,1]]},"references-count":23,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamadermatol.2025.0733","relation":{},"ISSN":["2168-6068"],"issn-type":[{"value":"2168-6068","type":"print"}],"subject":[],"published":{"date-parts":[[2025,7,1]]}}}