{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:15:16Z","timestamp":1787008516858,"version":"build-2736575974"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T00:00:00Z","timestamp":1754265600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013170","name":"Ono Pharmaceutical","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013170","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is an autoimmune connective tissue disease with a high risk of organ damage and mortality.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate whether tirabrutinib, an inhibitor of Bruton tyrosine kinase, is useful for treating SSc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This randomized double-arm 52-week phase I study investigated the safety, efficacy and putative mechanism of action of once-\u00addaily tirabrutinib in adults with SSc (Japan Registry of Clinical Trials jRCT2031200315). The primary endpoints were safety, including treatment-emergent adverse events (TEAEs), and pharmacokinetics. Exploratory efficacy endpoints included the modified Rodnan skin score (mRSS) and mechanism of action determined via immunophenotyping and RNA sequencing (RNAseq).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Sixteen patients were enrolled and treated with 40\u2005mg or 80\u2005mg tirabrutinib (n = 8 per group). All 16 patients experienced grade 1 or 2 TEAEs. Plasma tirabrutinib concentrations in steady-state conditions were within the expected ranges. The mean (SD) change in mRSS from baseline to week 52 was \u22124.0 (6.1) and \u22124.7 (3.6) in the 40-mg and 80-mg groups, respectively. The percentage of na\u00efve B cells tended to increase, and the percentages of nonswitched memory B cells, activated memory CD95+ B cells, and plasmablasts tended to decrease in both groups. Immunophenotyping and RNAseq suggested that suppression of B-cell activity was involved in the mechanism of action of tirabrutinib.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This study suggests that tirabrutinib is tolerable in patients with SSc and acts by suppressing B-cell activity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf168","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T11:47:49Z","timestamp":1753876069000},"page":"434-441","source":"Crossref","is-referenced-by-count":3,"title":["An open-label randomized parallel-group phase I study of the oral Bruton tyrosine kinase inhibitor tirabrutinib in systemic sclerosis"],"prefix":"10.1093","volume":"193","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6755-8047","authenticated-orcid":false,"given":"Kazuki 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