Annals of the Rheumatic Diseases最新文献

{"title":"Correspondence on: 'CD19-CAR T-cell therapy induces deep tissue depletion of B cells' by Tur et al.","authors":"Cary M Looney, Elsa Martins, Thomas Schindler, Rachel Jones","doi":"10.1016/j.ard.2025.08.030","DOIUrl":"https://doi.org/10.1016/j.ard.2025.08.030","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthy human enthesis stromal cells mediate immunoregulation via the CD39/CD73 adenosine ectonucleotidase pathway.","authors":"Ala Altaie, Davide Simone, Nicole McDermott, Heather Owston, Moustafa Attar, Liying Jin, Chi Wong, Peter R Loughenbury, Borse Vishal, Tristan McMillan, Christopher D Buckley, Stephen N Sansom, Dennis McGonagle","doi":"10.1016/j.ard.2025.09.001","DOIUrl":"https://doi.org/10.1016/j.ard.2025.09.001","url":null,"abstract":"<p><strong>Objectives: </strong>Entheseal inflammation (ligament and tendon insertions) and subclinical intestinal inflammation are both hallmarks of the seronegative spondyloarthropathy (SpA) diseases. While regulatory T cells (Tregs) are key to intestinal homeostasis, entheseal homeostatic mechanisms are poorly understood in humans.</p><p><strong>Methods: </strong>Single-cell RNA sequencing of entheseal tissue, comparative transcriptomic analysis with intestinal tissue datasets, and functional analysis of entheseal stromal populations were undertaken. Functional immunomodulation by entheseal mesenchymal stromal cells (MSCs) was evaluated via coculture with activated T cells. CD39/CD73 pathway involvement was confirmed using pharmacological inhibition and transcriptional profiling.</p><p><strong>Results: </strong>Single-cell RNA sequencing of 27,348 entheseal cells revealed a lower frequency of Tregs in the T cells of the enthesis (2.60% ± 0.36%) compared to those of the ileum (7.37% ± 4.47%) and colon (18% ± 8.59%). We found that entheseal fibroblasts expressed key immunomodulatory markers, including CD39 (ENTPD1) and CD73 (NT5E), which were further upregulated upon coculture with activated T cells. Entheseal MSCs significantly suppressed T cell proliferation (up to 89%, P < .0001) in an adenosine-dependent manner. Transcriptional profiling revealed that entheseal MSC cocultured with activated T cells upregulated genes of known functional importance in Treg, including IL10, IDO1, PTGS2, HLA-G, and CD274. In this assay, dual CD39/CD73 inhibition restored T cell proliferation by ∼48% (P = .0004), confirming that entheseal MSC-mediated immunomodulation acts in part through an adenosine-mediated mechanism.</p><p><strong>Conclusions: </strong>The normal spinal enthesis harbours an immunoregulatory cellular environment related to entheseal MSCs that utilises the CD39/CD73 adenosine ectonucleotidase axis that may help maintain local immune homeostasis, while the same adenosine ectonucleotidase immunoregulatory pathway is likely dependent on Treg function in the intestine. This has broad implications for understanding the cellular bases of immune dysregulation in the gut-joint axis and could help guide tissue-specific therapy in SpA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced proteasome activity in perifascicular myofibres is a hallmark of dermatomyositis and its inhibition is efficient in preclinical models.","authors":"Léa Debrut, Margherita Giannini, Giulia Quiring, Simone Perniola, Daniela Rovito, Céline Keime, Béatrice Lannes, Aleksandra Nadaj-Pakleza, Jean-Baptiste Chanson, Anne-Laure Charles, Bernard Geny, Daniel Metzger, Gilles Laverny, Alain Meyer","doi":"10.1016/j.ard.2025.08.031","DOIUrl":"https://doi.org/10.1016/j.ard.2025.08.031","url":null,"abstract":"<p><strong>Objectives: </strong>This study aims to characterise the molecular pathways underpinning perifascicular muscle fibre alterations to identify repositionable molecules for dermatomyositis (DM) treatment, and validate potential candidates in preclinical models.</p><p><strong>Methods: </strong>RNA-sequencing was performed to determine the transcriptome of microdissected peri- and endofascicular myofibres from 7 patients with untreated and early DM (symptoms <6 months), 6 with other inflammatory myopathies and 5 without neuromuscular disease. The molecular pathways characterising DM perifascicular fibres were determined and used to explore databases of repositionable drugs. The top candidate molecule was validated in cellular and animal preclinical models.</p><p><strong>Results: </strong>Microdissected myofibre transcriptomic analysis revealed that upregulation of the proteasome pathway, prevailing in perifascicular myofibres, is a hallmark of DM. Immunostaining experiments conducted in a validation cohort showed that in patients with DM, β5i (encoded by PSMB8) was predominantly expressed in the cytoplasm of muscle fibres within the perifascicular region, which also predominantly expressed MxA and HLA-I. Experiments in human myotubes showed that interferon (IFN)-β enhances the expression of proteasome catalytic subunit β5i and chymotrypsin-like activity in myofibres. Computational drug repurposing analysis based on the DM perifascicular myofibre transcriptomic signature identified ixazomib (a proteasome inhibitor) as the drug with the highest therapeutic potential. In human myotubes, ixazomib prevented IFN-β-induced DM-like lesions (atrophy, major histocompatibility complex class I [MHC-I] expression and mitochondrial dysfunctions) without impacting the expression of interferon-stimulated genes (ISGs). Moreover, experimental myositis (EM) mice treated with ixazomib recovered muscle strength and normalised serum creatine kinase levels. While ISG expression was unchanged in muscles of ixazomib-treated EM mice, sarcolemmal MHC-I expression was abolished, myofibre size variability was normalised, and inflammatory infiltrate was decreased.</p><p><strong>Conclusions: </strong>Enhanced proteasome activity in perifascicular myofibres is a hallmark of DM; its inhibition, deemed effective in preclinical models, may represent a new therapeutic strategy for this disease.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Innate immune cell subsets are enriched in synovial fluid of ACPA-negative rheumatoid arthritis and characterized by distinct type I IFN gene signatures.","authors":"Alexandra Argyriou, Marc H Wadsworth, Joshua Fienman, Ana Cristina Gonzalez-Sanchez, Salim Ghannoum, Chirag Krishna, Christina Gerstner, Begum Horuluoglu, Merel Sijbranda, Lars Rönnblom, Maija-Leena Eloranta, Marie Wahren-Herlenius, Aase Hensvold, Sara Turcinov, Aaron Winkler, Vivianne Malmström, Karine Chemin","doi":"10.1016/j.ard.2025.07.029","DOIUrl":"https://doi.org/10.1016/j.ard.2025.07.029","url":null,"abstract":"<p><strong>Objectives: </strong>Around 30% of patients with rheumatoid arthritis (RA) lack rheumatoid factor and anti-citrullinated protein antibodies (ACPA) complicating diagnosis and potentially delaying treatment. We hypothesised that innate immune mechanisms might be more prominent in ACPA- RA.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing of mononuclear cells from peripheral blood (PBMC) and synovial fluid (SFMC) of patients with ACPA- and ACPA+ RA (n = 4 per group: discovery cohort; n = 8 per group: validation cohort). Dendritic cells and proinflammatory cytokine production were analysed by flow cytometry on SFMC from patients with ACPA- RA, ACPA+ RA, and psoriatic arthritis. Interferon (IFN) levels in synovial fluid (SF) and serum were measured in these groups.</p><p><strong>Results: </strong>Several macrophage subsets and cDC2 were enriched in ACPA- RA SF whereas the frequency of Tph and B cells was increased in ACPA+ RA SF. Type I IFN-stimulated genes were detected in SFMC, but not PBMC, of patients with ACPA- RA. A type I IFN signature was also observed in synovial tissue from two patients with ACPA- RA in an independent dataset. IFN levels were higher in SF than serum but IFN-α/β production did not differ between ACPA+ and ACPA- RA.</p><p><strong>Conclusions: </strong>This study identifies a distinct innate cell composition and type I IFN gene response in synovial joints, but not in peripheral blood, of patients with ACPA- RA. Similar IFN levels across groups suggest the IFN signature may have been primed before the cells entered the joints. These findings provide a foundation for future research on type I IFN responses in ACPA- RA.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.6,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antimitochondrial antibodies in systemic sclerosis target enteric neurons and are associated with GI dysmotility.","authors":"Zsuzsanna H McMahan, Srinivas N Puttapaka, Livia Casciola-Rosen, Timothy Kaniecki, Laura Gutierrez-Alamillo, Su Hong Ming, Philippa Seika, Subhash Kulkarni","doi":"10.1016/j.ard.2025.06.2119","DOIUrl":"10.1016/j.ard.2025.06.2119","url":null,"abstract":"<p><strong>Objectives: </strong>Most patients with systemic sclerosis (SSc) experience gastrointestinal (GI) dysmotility. The enteric nervous system (ENS) regulates GI motility, and its dysfunction causes dysmotility. A subset of SSc patients harbour antimitochondrial M2 autoantibodies (AM₂A). Here, we investigate whether M2 is expressed by specific ENS cells, and if AM₂A are associated with GI dysmotility in SSc patients.</p><p><strong>Methods: </strong>Sera from 154 well-characterised patients with SSc were screened for AM₂A by enzyme-linked immunosorbent assay. Clinical features and GI transit data were compared between AM₂A-positive and AM₂A-negative patients. Hepatocellular carcinoma cell line 2 (HepG2) cells were cultured with these sera and costained with AM₂A.</p><p><strong>Results: </strong>Nineteen of 147 patients (12.9%) were AM₂A-positive. AM₂A positivity was significantly associated with slower transit in the oesophagus (β -14.4, 95%CI, -26.2, -2.6) and stomach (β -7.9, 95% CI, -14.1, -1.6). Immunostaining demonstrated pan-mitochondrial antigens TOM-20 and M2 enrichment in human ENS neurons, specifically in mesoderm-derived enteric neurons (MENS). Autoantibodies in SSc sera penetrated live adult murine MENs and HepG2 cells when adult murine longitudinal muscle containing myenteric plexus tissue and HepG2 cells were cultured in the presence of SSc sera. Upon penetrating live cells, AM₂A localised to mitochondria, and immunoprecipitation demonstrated binding to the M2 antigen. Seahorse assays show that penetration of HepG2 cells with SSc-AM₂A altered cellular respiration suggesting that penetrating AM₂A is pathogenic.</p><p><strong>Conclusions: </strong>AM₂A in SSc patients are associated with slower GI transit. SSc autoantibodies penetrate live cells in vitro, and SSc-AM2A penetrates live cells to target the mitochondrial M2 antigen and cause functional deficits. Because a subset of enteric neurons (MENs) is enriched in mitochondria, which are similarly penetrated by SSc-AM₂A in vitro, the presence of GI dysmotility in SSc patients harbouring AM₂A suggests that SSc-AM₂A may penetrate MENs in vivo, driving ENS and GI dysfunction. Further studies are warranted to test how AM₂A alter ENS functions in vivo to contribute to GI dysmotility in SSc.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1721-1732"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144526220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Collagen-binding integrin α11β1 contributes to joint destruction in arthritic hTNFtg mice.","authors":"Anna De Giuseppe, Adrian Deichsel, Alina Reese, Simon Kleimann, Deniz Wawersig, Isabel Zeinert, Kerstin K Rauwolf, Denise Beckmann, Uwe Hansen, Jordana Miranda de Souza Silva, Annika Krause, Beate Eckes, Daniel Kronenberg, Corinna Wehmeyer, Berno Dankbar, Ning Lu, Donald Gullberg, Thomas Pap, Adelheid Korb-Pap","doi":"10.1016/j.ard.2025.07.011","DOIUrl":"10.1016/j.ard.2025.07.011","url":null,"abstract":"<p><strong>Objectives: </strong>In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) acquire an aggressive, tumour-like phenotype characterised by increased adhesion to extracellular matrix, contributing to joint degradation. The collagen-binding integrin alpha11beta1 is involved in similar processes in cancer-associated fibroblasts, but its role in RA and arthritic mice remains unclear.</p><p><strong>Methods: </strong>Integrin α11 expression was analysed in synovial tissue and FLS from RA and osteoarthritis patients and human tumour necrosis factor transgenic (hTNFtg) and wild-type mice supported by Accelerating Medicines Partnership Rheumatoid Arthritis and Pathobiology of Early Arthritis Cohort data. A novel 3-dimensional (3D) organoid coculture model and electron microscopy were used to analyse FLS invasion into cartilage explants, Itga11^-/- were crossed with hTNFtg mice, and disease severity was evaluated using microcomputed tomography (µCT) and histology. Functional assays using FLS included cell morphology, adhesion, degradation, and matrix metalloproteinase expression and were complemented by osteoclast and coculture studies.</p><p><strong>Results: </strong>In the context of RA, strong α11 expression was detected in the synovium, particularly in sublining clusters of FLS within fibroid-type synovial tissue in vivo and at focal adhesions of arthritic FLS and at invasion sites within the 3D coculture model in vitro. Clinical scores, µCT imaging, and histomorphological analyses revealed significantly reduced cartilage degradation, bone erosions, and FLS attachment to cartilage in Itga11^-/-hTNFtg compared to hTNFtg mice. In vitro studies revealed that α11 deficiency led to a decreased receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio along with reduced TNFα-induced proteolytic degradation activity, and signalling pathway activation.</p><p><strong>Conclusions: </strong>Integrin α11 levels are increased in RA, and its deficiency notably diminishes joint destruction in hTNFtg mice, emphasising its potential as promising therapeutic target.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1649-1659"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144858857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correspondence on 'Radiographic structural damage in axial spondyloarthritis: is there a preferred way to quantify progression over time? Comparison of blinded versus unblinded mSASSS scoring' by Protopopov et al.","authors":"Robert B M Landewé, Desiree van der Heijde","doi":"10.1016/j.ard.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.ard.2025.07.013","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 10","pages":"e45-e46"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to the correspondence on \"Radiographic structural damage in axial spondyloarthritis: is there a preferred way to quantify progression over time?\"","authors":"Xenofon Baraliakos, Mikhail Protopopov, Joachim Sieper, Juergen Braun, Martin Rudwaleit, Denis Poddubnyy","doi":"10.1016/j.ard.2025.08.004","DOIUrl":"https://doi.org/10.1016/j.ard.2025.08.004","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 10","pages":"e47-e49"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Frontoparietal functional connectivity is related to active disease and processing speed in adolescents with childhood-onset lupus.","authors":"Diana Valdés Cabrera, Oscar Mwizerwa, Busi Zapparoli, Asha Jeyanathan, Lawrence Ng, Tala El Tal, Birgit Ertl-Wagner, Ann Yeh, Helen Branson, Adrienne Davis, Linda Hiraki, Deborah Levy, Ashley Danguecan, Andrea Knight","doi":"10.1016/j.ard.2025.06.2129","DOIUrl":"10.1016/j.ard.2025.06.2129","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate brain functional connectivity (FC) with resting-state magnetic resonance imaging (rs-fMRI) in adolescents with childhood-onset systemic lupus erythematosus (cSLE) compared to healthy controls (HCs) and to evaluate associations among FC, disease characteristics, and cognitive performance.</p><p><strong>Methods: </strong>Patients with cSLE aged 11 to 17 years, and age- and sex-matched HCs, underwent rs-fMRI at 3T and clinical (current and cumulative cSLE activity and glucocorticoid dose, anti-dsDNA positivity, nephritis diagnosis) and cognitive (attention, working memory, processing speed, inhibition) data collection. Group differences in FC between brain regions of interest (ROI) within/across resting-state networks as well as associations between FC and clinical and cognitive variables were evaluated with age-adjusted general linear models. Analyses were corrected for multiple comparisons with family-wise error (FWE) methods (threshold-free cluster enhancement P-FWE < .05, individual pairs of ROI connections P < .01).</p><p><strong>Results: </strong>Participants included 60 patients (14.9 ± 1.84 years, 52 females) with cSLE and 59 HCs. Patients had lower FC compared to HCs in frontoparietal connections that were exacerbated in subgroups with active cSLE features (all P-FWE ≤ .049). In cSLE patients, lower FC in frontocerebellar connections were associated with higher cumulative disease activity and glucocorticoid use (P-FWE ≤ .018). Positive associations were found between FC in frontoparietal-occipital connections and processing speed scores in cSLE patients (P-FWE = .010) but not in HCs.</p><p><strong>Conclusions: </strong>Adolescents with cSLE, compared to HCs, exhibited lower brain FC in frontoparietal regions of the dorsal attention and somatosensory regions, which was associated with greater disease activity. Higher FC in frontoparietal-occipital regions, critical for visual attention, was associated with better processing speed, which could be compensatory to disease effects.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1684-1695"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Highly selective tyrosine kinase 2 inhibition with zasocitinib (TAK-279) improves outcomes in patients with active psoriatic arthritis: a randomised phase 2b study.","authors":"Alan Kivitz, Xenofon Baraliakos, Elena Tomaselli Muensterman, Arthur Kavanaugh, Désirée van der Heijde, Piotr A Klimiuk, Guillermo Valenzuela, Eva Dokoupilova, Gabrielle Poirier, Bhaskar Srivastava, Sue Dasen, Xinyan Zhang, Ting Hong, Jingjing Chen, Peter Pothula, Haoling Holly Weng, Mona Trivedi, Apinya Lertratanakul","doi":"10.1016/j.ard.2025.05.023","DOIUrl":"10.1016/j.ard.2025.05.023","url":null,"abstract":"<p><strong>Objectives: </strong>To assess the efficacy, safety, and tolerability of the investigational, oral, allosteric, highly selective, and potent tyrosine kinase 2 inhibitor zasocitinib (TAK-279) in patients with active psoriatic arthritis (PsA).</p><p><strong>Methods: </strong>In this phase 2b, randomised, multicentre, double-blind, placebo-controlled, multiple-dose study, patients (≥18 years, with PsA symptoms for ≥6 months) received 30 mg, 15 mg, or 5 mg zasocitinib or placebo (1:1:1:1) once daily for 12 weeks, with a 4-week safety follow-up. The primary endpoint was American College of Rheumatology (ACR)20 response at week 12. Secondary efficacy endpoints included ACR50 response, ACR70 response, Psoriasis Area and Severity Index (PASI) 75 response among those with ≥3% body surface area at baseline and minimal disease activity (MDA) at week 12.</p><p><strong>Results: </strong>Overall, 290 patients (mean [SD] age, 49.9 [11.6] years; 57.2% female) received treatment. At week 12, 30 mg or 15 mg zasocitinib treatment resulted in significantly higher ACR20 responses (54.2%; P = .002 and 53.3%; P = .002, respectively) than placebo (29.2%). A numerically higher number of ACR50 responses were achieved at week 12 with 30 mg (26.4%; nominal P = .009) or 15 mg (26.7%; nominal P = .005) zasocitinib than placebo (9.7%). In addition, 30 mg zasocitinib demonstrated a numerically higher number of ACR70 responses (13.9% versus 5.6%, respectively; nominal P = .158), PASI 75 responses (45.7% versus 15.4%, respectively; nominal P = .002), and MDA (29.2% versus 12.5%, respectively; nominal P = .014) at week 12 versus placebo. In this small study of limited duration, most adverse events were mild/moderate and were more frequently observed in the higher dose group. In this small sample size, no new safety signals or clear dose-dependent laboratory parameter changes were identified.</p><p><strong>Conclusions: </strong>Here, 30 mg and 15 mg zasocitinib demonstrated efficacy across core domains in patients with active PsA with no new safety signals. These findings will be confirmed in ongoing larger studies of longer duration.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"1660-1674"},"PeriodicalIF":20.6,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}