Annals of the Rheumatic Diseases最新文献

{"title":"GZMK⁺CD8⁺ T cells target a specific acinar cell type in Sjögren's disease.","authors":"Thomas J F Pranzatelli, Paola Perez, Anson Ku, Bruno Matuck, Khoa Huynh, Shunsuke Sakai, Mehdi Abed, Shyh-Ing Jang, Eiko Yamada, Kalie Dominick, Zara Ahmed, Amanda J Oliver, Rachael Bogle, Quinn T Easter, Alan N Baer, Eileen Pelayo, Zohreh Khavandgar, David E Kleiner, M Teresa Magone, Sarthak Gupta, Christopher Lessard, A Darise Farris, Peter D Burbelo, Daniel Martin, Robert J Morell, Changyu Zheng, Nicholas Rachmaninoff, Jose Maldonado-Ortiz, Katarzyna M Tyc, Xufeng Qu, Marit Aure, Mohammad H Dezfulian, Ross Lake, Sarah A Teichmann, Daniel L Barber, Lam C Tsoi, Adam G Sowalsky, Jinze Liu, Johann Gudjonsson, Kevin M Byrd, Philip L F Johnson, John A Chiorini, Blake M Warner","doi":"10.1016/j.ard.2025.08.014","DOIUrl":"10.1016/j.ard.2025.08.014","url":null,"abstract":"<p><strong>Objectives: </strong>Sjögren's disease (SjD) is a systemic autoimmune disorder characterized by dysfunction of exocrine glands, particularly the salivary and lacrimal glands, with no clear etiology or effective therapy. This study explores the complex interplay of varied cell types in the salivary glands and their role in the pathology of Sjögren's disease.</p><p><strong>Methods: </strong>Utilizing single-cell and spatial transcriptomics alongside spatial immunophenotyping to analyze human minor salivary glands, we developed a comprehensive understanding of the cellular landscape of non-SjD salivary glands and how that landscape changes in SjD patients. In vitro cellular assays and novel patient-derived primary epithelial cells were co-cultured with autologous T cells to confirm effector states and the delivery and effect of disease-associated granzymes.</p><p><strong>Results: </strong>We identified previously unrecognized heterogeneity among acinar cells, including a PRR4⁺CST3⁺WFDC2⁻ seromucous acinar population that is selectively lost in Sjögren's disease. Expression and organizational changes were linked to clinical features: (i) T cells in the glands of SSA⁺, high-focus score patients showed increased transcriptional signatures of activation, antigen presentation, and apoptosis resistance compared with patients with mild or moderate disease, and (ii) patients with low immune infiltration exhibited distinct epithelial organization. Notably, GZMK⁺CD8⁺ T cells, which accumulate with disease severity, displayed a cytotoxic transcriptional program, degranulated upon stimulation ex vivo, and localized spatially with immune-engaged epithelial cells. Functional assays demonstrated that GZMK activates interferon signaling in vitro, and autologous co-cultures of patient-derived T cells and epithelial cells validated these findings.</p><p><strong>Conclusions: </strong>Using single-cell and spatial transcriptomics and proteomics, this study identifies a selective loss of PRR4⁺CST3⁺WFDC2⁻ seromucous acinar cells and a rise in GZMK⁺CD8⁺ T cells in Sjögren's disease, revealing distinct immune-mediated epithelial remodeling and interferon-driven dysfunction across diverse clinical presentations. These findings uncover a novel sub-cytolytic effector mechanism by which GZMK⁺CD8⁺ T cells impair mitochondrial integrity and activate innate immune signaling, linking epithelial injury to type I interferon responses and offering new therapeutic targets.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"880-898"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12854051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic stratification predicts response to rituximab, abatacept, or the association of hydroxychloroquine and leflunomide in 3 randomised controlled clinical trials of Sjögren's disease.","authors":"Baptiste Chevet, Valérie Devauchelle-Pensec, Elena Pontarini, Valentin Baloche, Michele Bombardieri, Simon J Bowman, Michael Barnes, Antoine G Sreih, Jinqi Liu, Sheila Kelly, Antonia Christodoulou, Philippe Moingeon, Laurence Laigle, Perrine Soret, Christelle Le Dantec, Jacques-Olivier Pers, Marta E Alarcon-Riquelme, Guillermo Barturen, Xavier Mariette, Joel van Roon, Raphaèle Seror, Gaetane Nocturne, Divi Cornec, Nathan Foulquier","doi":"10.1016/j.ard.2025.11.017","DOIUrl":"10.1016/j.ard.2025.11.017","url":null,"abstract":"<p><strong>Objectives: </strong>Sjögren's disease (SjD) is clinically and biologically heterogeneous, and no immunomodulatory drug has yet demonstrated efficacy in phase 3 trials. We previously identified 4 transcriptomic endotypes in SjD patients using whole-blood RNA sequencing. We hypothesised that these endotypes may predict differential therapeutic responses.</p><p><strong>Methods: </strong>We analysed clinical, biological, and transcriptomic data from 3 randomised controlled trials evaluating hydroxychloroquine-leflunomide (HCQ-LEF; n = 18; RepurpSS-I trial), rituximab (RTX; n = 56; TRACTISS trial), and abatacept (n = 117). Patients were assigned to the 4 endotypes using semisupervised uniform manifold approximation and projection combined with a support vector machine model. Demographics, disease activity, and therapeutic response, as defined by the Sjögren Tool for Assessing Response index, were compared across clusters in both pooled and individual trial analyses.</p><p><strong>Results: </strong>Of 170 patients, 81, 24, 80, and 6 were classified into clusters 1 to 4, respectively. European Alliance of Associations for Rheumatology (EULAR) Sjögren's Syndrome Patient Reported Index scores were comparable across clusters, while the EULAR Sjögren's Syndrome Disease Activity Index was significantly higher in clusters 3 and 4 vs clusters 1 and 2 (P = .003). In pooled analyses, patients in cluster 1 had significantly greater response rates with active treatment vs placebo (61.5% vs 32.6%: P = .016), with a similar trend in the RTX trial. In contrast, patients in cluster 3 benefitted from HCQ-LEF, whereas cluster 2 (healthy-like patients) showed no significant response to any therapy.</p><p><strong>Conclusions: </strong>Transcriptomic stratification of SjD patients revealed differential responses to HCQ-LEF and RTX. Notably, healthy-like patients exhibited minimal treatment response, suggesting they may be unsuitable candidates for future therapeutic trials.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"873-879"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145832964","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":"Ultrasound localisation microscopy reveals mural neovascularisation to diagnose and track giant cell arteritis.","authors":"Tan Li, Yifei Gai, Chunyan Ma","doi":"10.1016/j.ard.2025.10.017","DOIUrl":"10.1016/j.ard.2025.10.017","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"955-957"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501487","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":"From the grey area of pre-systemic sclerosis to very early disease and irreversible tissue damage: the challenge of defining at-risk patients for future preventive trials in systemic sclerosis.","authors":"Alain Lescoat, Yannick Allanore, Francesco Del Galdo, Masataka Kuwana, Silvia Bellando-Randone, Christopher P Denton, Dinesh Khanna, Marco Matucci-Cerinic","doi":"10.1016/j.ard.2025.11.021","DOIUrl":"10.1016/j.ard.2025.11.021","url":null,"abstract":"<p><p>This viewpoint aims to explore whether precondition trials could be applied in systemic sclerosis (SSc)-the systemic autoimmune rheumatic disease (SARD) associated with the highest mortality and substantial morbidity. In contrast to type 1 diabetes and rheumatoid arthritis (RA), where predisease states have been more clearly defined, a consensus definition for pre-SSc is still lacking. A consensus framework for patients with signs and symptoms also common to other SARDs/connective tissue diseases, but that potentially identify a patient at a pre-SSc stage, needs to be collectively drafted. Such a framework would provide the basis for earlier recognition, risk stratification, and ultimately, timely intervention in pre-SSc. Considering the paradigm shift already achieved in type 1 diabetes and RA, a similar strategy targeting patients at risk of SSc could foster the development of innovative approaches to SSc management-preventing the onset of key SSc-related signs and symptoms, promoting long-term remission, and reducing SSc-related morbidity and mortality.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"781-786"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145826852","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 \"ChatGPT vs rheumatologists: cross-sectional study on accuracy and patient perception of AI-generated information for psoriatic arthritis\" by Forte et al.","authors":"Jiding Xie, Lei Shi, Jie Cui, Leiyong Wang, Jingang Dai","doi":"10.1016/j.ard.2025.12.016","DOIUrl":"https://doi.org/10.1016/j.ard.2025.12.016","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"85 5","pages":"e47-e48"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147855622","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":"Shared and unique molecular signatures across different autoantibody groups in systemic sclerosis: a multiomics analysis.","authors":"Wanyi Lin, Zhangyi Zhao, Chenhan Jia, Ruru Guo, Fenglin Wu, Chaoyu Gu, Rui Li, Yuankai Sun, Zhe Ding, Xuesong Liu, Aiting Wang, Xianting Ding, Liangjing Lu, Hanlin Yin","doi":"10.1016/j.ard.2025.11.020","DOIUrl":"10.1016/j.ard.2025.11.020","url":null,"abstract":"<p><strong>Objectives: </strong>Each autoantibody associated with systemic sclerosis (SSc) is linked to distinct clinical features, suggesting underlying molecular heterogeneity. Although studies have characterised molecular signatures in anticentromere (ACA), antitopoisomerase I (ATA), and anti-RNA polymerase III (ARA) antibodies in patients who are SSc-positive, less frequent autoantibody groups remain unexplored. Our study employed multiomics analysis to identify shared and unique molecular profiles across SSc-associated autoantibody subgroups.</p><p><strong>Methods: </strong>We enrolled 166 patients with SSc stratified by antibody status (ACA = 55, ATA = 58, ARA = 24, anti-U1 ribonucleoprotein [U1RNP] = 12, anti-U3 ribonucleoprotein [U3RNP] = 8, anti-Ku [Ku] = 4, and anti-Th/To [Th/To] = 5). We performed multiomics profiling, including plasma proteomics, peripheral blood mononuclear cells (PBMCs) transcriptomics, immune cell phenotyping, and plasma metabolomics to identify shared and distinct features across groups.</p><p><strong>Results: </strong>All SSc subsets demonstrated common pathogenic features, including endothelial injury, extracellular matrix deposition identified by plasma proteomics, upregulated type I interferon (IFN) signalling revealed by transcriptomic analysis, and decreased regulatory B cells observed by immune cell profiling. Meanwhile, each autoantibody subgroup exhibited unique disease mechanisms, such as calcinosis in ACA-positive patients, metabolic oxidative stress in ATA-positive patients, activation of oncogenic signalling in ARA-positive patients, enhanced chromatin remodelling activity in U1RNP-positive patients, muscle involvement in U3RNP/Ku groups, and unique metabolic signalling related to pulmonary hypertension in Th/To-positive cases.</p><p><strong>Conclusions: </strong>Our study addresses a critical gap by providing a comprehensive multiomics characterisation of both common and rare SSc-associated autoantibody groups, revealing shared and distinct molecular signatures that correlate with clinical features. Our findings highlight the potential for autoantibody-based stratification to guide precision management of SSc, paving the way for biomarker-driven approaches in SSc care.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"899-910"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793044","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":"An unusual cause of lumbar back pain.","authors":"Ying Cai, Fan Yang, Chong Chen, Xian-Zheng Tan","doi":"10.1016/j.ard.2025.10.027","DOIUrl":"10.1016/j.ard.2025.10.027","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"953-954"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534201","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 to: 'Post hoc comparison of the effectiveness of tocilizumab, rituximab, mycophenolate mofetil, and cyclophosphamide in patients with SSc-ILD from the EUSTAR database'.","authors":"Yan-Li Yang, Rong-Hong Guo, James Cheng-Chung Wei, Li-Yun Zhang","doi":"10.1016/j.ard.2025.04.026","DOIUrl":"10.1016/j.ard.2025.04.026","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"e51-e52"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144332369","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":"CD40-CD40L inhibition attenuates platelet-neutrophil interaction and neutrophil extracellular trap release in primary antiphospholipid syndrome.","authors":"Stavros Naoum, Charilaos Spyropoulos, Andriani Angelopoulou, Harikleia Gakiopoulou, Michalis Katsimpoulas, Vassilis G Gorgoulis, Petros P Sfikakis, Konstantinos Ritis, Ioanna-Evdokia Galani, Konstantinos Kambas, Maria G Tektonidou","doi":"10.1016/j.ard.2025.12.012","DOIUrl":"10.1016/j.ard.2025.12.012","url":null,"abstract":"<p><strong>Objectives: </strong>Neutrophil extracellular traps (NETs) are increasingly recognised for their role in primary antiphospholipid syndrome (PAPS) pathogenesis. Herein, we examined underlying mechanisms driving NET formation and the thrombogenic effects of NETs in patients with PAPS, along with potential inhibitors.</p><p><strong>Methods: </strong>We examined NET release in PAPS, asymptomatic antiphospholipid autoantibodies (aPLs) carriers, and healthy controls (HCs) as well as NET-bound proteins by immunofluorescence, immunoblotting, quantitative polymerase chain reaction (PCR), and enzyme-linked immunosorbent assay (ELISA). We assessed platelet-neutrophil aggregates by flow cytometry (CD61/CD66b staining) and autophagy using LC3B immunofluorescence and immunoblotting. Immunofluorescence was performed in paraffin-embedded kidney, skin ulcer, and endoarterial thrombus tissues from patients with PAPS. Suppression of NET release via CD40-CD40L inhibition was tested in in vitro and venous thrombosis mouse models.</p><p><strong>Results: </strong>Neutrophils from patients with PAPS exhibited increased NET release compared with asymptomatic aPL carriers and HCs. NETs from patients with PAPS expressed tissue factor (TF) that induced thrombin generation in platelet-poor plasma from HCs. aPL induced in vitro intracellular TF expression in HC neutrophils. TF-expressing NETs were abundant in the kidney, skin ulcer, and endoarterial thrombus tissues from patients with PAPS, and colocalised with fibrinogen. NET release in PAPS neutrophils was driven by aPL-mediated platelet activation, subsequent platelet-neutrophil interaction, and autophagy induction. CD40-CD40L blockade reduced platelet activation, autophagy, and NET formation in patients with PAPS. In a mouse model, inhibition of CD40-CD40L reduced neutrophil-platelet aggregates and myeloperoxidase (MPO)-DNA complexes in mouse peripheral blood, and the presence of NETs in the formed thrombi.</p><p><strong>Conclusions: </strong>Targeting the platelet-neutrophil/autophagy/TF-expressing NETs axis by CD40-CD40L inhibition attenuates thromboinflammation in PAPS and should be explored as a potential therapeutic target.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"858-872"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028243","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":"Effects of clofutriben, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, on the efficacy and toxicity of prednisolone in patients with polymyalgia rheumatica: a single-blind controlled trial with sequential cohorts.","authors":"Frank Buttgereit, Andrea Everding, Ioana Andreica, Herbert L Kellner, Florian Schuch, Cornelia Weyand, Paul M Stewart, Peter A Merkel, Christian Dejaco, Frank S Czerwiec, Ketan Desai, David A Katz","doi":"10.1016/j.ard.2025.10.015","DOIUrl":"10.1016/j.ard.2025.10.015","url":null,"abstract":"<p><strong>Objectives: </strong>Glucocorticoids effectively treat many diseases, but toxicity limits their utility. We aimed to learn whether, by reducing active intracellular glucocorticoid exposures, the 11β-hydroxysteroid dehydrogenase type 1 inhibitor clofutriben could selectively reduce glucocorticoid efficacy but reduce toxicity more strongly. We hypothesised that by increasing the prednisolone dose, it might be possible to restore efficacy back to the original level, thereby improving the benefit-risk profile.</p><p><strong>Methods: </strong>In sequential cohorts, adults with polymyalgia rheumatica received (single blind) prednisolone 10 mg/d with placebo for 2 weeks, then clofutriben with either prednisolone 10, 15, 20, or 30 mg/d for 2 weeks.</p><p><strong>Results: </strong>Forty-nine and 47 participants completed each trial period with evaluable data. Five who received prednisolone 10 mg/d with clofutriben experienced clinical relapse. No clinical relapses occurred during other treatments. Participants reported more severe symptoms and physical disability when prednisolone 10 mg/d or 15 mg/d, but not 20 mg/d or 30 mg/d, was given with clofutriben. Inflammatory biomarkers followed a similar pattern. Across all prednisolone doses, clofutriben coadministration mitigated glucocorticoid-related adverse effects on biomarkers of bone turnover, lipid metabolism, hypercoagulability, and cardiovascular and adrenal function.</p><p><strong>Conclusions: </strong>Further trials to assess clofutriben's potential to improve the benefit-risk profile of prednisolone are warranted.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":"921-931"},"PeriodicalIF":20.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145501543","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}