Annals of the Rheumatic Diseases最新文献

{"title":"Correspondence on: 'EULAR recommendations for the treatment of systemic sclerosis: 2023 update' by Del Galdo et al.","authors":"Alper Sari, Ali Akdogan","doi":"10.1016/j.ard.2024.10.001","DOIUrl":"https://doi.org/10.1016/j.ard.2024.10.001","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397802","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":"Efficacy of Janus kinase inhibitors in immune-mediated inflammatory diseases-a systematic literature review informing the 2024 update of an international expert consensus statement.","authors":"Victoria Konzett, Josef S Smolen, Peter Nash, Daniel Aletaha, Kevin Winthrop, Thomas Dörner, Roy Fleischmann, Yoshiya Tanaka, Jette Primdahl, Xenofon Baraliakos, Iain B McInnes, Michael Trauner, Naveed Sattar, Maarten de Wit, Jan W Schoones, Andreas Kerschbaumer","doi":"10.1016/j.ard.2025.01.023","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.023","url":null,"abstract":"<p><strong>Objective: </strong>This systematic literature review (SLR) on efficacy outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi).</p><p><strong>Methods: </strong>An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For efficacy, randomised, placebo (PLC)- or active-controlled trials on all JAKi investigated in IMIDs, as well as cohort and claims data for conditions where such studies were not available, were included.</p><p><strong>Results: </strong>In total, 10,556 records were screened, and 182 articles were included in the final analysis, investigating 21 JAKi in 51 IMIDs. Forty-three phase 2 and 59 phase 3 trials as well as 9 strategic trials and 72 pilot or cohort studies and case series were considered. JAKi demonstrated efficacy both in PLC-controlled trials as well as in head-to-head comparisons against active comparators, with 93 of 102 randomised controlled trials (RCTs) meeting their primary endpoints. Since 2019, 8 JAKi have received approval by the Federal Drug Agency and the European Medicine Agency for treatment of 11 IMIDs; of these, for 2, no approved disease-modifying antirheumatic drug (DMARD) therapy had previously been available.</p><p><strong>Conclusions: </strong>JAKi are effective for treating IMIDs, and various compounds have recently been approved. The impact of Janus kinase (JAK) selectivity for distinct JAK-STAT pathways needs further investigation, and few data are also available on sustained disease control upon tapering or withdrawal or on the optimal strategic placement of JAKi in international treatment algorithms.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397805","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":"AI-driven histologic analysis of human Achilles tendinopathy provides a roadmap to unravel pathogenesis.","authors":"Guillaume Planckaert, Arne Burssens, Flore Stappers, Julie Coudenys, Sofía Demolder, Irem Kaya, Malaïka Van der Linden, Amanda Gonçalves, Kelly Lemeire, Benjamin Pavie, Edwin Van Ovost, Peter Burssens, Amber Vanhaecke, Jo Van Dorpe, Lauren Pringels, Evi Wezenbeek, Jess Snedeker, Katrien De Bock, Fiona Bonar, Jill Cook, Jan Victor, Dirk Elewaut, Eric Gracey","doi":"10.1016/j.ard.2025.01.027","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.027","url":null,"abstract":"<p><strong>Objectives: </strong>Achilles tendinopathy is a common source of pain and dysfunction, yet its pathogenesis remains poorly understood. Research on human tendons is hampered by lack of standardisation in tissue sample validation, making interpretation of results challenging. We sought to develop an automated and operator-independent approach to histologically score human tendons.</p><p><strong>Methods: </strong>We assembled a cohort of 15 tendinopathic and 10 normal control Achilles tendon samples. We stained longitudinal sections with haematoxylin and eosin and Alcian blue and developed a low temperature epitope-retrieval protocol for immunostaining of blood vessels. Histologic sections were scored by pathologists using the current gold standard Bonar score. Whole sections were then analysed with open-source software (QuPath). Histologic features were automatically quantified across the entire section and summarised in the BonAIr score. Tissue from the same patients was subsequently analysed by quantitative polymerase chain reaction and flow cytometry to validate elements of the BonAIr score.</p><p><strong>Results: </strong>We observed increased cell roundness, collagen disarrangement, ground substance, and vascularity in tendinopathy using both the Bonar and BonAIr scores. Increased cellularity was only detected by the BonAIr score. Cellular and transcriptomic analyses corroborated tendinopathic shifts in all elements of the BonAIr score and further identified elevated THY1/CD90 expression in tendinopathy. CD90⁺ cells were found to localise to areas of low collagen alignment. These results align with the concept of stromal cell dysregulation in tendinopathy.</p><p><strong>Conclusions: </strong>Automated analysis of whole tendon sections refines conventional histopathologic scoring and predicts cellular and molecular changes found in tendinopathy. The BonAIr score should be further developed for standardised assessment of tendons samples across other anatomical locations and different research centres.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373756","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":"The giant cell arteritis (GCA) ultrasound score (OGUS) at diagnosis and after initial treatment predicts future relapses in GCA patients: results of a multicentre prospective study.","authors":"Sara Monti, Cristina Ponte, Valentin S Schäfer, Davide Rozza, Carlo Scirè, Giulia Franchi, Alessandra Milanesi, Nikita Khmelinskii, Simon M Petzinna, Greta Carrara, Cristina Di Nicola, João Eurico Fonseca, Carlomaurizio Montecucco, Wolfgang A Schmidt, Christian Dejaco, Raashid A Luqmani","doi":"10.1016/j.ard.2025.01.018","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.018","url":null,"abstract":"<p><strong>Objectives: </strong>To test the prognostic role of ultrasonography at diagnosis of giant cell arteritis (GCA) and the change of ultrasound abnormalities during the initial weeks of follow-up for the prediction of relapse, vascular complications, or initiation of disease-modifying antirheumatic drugs (DMARDs).</p><p><strong>Methods: </strong>Prospective, multicentre study of patients with new onset GCA undergoing serial ultrasound assessment at fixed time points. The Outcome Measures in Rheumatology (OMERACT) GCA ultrasonography score (OGUS) was used to quantify vessel wall abnormalities. Relapse was defined as recurrence of GCA-related symptoms or rise of inflammatory markers requiring treatment. A multivariable Poisson model with robust variance estimator was applied, including age, sex, large vessel GCA, glucocorticoid cumulative dose, and baseline OGUS as covariates.</p><p><strong>Results: </strong>Ninety-seven patients were assessed in 849 visits. Thirty-five (36.1%) patients experienced a total of 66 relapses, with median time to relapse of 210 days (IQR, 94.5-323.5). Higher OGUS at diagnosis was associated with an increased risk of relapse within 12 months (incidence rate ratio [IRR] for each 1 point increase in OGUS: 1.85; 95% CI, 1.05-3.32). At multivariable analysis, OGUS normalisation (score <1) over the first 3 weeks was negatively associated with subsequent relapses (IRR, 0.44; 95% CI, 0.22-0.88) and predicted time to first relapse. OGUS reduction over the first 12 weeks was inversely associated with initiation of DMARDs. Ischaemic/aortic complications were rare.</p><p><strong>Conclusions: </strong>Ultrasonography has a prognostic role in GCA and can inform risk stratification. Higher OGUS at diagnosis is associated with relapse, while a higher degree and rapidity of improvement in the first weeks are linked with lower relapse rate.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370130","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":"Impact of clinical subtype and sex on first-line biologic therapy discontinuation in axial spondyloarthritis.","authors":"Patricia Remalante-Rayco, Emmanuel S Baja, Zeynep Baskurt, Tina Chim, Carlo Irwin A Panelo, Evelyn Osio-Salido, Robert D Inman, Leonila F Dans, Nigil Haroon","doi":"10.1016/j.ard.2025.01.007","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.007","url":null,"abstract":"<p><strong>Objectives: </strong>To estimate the main and interaction effects of axial spondyloarthritis (axSpA) subtype and sex on first biologic disease-modifying antirheumatic drug (bDMARD) discontinuation.</p><p><strong>Methods: </strong>This retrospective cohort study included nonradiographic axSpA (nr-axSpA) and radiographic axSpA (r-axSpA) patients initiating tumour necrosis factor or interleukin-17 inhibitors. Modified Poisson regressions were used to estimate risk ratios (RRs) for the association of subtype and sex with discontinuation, adjusting for baseline covariates. Interaction was assessed using the relative excess risk due to interaction (RERI) and ratio of RRs. In addition, bDMARD survival rates were analysed using Kaplan-Meier curves.</p><p><strong>Results: </strong>Among 469 patients, 64% discontinued their first bDMARD. Nr-axSpA (RR, 1.80; 95% CI, 1.26-2.59) and female sex (RR, 1.49; 95% CI, 1.081-2.045) were significantly associated with discontinuation. Positive interaction trends between subtype and sex were observed on additive (RERI 0.49, 95% CI, -0.78 to 1.75) and multiplicative (RR ratio, 1.05; 95% CI, 0.55-2.03) scales, though not statistically significant. Nr-axSpA females had twice the discontinuation risk of r-axSpA males (hazard ratio, 2.30; 95% CI, 1.68-3.15, P < .001). bDMARD survival over 20 years was significantly lower in nr-axSpA and female patients.</p><p><strong>Conclusions: </strong>Nr-axSpA and female patients face a significantly higher risk of bDMARD discontinuation and shorter bDMARD survival. Although the combined effect of subtype and sex trended higher, it was not statistically significant. These findings underscore the need to address potential treatment challenges in female nr-axSpA patients.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370208","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":"Biologic classification and clinical classification of axSpA: related but not (yet) synonymous.","authors":"Zoya Qaiyum, Robert D Inman","doi":"10.1016/j.ard.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.ard.2024.12.003","url":null,"abstract":"","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370263","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":"GM-CSF drives IL-6 production by macrophages in polymyalgia rheumatica.","authors":"William F Jiemy, Anqi Zhang, Wayel H Abdulahad, Rosanne D Reitsema, Yannick van Sleen, Maria Sandovici, Guillermo Carvajal Alegria, Divi Cornec, Valérie Devauchelle-Pensec, Patrice Hemon, Baptiste Quéré, Sara Boukhlal, Caroline Roozendaal, Thomas Christian Kwee, Bhaskar Dasgupta, Arjan Diepstra, Peter Heeringa, Elisabeth Brouwer, Kornelis S M van der Geest","doi":"10.1016/j.ard.2025.01.004","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.004","url":null,"abstract":"<p><strong>Objectives: </strong>Insight into the immunopathology of polymyalgia rheumatica (PMR) is scarce and mainly derived from peripheral blood studies. The limited data available point towards macrophages as potential key players in PMR. This study aimed to identify the factors driving proinflammatory macrophage development and their functions in the immunopathology of PMR.</p><p><strong>Methods: </strong>Monocyte phenotypes were investigated by flow cytometry in peripheral blood (PMR, n = 22; healthy controls, n = 20) and paired subacromial-subdeltoid (SASD) bursal fluid (PMR, n = 9). Macrophages in SASD bursa were characterised by immunohistochemistry and immunofluorescence (PMR, n = 12; controls undergoing shoulder replacement surgery, n = 10). The functions of cytokines expressed in PMR-affected tissue were examined using macrophage differentiation cultures (PMR, n = 7; healthy controls, n = 7).</p><p><strong>Results: </strong>Monocytes (CD14^highCD16^- and CD14^highCD16⁺) were increased in blood of PMR patients and activated in bursal fluid. Macrophages dominated immune infiltrates in PMR-affected tissue, expressing various proinflammatory cytokines. While interleukin (IL)-6 and interferon-gamma (IFN-γ) expression was abundant in both PMR and control tissue, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) were significantly increased in PMR tissue. Macrophages in PMR-affected tissue showed an elevated CD206/folate receptor β ratio, reflecting a GM-CSF skewed signature. A combination of GM-CSF/M-CSF/IFN-γ significantly boosted IL-6 production in vitro, while limited IL-6 production was observed without GM-CSF.</p><p><strong>Conclusions: </strong>The monocyte compartment is expanded and activated in PMR. Macrophages in PMR-affected tissue produce abundant proinflammatory cytokines such as IL-6. A network of locally expressed cytokines, including GM-CSF, M-CSF, and IFN-γ, may drive the proinflammatory functions of these macrophages. Overall, macrophages may constitute key therapeutic targets for PMR.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143363344","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":"Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness.","authors":"Satoshi Kubo, Yusuke Miyazaki, Takahiro Nishino, Yuya Fujita, Michihiro Kono, Tsugumi Kawashima, Kazuyoshi Ishigaki, Katsuhide Kusaka, Hiroaki Tanaka, Masanobu Ueno, Yurie Satoh-Kanda, Yoshino Inoue, Yasuyuki Todoroki, Ippei Miyagawa, Kentaro Hanami, Shingo Nakayamada, Yoshiya Tanaka","doi":"10.1136/ard-2024-226228","DOIUrl":"10.1136/ard-2024-226228","url":null,"abstract":"<p><strong>Objective: </strong>Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).</p><p><strong>Methods: </strong>Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA.</p><p><strong>Results: </strong>Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4⁺ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as 'expected' whereas the 'non-expected' group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend.</p><p><strong>Conclusion: </strong>Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 2","pages":"210-220"},"PeriodicalIF":20.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370259","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":"Vascular occlusion for optimising the functional improvement in patients with knee osteoarthritis: a randomised controlled trial.","authors":"Ewoud Jacobs, Lenka Stroobant, Jan Victor, Dirk Elewaut, Thomas Tampere, Steven Wallaert, Erik Witvrouw, Joke Schuermans, Evi Wezenbeek","doi":"10.1136/ard-2024-226579","DOIUrl":"10.1136/ard-2024-226579","url":null,"abstract":"<p><strong>Objectives: </strong>Knee osteoarthritis (KOA) is a leading cause of global disability with conventional exercise yielding only modest improvements. Here we aimed to investigate the benefits of integrating blood flow restriction (BFR) into traditional exercise programmes to enhance treatment outcomes.</p><p><strong>Methods: </strong>The Vascular Occlusion for optimizing the Functional Improvement in patients with Knee Osteoarthritis randomised controlled trial enrolled 120 patients with KOA at Ghent University Hospital, randomly assigning them to either a traditional exercise programme or a BFR-enhanced programme over 24 sessions in 12 weeks. Assessments were conducted at baseline, 6 weeks, 12 weeks and 3 months postintervention using linear mixed models with Dunn-Sidak corrections for multiple comparisons. Primary outcome was the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire at 3 months follow-up with knee strength, Pain Catastrophizing Scale questionnaire and functional tests as secondary outcomes. Analysis followed an intention-to-treat approach (NCT04996680).</p><p><strong>Results: </strong>The BFR group showed greater improvements in KOOS pain subscale (effect size (ES)=0.58; p=0.0009), quadriceps strength (ES=0.81; p<0.0001) and functional tests compared with the control group at 12 weeks. At 3 months follow-up, the BFR group continued to exhibit superior improvements in KOOS pain (ES=0.55; p=0.0008), symptoms (ES=0.59; p=0.0004) and quality of life (QoL) (ES=0.66; p=0.0001) with sustained benefits in secondary outcomes. Drop-out rates were similar in both groups.</p><p><strong>Conclusion: </strong>Incorporating BFR into traditional exercise programmes significantly enhances short-term and long-term outcomes for patients with KOA demonstrating persistent improvements in pain, symptoms, QoL and functional measures compared with conventional exercise alone. These findings suggest that BFR can provide the metabolic stimulus needed to achieve muscle strength and functional gains with lower mechanical loads. Reduced pain and increased strength support a more active lifestyle, potentially maintaining muscle mass, functionality and QoL even beyond the supervised intervention period.</p><p><strong>Trial registration number: </strong>NCT04996680.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":"84 2","pages":"341-350"},"PeriodicalIF":20.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143370331","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":"Dysfunctional KLRB1⁺CD8⁺ T-cell responses are generated in chronically inflamed systemic sclerosis skin.","authors":"Alyxzandria M Gaydosik, Tracy Tabib, Jishnu Das, Adriana Larregina, Robert Lafyatis, Patrizia Fuschiotti","doi":"10.1016/j.ard.2025.01.022","DOIUrl":"https://doi.org/10.1016/j.ard.2025.01.022","url":null,"abstract":"<p><strong>Objectives: </strong>To analyse the immune mechanisms of diffuse cutaneous systemic sclerosis (dcSSc) skin disease focusing on CD8⁺ T-cell responses in the affected skin of patients because chronic inflammation, vasculopathy, and extensive cutaneous fibrosis are prominent features of dcSSc skin disease, causing pain and disability in patients, with no effective therapy.</p><p><strong>Methods: </strong>Single-cell transcriptomics and epigenomics were applied to well-characterised patient skin samples to identify transcriptomes and key regulators of skin-resident CD8⁺ T-cell subsets. Multicolor immunofluorescence miscoscopy was used to validate molecular findings. Ex vivo skin explant assays were used to functionally characterise dysfunctional CD8⁺ T-cell subsets on nonlesional autologous skin.</p><p><strong>Results: </strong>We identified 2 major developmentally connected CD8⁺ T-cell subpopulations that were expanded in SSc skin lesions compared with healthy control skin. The first was a heterogeneous subset of effector-memory CD8⁺KLRB1⁺IL7R⁺ cells characterised by increased cytolytic and Tc2/Tc17 effector functions that appear to induce tissue damage and fibrosis in early-stage dcSSc skin lesions. The second, found primarily in patients with late-stage disease, was an exhausted CD8⁺KLRG1⁺IL7R^- subset that exhibited transcriptional features of long-lived effector cells, likely contributing to chronic inflammation. Significantly, both subsets were also expanded in other benign dermatoses, implicating these cell populations in the pathogenesis of chronic human skin inflammation.</p><p><strong>Conclusions: </strong>This study provides new insight into core regulatory programmes modulating skin-resident CD8⁺ T-cell plasticity and identifies distinct CD8⁺ T-cell subpopulations that contribute to initiation and chronicity of inflammatory responses in systemic sclerosis skin lesions. These findings reveal prospective molecular targets for new therapeutic strategies against this incurable disease.</p>","PeriodicalId":8087,"journal":{"name":"Annals of the Rheumatic Diseases","volume":" ","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078495","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}