{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:30:01Z","timestamp":1791815401511,"version":"4.3.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic sclerosis (SSc) is a multisystem autoimmune disease in which skin, lung, and gastrointestinal involvement often co-occur. Whether increasing organ co-involvement burden is accompanied by coherent circulating biomarker changes remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To characterize immune, inflammatory, and nutritional biomarker patterns across skin\u2013lung\u2013gut burden groups in SSc.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a retrospective cross-sectional study of 314 patients with SSc fulfilling the 2013 ACR\/EULAR classification criteria. Three prespecified axes were used to define organ burden: skin axis, modified Rodnan skin score (mRSS) \u226514; lung axis, interstitial lung disease (ILD); and gut axis, broad gastrointestinal involvement (bGI). Patients were classified into four mutually exclusive groups according to the number of involved axes: 0-Axis, 1-Axis, 2-Axis, and 3-Axis. Clinical characteristics and biomarker distributions were compared across groups. Multinomial logistic regression was performed using 0-Axis as the reference group, with prespecified sensitivity analyses including ordinal and treatment-adjusted models, subtype-informed analyses, and axis-specific adjusted analyses. Unsupervised clustering was used as an exploratory complementary analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 314 patients, 37 (11.8%) were classified as 0-Axis, 136 (43.3%) as 1-Axis, 118 (37.6%) as 2-Axis, and 23 (7.3%) as 3-Axis. Anti-Scl-70 positivity increased across burden groups, from 51.4% in the 0-Axis group to 71.9% in the 1-Axis group, 83.1% in the 2-Axis group, and 91.3% in the 3-Axis group (p&amp;lt;0.001). hs-CRP differed across groups and was higher in the 2-Axis group than in the 1-Axis group (9.60 [3.13\u201319.40] vs 4.50 [1.79\u201312.03] mg\/L, p=0.012 overall). Albumin decreased across groups and was lower in the 3-Axis group than in the 0-Axis group (31.70 [27.10\u201333.60] vs 34.30 [31.80\u201337.50] g\/L, p=0.005 overall). In adjusted multinomial joint models, Anti-Scl-70 positivity was associated with 2-Axis versus 0-Axis (OR 3.86, 95% CI 1.46\u201310.22, p=0.007) and 3-Axis versus 0-Axis (OR 12.78, 95% CI 1.86\u201387.91, p=0.010). Lower albumin was associated with 2-Axis versus 0-Axis (OR 0.52, 95% CI 0.31\u20130.89, p=0.017) and 3-Axis versus 0-Axis (OR 0.38, 95% CI 0.18\u20130.79, p=0.009). Higher total cholesterol was associated with 3-Axis versus 0-Axis (OR 2.81, 95% CI 1.11\u20137.13, p=0.030). hs-CRP showed an inverse association for 1-Axis versus 0-Axis (OR 0.60, 95% CI 0.37\u20130.98, p=0.039), but was not associated with 2-Axis versus 0-Axis (OR 0.66, 95% CI 0.42\u20131.04, p=0.074) or 3-Axis versus 0-Axis (OR 1.04, 95% CI 0.60\u20131.81, p=0.890) after joint adjustment. Unsupervised clustering identified three biomarker-defined clusters with differing centroid profiles and differing axis-burden distributions. Supplementary analyses supported the robustness of the principal Anti-Scl-70 and albumin signals while clarifying the contributions of subtype structure, lung-axis predominance, treatment exposure, and GI heterogeneity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Increasing skin\u2013lung\u2013gut co-involvement burden in SSc was associated with structured circulating biomarker patterning. The most consistent adjusted signals were Anti-Scl-70 positivity and lower albumin in higher burden groups. These findings support a clinically anchored, biomarker-informed perspective on multisystem involvement in SSc, while remaining complementary to conventional subtype-based classification and requiring cautious interpretation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1841944","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T05:45:24Z","timestamp":1784267124000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Biomarker patterns across skin\u2013lung\u2013gut burden in systemic sclerosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Huichen","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital of Guangxi Medical University","place":["Nanning, Guangxi, China"]},{"name":"Department of Rheumatology and Immunology, The First Affiliated Hospital of University of South China","place":["Hengyang, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danhui","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neonatology, The First Affiliated Hospital of University of South China","place":["Hengyang, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.4078\/jrd.2024.0129","article-title":"Pathogenesis of systemic sclerosis: an integrative review of recent advances","volume":"32","author":"Son","year":"2025","journal-title":"J Rheum Dis"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01692-0","article-title":"Systemic sclerosis","volume":"401","author":"Volkmann","year":"2023","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1551911","article-title":"A review of recent studies on the pathogenesis of systemic sclerosis: focus on fibrosis pathways","volume":"16","author":"Jimenez","year":"2025","journal-title":"Front Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-025-01349-z","article-title":"Mechanisms of fibrotic tissue remodelling: insights from systemic sclerosis","author":"Distler","year":"2026","journal-title":"Nat Rev Rheumatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000001063","article-title":"A scoping review of the epidemiology of systemic sclerosis and its organ manifestations: 2018-2024","volume":"37","author":"Good","year":"2025","journal-title":"Curr Opin Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.12.008","article-title":"The incidence of interstitial lung disease in patients with systemic sclerosis: rate, risk factors and prognostic implications in a EUSTAR cohort analysis (CP 133)","author":"Petelytska","year":"2026","journal-title":"Ann Rheum Dis"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-022-00900-6","article-title":"Systemic sclerosis gastrointestinal dysmotility: risk factors, pathophysiology, diagnosis and management","volume":"19","author":"McMahan","year":"2023","journal-title":"Nat Rev Rheumatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-024-07123-y","article-title":"Biomarkers reflecting the pathogenesis, clinical manifestations, and guide therapeutic approach in systemic sclerosis: a narrative review","volume":"43","author":"Bazs\u00f3","year":"2024","journal-title":"Clin Rheumatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keag008","article-title":"Clinical predictors of mortality in critically ill systemic sclerosis patients: a 6-year retrospective cohort study","volume":"65","author":"Wattanarat","year":"2026","journal-title":"Rheumatol (Oxford)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1136\/thorax-2023-220820","article-title":"Outcomes of systemic sclerosis associated interstitial lung disease patients with a persistent inflammatory phenotype based on serial CRP measurements","volume":"78","author":"Volkmann","year":"2023","journal-title":"Thorax"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen-2024-004240","article-title":"Development of a multivariable prediction model for progression of systemic sclerosis-associated interstitial lung disease","volume":"10","author":"Kuwana","year":"2024","journal-title":"RMD Open"},{"key":"B12","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1038\/s41746-025-01962-y","article-title":"Deep hierarchical subtyping of multi-organ systemic sclerosis trajectories - a EUSTAR study","volume":"8","author":"Trottet","year":"2025","journal-title":"NPJ Digit Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/art.70043","article-title":"Impact of evolving treatment patterns on interstitial lung disease progression in systemic sclerosis using the EUSTAR database","author":"Campochiaro","year":"2026","journal-title":"Arthritis Rheumatol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1691988","article-title":"The clinical utility of autoantibodies in systemic sclerosis: a review with a focus on cohort differences and standardization","volume":"16","author":"Komura","year":"2025","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.11.020","article-title":"Shared and unique molecular signatures across different autoantibody groups in systemic sclerosis: a multiomics analysis","author":"Lin","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1395993","article-title":"The association between the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and monocyte-to-lymphocyte ratio and systemic sclerosis and its complications: a systematic review and meta-analysis","volume":"15","author":"Zinellu","year":"2024","journal-title":"Front Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-024-07039-7","article-title":"Prediction of prognosis in patients with systemic sclerosis based on a machine-learning model","volume":"43","author":"Zheng","year":"2024","journal-title":"Clin Rheumatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejim.2023.07.017","article-title":"GLIM-diagnosed malnutrition predicts mortality and risk of hospitalization in systemic sclerosis: a retrospective study","volume":"117","author":"Rosato","year":"2023","journal-title":"Eur J Intern Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/art.43370","article-title":"Skin biopsies enhance prediction of clinical trajectory in diffuse cutaneous systemic sclerosis","volume":"78","author":"Lakin","year":"2026","journal-title":"Arthritis Rheumatol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1568683","article-title":"Identifying inflammatory phenotypes associated with lung involvement in systemic sclerosis: k-means clustering approach","volume":"16","author":"Cano-Garc\u00eda","year":"2025","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative","volume":"72","author":"van den Hoogen","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B22","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/S0140-6736(11)60982-3","article-title":"Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial","volume":"378","author":"Burt","year":"2011","journal-title":"Lancet"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ard.2025.05.890","article-title":"POS0508\u2005Methotrexate monotherapy in early systemic sclerosis: a real life monocentric Italian experience","volume":"84","author":"Iannone","year":"2025","journal-title":"Ann Rheum Dis"},{"key":"B24","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1186\/s12931-025-03375-7","article-title":"The importance of considering progression speed in systemic sclerosis-associated interstitial lung diseases: application of 2022 and 2024 clinical practice guidelines for progressive pulmonary fibrosis, a retrospective cohort study","volume":"26","author":"Roeser","year":"2025","journal-title":"Respir Res"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaf457","article-title":"Gastrointestinal involvement in very early and established systemic sclerosis: insights from the SPRING-SIR national Italian registry","volume":"65","author":"Bonomi","year":"2026","journal-title":"Rheumatol (Oxford)"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1755076","article-title":"Systemic sclerosis-associated pulmonary arterial hypertension and pulmonary fibrosis: exploring biomarker discriminators with advanced omics in a Caucasian cohort","volume":"17","author":"Mohamed-Ali","year":"2026","journal-title":"Front Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1713221","article-title":"The immune landscape of systemic sclerosis: from pathogenic mechanisms to precision therapeutic breakthroughs","volume":"17","author":"Liu","year":"2026","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2025.11.047","article-title":"Systemic sclerosis-associated interstitial lung disease: what we know and how to incorporate guidelines into clinical practice","author":"Esposito","year":"2025","journal-title":"Chest"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26167685","article-title":"The relationship between microbiota, nutrition, and gastrointestinal tract symptoms in patients with systemic sclerosis: a systematic review of the literature","volume":"26","author":"Gori","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1097\/BOR.0000000000001111","article-title":"Patient-reported outcomes in systemic sclerosis: insights into quality of life and disease burden","volume":"37","author":"Lescoat","year":"2025","journal-title":"Curr Opin Rheumatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.berh.2026.102117","article-title":"Gastrointestinal involvement in systemic sclerosis: a spotlight on small bowel involvement, complications and management","author":"Alcala-Gonzalez","year":"2026","journal-title":"Best Pract Res Clin Rheumatol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2026.103988","article-title":"Gastrointestinal histology of systemic sclerosis: a systematic review","volume":"25","author":"Strother","year":"2026","journal-title":"Autoimmun Rev"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25672","article-title":"Systemic sclerosis-associated myopathy in a large single-center cohort: autoantibody profiles, histologic features, and independent risk of death","author":"Paik","year":"2025","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/acr.25623","article-title":"International investigation of the gut-lung axis in systemic sclerosis-interstitial lung disease","volume":"78","author":"Andr\u00e9asson","year":"2026","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/acr2.90013","article-title":"Performance of circulating inflammatory biomarkers and Krebs von den Lungen 6 for predicting progressive pulmonary fibrosis in patients with systemic sclerosis-associated interstitial lung disease","volume":"8","author":"Yomono","year":"2026","journal-title":"ACR Open Rheumatol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1186\/s13075-025-03685-7","article-title":"Clinical significance of inflammation-coagulation-autoantibody triad in systemic sclerosis-associated interstitial lung disease: a retrospective study","volume":"27","author":"Guo","year":"2025","journal-title":"Arthritis Res Ther"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keae606","article-title":"Neutrophil-to-lymphocyte ratio as a biomarker for clinical response after autologous haematopoietic stem cell transplantation in systemic sclerosis","volume":"64","author":"Keret","year":"2025","journal-title":"Rheumatol (Oxford)"},{"key":"B38","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1007\/s00296-025-05932-1","article-title":"Classic lipid profile and lipoprotein(a) in systemic sclerosis: a systematic review and meta-analysis of case-control studies","volume":"45","author":"Mastori-Kourmpani","year":"2025","journal-title":"Rheumatol Int"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1530909","article-title":"Aberrant lipid profiles and lymphocyte counts in systemic sclerosis population, reassessing predictive value for concurrent cardiovascular diseases","volume":"16","author":"Guo","year":"2025","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.55563\/clinexprheumatol\/qcnuhv","article-title":"Gastrointestinal disorders in systemic sclerosis: cluster analysis and prognosis from a French prospective cohort","volume":"42","author":"Molli\u00e8re","year":"2024","journal-title":"Clin Exp Rheumatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1045523","article-title":"Comprehensive autoantibody profiles in systemic sclerosis: clinical cluster analysis","volume":"13","author":"H\u00f6ppner","year":"2023","journal-title":"Front Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1841944\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T14:35:42Z","timestamp":1784730942000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1841944\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":41,"alternative-id":["10.3389\/fimmu.2026.1841944"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1841944","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]},"article-number":"1841944"}}