{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:31:13Z","timestamp":1785403873620,"version":"3.56.0"},"reference-count":38,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006315","name":"ReumaNederland","doi-asserted-by":"crossref","award":["24-2-402"],"award-info":[{"award-number":["24-2-402"]}],"id":[{"id":"10.13039\/501100006315","id-type":"DOI","asserted-by":"crossref"}]},{"award":["24-2-402"],"award-info":[{"award-number":["24-2-402"]}],"id":[{"id":"https:\/\/ror.org\/05dr3r825","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by inflammation, vasculopathy, and fibrosis. It is associated with the highest mortality among rheumatic diseases. Very early SSc may represent a critical phase with risk of developing progressive disease. Although timely treatment may be effective in patients with progressive disease, it carries risks of adverse events, underscoring the need for early identification of individuals at risk. Biomarkers for progression in the early stage offer opportunities for timely intervention and improved long-term outcomes. Therefore, validating biomarkers that predict progression is an important research priority. In this narrative literature review, we summarize and evaluate blood circulating biomarkers associated with different progression endpoints in (very) early SSc. Methods: The literature search was conducted using PubMed. Eligible studies assessed biomarkers in very early SSc or early SSc cohorts with longitudinal follow-up and progression-related outcomes. Results: The identified studies investigated biomarkers associated with interstitial lung disease (ILD), skin progression, overall disease progression, and mortality. Anti-topoisomerase I was associated with ILD development. A high interferon score was linked to reduced lung function and mortality. KL-6 was associated with progression in early SSc-ILD. PRO-C3 and PRO-C6 showed the strongest associations with skin involvement. Finally, IgG anti-centromere antibody was associated with organ involvement and progression to definite SSc. CXCL10 and TNFRII were linked to progression and significant survival differences in the discovery and replication cohorts. However, effect sizes were often modest, and findings were inconsistent across cohorts. Substantial heterogeneity in study design, populations, endpoints, and biomarker assessment methods limited comparability. Moreover, most biomarkers demonstrated associations at the group level but lacked sufficient discriminatory power for individual risk prediction. Only a minority of studies included validation cohorts, and replication of findings was limited. Conclusions: Multiple biomarkers show promising associations with progression in very early and early SSc, but a single biomarker is unlikely to reliably predict disease progression.<\/jats:p>","DOI":"10.3390\/jpm16070355","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:26:15Z","timestamp":1782807975000},"page":"355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Available Biomarkers for Personalized Prognostication in Early and Very Early Systemic Sclerosis: A Narrative Review of the Current Literature"],"prefix":"10.3390","volume":"16","author":[{"given":"Isabel","family":"Dirven","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0476-0271","authenticated-orcid":false,"given":"Marre W.","family":"Kamminga","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9740-5607","authenticated-orcid":false,"given":"Lise M.","family":"Verhoef","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Department of Rheumatology, Sint Maartenskliniek, 6574 NA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4054-0290","authenticated-orcid":false,"given":"Rogier M.","family":"Thurlings","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2862-1058","authenticated-orcid":false,"given":"Ruben L.","family":"Smeets","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine\u2014Medical Immunology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"},{"name":"Radboudumc Laboratory for Diagnostics, Department of Laboratory Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5473-4884","authenticated-orcid":false,"given":"Arjan van","family":"Caam","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2266-9907","authenticated-orcid":false,"given":"Madelon C.","family":"Vonk","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3606","DOI":"10.1093\/rheumatology\/keae698","article-title":"Biological hallmarks of systemic sclerosis are present in the skin and serum of patients with Very Early Diagnosis of Systemic Sclerosis (VEDOSS)","volume":"64","author":"Ross","year":"2025","journal-title":"Rheumatology"},{"key":"ref_2","unstructured":"Adigun, R., Goyal, A., and Hariz, A. (2024). Systemic sclerosis (scleroderma). StatPearls [Internet], StatPearls Publishing."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1097\/BOR.0b013e32834ff2e8","article-title":"Epidemiology of systemic sclerosis: Incidence, prevalence, survival, risk factors, malignancy, and environmental triggers","volume":"24","author":"Barnes","year":"2012","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1177\/2397198320924873","article-title":"Overall mortality","volume":"6","author":"Moore","year":"2021","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1007\/s12016-009-8193-3","article-title":"The pathogenesis of systemic sclerosis revisited","volume":"40","author":"Geyer","year":"2011","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/kjm2.12505","article-title":"Pathophysiology of systemic sclerosis (scleroderma)","volume":"38","author":"Rosendahl","year":"2022","journal-title":"Kaohsiung J. Med. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1097\/BOR.0000000000000711","article-title":"Management of systemic sclerosis: The first five years","volume":"32","author":"Roofeh","year":"2020","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1136\/ard.2009.114264","article-title":"Causes and risk factors for death in systemic sclerosis: A study from the EULAR Scleroderma Trials and Research (EUSTAR) database","volume":"69","author":"Tyndall","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1136\/annrheumdis-2013-203716","article-title":"Preliminary analysis of the very early diagnosis of systemic sclerosis (VEDOSS) EUSTAR multicentre study: Evidence for puffy fingers as a pivotal sign for suspicion of systemic sclerosis","volume":"73","author":"Minier","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e834","DOI":"10.1016\/S2665-9913(21)00244-7","article-title":"Progression of patients with Raynaud\u2019s phenomenon to systemic sclerosis: A five-year analysis of the European Scleroderma Trial and Research group multicentre, longitudinal registry study for Very Early Diagnosis of Systemic Sclerosis (VEDOSS)","volume":"3","author":"Lepri","year":"2021","journal-title":"Lancet Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.rdc.2023.01.006","article-title":"Gastrointestinal tract considerations part I: How should a rheumatologist best manage common upper gastrointestinal tract complaints in systemic sclerosis?","volume":"49","author":"Quinlivan","year":"2023","journal-title":"Rheum. Dis. Clin. North Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e005776","DOI":"10.1136\/rmdopen-2025-005776","article-title":"New horizons in systemic sclerosis treatment: Advances and emerging therapies in 2025","volume":"11","author":"Santos","year":"2025","journal-title":"RMD Open"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/j.ero.2026.02.006","article-title":"Early progression of systemic sclerosis: A longitudinal cohort study on disease evolution and microvascular changes","volume":"2","author":"Haverkort","year":"2026","journal-title":"EULAR Rheumatol. Open"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/ard.2010.136929","article-title":"Preliminary criteria for the very early diagnosis of systemic sclerosis: Results of a Delphi Consensus Study from EULAR Scleroderma Trials and Research Group","volume":"70","author":"Avouac","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"519","DOI":"10.3899\/jrheum.2025-0532","article-title":"Type III and type VI collagen neoepitopes with disease severity in systemic sclerosis","volume":"53","author":"Ayla","year":"2025","journal-title":"J. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e403","DOI":"10.1016\/S2665-9913(24)00403-X","article-title":"Serum type I interferon score as a disease activity biomarker in patients with diffuse cutaneous systemic sclerosis: A retrospective cohort study","volume":"7","author":"Hinchcliff","year":"2025","journal-title":"Lancet Rheumatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"De Luca, G., Campochiaro, C., Burastero, S.E., Matucci-Cerinic, M., Doglioni, C., and Dagna, L. (2024). Periostin expression in uninvolved skin as a potential biomarker for rapid cutaneous progression in systemic sclerosis patients: A preliminary explorative study. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1214523"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2338","DOI":"10.1002\/art.41814","article-title":"Anticentromere antibody levels and isotypes and the development of systemic sclerosis","volume":"73","author":"Boonstra","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.3899\/jrheum.170518","article-title":"KL-6 but not CCL-18 is a predictor of early progression in systemic sclerosis-related interstitial lung disease","volume":"45","author":"Salazar","year":"2018","journal-title":"J. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1136\/annrheumdis-2017-211912","article-title":"Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study","volume":"77","author":"Herrick","year":"2018","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2359","DOI":"10.1002\/art.40243","article-title":"Earliest phase of systemic sclerosis typified by increased levels of inflammatory proteins in the serum","volume":"69","author":"Cossu","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1871","DOI":"10.1002\/art.40171","article-title":"CCL2 in the circulation predicts long-term progression of interstitial lung disease in patients with early systemic sclerosis: Data from two independent cohorts","volume":"69","author":"Wu","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.3899\/jrheum.160339","article-title":"Elevated serum Krebs von den Lungen-6 in early disease predicts subsequent deterioration of pulmonary function in patients with systemic sclerosis and interstitial lung disease","volume":"43","author":"Kuwana","year":"2016","journal-title":"J. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hasegawa, M., Asano, Y., Endo, H., Fujimoto, M., Goto, D., Ihn, H., Inoue, K., Ishikawa, O., Kawaguchi, Y., and Kuwana, M. (2014). Serum adhesion molecule levels as prognostic markers in patients with early systemic sclerosis: A multicentre, prospective, observational study. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088150"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1002\/acr.21968","article-title":"Does C-reactive protein predict the long-term progression of interstitial lung disease and survival in patients with early systemic sclerosis?","volume":"65","author":"Liu","year":"2013","journal-title":"Arthritis Care Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"R188","DOI":"10.1186\/ar4019","article-title":"Early systemic sclerosis: Short-term disease evolution and factors predicting the development of new manifestations of organ involvement","volume":"14","author":"Valentini","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/rheumatology\/ker333","article-title":"Investigation of prognostic factors for skin sclerosis and lung function in Japanese patients with early systemic sclerosis: A multicentre prospective observational study","volume":"51","author":"Hasegawa","year":"2012","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1136\/ard.2009.127621","article-title":"Skin thickness progression rate: A predictor of mortality and early internal organ involvement in diffuse scleroderma","volume":"70","author":"Domsic","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"R166","DOI":"10.1186\/ar3125","article-title":"Predictors of interstitial lung disease in early systemic sclerosis: A prospective longitudinal study of the GENISOS cohort","volume":"12","author":"Assassi","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.3899\/jrheum.141182","article-title":"Connective tissue disease-associated interstitial lung diseases (CTD-ILD)\u2014Report from OMERACT CTD-ILD Working Group","volume":"42","author":"Khanna","year":"2015","journal-title":"J. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1002\/art.42861","article-title":"2023 American College of Rheumatology (ACR)\/American College of Chest Physicians (CHEST) guideline for the treatment of interstitial lung disease in people with systemic autoimmune rheumatic diseases","volume":"76","author":"Johnson","year":"2024","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.ard.2025.08.021","article-title":"ERS\/EULAR clinical practice guidelines for connective tissue diseases associated interstitial lung disease of the European Respiratory Society (ERS) and the European Alliance of Associations for Rheumatology (EULAR) Endorsed by the European Reference Network on rare respiratory diseases (ERN-LUNG)","volume":"85","author":"Antoniou","year":"2025","journal-title":"Ann. Rheum. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10354","DOI":"10.1038\/s41598-024-61159-3","article-title":"Levels of anti-topoisomerase I antibody correlated with short onset of cardiopulmonary involvement in Thai systemic sclerosis patients","volume":"14","author":"Mulalin","year":"2024","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1007\/s12016-022-08946-w","article-title":"Systemic sclerosis-specific antibodies: Novel and classical biomarkers","volume":"64","author":"Cavazzana","year":"2023","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s13075-024-03418-2","article-title":"Does regression of skin thickening predict improvement of internal organ involvement and survival in patients with diffuse cutaneous systemic sclerosis? A EUSTAR analysis","volume":"26","author":"Wyss","year":"2024","journal-title":"Arthritis Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.3899\/jrheum.180042","article-title":"Ethnic variations in systemic sclerosis disease manifestations, internal organ involvement, and mortality","volume":"46","author":"Ahmad","year":"2019","journal-title":"J. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1093\/rheumatology\/keab931","article-title":"Outcomes in patients with systemic sclerosis undergoing early vs delayed intervention with potential disease-modifying therapies","volume":"61","author":"Yomono","year":"2022","journal-title":"Rheumatology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1093\/rheumatology\/keae156","article-title":"Efficacy of methylprednisolone in very early systemic sclerosis: Results of the \u2018Hit Hard and Early\u2019randomized controlled trial","volume":"64","author":"Kersten","year":"2025","journal-title":"Rheumatology"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/7\/355\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:23:55Z","timestamp":1783052635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/16\/7\/355"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":38,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["jpm16070355"],"URL":"https:\/\/doi.org\/10.3390\/jpm16070355","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}