{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T17:37:34Z","timestamp":1783705054976,"version":"3.55.0"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"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:p>The pathogenesis of connective tissue diseases (CTDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), is characterized by derangements of the innate and adaptive immune system, and inflammatory pathways leading to autoimmunity, chronic cytokine production, and chronic inflammation. The diagnosis of these diseases is based on meeting established criteria with symptoms, signs and autoantibodies. However, there are pre-clinical states where criteria are not fulfilled but biochemical and autoimmune derangements are present. Understanding the underlying processes responsible for disease pathogenesis in pre-clinical states, which place patients at increased risk for the development of established connective tissue diseases, represents an opportunity for early identification and potentially enables timely treatment with the goal of limiting disease progression and improved prognosis. This scoping review describes the role of the innate and adaptive immune responses in the pre-clinical states of undifferentiated CTD at risk for SSc and prescleroderma, the evolution of antibodies from nonspecific to specific antinuclear antibodies prior to SLE development, and the signaling pathways and inflammatory markers of fibroblast, endothelial, and T cell activation underlying immune dysregulation in these pre-clinical states.<\/jats:p>","DOI":"10.3389\/fimmu.2022.869172","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T12:55:45Z","timestamp":1651755345000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Precursors to Systemic Sclerosis and Systemic Lupus Erythematosus: From Undifferentiated Connective Tissue Disease to the Development of Identifiable Connective Tissue Diseases"],"prefix":"10.3389","volume":"13","author":[{"given":"Leonardo","family":"Martin Calderon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet E.","family":"Pope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"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":"B2","doi-asserted-by":"publisher","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":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2014.11.002","article-title":"Undifferentiated Connective Tissue Disease at Risk for Systemic Sclerosis (SSc) (So Far Referred to as Very Early\/Early SSc or Pre-SSc)","volume":"14","author":"Valentini","year":"2015","journal-title":"Autoimmun Rev"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2012-202295","article-title":"Very Early Versus Early Disease: The Evolving Definition of the \u2018Many Faces\u2019 of Systemic Sclerosis","volume":"72","author":"Matucci-Cerinic","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/art.24038","article-title":"Autoantibodies and Microvascular Damage are Independent Predictive Factors for the Progression of Raynaud\u2019s Phenomenon to Systemic Sclerosis: A Twenty-Year Prospective Study of 586 Patients, With Validation of Proposed Criteria for Early Systemic Sclerosis","volume":"58","author":"Koenig","year":"2008","journal-title":"Arthritis Rheumatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1002\/acr.22304","article-title":"Early Systemic Sclerosis: Analysis of the Disease Course in Patients With Marker Autoantibody and\/or Capillaroscopic Positivity","volume":"66","author":"Valentini","year":"2014","journal-title":"Arthritis Care Res (Hoboken)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"102659","DOI":"10.1016\/j.autrev.2020.102659","article-title":"Undifferentiated Connective Tissue Disease at Risk for Systemic Sclerosis: Which Patients Might be Labeled Prescleroderma","volume":"19","author":"Valentini","year":"2020","journal-title":"Autoimmun Rev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"ITC81","DOI":"10.7326\/AITC202006020","article-title":"Systemic Lupus Erythematosus","volume":"172","author":"Kiriakidou","year":"2020","journal-title":"Ann Intern Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/art.40674","article-title":"Brief Report: How Do Patients With Newly Diagnosed Systemic Lupus Erythematosus Present? 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