{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T03:29:22Z","timestamp":1779247762479,"version":"3.51.4"},"reference-count":57,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Systemic sclerosis (SSc) is an autoimmune disease with fibrosis of the skin and\/or internal organs, causing a decrease in quality of life and survival. There is no causative therapy, and the pathophysiology of the SSc remains unclear. Studies showed that lipid metabolism was relevant for autoimmune diseases, but little is known about the role of lipids in SSc. In the present study, we sought to explore the phospholipid profile of SSc by using the lipidomics approach. We also aimed to analyze lipidomics results for different clinical manifestations of SSc. Experiments were performed using high-performance liquid chromatography coupled to mass spectrometry for the lipidomic profiling of plasma samples from patients with SSc. Our study showed, for the first time, significant changes in the level of phospholipids such as plasmalogens and sphingomyelins from the plasma of SSc patients as compared to controls. Phosphatidylcholine plasmalogens species and sphingomyelins were significantly increased in SSc patients as compared to controls. Our results also demonstrated a significant association of changes in the metabolism of phospholipids (phosphatidylcholine and phosphatidylethanolamine plasmalogens species and sphingomyelins) with different clinical manifestations of SSc. Further lipidomic studies might lead to the detection of lipids as new biomarkers or therapeutic targets of SSc.<\/jats:p>","DOI":"10.3390\/diagnostics11112116","type":"journal-article","created":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T08:19:20Z","timestamp":1636964360000},"page":"2116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Changes in Plasma Phospholipid Metabolism Are Associated with Clinical Manifestations of Systemic Sclerosis"],"prefix":"10.3390","volume":"11","author":[{"given":"Marija","family":"Geroldinger-Simi\u0107","sequence":"first","affiliation":[{"name":"Department of Dermatology, Ordensklinikum Linz Elisabethinen, 4020 Linz, Austria"},{"name":"Faculty of Medicine, Johannes Kepler University Linz, 4040 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8245-5209","authenticated-orcid":false,"given":"Thomas","family":"B\u00f6gl","sequence":"additional","affiliation":[{"name":"Institute for Analytical and General Chemistry, Johannes Kepler University Linz, 4040 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Himmelsbach","sequence":"additional","affiliation":[{"name":"Institute for Analytical and General Chemistry, Johannes Kepler University Linz, 4040 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Norbert","family":"Sepp","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Ordensklinikum Linz Elisabethinen, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6982-0558","authenticated-orcid":false,"given":"Wolfgang","family":"Buchberger","sequence":"additional","affiliation":[{"name":"Institute for Analytical and General Chemistry, Johannes Kepler University Linz, 4040 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,15]]},"reference":[{"key":"ref_1","first-page":"202","article-title":"Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis","volume":"15","author":"LeRoy","year":"1988","journal-title":"J. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2737","DOI":"10.1002\/art.38098","article-title":"2013 classification criteria for systemic sclerosis: An American College of Rheumatology\/European League against Rheumatism collaborative initiative","volume":"65","author":"Khanna","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1136\/annrheumdis-2016-209909","article-title":"Update of EULAR recommendations for the treatment of systemic sclerosis","volume":"76","author":"Fransen","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_4","first-page":"1596","article-title":"Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. Reply","volume":"381","author":"Distler","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/j.jpba.2019.06.005","article-title":"Lipidomics in autoimmune diseases with main focus on systemic lupus erythematosus","volume":"174","author":"Ferreira","year":"2019","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2826","DOI":"10.1016\/j.jprot.2011.06.023","article-title":"Lipidomic investigations for the characterization of circulating serum lipids in multiple sclerosis","volume":"74","author":"Pieragostino","year":"2011","journal-title":"J. Proteom."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Vergara, D., D\u2019Alessandro, M., Rizzello, A., De Riccardis, L., Lunetti, P., Del Boccio, P., De Robertis, F., Trianni, G., Maffia, M., and Giudetti, A.M. (2015). A lipidomic approach to the study of human CD4(+) T lymphocytes in multiple sclerosis. BMC Neurosci., 16.","DOI":"10.1186\/s12868-015-0183-1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"108672","DOI":"10.1016\/j.abb.2020.108672","article-title":"Serum phospholipidomics reveals altered lipid profile and promising biomarkers in multiple sclerosis","volume":"697","author":"Ferreira","year":"2021","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.abb.2018.07.021","article-title":"Plasma lipidomic profile signature of rheumatoid arthritis versus Lyme arthritis patients","volume":"654","author":"Domingues","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13075-018-1579-y","article-title":"Targeted lipidomics analysis identified altered serum lipid profiles in patients with polymyositis and dermatomyositis","volume":"20","author":"Raouf","year":"2018","journal-title":"Arthritis Res. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s00296-004-0580-8","article-title":"Lipoprotein profile in limited systemic sclerosis","volume":"25","author":"Borba","year":"2005","journal-title":"Rheumatol. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"168","DOI":"10.7150\/ijms.6.168","article-title":"Elevated serum levels of arachidonoyl-lysophosphatidic acid and sphingosine 1-phosphate in systemic sclerosis","volume":"6","author":"Tokumura","year":"2009","journal-title":"Int. J. Med. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13075-019-1881-3","article-title":"Antifibrotic effects of 2-carba cyclic phosphatidic acid (2ccPA) in systemic sclerosis: Contribution to the novel treatment","volume":"21","author":"Higuchi","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4062\/biomolther.2014.109","article-title":"Promising pharmacological directions in the world of lysophosphatidic Acid signaling","volume":"23","author":"Stoddard","year":"2015","journal-title":"Biomol. Ther. (Seoul)"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/exd.12752","article-title":"Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin","volume":"24","author":"Ohashi","year":"2015","journal-title":"Exp. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"822","DOI":"10.3389\/fimmu.2020.00822","article-title":"Fatty Acid and Carnitine Metabolism Are Dysregulated in Systemic Sclerosis Patients","volume":"11","author":"Ottria","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/j.bbamem.2017.04.006","article-title":"The critical role of phosphatidylcholine and phosphatidylethanolamine metabolism in health and disease","volume":"1859","author":"Kennelly","year":"2017","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0021-9258(19)50785-2","article-title":"The function of cytidine coenzymes in the biosynthesis of phospholipides","volume":"222","author":"Kennedy","year":"1956","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2670","DOI":"10.1172\/JCI97944","article-title":"Phospholipid signaling in innate immune cells","volume":"128","author":"Rossjohn","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1016\/j.bbadis.2012.05.008","article-title":"Functions of plasmalogen lipids in health and disease","volume":"1822","author":"Braverman","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wallner, S., Ors\u00f3, E., Grandl, M., Konovalova, T., Liebisch, G., and Schmitz, G. (2018). Phosphatidylcholine and phosphatidylethanolamine plasmalogens in lipid loaded human macrophages. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205706"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.bbalip.2008.07.008","article-title":"Mass spectrometric analysis of lipid species of human circulating blood cells","volume":"1781","author":"Leidl","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/j.chemphyslip.2011.06.008","article-title":"Plasmalogens the neglected regulatory and scavenging lipid species","volume":"164","author":"Wallner","year":"2011","journal-title":"Chem. Phys. Lipids"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"C1055","DOI":"10.1152\/ajpcell.00003.2020","article-title":"The role of the sphingolipid pathway in liver fibrosis: An emerging new potential target for novel therapies","volume":"318","author":"Ishay","year":"2020","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.tem.2017.03.005","article-title":"Sphingolipids and Lipoproteins in Health and Metabolic Disorders","volume":"28","author":"Iqbal","year":"2017","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1038\/cdd.2014.4","article-title":"High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A","volume":"21","author":"Boya","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11","DOI":"10.5301\/jsrd.5000231","article-title":"Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis","volume":"2","author":"Khanna","year":"2017","journal-title":"J. Scleroderma Relat. Disord."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A simple method for the isolation and purification of total lipides from animal tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1136\/ard.51.10.1143","article-title":"Dietary intake and nutritional status in patients with systemic sclerosis","volume":"51","author":"Lundberg","year":"1992","journal-title":"Ann. Rheum. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.3389\/fimmu.2017.01242","article-title":"Sphingosine-1-Phosphate Receptor 5 Modulates Early-Stage Processes during Fibrogenesis in a Mouse Model of Systemic Sclerosis: A Pilot Study","volume":"8","author":"Schmidt","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.freeradbiomed.2016.11.006","article-title":"Oxidative stress leads to reduction of plasmalogen serving as a novel biomarker for systemic lupus erythematosus","volume":"101","author":"Hu","year":"2016","journal-title":"Free Radic. Biol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"8723460","DOI":"10.1155\/2019\/8723460","article-title":"Oral Phosphatidylcholine Improves Intestinal Barrier Function in Drug-Induced Liver Injury in Rats","volume":"2019","author":"Chen","year":"2019","journal-title":"Gastroenterol. Res. Pract."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"27155","DOI":"10.1074\/jbc.M704408200","article-title":"Anti-inflammatory effects of phosphatidylcholine","volume":"282","author":"Treede","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/gigascience\/gix087","article-title":"Lipidomics profiling reveals the role of glycerophospholipid metabolism in psoriasis","volume":"6","author":"Zeng","year":"2017","journal-title":"Gigascience"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1136\/ard.49.11.901","article-title":"Correlation of fatty acid composition of adipose tissue lipids and serum phosphatidylcholine and serum concentrations of micronutrients with disease duration in rheumatoid arthritis","volume":"49","author":"Jacobsson","year":"1990","journal-title":"Ann. Rheum. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"476","DOI":"10.3109\/00365513.2015.1050690","article-title":"Association of anti phosphatidyl ethanolamine antibodies and low complement levels in systemic sclerosis patients\u2014results of a cross-sectional study","volume":"75","author":"Dan","year":"2015","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Vazquez-de-Lara, L.G., Tlatelpa-Romero, B., Romero, Y., Fern\u00e1ndez-Tamayo, N., Vazquez-de-Lara, F., Justo-Janeiro, J.M., Garcia-Carrasco, M., de-la-Rosa Paredes, R., Cisneros-Lira, J.G., and Mendoza-Milla, C. (2018). Phosphatidylethanolamine Induces an Antifibrotic Phenotype in Normal Human Lung Fibroblasts and Ameliorates Bleomycin-Induced Lung Fibrosis in Mice. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19092758"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2174\/1874312901206010123","article-title":"Sphingolipid regulation of tissue fibrosis","volume":"6","author":"Shea","year":"2012","journal-title":"Open Rheumatol. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.matbio.2018.01.006","article-title":"Sphingolipid signaling in renal fibrosis","volume":"68\u201369","author":"Huwiler","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00403-016-1709-9","article-title":"Increase in circulating sphingosine-1-phosphate and decrease in ceramide levels in psoriatic patients","volume":"309","author":"Baran","year":"2017","journal-title":"Arch. Dermatol. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.bone.2016.04.007","article-title":"Characterisation of matrix vesicles in skeletal and soft tissue mineralisation","volume":"87","author":"Cui","year":"2016","journal-title":"Bone"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/ki.2013.75","article-title":"Autophagy and matrix vesicles: New partners in vascular calcification","volume":"83","author":"Shanahan","year":"2013","journal-title":"Kidney Int."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1007\/s11926-003-0071-z","article-title":"Matrix vesicles and calcification","volume":"5","author":"Anderson","year":"2003","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"822","DOI":"10.2741\/1576","article-title":"The role of matrix vesicles in growth plate development and biomineralization","volume":"10","author":"Anderson","year":"2005","journal-title":"Front. Biosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1001\/archopht.116.7.849","article-title":"Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality","volume":"116","author":"Shine","year":"1998","journal-title":"Arch. Ophthalmol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.jns.2007.01.043","article-title":"Cholinergic precursors in the treatment of cognitive impairment of vascular origin: Ineffective approaches or need for re-evaluation?","volume":"257","author":"Parnetti","year":"2007","journal-title":"J. Neurol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Choi, J.J., Hwang, J.S., and Shin, Y.J. (2020). Effect of Oral Choline Alfoscerate on Patients with Keratoconjunctivitis Sicca. Nutrients, 12.","DOI":"10.3390\/nu12051526"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-018-0685-9","article-title":"Plasmalogen lipids: Functional mechanism and their involvement in gastrointestinal cancer","volume":"17","author":"Messias","year":"2018","journal-title":"Lipids Health Dis."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Perrotti, F., Rosa, C., Cicalini, I., Sacchetta, P., Del Boccio, P., Genovesi, D., and Pieragostino, D. (2016). Advances in Lipidomics for Cancer Biomarkers Discovery. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17121992"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2315","DOI":"10.1007\/s00216-012-5841-x","article-title":"Analysis of colorectal adenocarcinoma tissue by desorption electrospray ionization mass spectrometric imaging","volume":"403","author":"Gerbig","year":"2012","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ritchie, S.A., Akita, H., Takemasa, I., Eguchi, H., Pastural, E., Nagano, H., Monden, M., Doki, Y., Mori, M., and Jin, W. (2013). Metabolic system alterations in pancreatic cancer patient serum: Potential for early detection. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-416"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s11745-007-3133-6","article-title":"A reliable biomarker derived from plasmalogens to evaluate malignancy and metastatic capacity of human cancers","volume":"43","author":"Smith","year":"2008","journal-title":"Lipids"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"36622","DOI":"10.18632\/oncotarget.9124","article-title":"Plasma lipidomics profiling identified lipid biomarkers in distinguishing early-stage breast cancer from benign lesions","volume":"7","author":"Chen","year":"2016","journal-title":"Oncotarget"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/bs.apcsb.2015.08.001","article-title":"Antitumor Lipids\u2014Structure, Functions, and Medical Applications","volume":"101","author":"Kostadinova","year":"2015","journal-title":"Adv. Protein Chem. Struct. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.bbalip.2012.10.008","article-title":"Anticancer mechanisms and clinical application of alkylphospholipids","volume":"1831","author":"Verheij","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.3389\/fimmu.2018.03112","article-title":"Intriguing Relationships Between Cancer and Systemic Sclerosis: Role of the Immune System and Other Contributors","volume":"9","author":"Maria","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_57","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."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/11\/2116\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:33Z","timestamp":1760167833000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/11\/11\/2116"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,15]]},"references-count":57,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["diagnostics11112116"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics11112116","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,15]]}}}