{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T23:05:43Z","timestamp":1777417543852,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,5,14]],"date-time":"2017-05-14T00:00:00Z","timestamp":1494720000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bio &amp; Medical Technology Development Program of the NRF","award":["2016M3A9B694241"],"award-info":[{"award-number":["2016M3A9B694241"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p> Rheumatoid arthritis (RA) is a chronic autoimmune disease that progresses into systemic inflammation and joint deformity. RA diagnosis is a complicated procedure, and early diagnostic methods are insufficient. Therefore, in this study, we attempted to identify new markers to improve the accuracy of RA prescreening. e identified differentially expressed proteins (DEPs) by using liquid chromatography tandem-mass spectrometry in health-prescreening sera with high rheumatoid factor (RF) values, and compared the findings with those from sera with normal RF values. We identified 93 DEPs; of these, 36 were upregulated, and 57 were downregulated in high-RF sera. Pathway analysis revealed that these DEPs were related to immune responses. Additionally, four DEPs were statistically analyzed by proteomic analysis; of these, SAA4 was significantly validated in individual enzyme-linked immunosorbent assays. Moreover, SAA4 was significantly upregulated in RA patients (n = 40, 66.43 \u00b1 12.97 ng\/mL) compared with normal controls (n = 40, 4.79 \u00b1 0.95 ng\/mL) and had a higher area under the curve than C-reactive protein. Thus, we identified SAA4 as a protein that was positively correlated with RF and RA. SAA4 may represent a novel prescreening marker for the diagnosis of RA.<\/jats:p>","DOI":"10.3390\/molecules22050805","type":"journal-article","created":{"date-parts":[[2017,5,15]],"date-time":"2017-05-15T12:16:12Z","timestamp":1494850572000},"page":"805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Identification and Validation of SAA4 as a Rheumatoid Arthritis Prescreening Marker by Liquid Chromatography Tandem-mass Spectrometry"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4234-9879","authenticated-orcid":false,"given":"AeEun","family":"Seok","sequence":"first","affiliation":[{"name":"Laboratory of Signal Transduction and Disease Biomarker Discovery, Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Korea"},{"name":"Research Institute of DongDeok Pharmaceutical, Chungcheongbuk-do 27864, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun-Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam-si, Gyeonggi-do 13135, Korea"},{"name":"Department of Laboratory Medicine, Korea Cancer Center Hospital, Seoul 01812, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5871-9278","authenticated-orcid":false,"given":"Sungeun","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of DongDeok Pharmaceutical, Chungcheongbuk-do 27864, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-4109","authenticated-orcid":false,"given":"Jiyeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam-si, Gyeonggi-do 13135, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sora","family":"Mun","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and Disease Biomarker Discovery, Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arum","family":"Park","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and Disease Biomarker Discovery, Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yeon-Tae","family":"Chun","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and Disease Biomarker Discovery, Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Korea"},{"name":"Integrative Research Support Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Hyeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of DongDeok Pharmaceutical, Chungcheongbuk-do 27864, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee-Joung","family":"Lim","sequence":"additional","affiliation":[{"name":"Forensic Science R&D Lab., Police Science Institute, Chungcheongnam-do 31539, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8690-2483","authenticated-orcid":false,"given":"Hee-Gyoo","family":"Kang","sequence":"additional","affiliation":[{"name":"Laboratory of Signal Transduction and Disease Biomarker Discovery, Department of Senior Healthcare, BK21 Plus Program, Graduate School, Eulji University, Daejeon 34824, Korea"},{"name":"Department of Biomedical Laboratory Science, College of Health Sciences, Eulji University, Seongnam-si, Gyeonggi-do 13135, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2017,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1093\/oxfordjournals.rheumatology.a031490","article-title":"Prognostic factors in early rheumatoid arthritis","volume":"39","author":"Scott","year":"2000","journal-title":"Rheumatology (Oxford, England)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S0140-6736(01)06075-5","article-title":"Rheumatoid arthritis","volume":"358","author":"Lee","year":"2001","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S62","DOI":"10.2337\/dc10-S062","article-title":"Diagnosis and classification of diabetes mellitus","volume":"33","author":"Association","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1016\/S0140-6736(10)60826-4","article-title":"Rheumatoid arthritis","volume":"376","author":"Scott","year":"2010","journal-title":"Lancet"},{"key":"ref_5","first-page":"33","article-title":"Patient-driven outcomes in rheumatoid arthritis","volume":"82","author":"Wells","year":"2009","journal-title":"J. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1136\/ard.2003.017574","article-title":"Rheumatoid factor and anticitrullinated protein antibodies in rheumatoid arthritis: Diagnostic value, associations with radiological progression rate, and extra-articular manifestations","volume":"63","author":"Peene","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.autrev.2004.09.002","article-title":"Epidemiology of adult rheumatoid arthritis","volume":"4","author":"Alamanos","year":"2005","journal-title":"Autoimmun. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1136\/annrheumdis-2012-201960","article-title":"The incidence of rheumatoid arthritis in the uk: Comparisons using the 2010 acr\/eular classification criteria and the 1987 acr classification criteria. Results from the norfolk arthritis register","volume":"72","author":"Humphreys","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3","article-title":"The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide","volume":"43","author":"Schellekens","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1002\/art.10705","article-title":"Survival in rheumatoid arthritis: A population-based analysis of trends over 40 years","volume":"48","author":"Gabriel","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1002\/art.1780370408","article-title":"The mortality of rheumatoid arthritis","volume":"37","author":"Wolfe","year":"1994","journal-title":"Arthritis Rheum."},{"key":"ref_12","first-page":"1009","article-title":"Mortality trends in rheumatoid arthritis: The role of rheumatoid factor","volume":"35","author":"Gonzalez","year":"2008","journal-title":"J. Rheum."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1097\/00002281-200405000-00013","article-title":"Rheumatoid factor revisited","volume":"16","author":"Egerer","year":"2004","journal-title":"Curr. Opin. Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/qjmed\/hcp165","article-title":"Autoantibodies in rheumatoid arthritis: Rheumatoid factors and anticitrullinated protein antibodies","volume":"103","author":"Song","year":"2010","journal-title":"Qjm"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1002\/art.27584","article-title":"2010 Rheumatoid arthritis classification criteria: An american college of rheumatology\/european league against rheumatism collaborative initiative","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"48487","DOI":"10.1074\/jbc.R400025200","article-title":"C-Reactive protein","volume":"279","author":"Black","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_17","first-page":"11","article-title":"The erythrocyte sedimentation rate: Old and new clinical applications","volume":"4","author":"Saadeh","year":"1998","journal-title":"Women"},{"key":"ref_18","first-page":"1477","article-title":"Comparative usefulness of c-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis","volume":"24","author":"Wolfe","year":"1997","journal-title":"J. Rheum."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Suzuki, K., Sawada, T., Murakami, A., Matsui, T., Tohma, S., Nakazono, K., Takemura, M., Takasaki, Y., Mimori, T., and Yamamoto, K. (2009). High diagnostic performance of elisa detection of antibodies to citrullinated antigens in rheumatoid arthritis. Scand. J. Rheum., 32.","DOI":"10.1080\/03009740310003677"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10049","DOI":"10.1073\/pnas.86.24.10049","article-title":"Hla-dr4 subtype frequencies in rheumatoid arthritis indicate that drb1 is the major susceptibility locus within the hla class ii region","volume":"86","author":"Wordsworth","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1111\/j.1399-0039.1990.tb01834.x","article-title":"Rheumatoid arthritis may be primarily associated with hla-dr4 molecules sharing a particular sequence at residues 67\u201374","volume":"36","author":"Spurkland","year":"1990","journal-title":"Tissue Antigens"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1097\/COH.0b013e32833ed177","article-title":"What are biomarkers?","volume":"5","author":"Strimbu","year":"2010","journal-title":"Curr. Opin. HIV AIDS"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1038\/nature06916","article-title":"Mining the plasma proteome for cancer biomarkers","volume":"452","author":"Hanash","year":"2008","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1074\/mcp.M600160-MCP200","article-title":"Mass spectrometric detection of tissue proteins in plasma","volume":"6","author":"Zhang","year":"2007","journal-title":"Mol. Cell. Proteom."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.molonc.2008.12.001","article-title":"Targeted proteomic strategy for clinical biomarker discovery","volume":"3","author":"Schiess","year":"2009","journal-title":"Mol. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1002\/pmic.200300670","article-title":"Quantification of c-reactive protein in the serum of patients with rheumatoid arthritis using multiple reaction monitoring mass spectrometry and 13c-labeled peptide standards","volume":"4","author":"Kuhn","year":"2004","journal-title":"Proteomics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3792","DOI":"10.1002\/art.20720","article-title":"Use of mass spectrometry to identify protein biomarkers of disease severity in the synovial fluid and serum of patients with rheumatoid arthritis","volume":"50","author":"Liao","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1136\/ard.2009.118919","article-title":"Itraq-based proteomic identification of leucine-rich \u03b1-2 glycoprotein as a novel inflammatory biomarker in autoimmune diseases","volume":"69","author":"Serada","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1177\/1753425910393370","article-title":"Adipocyte-macrophage interaction may mediate lps-induced low-grade inflammation: Potential link with metabolic complications","volume":"18","author":"Nakarai","year":"2012","journal-title":"Innate Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.bbrc.2014.07.054","article-title":"Characterization of rat serum amyloid a4 (saa4): A novel member of the saa superfamily","volume":"450","author":"Rossmann","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","first-page":"1","article-title":"Serum amyloid a as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis","volume":"2014","author":"Majdan","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/art.21518","article-title":"Acute-phase serum amyloid a stimulation of angiogenesis, leukocyte recruitment, and matrix degradation in rheumatoid arthritis through an nf-\u03bab-dependent signal transduction pathway","volume":"54","author":"Mullan","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13075-016-1009-y","article-title":"Differential response of serum amyloid a to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker","volume":"18","author":"Hwang","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/art.33455","article-title":"Acute-phase serum amyloid a regulates tumor necrosis factor \u03b1 and matrix turnover and predicts disease progression in patients with inflammatory arthritis before and after biologic therapy","volume":"64","author":"Connolly","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1016\/j.molimm.2015.03.254","article-title":"An involvement of sr-b1 mediated p38 mapk signaling pathway in serum amyloid a-induced angiogenesis in rheumatoid arthritis","volume":"66","author":"Hong","year":"2015","journal-title":"Mol. Immun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.4049\/jimmunol.166.4.2801","article-title":"Serum amyloid a (aposaa) expression is up-regulated in rheumatoid arthritis and induces transcription of matrix metalloproteinases","volume":"166","author":"Vallon","year":"2001","journal-title":"J. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.talanta.2014.03.017","article-title":"Comprehensive plasma profiling for the characterization of graft-versus-host disease biomarkers","volume":"125","author":"Beguin","year":"2014","journal-title":"Talanta"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/1559-0275-9-14","article-title":"Ovarian cyst fluid is a rich proteome resource for detection of new tumor biomarkers","volume":"9","author":"Kristjansdottir","year":"2012","journal-title":"Clin. Proteom."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1001\/jama.291.5.585","article-title":"C-Reactive protein and the risk of incident colorectal cancer","volume":"291","author":"Erlinger","year":"2004","journal-title":"Jama"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1136\/jech.2006.051292","article-title":"A systematic review of the association between circulating concentrations of c reactive protein and cancer","volume":"61","author":"Ebrahim","year":"2007","journal-title":"J. Epidemiol. Commun. Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/ajcp\/53.4.452","article-title":"Cholinesterase activity in patients with rheumatoid arthritis","volume":"53","author":"Milstoc","year":"1970","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.3346\/jkms.2014.29.9.1199","article-title":"Usefulness of serum leucine-rich alpha-2 glycoprotein as a disease activity biomarker in patients with rheumatoid arthritis","volume":"29","author":"Ha","year":"2014","journal-title":"J. Korean Med. Sci."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/5\/805\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:35:48Z","timestamp":1760207748000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/22\/5\/805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,14]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["molecules22050805"],"URL":"https:\/\/doi.org\/10.3390\/molecules22050805","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,14]]}}}