{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:26:49Z","timestamp":1760149609645,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of scientific Research at King Saud University","award":["G-1440-077"],"award-info":[{"award-number":["G-1440-077"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that causes multi-articular synovitis. The illness is characterized by worsening inflammatory synovitis, which causes joint swelling and pain. Synovitis erodes articular cartilage and marginal bone, resulting in joint deterioration. This bone injury is expected to be permanent. Cytokines play a prominent role in the etiology of RA and could be useful as early diagnostic biomarkers. This research was carried out at Riyadh\u2019s King Khalid University Hospital (KKUH). Patients were enrolled from the Rheumatology unit. Seventy-eight RA patients were recruited (67 (85.9%) females and 11 (14.1%) males). Patients were selected for participation by convenience sampling. Demographic data were collected, and disease activity measurements at 28 joints were recorded using the disease activity score (DAS-28). Age- and sex-matched controls from the general population were included in the study. A panel of 27 cytokines, chemokines, and growth factors was determined in patient and control sera. Binary logistic regression (BLR) and discriminant analysis (DA) were used to analyze the data. We show that multiple cytokine biomarker profiles successfully distinguished RA patients from healthy controls. IL-17, IL-4, and RANTES were among the most predictive variables and were the only biomarkers incorporated into both BLR and DA predictive models for pooled participants (men and women). In the women-only models, the significant cytokines incorporated in the model were IL-4, IL-17, MIP-1b, and RANTES for the BLR model and IL-4, IL-1Ra, GM-CSF, IL-17, and eotaxin for the DA model. The BLR and DA men-only models contained one cytokine each, eotaxin for BLR and platelet-derived growth factor-bb (PDGF-BB) for DA. We show that BLR has a higher fidelity in identifying RA patients than DA. We also found that the use of gender-specific models marginally improves detection fidelity, indicating a possible benefit in clinical diagnosis. More research is needed to determine whether this conclusion will hold true in various and larger patient populations.<\/jats:p>","DOI":"10.3390\/biom13091305","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:25:33Z","timestamp":1692951933000},"page":"1305","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Fidelity of Rheumatoid Arthritis Multivariate Diagnostic Biomarkers Using Discriminant Analysis and Binary Logistic Regression"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2960-3927","authenticated-orcid":false,"given":"Wail M.","family":"Hassan","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nashwa","family":"Othman","sequence":"additional","affiliation":[{"name":"Central Research Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6735-8758","authenticated-orcid":false,"given":"Maha","family":"Daghestani","sequence":"additional","affiliation":[{"name":"Department of Zoology, College of Science, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arjumand","family":"Warsy","sequence":"additional","affiliation":[{"name":"Central Research Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maha A.","family":"Omair","sequence":"additional","affiliation":[{"name":"Department of Statistics and Operations Research, College of Sciences, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eman","family":"Alqurtas","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shireen","family":"Amin","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdulaziz","family":"Ismail","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afaf","family":"El-Ansary","sequence":"additional","affiliation":[{"name":"Central Research Laboratory, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2149-6239","authenticated-orcid":false,"given":"Ramesa Shafi","family":"Bhat","sequence":"additional","affiliation":[{"name":"Biochemistry Department, College of Science, Center for Science and Medical Studies for Girls, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed A.","family":"Omair","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1111\/1756-185X.12132","article-title":"Th17 Cells in Immunopathogenesis and treatment of rheumatoid arthritis","volume":"16","author":"Azizi","year":"2013","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s00296-007-0357-y","article-title":"Evidence-based review of biologic markers as indicators of disease progression and remission in rheumatoid arthritis","volume":"27","author":"Emery","year":"2007","journal-title":"Rheumatol. Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"954","DOI":"10.1136\/ard.2007.084459","article-title":"Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein against disease progression in patients with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate","volume":"68","author":"Wells","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/cyto.b.20452","article-title":"A comparison of multiplex suspension array large-panel kits for profiling cytokines and chemokines in rheumatoid arthritis patients","volume":"76","author":"Khan","year":"2009","journal-title":"Cytom. B Clin. Cytom."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/978-1-60327-527-9_9","article-title":"Cytokine multiplex immunoassay: Methodology and (clinical) applications","volume":"514","author":"Prakken","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/1440-1681.12946","article-title":"The role of interleukin-4 in rheumatic diseases","volume":"45","author":"Dong","year":"2018","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1007\/s11926-009-0052-y","article-title":"The role of interleukin-17 in the pathogenesis of rheumatoid arthritis","volume":"11","author":"Gaffen","year":"2009","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"802464","DOI":"10.3389\/fgene.2022.802464","article-title":"Genetically Determined Circulating Levels of Cytokines and the Risk of Rheumatoid Arthritis","volume":"13","author":"Qian","year":"2022","journal-title":"Front. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7937","DOI":"10.1038\/s41598-021-87199-7","article-title":"Eotaxin-1\/CCL11 is involved in cell migration in rheumatoid arthritis","volume":"11","author":"Wakabayashi","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3323","DOI":"10.1007\/s10067-020-05109-0","article-title":"Evaluation of plasma cytokine protein array profile: The highlighted PDGF-BB in rheumatoid arthritis","volume":"39","author":"Wang","year":"2020","journal-title":"Clin. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.clim.2004.12.009","article-title":"The fibroblast-like synovial cell in rheumatoid arthritis: A key player in inflammation and joint destruction","volume":"115","author":"Mor","year":"2005","journal-title":"Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1006\/clim.2000.4957","article-title":"CXCR3 and CCR5 ligands in rheumatoid arthritis synovium","volume":"98","author":"Patel","year":"2001","journal-title":"Clin. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1186\/ar318","article-title":"Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): Requirement for GM-CSF in the effector phase of disease","volume":"3","author":"Cook","year":"2001","journal-title":"Arthritis Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/ar3845","article-title":"Early diagnosis to enable early treatment of pre-osteoarthritis","volume":"14","author":"Chu","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1093\/comjnl\/9.1.60","article-title":"Computer programs for hierarchical polythetic classification (\u201csimilarity analyses\u201d)","volume":"9","author":"Lance","year":"1966","journal-title":"Comput. J."},{"key":"ref_16","first-page":"6","article-title":"Mixed-Data Classificatory Programs I\u2014Agglomerative Systems","volume":"1","author":"Lance","year":"1967","journal-title":"Autralian Comput. J."},{"key":"ref_17","first-page":"30","article-title":"A statistical method for evaluating systematic relationships","volume":"38","author":"Michener","year":"1958","journal-title":"Univ. Kans. Sci. Bull."},{"unstructured":"Warner, R.M. (2008). Applied Statistics: From Bivariate through Multivariate Techniques, Sage Publications, Inc.","key":"ref_18"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1080\/03610928008827941","article-title":"Goodness of fit tests for the multiple logistic regression model","volume":"9","author":"Hosmer","year":"1980","journal-title":"Commun. Stat.-Theory Methods"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1093\/biomet\/78.3.691","article-title":"A note on the general definition of the coefficient of determination","volume":"78","author":"Nagelkerke","year":"1991","journal-title":"Biometrika"},{"key":"ref_21","first-page":"73","article-title":"Discriminant Function Analysis: Concept and Application","volume":"33","year":"2008","journal-title":"Eurasian J. Educ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1177\/0013164494054003009","article-title":"The Relationship Between Canonical Correlation Analysis and Multivariate Multiple Regression","volume":"54","author":"Lutz","year":"1994","journal-title":"Educ. Psychol. Meas."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3102\/10769986016002101","article-title":"Standardized Discriminant Coefficients Revisited","volume":"16","author":"Nordlund","year":"1991","journal-title":"J. Educ. Stat."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"545493","DOI":"10.1155\/2014\/545493","article-title":"Cytokines as biomarkers in rheumatoid arthritis","volume":"2014","author":"Burska","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"263625","DOI":"10.1155\/2014\/263625","article-title":"Cytokine-mediated bone destruction in rheumatoid arthritis","volume":"2014","author":"Jung","year":"2014","journal-title":"J. Immunol. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1177\/1759720X10378372","article-title":"The role of interleukin 6 in the pathophysiology of rheumatoid arthritis","volume":"2","author":"Srirangan","year":"2010","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.jaut.2005.09.016","article-title":"Increased levels of bioactive IL-16 correlate with disease activity during relapsing experimental autoimmune encephalomyelitis (EAE)","volume":"25","author":"Skundric","year":"2005","journal-title":"J. Autoimmun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.4110\/in.2018.18.e8","article-title":"Regulation of Osteoclast Differentiation by Cytokine Networks","volume":"18","author":"Amarasekara","year":"2018","journal-title":"Immune Netw."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1023\/A:1023278606036","article-title":"Increased production of a Th2 cytokine profile by activated whole blood cells from rheumatoid arthritis patients","volume":"18","author":"Haddad","year":"1998","journal-title":"J. Clin. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1136\/ard.56.11.656","article-title":"Decrease in peripheral type 1 over type 2 T cell cytokine production in patients with rheumatoid arthritis correlates with an increase in severity of disease","volume":"56","author":"Verhoef","year":"1997","journal-title":"Ann. Rheum. Dis."},{"doi-asserted-by":"crossref","unstructured":"Iwaszko, M., Bialy, S., and Bogunia-Kubik, K. (2021). Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells, 10.","key":"ref_31","DOI":"10.3390\/cells10113000"},{"key":"ref_32","first-page":"155","article-title":"Different cytokine profiles in the synovial fluid of patients with osteoarthritis, rheumatoid arthritis and seronegative spondylarthropathies","volume":"14","author":"Schlaak","year":"1996","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1002\/art.27186","article-title":"Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis","volume":"62","author":"Kokkonen","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/nrrheum.2009.185","article-title":"Dendritic cells as targets for therapy in rheumatoid arthritis","volume":"5","author":"Khan","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1016\/j.autrev.2017.07.009","article-title":"Effects of Interleukin 17 on the cardiovascular system","volume":"16","author":"Robert","year":"2017","journal-title":"Autoimmun. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"828933","DOI":"10.3389\/fphar.2022.828933","article-title":"A Role of IL-17 in Rheumatoid Arthritis Patients Complicated With Atherosclerosis","volume":"13","author":"Wang","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nrrheum.2009.179","article-title":"IL-17 as a future therapeutic target for rheumatoid arthritis","volume":"5","author":"Miossec","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1007\/s10753-014-0020-1","article-title":"Increased plasma IL-17F levels in rheumatoid arthritis patients are responsive to methotrexate, anti-TNF, and T cell costimulatory modulation","volume":"38","author":"Jain","year":"2015","journal-title":"Inflammation"},{"key":"ref_39","first-page":"87","article-title":"Serum Interleukin-17 Level in Patients with Rheumatoid Arthritis and its Relation to Disease Activity","volume":"26","author":"Atwa","year":"2019","journal-title":"Zagazig Univ. Med. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1002\/art.21962","article-title":"RANTES and monocyte chemoattractant protein 1 as sensitive markers of disease activity in patients with juvenile rheumatoid arthritis: A six-year longitudinal study","volume":"54","author":"Yao","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/S1001-9294(09)60059-6","article-title":"Expression of CC chemokine ligand 5 in patients with rheumatoid arthritis and its correlation with disease activity and medication","volume":"24","author":"Yang","year":"2009","journal-title":"Chin. Med. Sci. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3264","DOI":"10.4049\/jimmunol.1500502","article-title":"Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis","volume":"196","author":"Charbonneau","year":"2016","journal-title":"J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"16192","DOI":"10.1038\/s41598-017-16443-w","article-title":"PDGFR Signaling Mediates Hyperproliferation and Fibrotic Responses of Subsynovial Connective Tissue Cells in Idiopathic Carpal Tunnel Syndrome","volume":"7","author":"Saito","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7879","DOI":"10.3892\/mmr.2017.7641","article-title":"PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics (Review)","volume":"16","author":"Ying","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e1186","DOI":"10.1038\/cddis.2014.161","article-title":"Identification and characterization of PDGFRalpha+ mesenchymal progenitors in human skeletal muscle","volume":"5","author":"Uezumi","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"123","DOI":"10.2147\/OARRR.S306378","article-title":"Influence of Age and Sex on Disease Course and Treatment in Rheumatoid Arthritis","volume":"13","author":"Nilsson","year":"2021","journal-title":"Open Access Rheumatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s13075-020-02413-7","article-title":"Predictors of radiographic erosion and joint space narrowing progression in patients with early rheumatoid arthritis: A cohort study","volume":"23","author":"Rydell","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"879","DOI":"10.55563\/clinexprheumatol\/4bcmdb","article-title":"Rheumatoid arthritis autoantibodies and their association with age and sex","volume":"39","author":"Pertsinidou","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_49","first-page":"18","article-title":"Serum levels of IL-17, IL-4, and INFgamma in Serbian patients with early rheumatoid arthritis","volume":"19","author":"Pavlovic","year":"2014","journal-title":"J. Res. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"703","DOI":"10.3233\/BMR-170903","article-title":"Relationship of hematologic markers with IL-17 and IL-1 beta in patients with rheumatoid arthritis","volume":"31","author":"Sag","year":"2018","journal-title":"J. Back. Musculoskelet. Rehabil."},{"key":"ref_51","first-page":"272","article-title":"Correlation study between interleukin-17 and ESR and CRP in serum and the synovial fluid of rheumatoid arthritis patients of accumulated dampness-heat obstruction in joints syndrome","volume":"34","author":"Liu","year":"2014","journal-title":"Zhongguo Zhong Xi Yi Jie He Za Zhi"},{"unstructured":"Tishkowski, K., and Gupta, V. (2023). StatPearls, StatPearls Publishing.","key":"ref_52"},{"key":"ref_53","first-page":"75369","article-title":"Association of Fibrinogen, Erythrocyte Sedimentation Rate, and C-Reactive Protein Levels with Rheumatoid Arthritis","volume":"4","author":"Babikir","year":"2017","journal-title":"Open Access Libr. J."},{"key":"ref_54","first-page":"331","article-title":"Regulation of fibrinogen biosynthesis by cytokines, consequences on the vascular risk","volume":"26","author":"Vasse","year":"1996","journal-title":"Haemostasis"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1305\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:38:44Z","timestamp":1760128724000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/9\/1305"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,25]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["biom13091305"],"URL":"https:\/\/doi.org\/10.3390\/biom13091305","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2023,8,25]]}}}