{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:22:59Z","timestamp":1792664579698,"version":"4.5.0"},"reference-count":56,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"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>The biomarker landscape in rheumatoid arthritis (RA) is evolving from reliance on traditional markers toward integrated, multimodal strategies enabling precision medicine approaches. To critically evaluate emerging biomarkers across serological, cellular, genetic, imaging, and multi-omic domains, distinguishing those approaching clinical readiness from those requiring further development. In this study, a narrative review of the literature published between 2000 and 2024 relevant to clinical decision-making in RA was conducted. Among novel serological markers, 14-3-3\u03b7 protein and anti-carbamylated protein antibodies show the strongest validation for seronegative disease and prognostic stratification. Calprotectin demonstrates utility for disease activity monitoring and de-escalation decisions. Multi-biomarker disease activity scores provide an objective assessment but lack outcome trial validation. Musculoskeletal ultrasound offers accessible imaging biomarker capability, while MRI bone marrow edema remains the strongest structural progression predictor. Synovial tissue pathotyping has demonstrated proof-of-concept for treatment stratification. Genetic, epigenetic, and metabolomic approaches remain investigational. Key clinical implications include using 14-3-3\u03b7 and calprotectin to inform seronegative diagnosis and de-escalation decisions, integrating ultrasound for remission verification, and recognizing that emerging biomarkers for extra-articular complications, including cardiovascular risk and venous thromboembolism, represent important unmet needs.<\/jats:p>","DOI":"10.3390\/diagnostics16020330","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:24:34Z","timestamp":1768901074000},"page":"330","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Biomarkers in Rheumatoid Arthritis: From Traditional Serology to Precision Medicine Integration"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9051-1810","authenticated-orcid":false,"given":"Muhammad","family":"Soyfoo","sequence":"first","affiliation":[{"name":"Department of Rheumatology, H\u00f4pital Universitaire de Bruxelles, Universit\u00e9 libre de Bruxelles, 1070 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6833-0044","authenticated-orcid":false,"given":"Julie","family":"Sarrand","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, H\u00f4pital Universitaire de Bruxelles, Universit\u00e9 libre de Bruxelles, 1070 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_2","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_3","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1002\/art.22353","article-title":"Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta-analysis","volume":"55","author":"Finckh","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3537","DOI":"10.1002\/art.27692","article-title":"Long-term impact of delay in assessment of patients with early arthritis","volume":"62","author":"Raza","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"797","DOI":"10.7326\/0003-4819-146-11-200706050-00008","article-title":"Meta-analysis: Diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis","volume":"146","author":"Nishimura","year":"2007","journal-title":"Ann. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"17372","DOI":"10.1073\/pnas.1114465108","article-title":"Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage","volume":"108","author":"Shi","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1136\/annrheumdis-2013-204154","article-title":"Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis","volume":"73","author":"Shi","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13075-015-0536-2","article-title":"Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage","volume":"17","author":"Brink","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Darrah, E., Giles, J.T., Davis, R.L., Naik, P., Wang, H., Konig, M.F., Cappelli, L.C., Bingham, C.O., Danoff, S.K., and Andrade, F. (2018). Autoantibodies to Peptidylarginine Deiminase 2 Are Associated With Less Severe Disease in Rheumatoid Arthritis. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.02696"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1097\/BOR.0000000000000452","article-title":"Rheumatoid arthritis and citrullination","volume":"30","author":"Darrah","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1136\/annrheumdis-2014-206785","article-title":"Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis","volume":"75","author":"Juarez","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1002\/art.38969","article-title":"Malondialdehyde-acetaldehyde adducts and anti-malondialdehyde-acetaldehyde antibodies in rheumatoid arthritis","volume":"67","author":"Thiele","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.3899\/jrheum.131446","article-title":"Serum 14-3-3\u03b7 is a novel marker that complements current serological measurements to enhance detection of patients with rheumatoid arthritis","volume":"41","author":"Maksymowych","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R99","DOI":"10.1186\/ar4547","article-title":"14-3-3\u03b7 is a novel mediator associated with the pathogenesis of rheumatoid arthritis and joint damage","volume":"16","author":"Maksymowych","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1016\/j.berh.2019.01.010","article-title":"The diagnostic value of 14-3-3\u03b7 protein levels in patients with rheumatoid arthritis","volume":"32","author":"Shovman","year":"2018","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1186\/s13075-016-1032-z","article-title":"Calprotectin and TNF trough serum levels identify power Doppler ultrasound synovitis in rheumatoid arthritis and psoriatic arthritis patients in remission or with low disease activity","volume":"18","author":"Ramirez","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Hurnakova, J., Hulejova, H., Zavada, J., Hanova, P., Komarc, M., Mann, H., Klein, M., Sleglova, O., Olejarova, M., and Forejtova, S. (2017). Relationship between serum calprotectin (S100A8\/9) and clinical, laboratory and ultrasound parameters of disease activity in rheumatoid arthritis: A large cohort study. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0183420"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e000654","DOI":"10.1136\/rmdopen-2018-000654","article-title":"Predictive value of serum calprotectin (S100A8\/A9) for clinical response after starting or tapering anti-TNF treatment in patients with rheumatoid arthritis","volume":"4","author":"Tweehuysen","year":"2018","journal-title":"RMD Open"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1016\/S0140-6736(23)01525-8","article-title":"Rheumatoid arthritis","volume":"402","author":"Bathon","year":"2023","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102392","DOI":"10.1016\/j.jaut.2019.102392","article-title":"An overview of autoantibodies in rheumatoid arthritis","volume":"110","author":"Huizinga","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.autrev.2012.05.007","article-title":"Closing the serological gap: Promising novel biomarkers for the early diagnosis of rheumatoid arthritis","volume":"12","author":"Trouw","year":"2012","journal-title":"Autoimmun. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1002\/art.11223","article-title":"Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis","volume":"48","author":"Berglin","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1002\/art.20018","article-title":"Specific autoantibodies precede the symptoms of rheumatoid arthritis: A study of serial measurements in blood donors","volume":"50","author":"Nielen","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1002\/acr.21767","article-title":"Validation of a novel multibiomarker test to assess rheumatoid arthritis disease activity","volume":"64","author":"Curtis","year":"2012","journal-title":"Arthritis Care Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1136\/annrheumdis-2013-204986","article-title":"Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: Results from the SWEFOT trial","volume":"74","author":"Hambardzumyan","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1002\/art.40019","article-title":"A multi-biomarker disease activity score and the choice of second-line therapy in early rheumatoid arthritis after methotrexate failure","volume":"69","author":"Hambardzumyan","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Razmjou, A.A., Brook, J., Elashoff, D., Kaeley, G., Choi, S., Kermani, T., and Ranganath, V.K. (2020). Ultrasound and multi-biomarker disease activity score for assessing and predicting clinical response to tofacitinib treatment in patients with rheumatoid arthritis. BMC Rheumatol., 4.","DOI":"10.1186\/s41927-020-00153-4"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e000428","DOI":"10.1136\/rmdopen-2016-000427","article-title":"Scoring ultrasound synovitis in rheumatoid arthritis: A EULAR-OMERACT ultrasound taskforce\u2014Part 1: Definition and development of a standardised, consensus-based scoring system","volume":"3","author":"Terslev","year":"2017","journal-title":"RMD Open"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/rheumatology\/kev006","article-title":"Predictive value of Doppler ultrasound-detected synovitis in relation to failed tapering of biologic therapy in patients with rheumatoid arthritis","volume":"54","author":"Naredo","year":"2015","journal-title":"Rheumatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1136\/annrheumdis-2012-203158","article-title":"EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis","volume":"72","author":"Colebatch","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1136\/ard.2007.071977","article-title":"Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: Bone marrow oedema predicts erosive progression","volume":"67","author":"Haavardsholm","year":"2008","journal-title":"Ann. Rheum. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1136\/ard.2008.088245","article-title":"MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA)","volume":"68","author":"Hetland","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.3899\/jrheum.141248","article-title":"The OMERACT MRI in Arthritis Working Group\u2014Update on Status and Future Research Priorities","volume":"42","author":"Bird","year":"2015","journal-title":"J. Rheumatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/ng.1076","article-title":"Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis","volume":"44","author":"Raychaudhuri","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature12873","article-title":"Genetics of rheumatoid arthritis contributes to biology and drug discovery","volume":"506","author":"Okada","year":"2014","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1136\/annrheumdis-2013-205009","article-title":"Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history","volume":"74","author":"Sparks","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1136\/annrheumdis-2012-201526","article-title":"DNA methylome signature in rheumatoid arthritis","volume":"72","author":"Nakano","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"102391","DOI":"10.1016\/j.autrev.2019.102391","article-title":"MicroRNAs in rheumatoid arthritis: From pathogenesis to clinical impact","volume":"18","author":"Evangelatos","year":"2019","journal-title":"Autoimmun. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Tatar, Z., Migne, C., Petera, M., Gaudin, P., Lequerre, T., Marotte, H., Tebib, J., Pujos-Guillot, E., and Soubrier, M. (2016). Variations in the metabolome in response to disease activity of rheumatoid arthritis. BMC Musculoskelet. Disord., 17.","DOI":"10.1186\/s12891-016-1214-5"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1136\/ard-2022-223356","article-title":"EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update","volume":"82","author":"Smolen","year":"2023","journal-title":"Ann. Rheum. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"492873","DOI":"10.1155\/2014\/492873","article-title":"Autoantibodies to posttranslational modifications in rheumatoid arthritis","volume":"2014","author":"Burska","year":"2014","journal-title":"Mediat. Inflamm."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.clim.2015.04.005","article-title":"Biomarkers for rheumatoid and psoriatic arthritis","volume":"161","author":"Verheul","year":"2015","journal-title":"Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1136\/annrheumdis-2018-214539","article-title":"Synovial cellular and molecular signatures stratify clinical response to csDMARD therapy and predict radiographic progression in early rheumatoid arthritis patients","volume":"78","author":"Humby","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S0140-6736(20)32341-2","article-title":"Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial","volume":"397","author":"Humby","year":"2021","journal-title":"Lancet"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1016\/j.celrep.2019.07.091","article-title":"Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes","volume":"28","author":"Lewis","year":"2019","journal-title":"Cell Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"R90","DOI":"10.1186\/ar4555","article-title":"Synovial phenotypes in rheumatoid arthritis correlate with response to biologic therapeutics","volume":"16","author":"Dennis","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1097\/BOR.0b013e32835fd8eb","article-title":"New learnings on the pathophysiology of RA from synovial biopsies","volume":"25","author":"Pitzalis","year":"2013","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Nerviani, A., Di Cicco, M., Mahto, A., Lliso-Ribera, G., Rivellese, F., Thorborn, G., Hands, R., Bellan, M., Mauro, D., and Boutet, M.-A. (2020). A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNF\u03b1-Blockade in Rheumatoid Arthritis Patients. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00845"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1002\/art.40428","article-title":"Identification of Three Rheumatoid Arthritis Disease Subtypes by Machine Learning Integration of Synovial Histologic Features and RNA Sequencing Data","volume":"70","author":"Orange","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1038\/s41591-022-01789-0","article-title":"Rituximab versus tocilizumab in rheumatoid arthritis: Synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial","volume":"28","author":"Rivellese","year":"2022","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"R95","DOI":"10.1186\/ar3819","article-title":"The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients","volume":"14","author":"Raterman","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Ghiti Moghadam, M., Lamers-Karnebeek, F.B.G., Vonkeman, H.E., ten Klooster, P.M., Tekstra, J., Schilder, A.M., Visser, H., Sasso, E.H., Chernoff, D., and Lems, W.F. (2018). Multi-biomarker disease activity score as a predictor of disease relapse in patients with rheumatoid arthritis stopping TNF inhibitor treatment. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192425"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"152249","DOI":"10.1016\/j.semarthrit.2023.152249","article-title":"Comparative effectiveness of treatments for rheumatoid arthritis in clinical practice: A systematic review","volume":"62","author":"Sparks","year":"2023","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Ouboussad, L., Burska, A.N., Melville, A., and Buch, M.H. (2019). Synovial Tissue Heterogeneity in Rheumatoid Arthritis and Changes With Biologic and Targeted Synthetic Therapies to Inform Stratified Therapy. Front. Med., 6.","DOI":"10.3389\/fmed.2019.00045"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e26953","DOI":"10.1097\/MD.0000000000026953","article-title":"Incidence of venous thromboembolism in rheumatoid arthritis, results from a \u201creal-life\u201d cohort and an appraisal of available literature","volume":"100","author":"Conforti","year":"2021","journal-title":"Medicine"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Conforti, A., Lavalle, G., Varini, F., Lucchetti, L., Cataldi, G., Faticoni, A., Ruggiero, M., Gentile, M., Gimignani, G., and Bassetti, M. (2025). Pro-Inflammatory Cytokines as Early Predictors of Chronic Rheumatologic Disease Following Chikungunya Virus Infection. J. Clin. Med., 14.","DOI":"10.3390\/jcm14196720"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/2\/330\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T09:40:59Z","timestamp":1768902059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/2\/330"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,20]]},"references-count":56,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["diagnostics16020330"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16020330","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,20]]}}}