Keywords
biomarkers
cytokines
proteomics
metabolomics
extracellular vesicles
Categories
How to Cite
Abstract
Synovial fluid offers a direct window into the intra-articular environment, but individual biomarkers rarely separate arthritis subtypes reliably. This narrative review compares conventional tests with cytokines, proteomic markers, extracellular vesicles, microRNAs, metabolomics, and machine-learning-assisted multi-omics across rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, periprosthetic joint infection, crystal-induced arthritis, connective tissue disease-associated arthritis, and Lyme arthritis. Relevant publications from 2017–2026 were identified through structured searches of PubMed, Scopus, Web of Science, and Google Scholar, supplemented by manual screening of reference lists; selection prioritized systematic and narrative reviews, translational studies, and clinically relevant biomarker investigations, and reporting followed the SANRA framework for narrative reviews. The most clinically mature applications remain conventional cell count, crystal analysis, microbiological testing, and alpha-defensin assessment for periprosthetic joint infection, whereas extracellular vesicles, microRNAs, and multi-omics remain largely translational.
References
1. Smolen JS, Aletaha D, Barton A, Burmester GR, Emery P, Firestein GS, et al. Rheumatoid arthritis. Nat Rev Dis Primers. 2018;4:18001. https://doi.org/10.1038/nrdp.2018.1
2. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. London, England; 2019;393:1745–59. https://doi.org/10.1016/S0140-6736(19)30417-9
3. Firestein G, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–96. https://doi.org/10.1016/j.immuni.2017.02.006
4. Peters H, Rockel JS, Little CB, Kapoor M. Synovial fluid as a complex molecular pool contributing to knee osteoarthritis. Nat Rev Rheumatol. Nature Publishing Group; 2025;21:447–64. https://doi.org/10.1038/s41584-025-01271-4
5. Pascual E, Jovaní V. Synovial fluid analysis. Best Practice & Research Clinical Rheumatology. 2005;19:371–86. https://doi.org/10.1016/j.berh.2005.01.004
6. Abdelattif Engy, Anthony J. Freemont, and DC Mangham, 'Assessment of synovial joint fluid', in Richard A. Watts, and others (eds), Oxford Textbook of Rheumatology, 4 edn, Oxford Textbook (Oxford, 2013; online edn, Oxford Academic, 1 May 2019), https://doi.org/10.1093/med/9780199642489.003.0072
7. Chen P, Zhang S, Wu L, Yong Z, Jin Q, Sun K. A comprehensive metabolomic dataset of human synovial fluid in osteoarthritis and healthy controls. Data in Brief. 2025;63:112224. https://doi.org/10.1016/j.dib.2025.112224
8. Munjal A, Bapat S, Hubbard D, Hunter M, Kolhe R, Fulzele S. Advances in Molecular biomarker for early diagnosis of Osteoarthritis. Biomolecular Concepts. 2019;10:111–9. https://doi.org/10.1515/bmc-2019-0014
9. Haraden CA, Huebner JL, Hsueh M-F, Li Y-J, Kraus VB. Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation. Arthritis Res Ther. 2019;21:146. https://doi.org/10.1186/s13075-019-1923-x
10. Altobelli E, Angeletti P, Piccolo D, Angelis R. Synovial Fluid and Serum Concentrations of Inflammatory Markers in Rheumatoid Arthritis, Psoriatic Arthritis and Osteoarthitis: A Systematic Review. Current Rheumatology Reviews. 2017;13:1–1. https://doi.org/10.2174/1573397113666170427125918
11. Meehan RT, Regan EA, Hoffman ED, Wolf ML, Gill MT, Crooks JL, et al. Synovial Fluid Cytokines, Chemokines and MMP Levels in Osteoarthritis Patients with Knee Pain Display a Profile Similar to Many Rheumatoid Arthritis Patients. J Clin Med. 2021;10:5027. https://doi.org/10.3390/jcm10215027
12. Steinmeyer J. Phospholipids and sphingolipids in osteoarthritis. Biomolecules. 2025;15(2):250. https://doi.org/10.3390/biom15020250
13. Bader JM, Albrecht V, Mann M. MS-Based Proteomics of Body Fluids: The End of the Beginning. Mol Cell Proteomics. 2023;22:100577. https://doi.org/10.1016/j.mcpro.2023.100577
14. Bartikoski BJ, De Oliveira MS, Do Espírito Santo RC, Dos Santos LP, Dos Santos NG, Xavier RM. A review of metabolomic profiling in rheumatoid arthritis: bringing new insights in disease pathogenesis, treatment and comorbidities. Metabolites. 2022;12(5):394. https://doi.org/10.3390/metabo12050394
15. Mateos Martín J, Lourido L, Fernández-Puente P, Calamia V, Fernández-López C, Oreiro N, et al. Differential protein profiling of synovial fluid from rheumatoid arthritis and osteoarthritis patients using LC-MALDI TOF/TOF. Journal of proteomics. 2012;75:2869–78. https://doi.org/10.1016/j.jprot.2011.12.042
16. Tynan Ó, Hanlon MM, Floudas A, Wade S, Fearon U, Veale DJ. Circulatory microRNA signature distinguishing rheumatoid arthritis and psoriatic arthritis. Rheumatology (Oxford). 2026;65:keag246. https://doi.org/10.1093/rheumatology/keag246
17. Picotti P, Aebersold R. Selected reaction monitoring–based proteomics: workflows, potential, pitfalls and future directions. Nat Methods. Nature Publishing Group; 2012;9:555–66. https://doi.org/10.1038/nmeth.2015
18. Tanaka T, Narazaki M, Kishimoto T. IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harb Perspect Biol. Cold Spring Harbor Lab; 2014;6:a016295. https://doi.org/10.1101/cshperspect.a016295
19. Szekanecz Z, Gunkl-Tóth L, Szamosi S, van der Woude D, McInnes I, Nagy G. Diagnostic, prognostic and therapeutic biomarkers in rheumatoid arthritis. Nat Rev Rheumatol. 2026;22(8):496–513. https://doi.org/10.1038/s41584-026-01391-5
20. Feldmann M, Maini RN. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med. Nature Publishing Group; 2003;9:1245–50. https://doi.org/10.1038/nm939
21. Ritchlin CT, Colbert RA, Gladman DD. Psoriatic arthritis. N Engl J Med. 2017;376(10):957-970. https://doi.org/10.1056/NEJMra1505557
22. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacology & Therapeutics. 2008;117:244–79. https://doi.org/10.1016/j.pharmthera.2007.10.001
23. Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol. 2011;7(1):33-42. https://doi.org/10.1038/nrrheum.2010.196
24. Ouboussad L, Burska AN, Melville A, Buch MH. Synovial Tissue Heterogeneity in Rheumatoid Arthritis and Changes With Biologic and Targeted Synthetic Therapies to Inform Stratified Therapy. Frontiers in Medicine. Frontiers Media S.A.; 2019;6. https://doi.org/10.3389/fmed.2019.00045
25. Wu CL, Harasymowicz NS, Klimak MA, Collins KH, Guilak F. The role of macrophages in osteoarthritis and cartilage repair. Osteoarthritis Cartilage. 2020;28(5):544-554. https://doi.org/10.1016/j.joca.2019.12.007
26. Boffa A, Merli G, Andriolo L, Lattermann C, Salzmann GM, Filardo G. Synovial Fluid Biomarkers in Knee Osteoarthritis: A Systematic Review and Quantitative Evaluation Using BIPEDs Criteria. CARTILAGE. 2021;13(1_suppl):82S-103S. doi:10.1177/1947603520942941
27. Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci. 2006;11:529–43. https://doi.org/10.2741/1817
28. Xue M, Wang H, Campos F, Jackson CJ, March L. Rheumatoid Arthritis: Biomarkers and the Latest Breakthroughs. Int J Mol Sci. 2025;26:10594. https://doi.org/10.3390/ijms262110594
29. Hu Q, Ecker M. Overview of MMP-13 as a Promising Target for the Treatment of Osteoarthritis. Int J Mol Sci. 2021;22:1742. https://doi.org/10.3390/ijms22041742
30. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. Nature Publishing Group; 2007;7:429–42. https://doi.org/10.1038/nri2094
31. Huang Y, Liu Y, Huang Q, Sun S, Ji Z, Huang L, et al. TMT-Based Quantitative Proteomics Analysis of Synovial Fluid-Derived Exosomes in Inflammatory Arthritis. Front Immunol. Frontiers; 2022;13. https://doi.org/10.3389/fimmu.2022.800902
32. Smolinska V, Klimova D, Danisovic L, Harsanyi S. Synovial fluid markers and extracellular vesicles in rheumatoid arthritis. Medicina (Kaunas). 2024;60(12):1945. https://doi.org/10.3390/medicina60121945
33. Peng X, Wang Q, Li W, Ge G, Peng J, Xu Y, Yang H, Bai J, Geng D. Comprehensive overview of microRNA function in rheumatoid arthritis. Bone Res. 2023;11:8. https://doi.org/10.1038/s41413-023-00244-1
34. Sacco I, Saadan C, Pina Vegas L, Chevalier X, Souhail B, Lepeule R, et al. A new biochemical score from synovial fluid for diagnosing septic arthritis. Joint Bone Spine. 2026;93:105980. https://doi.org/10.1016/j.jbspin.2025.105980
35. Deng M, Tang C, Yin L, Jiang Y, Huang Y, Feng Y, et al. Clinical and omics biomarkers in osteoarthritis diagnosis and treatment. Journal of Orthopaedic Translation. 2025;50:295–305. https://doi.org/10.1016/j.jot.2024.12.007
36. Dubey S, Chan A, Adebajo AO, Walker D, Bukhari M. Artificial intelligence and machine learning in rheumatology. Rheumatology (Oxford). 2024;63(8):2040-2041. https://doi.org/10.1093/rheumatology/keae092
37. Shumnalieva R, Kotov G, Ermencheva P, Monov S. Pathogenic Mechanisms and Therapeutic Approaches in Obesity-Related Knee Osteoarthritis. Biomedicines. 2023;12:9. https://doi.org/10.3390/biomedicines12010009
38. Shumnalieva R, Kotov G, Monov S. Obesity-Related Knee Osteoarthritis-Current Concepts. Life (Basel). Basel, Switzerland; 2023;13:1650. https://doi.org/10.3390/life13081650
39. Nelson SB, Pinkney JA, Chen AF, Tande AJ. Periprosthetic joint infection: current clinical challenges. Clin Infect Dis. 2023;77(7):e34-e45. https://doi.org/10.1093/cid/ciad360
40. Bonanzinga T, Zahar A, Dütsch M, Lausmann C, Kendoff D, Gehrke T. How Reliable Is the Alpha-defensin Immunoassay Test for Diagnosing Periprosthetic Joint Infection? A Prospective Study. Clin Orthop Relat Res. 2017;475:408–15. https://doi.org/10.1007/s11999-016-4906-0
41. Liu Y, Wang J, Li J. Role of NLRP3 in the pathogenesis and treatment of gout arthritis. Front Immunol [Internet]. Frontiers; 2023;14. https://doi.org/10.3389/fimmu.2023.1137822
42. Melicherčík P, Mazura M, Hodík M, Dundrová K, Landor I, Jahoda D, et al. Synovial fluid alpha-defensins in Lyme arthritis—a useful marker. Folia Microbiol. 2024;69:1355–62. https://doi.org/10.1007/s12223-024-01173-0
43. Sippl N, Faustini F, Rönnelid J, Turcinov S, Chemin K, Gunnarsson I, Malmström V. Arthritis in systemic lupus erythematosus is characterized by local IL-17A and IL-6 expression in synovial fluid. Clin Exp Immunol. 2021;205(1):44-52. https://doi.org/10.1111/cei.13585
44. Foers AD, Chatfield S, Dagley LF, Scicluna BJ, Webb AI, Cheng L, Hill AF, Wicks IP, Pang KC. Enrichment of extracellular vesicles from human synovial fluid using size exclusion chromatography. J Extracell Vesicles. 2018;7(1):1490145. https://doi.org/10.1080/20013078.2018.1490145
45. Nocton JJ, Dressler F, Rutledge BJ, Rys PN, Persing DH, Steere AC. Detection of Borrelia burgdorferi DNA by polymerase chain reaction in synovial fluid from patients with Lyme arthritis. N Engl J Med. 1994;330(4):229-234. https://doi.org/10.1056/NEJM199401273300401
46. Li, Z., Li, C., Wang, G. et al. Diagnostic accuracy of synovial fluid D-lactate for periprosthetic joint infection: a systematic review and meta-analysis. J Orthop Surg Res 16, 606 (2021). https://doi.org/10.1186/s13018-021-02778-8
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Vassilia Terzieva, Mariana Ivanova, Georgi Kotov (Author)