{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:08:23Z","timestamp":1792177703595,"version":"4.4.0"},"reference-count":96,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:00:00Z","timestamp":1756080000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic inflammation underpins the pathogenesis of both rheumatoid arthritis (RA) and neurodegenerative conditions such as Alzheimer\u2019s disease (AD). This narrative review explores the role of C-reactive protein (CRP), particularly its monomeric form (mCRP), as a central molecular link connecting systemic autoimmune inflammation with neuroinflammatory and vascular pathology. In RA, fibroblast-like synoviocytes (FLSs) are activated by CRP through CD32\/CD64-mediated signaling, triggering proinflammatory cascades involving NF-\u03baB and p38 MAPK. Recent studies have highlighted that locally synthesized CRP within the synovium may convert to mCRP, amplifying inflammation and tissue damage. Beyond RA, mCRP has been identified within amyloid-beta (A\u03b2) plaques in AD brains, suggesting a direct role in neurodegenerative pathology. Experimental models also demonstrate that mCRP is upregulated in stroke-affected brain regions and associated with complement activation and blood\u2013brain barrier (BBB) disruption, which is central to AD progression. The convergence of pathways involving IL-6, RAGE (receptor for advanced glycation end-products), and mCRP-mediated complement activation reveals a shared axis of inflammation between RA and AD. This highlights the potential of mCRP not only as a biomarker of chronic inflammation but also as a therapeutic target. Furthermore, evidence from periodontal disease and cardiovascular comorbidities highlights the systemic nature of mCRP-driven inflammation, offering insights into the mechanisms of disease overlap. This review advocates for further mechanistic studies into mCRP signaling, particularly its role at the interface of systemic and neuroinflammation, with the goal of identifying new interventional strategies for patients with RA at elevated risk of neurodegenerative and vascular complications.<\/jats:p>","DOI":"10.3390\/ijms26178227","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T06:08:37Z","timestamp":1756102117000},"page":"8227","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Beyond the Biomarker: Monomeric CRP as a Driver of Multisystem Pathology in Rheumatoid Arthritis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0165-7972","authenticated-orcid":false,"given":"Andreea","family":"Lazarut-Nistor","sequence":"first","affiliation":[{"name":"Rheumatology Clinic, County Emergency Clinical Hospital, 540136 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3767-4861","authenticated-orcid":false,"given":"Mark","family":"Slevin","sequence":"additional","affiliation":[{"name":"Centre for Advanced Medical and Pharmaceutical Research, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Fujita, C., Sakurai, Y., Yasuda, Y., Homma, R., Huang, C.-L., and Fujita, M. (2022). mCRP as a Biomarker of Adult-Onset Still\u2019s Disease: Quantification of mCRP by ELISA. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.938173"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.semarthrit.2020.11.005","article-title":"C-reactive protein and implications in rheumatoid arthritis and associated comorbidities","volume":"51","author":"Pope","year":"2021","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s13075-015-0563-z","article-title":"Role of C-reactive protein in osteoclastogenesis in rheumatoid arthritis","volume":"17","author":"Kim","year":"2015","journal-title":"Arthritis Res. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R39","DOI":"10.1186\/ar2645","article-title":"Serum levels of soluble receptor for advanced glycation end products and of S100 proteins are associated with inflammatory, autoantibody, and classical risk markers of joint and vascular damage in rheumatoid arthritis","volume":"11","author":"Chen","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chang, C.-K., Chiang, E.-P.I., Chang, K.-H., Tang, K.-T., Chen, P.-K., Yip, H.-T., Chen, C.-H., and Chen, D.-Y. (2023). The Sizes and Composition of HDL-Cholesterol Are Significantly Associated with Inflammation in Rheumatoid Arthritis Patients. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310645"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"402","DOI":"10.2119\/molmed.2009.00052","article-title":"Osteopontin Is Associated with Increased Arterial Stiffness in Rheumatoid Arthritis","volume":"15","author":"Bazzichi","year":"2009","journal-title":"Mol. Med."},{"key":"ref_7","first-page":"922","article-title":"Toll-like receptor 3 and interleukin 1\u03b2 expression in CD34+ cells from patients with rheumatoid arthritis: Association with inflammation and vascular involvement","volume":"32","author":"Mandraffino","year":"2014","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuint.2011.12.007","article-title":"Promotion of \u03b2-amyloid production by C-reactive protein and its implications in the early pathogenesis of Alzheimer\u2019s disease","volume":"60","author":"Bi","year":"2012","journal-title":"Neurochem. Int."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S3775","DOI":"10.4103\/jpbs.jpbs_975_24","article-title":"Exploring the Link between Periodontal Disease and Systemic Conditions: Implications for Alzheimer\u2019s, Parkinson\u2019s, and Rheumatoid Arthritis","volume":"16","author":"Kanimozhi","year":"2024","journal-title":"J. Pharm. Bioallied Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1002\/1529-0131(200007)43:7<1473::AID-ANR9>3.0.CO;2-N","article-title":"Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis","volume":"43","author":"Plant","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1136\/ard.60.10.924","article-title":"Predictors of radiographic joint damage in patients with early rheumatoid arthritis","volume":"60","author":"Jansen","year":"2001","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","first-page":"9","article-title":"The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome","volume":"24","author":"Devlin","year":"1997","journal-title":"J. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14188","DOI":"10.1038\/ncomms14188","article-title":"Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites","volume":"8","author":"Braig","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_14","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_15","doi-asserted-by":"crossref","unstructured":"Sproston, N.R., and Ashworth, J.J. (2018). Role of C-Reactive Protein at Sites of Inflammation and Infection. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00754"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1161\/CIRCULATIONAHA.113.007124","article-title":"Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation","volume":"130","author":"Thiele","year":"2014","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1172\/JCI200318921","article-title":"C-reactive protein: A critical update","volume":"111","author":"Pepys","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"372432","DOI":"10.1155\/2015\/372432","article-title":"Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes","volume":"2015","author":"Thiele","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1186\/s13075-016-1178-8","article-title":"Extracellular vesicles in the pathogenesis of rheumatoid arthritis and osteoarthritis","volume":"18","author":"Withrow","year":"2016","journal-title":"Arthritis Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/emmm.201201846","article-title":"The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: The microparticle-associated immune complexes","volume":"5","author":"Cloutier","year":"2013","journal-title":"EMBO Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3481","DOI":"10.1007\/s10067-021-05614-w","article-title":"The role of extracellular vesicles in rheumatoid arthritis: A systematic review","volume":"40","author":"Schioppo","year":"2021","journal-title":"Clin. Rheumatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"110281","DOI":"10.1016\/j.clim.2024.110281","article-title":"A tale of two functions: C-reactive protein complement-ary structures and their role in rheumatoid arthritis","volume":"265","author":"Ciurtin","year":"2024","journal-title":"Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Jia, Z.-K., Li, H.-Y., Liang, Y.-L., Potempa, L.A., Ji, S.-R., and Wu, Y. (2018). Monomeric C-Reactive Protein Binds and Neutralizes Receptor Activator of NF-\u03baB Ligand-Induced Osteoclast Differentiation. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00234"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e97","DOI":"10.1161\/01.RES.0000193595.03608.08","article-title":"Pro-inflammatory Effects of Bacterial Recombinant Human C-Reactive Protein are Caused by Contamination with Bacterial Products not by C-Reactive Protein Itself","volume":"97","author":"Pepys","year":"2005","journal-title":"Circ. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1111\/j.1365-2567.2006.02516.x","article-title":"Structural and functional comparison of native pentameric, denatured monomeric and biotinylated C-reactive protein","volume":"120","author":"Taylor","year":"2007","journal-title":"Immunology"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Thiele, J.R., Zeller, J., Kiefer, J., Braig, D., Kreuzaler, S., Lenz, Y., Potempa, L.A., Grahammer, F., Huber, T.B., and Huber-Lang, M. (2018). A Conformational Change in C-Reactive Protein Enhances Leukocyte Recruitment and Reactive Oxygen Species Generation in Ischemia\/Reperfusion Injury. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00675"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Emerging Risk Factors Collaboration, Kaptoge, S., Angelantonio, E.D., Lowe, G., Pepys, M.B., Thompson, S.G., Collins, R., and Danesh, J. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: An individual participant meta-analysis. Lancet, 375, 132\u2013140.","DOI":"10.1016\/S0140-6736(09)61717-7"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1515\/hsz-2020-0117","article-title":"From the discovery to molecular understanding of cellular iron-sulfur protein biogenesis","volume":"401","author":"Lill","year":"2020","journal-title":"Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1161\/CIRCRESAHA.108.190611","article-title":"Dissociation of Pentameric to Monomeric C-Reactive Protein on Activated Platelets Localizes Inflammation to Atherosclerotic Plaques","volume":"105","author":"Eisenhardt","year":"2009","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/S0969-2126(99)80023-9","article-title":"The physiological structure of human C-reactive protein and its complex with phosphocholine","volume":"7","author":"Thompson","year":"1999","journal-title":"Structure"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/art.30444","article-title":"Collagen-Induced Arthritis is Exacerbated in C-Reactive Protein Deficient Mice","volume":"63","author":"Jones","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Olson, M.E., Hornick, M.G., Stefanski, A., Albanna, H.R., Gjoni, A., Hall, G.D., Hart, P.C., Rajab, I.M., and Potempa, L.A. (2023). A biofunctional review of C-reactive protein (CRP) as a mediator of inflammatory and immune responses: Differentiating pentameric and modified CRP isoform effects. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1264383"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Karasu, E., Halbgebauer, R., Sch\u00fctte, L., Greven, J., Bl\u00e4sius, F.M., Zeller, J., Winninger, O., Braig, D., Messerer, D.A.C., and Berger, B. (2025). A conformational change of C-reactive protein drives neutrophil extracellular trap formation in inflammation. BMC Biol., 23.","DOI":"10.1186\/s12915-024-02093-8"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Rodr\u00edguez-Gonz\u00e1lez, D., Garc\u00eda-Gonz\u00e1lez, M., G\u00f3mez-Bernal, F., Quevedo-Abeledo, J.C., Gonz\u00e1lez-Rivero, A.F., Fern\u00e1ndez-Cladera, Y., Gonz\u00e1lez-L\u00f3pez, E., Ocejo-Vinyals, J.G., Jim\u00e9nez-Sosa, A., and Gonz\u00e1lez-Toledo, B. (2024). Complete Description of the Three Pathways of the Complement System in a Series of 430 Patients with Rheumatoid Arthritis. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25158360"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.molimm.2019.05.012","article-title":"Complement and its Environmental Determinants in the Progression of Human Rheumatoid Arthritis","volume":"112","author":"Bemis","year":"2019","journal-title":"Mol. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1002\/1529-0131(200105)44:5<997::AID-ANR178>3.0.CO;2-C","article-title":"Complement activation in patients with rheumatoid arthritis mediated in part by C-reactive protein","volume":"44","author":"Molenaar","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1136\/ard.2006.061309","article-title":"Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals","volume":"66","author":"Nieuwland","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"McFadyen, J.D., Kiefer, J., Braig, D., Loseff-Silver, J., Potempa, L.A., Eisenhardt, S.U., and Peter, K. (2018). Dissociation of C-Reactive Protein Localizes and Amplifies Inflammation: Evidence for a Direct Biological Role of C-Reactive Protein and Its Conformational Changes. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01351"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Fang, Z., Lv, J., Wang, J., Qin, Q., He, J., Wang, M., Zhou, G., Liu, G., Zhong, F., and Zheng, Y. (2020). C-Reactive Protein Promotes the Activation of Fibroblast-Like Synoviocytes From Patients With Rheumatoid Arthritis. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.00958"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Thom\u00e9, J., Limmer, J., Brose, T.Z., Zeller, J., Chevalier, N., Sch\u00e4fer, A.-L., Schneider, L., Lind, M., Christmann, T., and Dreck, M. (2025). C-reactive protein induced T cell activation is an indirect monocyte-dependent mechanism involving the CD80\/CD28 pathway. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1622865"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1084\/jem.192.9.1353","article-title":"C-Reactive Protein Binds to Apoptotic Cells, Protects the Cells from Assembly of the Terminal Complement Components, and Sustains an Antiinflammatory Innate Immune Response","volume":"192","author":"Gershov","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41374-021-00584-8","article-title":"Monomeric C reactive protein (mCRP) regulates inflammatory responses in human and mouse chondrocytes","volume":"101","author":"Francisco","year":"2021","journal-title":"Lab. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.joca.2018.09.007","article-title":"Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet","volume":"27","author":"Kozijn","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Rajab, I.M., Hart, P.C., and Potempa, L.A. (2020). How C-Reactive Protein Structural Isoforms With Distinctive Bioactivities Affect Disease Progression. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.02126"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5355","DOI":"10.4049\/jimmunol.167.9.5355","article-title":"Loss of pentameric symmetry of C-reactive protein is associated with promotion of neutrophil-endothelial cell adhesion","volume":"167","author":"Zouki","year":"2001","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14283","DOI":"10.1074\/jbc.M114.555318","article-title":"Topological Localization of Monomeric C-reactive Protein Determines Proinflammatory Endothelial Cell Responses","volume":"289","author":"Filep","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1477-5956-9-1","article-title":"A proteomic analysis of C-reactive protein stimulated THP-1 monocytes","volume":"9","author":"Eisenhardt","year":"2011","journal-title":"Proteome Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"103073","DOI":"10.1016\/j.jaut.2023.103073","article-title":"Extracellular vesicles opsonized by monomeric C-reactive protein (CRP) are accessible as autoantigens in patients with systemic lupus erythematosus and associate with autoantibodies against CRP","volume":"139","author":"Karlsson","year":"2023","journal-title":"J. Autoimmun."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"D\u2019Cruz, L.G., McEleney, K.G., Cochrane, C., Tan, K.B.C., Shukla, P., Gardiner, P.V., Small, D., Zhang, S.-D., and Gibson, D.S. (2020). Assessment of a dried blood spot C-reactive protein method to identify disease flares in rheumatoid arthritis patients. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-77826-0"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"277","DOI":"10.3892\/etm.2022.11206","article-title":"Monomeric C-reactive protein level is associated with osteoarthritis","volume":"23","author":"Liang","year":"2022","journal-title":"Exp. Ther. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"k1036","DOI":"10.1136\/bmj.k1036","article-title":"Increased cardiovascular risk in rheumatoid arthritis: Mechanisms and implications","volume":"361","author":"England","year":"2018","journal-title":"Br. Med. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1002\/art.21204","article-title":"Baseline levels of C-reactive protein and prediction of death from cardiovascular disease in patients with inflammatory polyarthritis: A ten-year followup study of a primary care-based inception cohort","volume":"52","author":"Goodson","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1136\/ard.2003.018333","article-title":"Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis","volume":"63","author":"McColl","year":"2004","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1001\/jama.286.1.64","article-title":"Effect of Statin Therapy on C-Reactive Protein LevelsThe Pravastatin Inflammation\/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study","volume":"286","author":"Albert","year":"2001","journal-title":"J. Am. Med. Assoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.cca.2008.10.002","article-title":"Reduced serum levels of autoantibodies against monomeric C-reactive protein (CRP) in patients with acute coronary syndrome","volume":"400","author":"Nilsson","year":"2009","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"821","DOI":"10.3899\/jrheum.200916","article-title":"Soluble Vascular Biomarkers in Rheumatoid Arthritis and Ankylosing Spondylitis: Effects of 1-year Antitumor Necrosis Factor-\u03b1 Therapy","volume":"48","author":"Pusztai","year":"2021","journal-title":"J. Rheumatol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1002\/art.39574","article-title":"Brief Report: Proatherogenic Cytokine Microenvironment in the Aortic Adventitia of Patients With Rheumatoid Arthritis","volume":"68","author":"Ahmed","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/art.39419","article-title":"Association of Elevations of Specific T Cell And Monocyte Subpopulations in Rheumatoid Arthritis with Subclinical Coronary Artery Atherosclerosis","volume":"68","author":"Winchester","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"R158","DOI":"10.1186\/ar3116","article-title":"Atherosclerosis in early rheumatoid arthritis: Very early endothelial activation and rapid progression of intima media thickness","volume":"12","author":"Karp","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1007\/s12265-016-9678-0","article-title":"Plasma Levels of Endothelial Microparticles Bearing Monomeric C-reactive Protein Are Increased in Peripheral Artery Disease","volume":"9","author":"Crawford","year":"2016","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1016\/j.cca.2012.06.023","article-title":"Early verification of myocardial ischemia with a novel biomarker of acute tissue damage: C-reactive protein fractional forms","volume":"413","author":"Kiefer","year":"2012","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Mozos, I., Malainer, C., Horba\u0144czuk, J., Gug, C., Stoian, D., Luca, C.T., and Atanasov, A.G. (2017). Inflammatory Markers for Arterial Stiffness in Cardiovascular Diseases. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.01058"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"27092","DOI":"10.31083\/RCM27092","article-title":"Assessment of Carotid Stiffness and Strain Parameters Using Speckle Tracking Strain Ultrasonography in Rheumatoid Arthritis Patients","volume":"26","author":"Tasci","year":"2025","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.3899\/jrheum.100989","article-title":"Is Small Artery Elasticity Decreased Prior to Intima-Media Thickening in Patients with Longstanding Rheumatoid Arthritis?","volume":"38","author":"Hinkema","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"8","DOI":"10.5152\/eurjrheum.2024.24010","article-title":"Decreased Aortic Elasticity in Rheumatoid Arthritis: An Early Sign of Atherosclerosis and Predictive Factors","volume":"11","author":"Ucer","year":"2024","journal-title":"Eur. J. Rheumatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e030387","DOI":"10.1161\/JAHA.123.030387","article-title":"Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study","volume":"13","author":"Weber","year":"2024","journal-title":"J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1002\/art.30542","article-title":"Longitudinal Predictors of Progression of Carotid Atherosclerosis in Rheumatoid Arthritis","volume":"63","author":"Giles","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1136\/ard.2009.124362","article-title":"Increased Prevalence of Diastolic Dysfunction in Rheumatoid Arthritis","volume":"69","author":"Liang","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1136\/annrheumdis-2013-205058","article-title":"Systemic inflammation and cardiovascular risk factors predict rapid progression of atherosclerosis in rheumatoid arthritis","volume":"74","author":"Polak","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1177\/0300060517748527","article-title":"Coronary tortuosity is associated with an elevated high-sensitivity C-reactive protein concentration and increased risk of ischemic stroke in hypertensive patients","volume":"46","author":"Li","year":"2018","journal-title":"J. Int. Med. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1161\/01.CIR.0000055014.62083.05","article-title":"C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events","volume":"107","author":"Ridker","year":"2003","journal-title":"Circulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1056\/NEJMoa032804","article-title":"C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease","volume":"350","author":"Danesh","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e070284","DOI":"10.1136\/bmjopen-2022-070284","article-title":"Association of C-reactive protein with future development of diabetes: A population-based 7-year cohort study among Norwegian adults aged 30 and older in the Troms\u00f8 Study 2007\u20132016","volume":"13","author":"Tong","year":"2023","journal-title":"BMJ Open"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e1428","DOI":"10.4088\/JCP.14m09009","article-title":"Inflammation, obesity and metabolic syndrome in depression: Analysis of the 2009\u20132010 National Health and Nutrition Survey (NHANES)","volume":"75","author":"Rethorst","year":"2014","journal-title":"J. Clin. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Trzeciak, P., Herbet, M., and Dudka, J. (2021). Common Factors of Alzheimer\u2019s Disease and Rheumatoid Arthritis\u2014Pathomechanism and Treatment. Molecules, 26.","DOI":"10.3390\/molecules26196038"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1750-3639.2011.00539.x","article-title":"Amyloid plaques dissociate pentameric to monomeric C-reactive protein: A novel pathomechanism driving cortical inflammation in Alzheimer\u2019s disease?","volume":"22","author":"Strang","year":"2011","journal-title":"Brain Pathol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.jacc.2014.12.035","article-title":"Amyloid-Beta (1-40) and the Risk of Death From Cardiovascular Causes in Patients With Coronary Heart Disease","volume":"65","author":"Stamatelopoulos","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Slevin, M., Matou, S., Zeinolabediny, Y., Corpas, R., Weston, R., Liu, D., Boras, E., Di Napoli, M., Petcu, E., and Sarroca, S. (2015). Monomeric C-reactive protein-a key molecule driving development of Alzheimer\u2019s disease associated with brain ischaemia?. Sci. Rep., 5.","DOI":"10.1038\/srep13281"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1750-3639.2008.00256.x","article-title":"Modified C-Reactive Protein Is Expressed by Stroke Neovessels and Is a Potent Activator of Angiogenesis In Vitro","volume":"20","author":"Slevin","year":"2009","journal-title":"Brain Pathol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00296-019-04449-8","article-title":"Assessment of cognitive function in female rheumatoid arthritis patients: Associations with cerebrovascular pathology, depression and anxiety","volume":"40","author":"Kardos","year":"2020","journal-title":"Rheumatol. Int."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"McDowell, B., Marr, C., Holmes, C., Edwards, C.J., Cardwell, C., McHenry, M., Meenagh, G., and McGuinness, B. (2022). Prevalence of cognitive impairment in patients with rheumatoid arthritis: A cross sectional study. BMC Psychiatry, 22.","DOI":"10.1186\/s12888-022-04417-w"},{"key":"ref_83","unstructured":"Tachibana, A., Iga, J., Ozaki, T., Yoshida, T., Yoshino, Y., Shimizu, H., Mori, T., Furuta, Y., Shibata, M., and Ohara, T. (2024). Serum high-sensitivity C-reactive protein and dementia in a community-dwelling Japanese older population (JPSC-AD). Sci. Rep., 14."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1093\/gerona\/glab282","article-title":"Elevated C-Reactive Protein in Alzheimer\u2019s Disease Without Depression in Older Adults: Findings From the Health and Retirement Study","volume":"77","author":"Natale","year":"2021","journal-title":"J. Gerontol. A. Biol. Sci. Med. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Lin, T.-M., Chen, W.-S., Sheu, J.-J., Chen, Y.-H., Chen, J.-H., and Chang, C.-C. (2018). Autoimmune rheumatic diseases increase dementia risk in middle-aged patients: A nationwide cohort study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0186475"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"669","DOI":"10.3233\/JAD-2012-111736","article-title":"Midlife rheumatoid arthritis increases the risk of cognitive impairment two decades later: A population-based study","volume":"31","author":"Wallin","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1001\/jama.2019.9879","article-title":"Association of Lifestyle and Genetic Risk With Incidence of Dementia","volume":"322","author":"Lourida","year":"2019","journal-title":"J. Am. Med. Assoc."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1001\/jama.2019.10575","article-title":"Association of Midlife to Late-Life Blood Pressure Patterns With Incident Dementia","volume":"322","author":"Walker","year":"2019","journal-title":"J. Am. Med. Assoc."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1212\/WNL.0b013e3181b6bb95","article-title":"Systemic inflammation and disease progression in Alzheimer disease","volume":"73","author":"Holmes","year":"2009","journal-title":"Neurology"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Kowalska, K., Pasinska, P., Klimiec-Moskal, E., Pera, J., Slowik, A., Klimkowicz-Mrowiec, A., and Dziedzic, T. (2020). C-reactive protein and post-stroke depressive symptoms. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-58478-6"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1002\/art.24647","article-title":"Depression, inflammation, and pain in patients with rheumatoid arthritis","volume":"61","author":"Kojima","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"765","DOI":"10.31083\/j.jin2003081","article-title":"Comparing underlying mechanisms of depression in multiple sclerosis and rheumatoid arthritis","volume":"20","author":"Wenger","year":"2021","journal-title":"J. Integr. Neurosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1192\/bjp.2018.66","article-title":"Treatment-resistant depression and peripheral C-reactive protein","volume":"214","author":"Chamberlain","year":"2019","journal-title":"Br. J. Psychiatry"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Caprio, V., Badimon, L., Di Napoli, M., Fang, W.-H., Ferris, G.R., Guo, B., Iemma, R.S., Liu, D., Zeinolabediny, Y., and Slevin, M. (2018). pCRP-mCRP Dissociation Mechanisms as Potential Targets for the Development of Small-Molecule Anti-Inflammatory Chemotherapeutics. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01089"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1038\/nature04672","article-title":"Targeting C-reactive protein for the treatment of cardiovascular disease","volume":"440","author":"Pepys","year":"2006","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"e16236","DOI":"10.15252\/emmm.202216236","article-title":"A novel phosphocholine-mimetic inhibits a pro-inflammatory conformational change in C-reactive protein","volume":"15","author":"Zeller","year":"2022","journal-title":"EMBO Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8227\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:35:26Z","timestamp":1760034926000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/17\/8227"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,25]]},"references-count":96,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["ijms26178227"],"URL":"https:\/\/doi.org\/10.3390\/ijms26178227","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,25]]}}}