Abstract
Background: The aim of this study was to assess DKK-1 levels, in Gingival Crevicular Fluid (GCF) and serum, as a biomarker for bone loss and disease activity in periodontitis and early RA (eRA).
Methods: In this cross-sectional study, we obtained serum and GCF from 10 interproximal sites (Distal Buccal I/S, Mesio Buccal I/S, Distal Palatal/Lingual, Mesio Palatal/Lingual) according to the highest degree of inflammation by a patient for 240 sites from eRA patients. Patients received a periodontal assessment, a radiographic evaluation, tomography of interproximal sites, and DKK1 levels were determined by ELISA. Comparisons were performed by the Mann-Whitney U test and analysis by Chi2 test, and a logistic regression model was applied.
Results: The mean age was 46.33 ± 12.0 years, the Disease Activity Score (DAS-28-ESR) was 4.08 ± 1.4. Periodontitis was present in 65.2% of the patients, and 59.6% of these patients had bone loss in interproximal sites.
Discussion: Higher GCF-DKK1 levels were associated with serum-DKK1 (OR:2.41 IC95% 1.14-5.09, p=0.021) and were related with DAS28-ESR (p=0.001), Routine Assessment of Patient Index Data 3 (RAPID 3) (p=0.001), and tender joints (p=0.040). Foot bone erosion and juxta-articular osteopenia were associated with high levels of serum-DKK1 (p=0.009 and 0.001, respectively). Serum-DKK1 were associated with SDAI (OR: 2.38 IC95% 1.03-5.52, p=0.043), RAPID 3 (p=0.001), and rheumatoid factor (p=0.018).
The GCF-DKK1 levels were associated with periodontal bone loss (p=0.011), periodontitis (p=0.070) and its severity (OR: 2.58 IC95% 2.28-7.28, p=0.001). Bone loss was more frequent in buccal sites (73.5%) and was associated with increased levels of DKK1 (p=0.033).
Conclusion: In the early stages of the eRA disease, serum and GCF-DKK1 could be a biomarker for clinical disease activity and periodontal and articular bone erosion.
Keywords: Early rheumatoid arthritis, periodontitis, Dickkopf-1 protein, bone loss, gingival crevicular fluid, serum.
Graphical Abstract
[1]
Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet 2009; 373(9664): 659-72.
[http://dx.doi.org/10.1016/S0140-6736(09)60008-8] [PMID: 19157532]
[http://dx.doi.org/10.1016/S0140-6736(09)60008-8] [PMID: 19157532]
[2]
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 388(10055): 2023-38.
[http://dx.doi.org/10.1016/S0140-6736(16)30173-8] [PMID: 27156434]
[http://dx.doi.org/10.1016/S0140-6736(16)30173-8] [PMID: 27156434]
[3]
Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996; 39(5): 732-5.
[http://dx.doi.org/10.1002/art.1780390504] [PMID: 8639169]
[http://dx.doi.org/10.1002/art.1780390504] [PMID: 8639169]
[4]
Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987; 30(11): 1205-13.
[http://dx.doi.org/10.1002/art.1780301102] [PMID: 2446635]
[http://dx.doi.org/10.1002/art.1780301102] [PMID: 2446635]
[5]
Hochberg MC, Johnston SS, John AK. The incidence and prevalence of extra-articular and systemic manifestations in a cohort of newly-diagnosed patients with rheumatoid arthritis between 1999 and 2006. Curr Med Res Opin 2008; 24(2): 469-80.
[http://dx.doi.org/10.1185/030079908X261177] [PMID: 18179735]
[http://dx.doi.org/10.1185/030079908X261177] [PMID: 18179735]
[6]
Gerlag DM, Raza K, van Baarsen LG, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: Report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis 2012; 71(5): 638-41.
[http://dx.doi.org/10.1136/annrheumdis-2011-200990] [PMID: 22387728]
[http://dx.doi.org/10.1136/annrheumdis-2011-200990] [PMID: 22387728]
[7]
de Pablo P, Chapple IL, Buckley CD, Dietrich T. Periodontitis in systemic rheumatic diseases. Nat Rev Rheumatol 2009; 5(4): 218-24.
[http://dx.doi.org/10.1038/nrrheum.2009.28] [PMID: 19337286]
[http://dx.doi.org/10.1038/nrrheum.2009.28] [PMID: 19337286]
[8]
Hajishengallis G. Periodontitis: From microbial immune subversion to systemic inflammation. Nat Rev Immunol 2015; 15(1): 30-44.
[http://dx.doi.org/10.1038/nri3785] [PMID: 25534621]
[http://dx.doi.org/10.1038/nri3785] [PMID: 25534621]
[9]
Phipps KR, Stevens VJ. Relative contribution of caries and periodontal disease in adult tooth loss for an HMO dental population. J Public Health Dent 1995; 55(4): 250-2.
[http://dx.doi.org/10.1111/j.1752-7325.1995.tb02377.x] [PMID: 8551465]
[http://dx.doi.org/10.1111/j.1752-7325.1995.tb02377.x] [PMID: 8551465]
[10]
Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 2005; 366(9499): 1809-20.
[http://dx.doi.org/10.1016/S0140-6736(05)67728-8] [PMID: 16298220]
[http://dx.doi.org/10.1016/S0140-6736(05)67728-8] [PMID: 16298220]
[11]
Mercado FB, Marshall RI, Klestov AC, Bartold PM. Relationship between rheumatoid arthritis and periodontitis. J Periodontol 2001; 72(6): 779-87.
[http://dx.doi.org/10.1902/jop.2001.72.6.779] [PMID: 11453241]
[http://dx.doi.org/10.1902/jop.2001.72.6.779] [PMID: 11453241]
[12]
Rosenstein ED, Greenwald RA, Kushner LJ, Weissmann G. Hypothesis: The humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation 2004; 28(6): 311-8.
[http://dx.doi.org/10.1007/s10753-004-6641-z] [PMID: 16245073]
[http://dx.doi.org/10.1007/s10753-004-6641-z] [PMID: 16245073]
[13]
Walsh NC, Gravallese EM. Bone remodeling in rheumatic disease: A question of balance. Immunol Rev 2010; 233(1): 301-12.
[http://dx.doi.org/10.1111/j.0105-2896.2009.00857.x] [PMID: 20193007]
[http://dx.doi.org/10.1111/j.0105-2896.2009.00857.x] [PMID: 20193007]
[14]
Miao CG, Yang YY, He X, et al. Wnt signaling pathway in rheumatoid arthritis, with special emphasis on the different roles in synovial inflammation and bone remodeling. Cell Signal 2013; 25(10): 2069-78.
[http://dx.doi.org/10.1016/j.cellsig.2013.04.002] [PMID: 23602936]
[http://dx.doi.org/10.1016/j.cellsig.2013.04.002] [PMID: 23602936]
[15]
Seror R, Boudaoud S, Pavy S, et al. Increased Dickkopf-1 in recent-onset rheumatoid arthritis is a new biomarker of structural severity. Sci Rep 2016; 6: 18421.
[http://dx.doi.org/10.1038/srep18421] [PMID: 26785768]
[http://dx.doi.org/10.1038/srep18421] [PMID: 26785768]
[16]
Pinzone JJ, Hall BM, Thudi NK, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 2009; 113(3): 517-25.
[http://dx.doi.org/10.1182/blood-2008-03-145169] [PMID: 18687985]
[http://dx.doi.org/10.1182/blood-2008-03-145169] [PMID: 18687985]
[17]
Bartold PM, Cantley MD, Haynes DR. Mechanisms and control of pathologic bone loss in periodontitis. Periodontol 2000 2010; 53: 55-69.
[http://dx.doi.org/10.1111/j.1600-0757.2010.00347.x] [PMID: 20403105]
[http://dx.doi.org/10.1111/j.1600-0757.2010.00347.x] [PMID: 20403105]
[18]
Napimoga MH, Nametala C, da Silva FL, et al. Involvement of the Wnt-β-catenin signalling antagonists, sclerostin and Dickkopf-related protein 1, in chronic periodontitis. J Clin Periodontol 2014; 41(6): 550-7.
[http://dx.doi.org/10.1111/jcpe.12245] [PMID: 24576302]
[http://dx.doi.org/10.1111/jcpe.12245] [PMID: 24576302]
[19]
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League against rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9): 2569-81.
[http://dx.doi.org/10.1002/art.27584] [PMID: 20872595]
[http://dx.doi.org/10.1002/art.27584] [PMID: 20872595]
[20]
Eke PI, Page RC, Wei L, Thornton-Evans G, Genco RJ. Update of the case definitions for population-based surveillance of periodontitis. J Periodontol 2012; 83(12): 1449-54.
[http://dx.doi.org/10.1902/jop.2012.110664] [PMID: 22420873]
[http://dx.doi.org/10.1902/jop.2012.110664] [PMID: 22420873]
[21]
Bello-Gualtero JM, Lafaurie GI, Hoyos LX, et al. Periodontal disease in individuals with a genetic risk of developing arthritis and early rheumatoid arthritis: A cross-sectional study. J Periodontol 2016; 87(4): 346-56.
[http://dx.doi.org/10.1902/jop.2015.150455] [PMID: 26609697]
[http://dx.doi.org/10.1902/jop.2015.150455] [PMID: 26609697]
[22]
Boutaga K, van Winkelhoff AJ, Vandenbroucke-Grauls CM, Savelkoul PH. Periodontal pathogens: A quantitative comparison of anaerobic culture and real-time PCR. FEMS Immunol Med Microbiol 2005; 45(2): 191-9.
[http://dx.doi.org/10.1016/j.femsim.2005.03.011] [PMID: 15919188]
[http://dx.doi.org/10.1016/j.femsim.2005.03.011] [PMID: 15919188]
[23]
Boutaga K, van Winkelhoff AJ, Vandenbroucke-Grauls CM, Savelkoul PH. Comparison of real-time PCR and culture for detection of Porphyromonas gingivalis in subgingival plaque samples. J Clin Microbiol 2003; 41(11): 4950-4.
[http://dx.doi.org/10.1128/JCM.41.11.4950-4954.2003] [PMID: 14605122]
[http://dx.doi.org/10.1128/JCM.41.11.4950-4954.2003] [PMID: 14605122]
[24]
Morillo JM, Lau L, Sanz M, Herrera D, Silva A. Quantitative real- time PCR based on single copy gene sequence for detection of Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. J Periodontal Res 2003; 38(5): 518-24.
[http://dx.doi.org/10.1034/j.1600-0765.2003.00684.x] [PMID: 12941077]
[http://dx.doi.org/10.1034/j.1600-0765.2003.00684.x] [PMID: 12941077]
[25]
Morillo JM, Lau L, Sanz M, Herrera D, Martín C, Silva A. Quantitative real-time polymerase chain reaction based on single copy gene sequence for detection of periodontal pathogens. J Clin Periodontol 2004; 31(12): 1054-60.
[http://dx.doi.org/10.1111/j.1600-051x.2004.00608.x] [PMID: 15560805]
[http://dx.doi.org/10.1111/j.1600-051x.2004.00608.x] [PMID: 15560805]
[26]
Löe H. The gingival index, the plaque index, and the retention index systems. J Periodontol 1967; 38(6): 610-6.
[http://dx.doi.org/10.1902/jop.1967.38.6.610] [PMID: 5237684]
[http://dx.doi.org/10.1902/jop.1967.38.6.610] [PMID: 5237684]
[27]
Pincus T, Swearingen C, Wolfe F. Toward a Multidimensional Health Assessment Questionnaire (MDHAQ): Assessment of advanced activities of daily living and psychological status in the patient-friendly health assessment questionnaire format. Arthritis Rheum 1999; 42(10): 2220-30.
[http://dx.doi.org/10.1002/1529-0131(199910)42:10<2220::AID-ANR26>3.0.CO;2-5] [PMID: 10524697]
[http://dx.doi.org/10.1002/1529-0131(199910)42:10<2220::AID-ANR26>3.0.CO;2-5] [PMID: 10524697]
[28]
Smolen JS, Breedveld FC, Schiff MH, et al. A simplified disease activity index for rheumatoid arthritis for use in clinical practice. Rheumatology (Oxford) 2003; 42(2): 244-57.
[http://dx.doi.org/10.1093/rheumatology/keg072] [PMID: 12595618]
[http://dx.doi.org/10.1093/rheumatology/keg072] [PMID: 12595618]
[29]
Mol A, Balasundaram A. In vitro cone beam computed tomography imaging of periodontal bone. Dentomaxillofac Radiol 2008; 37(6): 319-24.
[http://dx.doi.org/10.1259/dmfr/26475758] [PMID: 18757716]
[http://dx.doi.org/10.1259/dmfr/26475758] [PMID: 18757716]
[30]
Goodarzi Pour D, Romoozi E, Soleimani Shayesteh Y. Accuracy of cone beam computed tomography for detection of bone loss. J Dent (Tehran) 2015; 12(7): 513-23.
[PMID: 26877741]
[PMID: 26877741]
[31]
van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol 2000; 27(1): 261-3.
[PMID: 10648051]
[PMID: 10648051]
[32]
Kastbom A, Strandberg G, Lindroos A, Skogh T. Anti-CCP antibody test predicts the disease course during 3 years in early rheumatoid arthritis (the Swedish TIRA project). Ann Rheum Dis 2004; 63(9): 1085-9.
[http://dx.doi.org/10.1136/ard.2003.016808] [PMID: 15308517]
[http://dx.doi.org/10.1136/ard.2003.016808] [PMID: 15308517]
[33]
Cardona-Rincón AD, Acevedo-Godoy MA, Bello-Gualtero JM, et al. Association of dickkopf-1 polymorphisms with radiological damage and periodontal disease in patients with early rheumatoid arthritis: A cross-sectional study. J Clin Rheumatol 2020; 26(7S Suppl 2): S187-94.
[http://dx.doi.org/10.1097/RHU.0000000000001391]
[http://dx.doi.org/10.1097/RHU.0000000000001391]
[34]
Ohmura K, Terao C, Maruya E, et al. Anti-citrullinated peptide antibody-negative RA is a genetically distinct subset: A definitive study using only bone-erosive ACPA-negative rheumatoid arthritis. Rheumatology (Oxford) 2010; 49(12): 2298-304.
[http://dx.doi.org/10.1093/rheumatology/keq273] [PMID: 20833643]
[http://dx.doi.org/10.1093/rheumatology/keq273] [PMID: 20833643]
[35]
van Dongen H, van Aken J, Lard LR, et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2007; 56(5): 1424-32.
[http://dx.doi.org/10.1002/art.22525] [PMID: 17469099]
[http://dx.doi.org/10.1002/art.22525] [PMID: 17469099]
[36]
Hajishengallis G. Immunomicrobial pathogenesis of periodontitis: Keystones, pathobionts, and host response. Trends Immunol 2014; 35(1): 3-11.
[http://dx.doi.org/10.1016/j.it.2013.09.001] [PMID: 24269668]
[http://dx.doi.org/10.1016/j.it.2013.09.001] [PMID: 24269668]
[37]
Fuggle NR, Smith TO, Kaul A, Sofat N. Hand to mouth: A systematic review and meta-analysis of the association between rheumatoid arthritis and periodontitis. Front Immunol 2016; 7: 80.
[http://dx.doi.org/10.3389/fimmu.2016.00080] [PMID: 26973655]
[http://dx.doi.org/10.3389/fimmu.2016.00080] [PMID: 26973655]
[38]
Scher JU, Ubeda C, Equinda M, et al. Periodontal disease and the oral microbiota in new-onset rheumatoid arthritis. Arthritis Rheum 2012; 64(10): 3083-94.
[http://dx.doi.org/10.1002/art.34539] [PMID: 22576262]
[http://dx.doi.org/10.1002/art.34539] [PMID: 22576262]
[39]
Ministerio de Salud y protección social. Cuarto Estudio Nacional de Salud Bucal-Colombia (ENSAB IV). Situación de Salud bucal. Estado periodontal 2014; 77-83.
[40]
Äyräväinen L, Leirisalo-Repo M, Kuuliala A, et al. Periodontitis in early and chronic rheumatoid arthritis: A prospective follow-up study in Finnish population. BMJ Open 2017; 7(1): e011916.
[http://dx.doi.org/10.1136/bmjopen-2016-011916] [PMID: 28143836]
[http://dx.doi.org/10.1136/bmjopen-2016-011916] [PMID: 28143836]
[41]
Rodríguez-Lozano B, González-Febles J, Garnier-Rodríguez JL, et al. Association between severity of periodontitis and clinical activity in rheumatoid arthritis patients: A case-control study. Arthritis Res Ther 2019; 21(1): 27.
[http://dx.doi.org/10.1186/s13075-019-1808-z] [PMID: 30658685]
[http://dx.doi.org/10.1186/s13075-019-1808-z] [PMID: 30658685]
[42]
Wolff B, Berger T, Frese C, et al. Oral status in patients with early rheumatoid arthritis: A prospective, case-control study. Rheumatology (Oxford) 2014; 53(3): 526-31.
[http://dx.doi.org/10.1093/rheumatology/ket362] [PMID: 24273047]
[http://dx.doi.org/10.1093/rheumatology/ket362] [PMID: 24273047]
[43]
Nair SP, Meghji S, Wilson M, Reddi K, White P, Henderson B. Bacterially induced bone destruction: Mechanisms and misconceptions. Infect Immun 1996; 64(7): 2371-80.
[http://dx.doi.org/10.1128/iai.64.7.2371-2380.1996] [PMID: 8698454]
[http://dx.doi.org/10.1128/iai.64.7.2371-2380.1996] [PMID: 8698454]
[44]
Vencovský J, Machácek S, Sedová L, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis 2003; 62(5): 427-30.
[http://dx.doi.org/10.1136/ard.62.5.427] [PMID: 12695154]
[http://dx.doi.org/10.1136/ard.62.5.427] [PMID: 12695154]
[45]
Hardy R, Juarez M, Naylor A, et al. Synovial DKK1 expression is regulated by local glucocorticoid metabolism in inflammatory arthritis. Arthritis Res Ther 2012; 14(5): R226.
[http://dx.doi.org/10.1186/ar4065] [PMID: 23079210]
[http://dx.doi.org/10.1186/ar4065] [PMID: 23079210]
[46]
Ray S, Khassawna TE, Sommer U, et al. Differences in expression of Wnt antagonist Dkk1 in healthy versus pathological bone samples. J Microsc 2017; 265(1): 111-20.
[http://dx.doi.org/10.1111/jmi.12469] [PMID: 27580425]
[http://dx.doi.org/10.1111/jmi.12469] [PMID: 27580425]
[47]
Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007; 13(2): 156-63.
[http://dx.doi.org/10.1038/nm1538] [PMID: 17237793]
[http://dx.doi.org/10.1038/nm1538] [PMID: 17237793]
[48]
Yeremenko N, Zwerina K, Rigter G, et al. Tumor necrosis factor and interleukin-6 differentially regulate Dkk-1 in the inflamed arthritic joint. Arthritis Rheumatol 2015; 67(8): 2071-5.
[http://dx.doi.org/10.1002/art.39183] [PMID: 25941031]
[http://dx.doi.org/10.1002/art.39183] [PMID: 25941031]
[49]
Liu YY, Long L, Wang SY, et al. Circulating Dickkopf-1 and osteoprotegerin in patients with early and longstanding rheumatoid arthritis. Chin Med J (Engl) 2010; 123(11): 1407-12.
[PMID: 20819596]
[PMID: 20819596]
[50]
de Rooy DP, Yeremenko NG, Wilson AG, et al. Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis. Ann Rheum Dis 2013; 72(5): 769-75.
[http://dx.doi.org/10.1136/annrheumdis-2012-202184] [PMID: 23041840]
[http://dx.doi.org/10.1136/annrheumdis-2012-202184] [PMID: 23041840]
[51]
Lamster IB, Ahlo JK. Analysis of gingival crevicular fluid as applied to the diagnosis of oral and systemic diseases. Ann N Y Acad Sci 2007; 1098: 216-29.
[http://dx.doi.org/10.1196/annals.1384.027] [PMID: 17435131]
[http://dx.doi.org/10.1196/annals.1384.027] [PMID: 17435131]
[52]
Baeza M, Garrido M, Hernández-Ríos P, et al. Diagnostic accuracy for apical and chronic periodontitis biomarkers in gingival crevicular fluid: An exploratory study. J Clin Periodontol 2016; 43(1): 34-45.
[http://dx.doi.org/10.1111/jcpe.12479] [PMID: 26556177]
[http://dx.doi.org/10.1111/jcpe.12479] [PMID: 26556177]
[53]
Zheng L, Hu F, Bian W, et al. Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis. Clin Rheumatol 2021.
[http://dx.doi.org/10.1007/s10067-021-05766-9] [PMID: 34013491]
[http://dx.doi.org/10.1007/s10067-021-05766-9] [PMID: 34013491]
[54]
Juarez M, McGettrick HM, Scheel-Toellner D, et al. DKK1 expression by synovial fibroblasts in very early rheumatoid arthritis associates with lymphocyte adhesion in an in vitro flow co-culture system. Arthritis Res Ther 2016; 18: 14.
[http://dx.doi.org/10.1186/s13075-016-0915-3] [PMID: 26782930]
[http://dx.doi.org/10.1186/s13075-016-0915-3] [PMID: 26782930]
[55]
Heredia-P AM, Lafaurie GI, Bautista-Molano W, et al. Predictive factors related to the progression of periodontal disease in patients with early rheumatoid arthritis: A cohort study. BMC Oral Health 2019; 19(1): 240.
[http://dx.doi.org/10.1186/s12903-019-0939-6] [PMID: 31703715]
[http://dx.doi.org/10.1186/s12903-019-0939-6] [PMID: 31703715]
[56]
Li J, Sarosi I, Cattley RC, et al. Dkk1-mediated inhibition of Wnt signaling in bone results in osteopenia. Bone 2006; 39(4): 754-66.
[http://dx.doi.org/10.1016/j.bone.2006.03.017] [PMID: 16730481]
[http://dx.doi.org/10.1016/j.bone.2006.03.017] [PMID: 16730481]
[57]
Biyikoğlu B, Buduneli N, Kardeşler L, Aksu K, Öder G, Kütükçüler N. Evaluation of t-PA, PAI-2, IL-1beta and PGE(2) in gingival crevicular fluid of rheumatoid arthritis patients with periodontal disease. J Clin Periodontol 2006; 33(9): 605-11.
[http://dx.doi.org/10.1111/j.1600-051X.2006.00961.x] [PMID: 16856901]
[http://dx.doi.org/10.1111/j.1600-051X.2006.00961.x] [PMID: 16856901]
Article Metrics
30
1