臺灣博碩士論文加值系統

牙周病與類風溼性關節炎皆為慢性發炎疾病，並共享類似的免疫發炎模式，造成了骨頭及周圍組織的破壞，使功能受損。類風溼性關節炎的成因相當多，包括基因、環境、賀爾蒙及細菌的感染。P. gingivalis 是慢性牙周炎主要致病菌之一，也是目前已知唯一會表現peptidyl-arginine deiminase(PPAD) 的原核生物，可將人類的蛋白質瓜胺酸化，就有可能使得一些易感性的宿主對瓜胺酸化蛋白質的免疫容忍度降低，產生抗環瓜胺酸&;#32957;抗體(anti-cyclic citrullinated peptide antibody; ACPA)，造成後續一連串的自體免疫反應發生，就有可能影響類風濕性關節炎的病程及疾病活性。
本研究的目的主要是想了解，在經過非手術性牙周病治療的牙周病病人(其中有5位為抽菸患者)，其血清中自體免疫抗體(ACPA、RF)、發炎因子(TNF-α、CRP、IL-1β、IL-6、MMP-3)及牙周病菌抗體(A. actinomycetemcomitans, P. intermedia, T. denticola, T. forsythia和F. nucleatum)的變化。分析治療前與治療後牙周狀況與血清中發炎因子、抗體的改變量，及治療前牙周狀況與血清中發炎因子與抗體間的相關性。
實驗方法則是分別收集31位牙周病患者在牙周治療前與後的血清，以酵素免疫分析法(ELISA)檢測血清中的自體免疫抗體、發炎因子及牙周病細菌抗體的量。
在本研究中，牙周病治療可有效降低F. nucleatum抗體量、ACPA和TNF-α，尤其在中重度牙周病患者的治療效果尤佳。拔除掉嚴重牙周病患齒的數量，也分別和ACPA及IL-1β的下降量呈正相關。說明了改善牙周病感染的狀況，會影響全身性的發炎狀況和自體免疫抗體產生的情形。抽菸病人對於牙周病治療的效果良好，但在改善ACPA及TNF-α的效果就相當有限。
總括，類風濕性關節炎的病人，甚至是類風溼性關節炎高危險群的病人，都應該要重視並接受牙周病的檢查和治療，並且維持口腔的清潔與衛生，以降低類風溼性關節炎的嚴重度。

Introduction: Chronic periodontitis and rheumatoid arthritis are the most common chronic inflammatory disease. They share a common immunoinflammatory profile, and demonstrate remarkably similar patterns of soft and hard tissue destruction. The pathogenesis of rheumatoid arthritis is complex, and there is a combination of genetic, environmental, hormonal, and infectious co-factors. It has been reported that serum anti-cyclic citrullinated peptide antibody(ACPA) titers and rheumatoid factor antibodies(RF) are significantly higher in the RA patients. P. gingivalis, a major periodontopathic bacteria, expresses peptidylarginine deimiase(PPAD) that mediates post-translational conversion of arginine to citrulline. We hypothesize that P. gingivalis infection might induce autoimmunity and is associated with elevated anti-CCP antibody titers in susceptible individuals. The aim of this study was to evaluate the effect of non-surgical periodontal treatment on serum inflammatory marker levels and autoimmune antibody titers.
Materials and Methods: 31 Taiwanese adults with chronic periodontitis were recruited from the dental clinic of National Taiwan University Hospital. Clinical periodontal examinations including probing depth (PD), clinical attachment level (CAL) and tooth number were performed. All subjects received full-mouth scaling and root planing within one month. Serum samples were collected before and 6-8 weeks after periodontal treatment. ACPA, RF, TNF-α, CRP, IL-1β, IL-6, MMP-3 and periodontopathic bacteria antibodies, including A. actinomycetemcomitans, P. intermedia, T. denticola, T. forsythia and F. nucleatum, were measured by ELISA method. Wilcoxon signed-rank test and Spearman’s rank correlation coefficient were used for statistics.
Results: After non-surgical periodontal treatment, patients showed significant reduction in percentage of PD, serum anti-F. nucleatum antibody titers, ACPA titers, and TNF-α levels, especially in moderate to severe periodontitis group. Besides, the number of extracted teeth was positively correlated with decreasing of ACPA and IL-1β serum levels separately. In smokers, the periodontal therapy improved the periodontal health, but had a limitation effect on inflammatory markers and autoimmune antibodies.
Conclusions: Periodontitis may affect systemic inflammation and autoimmune conditions. The periodontal therapy might improve the ACPA titers in rheumatoid arthritis patients. Therefore, the rheumatoid arthritis susceptible patients should pay more attention to oral hygiene and periodontal health in order to control disease activity.

誌謝 I
摘要 II
ABSTRACT III
目錄 V
圖目錄 VIII
表目錄 IX
第一章 緒論 1
第一節 類風溼性關節炎 (RHEUMATOID ARTHRITIS) 1
1-1類風溼性關節炎 1
1-2 類風溼性關節炎的病因 1
1-2-1 基因 2
1-2-2 抽菸 3
1-2-3 感染 4
1-3類風溼性關節炎的臨床表現和診斷 5
1-4 細胞激素在類風溼性關節炎的角色 7
1-5 生化因子在類風溼性關節炎的角色 8
1-6 類風溼性關節炎的治療 10
第二節 牙周病 12
2-1 牙周病 12
2-2 牙周病的病因 12
2-2-1生物薄膜及細菌 12
(I) Porphyromonas gingivalis 14
(II) Fusobacterium nucleatum 15
2-2-2 基因 16
2-2-3 抽菸 16
2-3 牙周病的臨床表現和診斷 17
2-4 自體免疫指數在牙周病的角色 18
2-5 細胞激素在牙周病的角色 18
2-6 生化因子在牙周病的角色 19
2-7 牙周病的治療 20
第三節 牙周病與類風濕性關節炎的關係 23
3-1 牙周病與類風濕性關節炎相關性的歷史 23
3-2牙周病致病菌與類風濕性關節炎的關係 23
3-3 發炎標記在牙周病與類風濕性關節炎的意義 25
3-4 目前牙周病治療對於類風濕性關節炎病人的類風濕預後 27
第二章 研究目的 28
第三章 實驗材料與方法 29
一、研究對象 29
二、臨床牙周檢查 30
三、血清中發炎指數及自體免疫抗體檢測與酵素免疫分析法(ENZYME-LINKED IMMUNOSORBENT ASSAY; ELISA) 31
3-1 血液處理 31
3-2酵素免疫分析法(Enzyme-linked immunosorbent assay; ELISA) 31
3-2-1 免疫因子及發炎指數 31
3-2-2抗環瓜胺酸&;#32957;抗體(ACPA) 31
3-2-3 類風濕性因子(RF) 32
3-2-4 腫瘤壞死因子(TNF-α) 32
3-2-5 高敏感性C 反應蛋白(hs-CRP) 32
3-2-6 間白質素(IL-1β、IL-6)及溶基質素(MMP-3) 33
3-2-7 細菌抗體(A. actinomycetemcomitans, P. intermedia, T.
denticola, T. forsythia和F. nucleatum) 34
四、統計分析 35
FLOW CHART OF THE PRESENT STUDY 36
第四章 結果 37
一、牙周病疾病嚴重程度分類 37
二、基本資料(如表一所示) 37
三、牙周健康狀況(如表一所示) 38
四、細菌抗體(如表一所示) 38
五、血清免疫、發炎因子狀況 38
1. hs-CRP (如圖一所示) 38
2. TNF-α(如圖二所示) 39
3. IL-1β(如圖三所示) 39
4. IL-6(如圖四所示) 39
5. MMP-3(如圖五所示) 39
6. ACPA(如圖六所示) 40
7. RF(如圖七所示) 40
六、治療前牙周狀況與血清中各項檢測數值的相關性 40
1.全部病人 40
2.中重度病人 41
3.輕度病人 41
七、全部病人各項治療前後改變量的相關性 42
八、抽菸病人 42
第五章 討論 44
參考文獻 77



圖目錄
圖 一、HS-CRP在牙周病治療前後的變化 53
圖 二、TNF-Α在牙周病治療前後的變化 54
圖 三、IL-1Β在牙周病治療前後的變化 55
圖 四、IL-6在牙周病治療前後的變化 56
圖 五、MMP-3在牙周病治療前後的變化 57
圖 六、ACPA在牙周病治療前後的變化 58
圖 七、RF在牙周病治療前後的變化 59
圖 八、全部病人分析下，牙齒數量和性別的關係性 60
圖 九、全部病人分析下，CRP和SITES WITH PD≧4 MM的關係性 61
圖 十、全部病人分析下，CRP和IL-1Β的關係性 62
圖 十一、全部病人分析下，IL-6和IL-1Β的關係性 63
圖 十二、全部病人分析下，RF和IL-6的關係性 64
圖 十三、全部病人分析下，RF和IL-1Β的關係性 65
圖 十四、中重度病人分析下，牙齒數量和性別的關係性 66
圖 十五、中重度病人分析下， IL-1Β和IL-6的關係性 67
圖 十六、中重度病人分析下，RF和IL-6的關係性 68
圖 十七、中重度病人分析下，RF和IL-1Β的關係性 69
圖 十八、輕度病人分析下，CRP和SITES WITH PD≧4 MM的關係性 70
圖 十九、輕度病人分析下，ACPA和TNF-Α的相關性 71
圖 二十、輕度病人分析下，MMP-3和IL-1Β的相關性 72
圖 二十一、全部病人治療前後分析下，ACPA改變量和牙齒數改變量的相關性 73
圖 二十二、全部病人治療前後分析下，IL-1Β改變量和牙齒數改變量的相關性 74
圖 二十三、全部病人治療前後分析下，IL-1Β改變量和IL-6改變量的相關性 75
圖 二十四、全部病人治療前後分析下，F. NUCLEATUM抗體改變量和TNF-Α改變量的相關性 76


表目錄
表 一、DEMOGRAPHIC AND CHARACTERISTICS OF PATIENTS WITH CHRONIC PERIODONTITIS 52

1.Myasoedova, E., et al., Is the incidence of rheumatoid arthritis rising?: results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum, 2010. 62(6): p. 1576-82.
2.Symmons, D.P., et al., The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol, 1994. 33(8): p. 735-9.
3.Scott, D.L., et al., Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet, 1987. 1(8542): p. 1108-11.
4.Rutger Persson, G., Rheumatoid arthritis and periodontitis - inflammatory and infectious connections. Review of the literature. J Oral Microbiol, 2012. 4.
5.Rosenstein, E.D., et al., Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation, 2004. 28(6): p. 311-8.
6.van der Woude, D., et al., Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann Rheum Dis, 2010. 69(8): p. 1554-61.
7.Mahdi, H., et al., Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet, 2009. 41(12): p. 1319-24.
8.MacGregor, A.J., et al., Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum, 2000. 43(1): p. 30-7.
9.Smolen, J.S., et al., New therapies for treatment of rheumatoid arthritis. Lancet, 2007. 370(9602): p. 1861-74.
10.Gregersen, P.K., J. Silver, and R.J. Winchester, The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum, 1987. 30(11): p. 1205-13.
11.Weyand, C.M. and J.J. Goronzy, Disease-associated human histocompatibility leukocyte antigen determinants in patients with seropositive rheumatoid arthritis. Functional role in antigen-specific and allogeneic T cell recognition. J Clin Invest, 1990. 85(4): p. 1051-7.
12.De Almeida, D.E., et al., Immune dysregulation by the rheumatoid arthritis shared epitope. J Immunol, 2010. 185(3): p. 1927-34.
13.Kurreeman, F.A., et al., A candidate gene approach identifies the TRAF1/C5 region as a risk factor for rheumatoid arthritis. PLoS Med, 2007. 4(9): p. e278.
14.Begovich, A.B., et al., A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet, 2004. 75(2): p. 330-7.
15.Kallberg, H., et al., Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet, 2007. 80(5): p. 867-75.
16.Klareskog, L., et al., Immunity to citrullinated proteins in rheumatoid arthritis. Annu Rev Immunol, 2008. 26: p. 651-75.
17.Liao, K.P., L. Alfredsson, and E.W. Karlson, Environmental influences on risk for rheumatoid arthritis. Curr Opin Rheumatol, 2009. 21(3): p. 279-83.
18.Karlson, E.W., et al., A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals. Arthritis Rheum, 1999. 42(5): p. 910-7.
19.Saag, K.G., et al., Cigarette smoking and rheumatoid arthritis severity. Ann Rheum Dis, 1997. 56(8): p. 463-9.
20.Lundberg, K., et al., Genetic and environmental determinants for disease risk in subsets of rheumatoid arthritis defined by the anticitrullinated protein/peptide antibody fine specificity profile. Ann Rheum Dis, 2013. 72(5): p. 652-8.
21.Klareskog, L., et al., A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum, 2006. 54(1): p. 38-46.
22.Wegner, N., et al., Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and alpha-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum, 2010. 62(9): p. 2662-72.
23.Martin, T., et al., Structure-function studies on a polyreactive (natural) autoantibody. Polyreactivity is dependent on somatically generated sequences in the third complementarity-determining region of the antibody heavy chain. J Immunol, 1994. 152(12): p. 5988-96.
24.Scher, J.U., et al., Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife, 2013. 2: p. e01202.
25.Arnett, F.C., et al., The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum, 1988. 31(3): p. 315-24.
26.van Venrooij, W.J., J.M. Hazes, and H. Visser, Anticitrullinated protein/peptide antibody and its role in the diagnosis and prognosis of early rheumatoid arthritis. Neth J Med, 2002. 60(10): p. 383-8.
27.Pincus, T. and T. Sokka, Laboratory tests to assess patients with rheumatoid arthritis: advantages and limitations. Rheum Dis Clin North Am, 2009. 35(4): p. 731-4, vi-vii.
28.McInnes, I.B. and G. Schett, Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol, 2007. 7(6): p. 429-42.
29.Choy, E., Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatology (Oxford), 2012. 51 Suppl 5: p. v3-11.
30.Paunovic, V., et al., Signalling, inflammation and arthritis: crossed signals: the role of interleukin (IL)-12, -17, -23 and -27 in autoimmunity. Rheumatology (Oxford), 2008. 47(6): p. 771-6.
31.Smolen, J.S. and G. Steiner, Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov, 2003. 2(6): p. 473-88.
32.Henderson, B. and E.R. Pettipher, Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol, 1989. 75(2): p. 306-10.
33.van de Loo, A.A. and W.B. van den Berg, Effects of murine recombinant interleukin 1 on synovial joints in mice: measurement of patellar cartilage metabolism and joint inflammation. Ann Rheum Dis, 1990. 49(4): p. 238-45.
34.Williams, R.O., M. Feldmann, and R.N. Maini, Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc Natl Acad Sci U S A, 1992. 89(20): p. 9784-8.
35.Wooley, P.H., et al., Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collagen-induced arthritis in mice. J Immunol, 1993. 151(11): p. 6602-7.
36.Joosten, L.A., et al., Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice. A comparative study using anti-TNF alpha, anti-IL-1 alpha/beta, and IL-1Ra. Arthritis Rheum, 1996. 39(5): p. 797-809.
37.Ghivizzani, S.C., et al., Constitutive intra-articular expression of human IL-1 beta following gene transfer to rabbit synovium produces all major pathologies of human rheumatoid arthritis. J Immunol, 1997. 159(7): p. 3604-12.
38.Ku, G., et al., Interleukin-1 beta converting enzyme inhibition blocks progression of type II collagen-induced arthritis in mice. Cytokine, 1996. 8(5): p. 377-86.
39.Cronstein, B.N., Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis. Bull NYU Hosp Jt Dis, 2007. 65 Suppl 1: p. S11-5.
40.Hashizume, M., N. Hayakawa, and M. Mihara, IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford), 2008. 47(11): p. 1635-40.
41.Xie, D.L., et al., Cartilage chondrolysis by fibronectin fragments is associated with release of several proteinases: stromelysin plays a major role in chondrolysis. Arch Biochem Biophys, 1994. 311(2): p. 205-12.
42.Constantin, A., et al., Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study. Arthritis Rheum, 2002. 46(7): p. 1754-62.
43.Lee, D.M., et al., Cadherin-11 in synovial lining formation and pathology in arthritis. Science, 2007. 315(5814): p. 1006-10.
44.Wolfe, F., Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. J Rheumatol, 1997. 24(8): p. 1477-85.
45.Brennan, F.M., et al., Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet, 1989. 2(8657): p. 244-7.
46.Maxwell, L. and J.A. Singh, Abatacept for rheumatoid arthritis. Cochrane Database Syst Rev, 2009(4): p. CD007277.
47.Saag, K.G., et al., American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum, 2008. 59(6): p. 762-84.
48.Saini, R., et al., Periodontitis, a true infection. J Glob Infect Dis, 2009. 1(2): p. 149-50.
49.Shangase, S.L., et al., The association between periodontitis and systemic health: an overview. SADJ, 2013. 68(1): p. 8, 10-2.
50.Kolenbrander, P.E. and J. London, Adhere today, here tomorrow: oral bacterial adherence. J Bacteriol, 1993. 175(11): p. 3247-52.
51.Whittaker, C.J., C.M. Klier, and P.E. Kolenbrander, Mechanisms of adhesion by oral bacteria. Annu Rev Microbiol, 1996. 50: p. 513-52.
52.Berglundh, T. and M. Donati, Aspects of adaptive host response in periodontitis. J Clin Periodontol, 2005. 32 Suppl 6: p. 87-107.
53.Liu, Y.C., U.H. Lerner, and Y.T. Teng, Cytokine responses against periodontal infection: protective and destructive roles. Periodontol 2000, 2010. 52(1): p. 163-206.
54.Silva, T.A., et al., Chemokines in oral inflammatory diseases: apical periodontitis and periodontal disease. J Dent Res, 2007. 86(4): p. 306-19.
55.Haffajee, A.D. and S.S. Socransky, Microbial etiological agents of destructive periodontal diseases. Periodontol 2000, 1994. 5: p. 78-111.
56.Socransky, S.S., et al., Microbial complexes in subgingival plaque. J Clin Periodontol, 1998. 25(2): p. 134-44.
57.Hamlet, S.M., Quantitative analysis of periodontal pathogens by ELISA and real-time polymerase chain reaction. Methods Mol Biol, 2010. 666: p. 125-40.
58.Grenier, D., et al., Role of gingipains in growth of Porphyromonas gingivalis in the presence of human serum albumin. Infect Immun, 2001. 69(8): p. 5166-72.
59.Furuta, N., H. Takeuchi, and A. Amano, Entry of Porphyromonas gingivalis outer membrane vesicles into epithelial cells causes cellular functional impairment. Infect Immun, 2009. 77(11): p. 4761-70.
60.Meuric, V., et al., Treponema denticola improves adhesive capacities of Porphyromonas gingivalis. Mol Oral Microbiol, 2013. 28(1): p. 40-53.
61.Kuboniwa, M., et al., P. gingivalis accelerates gingival epithelial cell progression through the cell cycle. Microbes Infect, 2008. 10(2): p. 122-8.
62.McAlister, A.D., et al., Gingipain enzymes from Porphyromonas gingivalis preferentially bind immobilized extracellular proteins: a mechanism favouring colonization? J Periodontal Res, 2009. 44(3): p. 348-53.
63.Vincents, B., et al., Cleavage of IgG1 and IgG3 by gingipain K from Porphyromonas gingivalis may compromise host defense in progressive periodontitis. FASEB J, 2011. 25(10): p. 3741-50.
64.Grenier, D. and S. Tanabe, Porphyromonas gingivalis gingipains trigger a proinflammatory response in human monocyte-derived macrophages through the p38alpha mitogen-activated protein kinase signal transduction pathway. Toxins (Basel), 2010. 2(3): p. 341-52.
65.Khalaf, H. and T. Bengtsson, Altered T-cell responses by the periodontal pathogen Porphyromonas gingivalis. PLoS One, 2012. 7(9): p. e45192.
66.Inagaki, S., et al., Porphyromonas gingivalis vesicles enhance attachment, and the leucine-rich repeat BspA protein is required for invasion of epithelial cells by "Tannerella forsythia". Infect Immun, 2006. 74(9): p. 5023-8.
67.Park, Y., et al., Short fimbriae of Porphyromonas gingivalis and their role in coadhesion with Streptococcus gordonii. Infect Immun, 2005. 73(7): p. 3983-9.
68.Verma, R.K., et al., Porphyromonas gingivalis and Treponema denticola Mixed Microbial Infection in a Rat Model of Periodontal Disease. Interdiscip Perspect Infect Dis, 2010. 2010: p. 605125.
69.Hajishengallis, G., et al., Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe, 2011. 10(5): p. 497-506.
70.Weiss, E.I., et al., Attachment of Fusobacterium nucleatum PK1594 to mammalian cells and its coaggregation with periodontopathogenic bacteria are mediated by the same galactose-binding adhesin. Oral Microbiol Immunol, 2000. 15(6): p. 371-7.
71.Signat, B., et al., Fusobacterium nucleatum in periodontal health and disease. Curr Issues Mol Biol, 2011. 13(2): p. 25-36.
72.Laine, M.L., B.G. Loos, and W. Crielaard, Gene polymorphisms in chronic periodontitis. Int J Dent, 2010. 2010: p. 324719.
73.Obeid, P. and P. Bercy, Effects of smoking on periodontal health: a review. Adv Ther, 2000. 17(5): p. 230-7.
74.Barbour, S.E., et al., Tobacco and smoking: environmental factors that modify the host response (immune system) and have an impact on periodontal health. Crit Rev Oral Biol Med, 1997. 8(4): p. 437-60.
75.de Heens, G.L., et al., Effects of smoking on the ex vivo cytokine production in periodontitis. J Periodontal Res, 2009. 44(1): p. 28-34.
76.Bulmanski, Z., et al., Cigarette smoke extract induces select matrix metalloproteinases and integrin expression in periodontal ligament fibroblasts. J Periodontol, 2012. 83(6): p. 787-96.
77.Lappin, D.F., et al., Influence of periodontal disease, Porphyromonas gingivalis and cigarette smoking on systemic anti-citrullinated peptide antibody titres. J Clin Periodontol, 2013. 40(10): p. 907-15.
78.The, J. and J.L. Ebersole, Rheumatoid factor (RF) distribution in periodontal disease. J Clin Immunol, 1991. 11(3): p. 132-42.
79.Dewhirst, F.E., et al., Purification and partial sequence of human osteoclast-activating factor: identity with interleukin 1 beta. J Immunol, 1985. 135(4): p. 2562-8.
80.Butler, L.D., et al., Interleukin 1-induced pathophysiology: induction of cytokines, development of histopathologic changes, and immunopharmacologic intervention. Clin Immunol Immunopathol, 1989. 53(3): p. 400-21.
81.Matsuki, Y., T. Yamamoto, and K. Hara, Interleukin-1 mRNA-expressing macrophages in human chronically inflamed gingival tissues. Am J Pathol, 1991. 138(6): p. 1299-305.
82.Tokoro, Y., T. Yamamoto, and K. Hara, IL-1 beta mRNA as the predominant inflammatory cytokine transcript: correlation with inflammatory cell infiltration into human gingiva. J Oral Pathol Med, 1996. 25(5): p. 225-31.
83.Reinhardt, R.A., et al., Gingival fluid IL-1 and IL-6 levels in refractory periodontitis. J Clin Periodontol, 1993. 20(3): p. 225-31.
84.Birkedal-Hansen, H., Role of cytokines and inflammatory mediators in tissue destruction. J Periodontal Res, 1993. 28(6 Pt 2): p. 500-10.
85.Ishimi, Y., et al., IL-6 is produced by osteoblasts and induces bone resorption. J Immunol, 1990. 145(10): p. 3297-303.
86.Shimada, Y., et al., The effect of periodontal treatment on serum leptin, interleukin-6, and C-reactive protein. J Periodontol, 2010. 81(8): p. 1118-23.
87.Yamamoto, M., et al., Molecular and cellular mechanisms for periodontal diseases: role of Th1 and Th2 type cytokines in induction of mucosal inflammation. J Periodontal Res, 1997. 32(1 Pt 2): p. 115-9.
88.Fiorentino, D.F., M.W. Bond, and T.R. Mosmann, Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med, 1989. 170(6): p. 2081-95.
89.Letra, A., et al., MMP3 and TIMP1 variants contribute to chronic periodontitis and may be implicated in disease progression. J Clin Periodontol, 2012. 39(8): p. 707-16.
90.Pepys, M.B. and G.M. Hirschfield, C-reactive protein: a critical update. J Clin Invest, 2003. 111(12): p. 1805-12.
91.Ross, R., Atherosclerosis--an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115-26.
92.Dye, B.A., et al., Serum antibodies to periodontal pathogens and markers of systemic inflammation. J Clin Periodontol, 2005. 32(12): p. 1189-99.
93.Prakash, S., K. Dhingra, and S. Priya, Similar hematological and biochemical parameters among periodontitis and control group subjects. Eur J Dent, 2012. 6(3): p. 287-94.
94.Agarwal, N., V.S. Kumar, and S.A. Gujjari, Effect of periodontal therapy on hemoglobin and erythrocyte levels in chronic generalized periodontitis patients: An interventional study. J Indian Soc Periodontol, 2009. 13(1): p. 6-11.
95.Hirschfeld, L. and B. Wasserman, A long-term survey of tooth loss in 600 treated periodontal patients. J Periodontol, 1978. 49(5): p. 225-37.
96.Ogrendik, M., et al., Serum antibodies to oral anaerobic bacteria in patients with rheumatoid arthritis. MedGenMed, 2005. 7(2): p. 2.
97.Moen, K., et al., Immunoglobulin G and A antibody responses to Bacteroides forsythus and Prevotella intermedia in sera and synovial fluids of arthritis patients. Clin Diagn Lab Immunol, 2003. 10(6): p. 1043-50.
98.Mercado, F., et al., Is there a relationship between rheumatoid arthritis and periodontal disease? J Clin Periodontol, 2000. 27(4): p. 267-72.
99.Joseph, R., et al., Association between chronic periodontitis and rheumatoid arthritis: a hospital-based case-control study. Rheumatol Int, 2013. 33(1): p. 103-9.
100.Kasser, U.R., et al., Risk for periodontal disease in patients with longstanding rheumatoid arthritis. Arthritis Rheum, 1997. 40(12): p. 2248-51.
101.Dissick, A., et al., Association of periodontitis with rheumatoid arthritis: a pilot study. J Periodontol, 2010. 81(2): p. 223-30.
102.Cantley, M.D., et al., Pre-existing periodontitis exacerbates experimental arthritis in a mouse model. J Clin Periodontol, 2011. 38(6): p. 532-41.
103.McGraw, W.T., et al., Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect Immun, 1999. 67(7): p. 3248-56.
104.Potempa, M. and J. Potempa, Protease-dependent mechanisms of complement evasion by bacterial pathogens. Biol Chem, 2012. 393(9): p. 873-88.
105.Sokolove, J., et al., Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS One, 2012. 7(5): p. e35296.
106.de Pablo, P., et al., The autoantibody repertoire in periodontitis: a role in the induction of autoimmunity to citrullinated proteins in rheumatoid arthritis? Ann Rheum Dis, 2014. 73(3): p. 580-6.
107.Quirke, A.M., et al., Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann Rheum Dis, 2014. 73(1): p. 263-9.
108.Maresz, K.J., et al., Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLoS Pathog, 2013. 9(9): p. e1003627.
109.Marchesan, J.T., et al., Porphyromonas gingivalis oral infection exacerbates the development and severity of collagen-induced arthritis. Arthritis Res Ther, 2013. 15(6): p. R186.
110.Astry, B., E. Harberts, and K.D. Moudgil, A cytokine-centric view of the pathogenesis and treatment of autoimmune arthritis. J Interferon Cytokine Res, 2011. 31(12): p. 927-40.
111.Hernandez, M., et al., Host-pathogen interactions in progressive chronic periodontitis. J Dent Res, 2011. 90(10): p. 1164-70.
112.Gumus, P., et al., Saliva and serum levels of B-cell activating factors and tumor necrosis factor-alpha in patients with periodontitis. J Periodontol, 2014. 85(2): p. 270-80.
113.Yen, J.H., et al., Correlation of tumor necrosis factor alpha levels with disease activity of rheumatoid arthritis. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi, 1992. 25(4): p. 232-43.
114.Ye, S., et al., Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem, 1996. 271(22): p. 13055-60.
115.Erciyas, K., et al., Effects of periodontal therapy on disease activity and systemic inflammation in rheumatoid arthritis patients. Oral Dis, 2013. 19(4): p. 394-400.
116.Al-Katma, M.K., et al., Control of periodontal infection reduces the severity of active rheumatoid arthritis. J Clin Rheumatol, 2007. 13(3): p. 134-7.
117.Okada, M., et al., Periodontal treatment decreases levels of antibodies to Porphyromonas gingivalis and citrulline in patients with rheumatoid arthritis and periodontitis. J Periodontol, 2013. 84(12): p. e74-84.
118.Martinez-Martinez, R.E., et al., Detection of periodontal bacterial DNA in serum and synovial fluid in refractory rheumatoid arthritis patients. J Clin Periodontol, 2009. 36(12): p. 1004-10.
119.Rantapaa-Dahlqvist, S., et al., Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum, 2003. 48(10): p. 2741-9.
120.Ustun, K., et al., Host modulation in rheumatoid arthritis patients with TNF blockers significantly decreases biochemical parameters in periodontitis. Inflammation, 2013. 36(5): p. 1171-7.
121.Romero, A.M., et al., [MMP-3 and MMP-8 levels in patients with chronic periodontitis before and after nonsurgical periodontal therapy]. Invest Clin, 2013. 54(2): p. 138-48.
122.Chen, K., et al., Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med, 2006. 12(4): p. 425-32.
123.Faggioni, R., K.R. Feingold, and C. Grunfeld, Leptin regulation of the immune response and the immunodeficiency of malnutrition. FASEB J, 2001. 15(14): p. 2565-71.