臺灣博碩士論文加值系統

研究背景：乾癬(psoriasis)是一種因免疫問題而造成皮膚慢性發炎的疾病。患有乾癬的病人幾乎占全世界人口總數的2%，其病徵通常是由皮膚帶有脫屑的紅色斑塊來表現。現階段致病機轉仍不明確，但有大量研究發現且將乾癬歸類為自體免疫疾病，且跟基因、遺傳有所關連。同時也發現細菌感染、藥物、外傷、及飲酒都有可能是造成或加重乾癬發生的可能原因。慢性牙周炎是一種因細菌感染而造成的牙科疾病。在三十歲的成年人裡幾乎有35%的人都患有慢性牙周炎，而在五十歲年紀的族群裡，患有慢性牙周炎的比例則提高到50%。牙周病的發生起因於牙周致病菌的感染、宿主本身的免疫功能進而受到影響、免疫功能失調使得牙周組織變成一個慢性發炎的狀況，連帶的影響牙周附連組織的喪失、齒槽骨的破壞，慢性牙周病就此產生。除此之外，一些口腔不良嗜好、環境因素、全身性的疾病甚至基因問題都有可能影響牙周病的表徵。而現今知識對乾癬及慢性牙周炎的了解：起因都可歸類於表皮層的細菌感染，後續引發宿主產生過度的免疫反應而造成疾病。而此類免疫功能的失調，樹突狀細胞(dendritic cell)扮演舉足輕重的角色，因為它是調節及連結先天性免疫(innate immunity)及後天性免疫(adaptive immunity)的橋梁。眾多研究指出：乾癬的免疫致病機轉是因為樹突狀細胞、T細胞(T cell)、角質細胞(keratinocytes)等過度或不正常的分泌發炎激素如介白素12(interleukin-12，IL-12)、介白素23(interleukin-23，IL-23)、介白素17(interleukin-17，IL-17)、腫瘤壞死因子α(tumor necrosis factor α，TNF-α)影響了正常發炎反應的過程，而造成乾癬疾病的發生。同樣地，在牙齦表皮組織裡、受到樹突狀細胞調節的T細胞，因後續免疫反應影響單核球(monocytes)分泌發炎激素如腫瘤壞死因子α及介白素1β(Interleukin-1β，IL-1β)，此類激素會使得細胞分泌基質金屬蛋白酶(matrix metalloproteinase, MMPs)，最終造成牙周軟組織及硬組織的破壞，產生牙周病。

總結來說，兩種疾病都有可能由細菌感染表皮細胞造成，而從免疫致病機制來檢視這兩種疾病，都是因為感染後續造成過度或失控的免疫反應、影響或破壞到宿主本身正常的組織而造成病徵，因而推測這兩種疾病可能存在著某些關連性。因此，本病例對照實驗主要是希望探討乾癬與牙周病之間的關連性，同時檢視牙周疾病程度與乾癬嚴重程度是否會有相關，也調查唾液中發炎激素的濃度是否會因為此兩種疾病產生變化。

材料與方法：三十四位乾癬患者與三十二位健康者由專業牙周病醫師進行全口牙周檢查，包含剩餘牙齒顆數統計(residual teeth)、牙周囊袋深度探測(periodontal pocket depth，PD)、牙齦萎縮程度(gingival recession)、牙菌斑指數(plaque index)與牙齦發炎指數(gingival index)的檢測；牙周囊袋深度與牙齦萎縮程度兩者加總而得到牙周臨床附連喪失(clinical attachment loss，CAL)，根據Page跟Eke等學者在2007年的分類方法來診斷受試者牙周病的有無；乾癬患者則由資深皮膚科專科醫師進行皮膚檢查，以乾癬病灶占皮膚表面積、body surface area (BSA)及乾癬嚴重度指數、Psoriasis area severity index(PASI)來評估乾癬嚴重程度。兩組病人同時也進行唾液收集，處理後以Bio-Rad懸浮陣列多重標的偵測系統測量唾液中發炎激素的濃度。最後以曼-懷特尼檢定(Mann-Whitney U test)檢驗乾癬與健康受試者中、兩組的臨床牙周檢查數值及唾液中發炎激素濃度是否有差別；另外以卡方檢定(Chi-squared test)檢驗得到乾癬或牙周病的機率是為獨立或有相關；並以斯皮曼等級相關係數(Spearman''s rank correlation coefficient)以檢驗牙周病臨床數據、乾癬嚴重度及唾液中發炎激素濃度之間的相關性。所有統計皆以第20版statistical product and service solution (SPSS)軟體完成，且設定顯著水準小於0.05達到統計上顯著差異。



結論：乾癬病人的牙周破壞程度都較一般健康受試者來的嚴重，其中包含牙周囊袋深度探測≧4釐米及牙周臨床附連喪失≧4釐米的百分比、兩組間都有達到統計上的顯著差異。同時，乾癬病患的牙周病盛行率也較健康受試者來的高且一樣達到統計上顯著差別。羅吉斯回歸分析結果顯示：牙周病可能為乾癬的一個危險因子。而有關唾液中的發炎激素，介白素1β及干擾素γ，在乾癬組裡的濃度較高且達到統計上顯著差異。唾液中的介白素1β已被證實跟鄰床牙周破壞程度有關連，而本實驗發現乾癬嚴重指數與唾液中介白素1β的濃度也呈現正相關；因此，未來也許可以考量將唾液中介白素1β的濃度視為觀察乾癬疾病活動程度的一種生物標誌。腫瘤壞死因子α濃度在乾癬組裡相對高，但卻沒有達到統計上的顯著差異，其原因可能來自於：乾癬病人有接近三分之一都有使用抑制腫瘤壞死因子α的生物治劑，可能造成唾液中濃度較低，而無法達到統計的差異。至於介白素12及介白素17，因在唾液中的濃度都極低，甚至無法測量，所以實驗結果可能會有偏差。總結來說：乾癬病患的牙周病破壞程度和盛行率較健康受試者來的高。但乾癬病人中，乾癬的嚴重程度跟牙周病的破壞程度在本實驗裡沒有發現相關性，未來需要更多研究來更加證實此關係。

Background: Psoriasis is a chronic, immunologically-mediated, inflammatory skin disease, affecting approximately 2% of the population. It is usually manifested as raised, well-demarcated, erythematous oval plaques with adherent silvery scales. There appears to be a significant component of autoimmune dysfunction in its basic pathophysiology, although it is more properly designated as a genetic, systemic, inflammatory, chronic disorder. Additionally, bacterial infections, drugs, trauma, alcoholism, and smoking are all aggravating or triggering factors of psoriasis. Chronic periodontitis is a bacteria-caused inflammatory disease, affecting about 35% of adults over 30 years of age, and up to 50% of those over 50 years. It is initialized by bacterial infection which leads to dysregulation of the host inflammatory response and then establishes an inflammatory environment within the supporting tissues of the teeth. Progressive attachment loss and alveolar bone resorption would come up afterwards. Also the behavioral, environmental, systemic, and genetic risk factors have been reported to influence its expression. Current understandings of the etiology of both diseases are characterized by an exaggerated immune response to the microbiota residing on epithelial surfaces. Dendritic cells play a critical role in driving this exaggerated immune response, and are crucial to the initiation and regulation of both innate and adaptive immunity. Psoriatic immunopathogenesis consists of the complex interplay among innate and acquired immune cell types and among immune factors produced by dendritic cells, T cells, and keratinocytes in the psoriatic plaque. The numerous studies have identified interleukin-12/23(IL-12/23), interleukin-17(IL-17) and tumor necrosis factor-α(TNF-α) as particularly major mediators governing the inflammatory cascade in psoriasis. Similarly, dendritic cells identified in gingival tissue in association with T cells in periodontitis patients suggest dendritic-cell-mediated T-cell activation in chronic periodontitis. Activation of monocytes by stimulated T lymphocytes initiates the production of large amounts of inflammatory mediators, such as TNF-α and interleukin-1β(IL-1β), which further stimulate the release of mediators, including matrix metalloproteinase(MMPs), eventually resulting in soft and hard periodontal tissue destruction. In brief, there seems to be a common link in the pathogenesis of psoriasis and chronic periodontitis, but the evidence of the associations between psoriasis and periodontitis are still limited. Therefore, the aim of this case-control study is to explore the possible associations of the clinical periodontal status and psoriasis severity in psoriasis patients, and also to seek the correlation of salivary cytokines level and psoriasis severity.

Material and methods: We included 34 psoriasis patients as study group and 32 systemically healthy subjects as control group. All subjects received comprehensive periodontal examination to survey periodontal condition, including probing depth(PD), clinical attachment loss(CAL), plaque index(PI) and gingival index(GI). Also, saliva of all subjects were collected for inflammatory cytokine defection, and 1β(IL-1β), interleukin 12(IL-12), interleukin 17(IL-17), interferon γ(IFN-γ) and tumor necrosis factor α(TNF-α) were analyzed by Bio-Rad Bio-Plex 200 multiplex array system. Besides, psoriasis severity was assessed by body surface area(BSA) and psoriasis area severity index(PASI). Finally, we sought for the possible association between two diseases. Mann–Whitney U test was used to assess the differences between clinical periodontal parameters and salivary cytokine concentration between the psoriasis and control groups. Chi-squared test was used to assess whether the probability of getting psoriasis or periodontal disease was independent or not. Spearman''s rank correlation coefficient was used to determine the relationship between clinical periodontal parameters, salivary cytokine and psoriasis severity levels. Analyses were performed using statistical product SPSS 22.0 (SPSS Inc., Chicago, IL). A p value of <0.05 was considered significant.

Results: Percentage of sites with PD≧4mm or sites with CAL≧4mm were both significantly greater among psoriasis group compared with those in healthy subjects. Meanwhile, prevalence of periodontitis was also higher in psoriasis group and reached statistical significance as well. Logistic regression also revealed periodontitis could be the risk factor of psoriasis. Furthermore, IL-1β and IFN-γ showed greater expression in saliva of patients with psoriasis than in control subjects, and there was a positive correlation between PASI score and IL-1β titer. TNF-α concentration was greater in psoriasis group than in healthy subjects but without significance. The approximately one-third of psoriasis patients who had taken anti-TNF medication may account for this finding. As to the results of IL-12 and IL-17 salivary levels, they were both less consistent with nearly undetectable values in saliva. Overall, the severity of psoriasis seemed not to associate with the extent of periodontal destructions. Further studies were warranted to clarify the mechanism.

致謝 I
中文摘要 II
Abstract V
第一章、緒論 1
第一節、乾癬(Psoriasis) 1
第二節、牙周病 6
第三節、乾癬與牙周病的關係 9
第二章、 研究目的 11
第三章、 實驗材料與方法 12
第一節、病人募集 12
第二節、臨床牙周檢查 12
第三節、臨床乾癬嚴重程度檢查 13
第四節、唾液收集與檢測 13
第五節、統計分析 14
實驗流程圖 15
第四章、 結果 16
一、 乾癬病人疾病情況與藥物使用情形 16
二、 乾癬病友與健康對照組的牙周健康情況分析 17
三、 乾癬病友與健康對照組唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、腫瘤壞死因子α (tumor necrosis factor-α, TNF-α)、干擾素γ(interferon-γ, IFN-γ)濃度分析：(表4) 18
四、 輕度乾癬病患與中度以上乾癬病患的的牙周健康情況分析 19
五、 輕度乾癬病友與中度以上乾癬病患的唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、腫瘤壞死因子α (tumor necrosis factor-α, TNF-α)、干擾素γ(interferon-γ, IFN-γ)濃度分析：(表7) 20
六、 牙周病與唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、腫瘤壞死因子α (tumor necrosis factor-α, TNF-α)、干擾素γ(interferon-γ, IFN-γ)的關係(表5, 6, 7)： 21
七、 乾癬嚴重程度與牙周病及與唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、腫瘤壞死因子α (tumor necrosis factor-α, TNF-α)、干擾素γ(interferon-γ, IFN-γ)的關係： 23
八、 患有乾癬性關節炎的乾癬病人與沒有關節炎的病患，其臨床牙周檢查數據及乾癬嚴重程度的比較 25
九、 合併有乾癬性關節炎的患者其牙周病與乾癬嚴重程度之相關性：(表12) 25
十、 乾癬與風險因子之間的相關性 (表13) 26
第五章、 討論 27
第六章、 結論 32
參考文獻 54

圖目錄
圖 1病例對照實驗流程圖 15
圖 2乾癬病友與健康對照組之間牙周囊袋深度的比較 33
圖 3乾癬病友與健康對照組之間牙周臨床附連喪失的比較 34
圖 4乾癬病友與健康對照組之間牙菌斑指數的比較 35
圖 5乾癬病友與健康對照組之間牙齦發炎指數的比較 36
圖 6乾癬病友與健康對照組唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、干擾素γ(interferon-γ, IFN-γ)、腫瘤壞死因子α (tumor necrosis factor-α, TNF-α)濃度比較 39
圖 7輕度乾癬病友與中度以上乾癬病友牙周囊袋深度的比較 40
圖 8輕度乾癬病友與中度以上乾癬病友牙周臨床附連喪失的比較 41
圖 9輕度乾癬病友與中度以上乾癬病友牙菌斑指數的比較 42
圖 10輕度乾癬病友與中度以上乾癬病友牙齦發炎指數的比較 43
圖 11輕度乾癬病友與中度以上乾癬病友的唾液中介白素1β (Interleukin 1β, IL-1β)、介白素12 (Interleukin 12, IL-12)、介白素17 (Interleukin 17, IL-17)、干擾素γ(interferon-γ, IFN-γ)、腫瘤壞死因子α(tumor necrosis factor-α, TNF-α)濃度比較 46
圖 12乾癬病人臨床牙周檢查數值、唾液中發炎激素及乾癬嚴重程度的關連性 47
圖 13健康受試者在牙周檢查數據與唾液中發炎激素的相關性 48

表目錄
表 1　Definition and classification of chronic periodontitis 49
表 2 Definition of plaque index and gingival index 49
表 3　Classification of psoriasis severity 49
表 4　Demographic data of study objects 50
表 5　Severity of periodontitis and distribution 50
表 6　The prevalence of localized periodontitis and generalized periodontitis in mild and moderate to severe psoriasis patients 50
表 7　The psoriasis patients are grouped into two groups according to severity 51
表 8　Correlations between factors in Psoriasis patients 51
表 9　Correlations between factors in Healthy controls 51
表 10 Correlations between Psoriasis severity factors in Psoriasis patients 52
表 11 The psoriasis patients are grouped into two groups by psoriatic arthritis 52
表 12 Correlations between Psoriasis severity factors in Psoriatic arthritis patients 52
表 13 Association of risk factors with Psoriasis in logistic regression model 53

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