- 學位論文
腫瘤壞死因子α啟動子的單一核苷酸多型性與類風濕性關節炎病人使用生物製劑Enbrel 及Humira的療效相關性研究
The Evaluation of Effects of TNF-α Promoter Polymorphism on the Therapeutic Response of Enbrel and Humira in Patients with Rheumatoid Arthritis
摘要
類風溼性關節炎(Rheumatoid arthritis)是一種全身性慢性的發炎性關節炎，也是一種自體免疫疾病。特徵為免疫細胞浸潤在關節中，伴隨著滑膜細胞活化、增殖，這些細胞產生大量分解性酵素，以及Th1細胞激素刺激巨噬細胞等分化成蝕骨細胞，導致軟骨、硬骨的損壞。 腫瘤壞死因子α是由巨噬細胞所分泌的細胞激素，對於類風濕性關節炎病理機轉扮演重要角色。影響腫瘤壞死因子α濃度的因子因此可能與疾病嚴重度有關，例如腫瘤壞死因子基因的單一核苷酸多型性，目前已有許多位於腫瘤壞死因子啟動子區域的單一核苷酸多型性被發現。 近年來，利用拮抗腫瘤壞死因子的方式治療類風濕性關節炎病人，已證明是有效的，這些抗腫瘤壞死因子的生物製劑，包括etanercept、adlimumab等。但臨床經驗顯示只有約70%的病人對藥物有良好反應，其他20~30%病人則沒有療效，造成其中差異原因仍不明。因此我們推測造成其中差異原因或許與腫瘤壞死因子啟動子的單一核苷酸多型性相關。 我們分析了啟動子上-237、-308、-857、-863及¬-1031等五個位置的基因多型性，與使用etanercept、adlimumab及rituximab的病人療效反應做統計分析。在我們的結果中發現，使用etanercept的61位病人中，其療效好壞與否與-857位置的基因型有達顯著相關， 基因型C/T相較於C/C所計算出的危險對比值OR=0.111，95% C.I.=0.013-0.92;而使用adlimumab的27位病人中，其療效好壞與-857位置的基因型也有達顯著相關，使用rituximab的29位病人，則是療效好壞與五個位置的基因型都沒有顯著相關。
並列摘要
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints. RA can also cause inflammation of the tissue around the joints, as well as in other organs of the body. The joint inflammation causes joint swelling, pain, stiffness, and redness in the joints in RA patients. The chronic inflammation leads to the destruction of the cartilage, bone, and ligaments, causing deformity of the joints. Tumor necrosis factor-α (TNF-α), a macrophage-derived cytokine, has been suggested to play a major role in the pathogenesis of RA. Factors related to TNF-α regulation, including genotypes of TNF-α gene, might play a crucial role in tissue inflammation. Many single nucleotide polymorphisms (SNPs) within the TNF- gene and in its promoter region have been identified. TNF-α antagonist has emerged as an effective therapeutic agent in the treatment of RA, including etanercept, infliximab and adalimumab. Recent studies had shown that most of RA patients (around 70% patients) responded well to biological agents. However, part of RA patients (around 20-30%) showed a late failure in continuous injections and needed to be changed to other biological agents. The determinants associated with therapeutic responses remained unknown. Thus, I examined whether the TNF- promoter polymorphism is associated with responsiveness to anti-TNF therapy in RA patients. Our result found that there was a significant association between -857 genotype and anti-TNF therapy efficiency of 61patients treated with Enbrel. The odd ratios (ORs) and 95% confidence intervals (CI) for C/T versus C/C genotype of TNF -857 C/T polymorphism were 0.111 (0.013–0.92). There was also a significant association between -857 genotype and anti-TNF therapy efficiency of 27 patients treated with Humira. Furthermore, there was no association between TNF SNP and therapy efficiency of patients treated with Rituximab.
參考文獻
延伸閱讀
- 陳宗伯（2011）。併用Doxorubicin或Paclitaxel與反譯寡核苷酸微脂粒對白血病細胞之療效探討〔碩士論文，臺北醫學大學〕。華藝線上圖書館。https://doi.org/10.6831/TMU.2011.00171
- 陳喜玲（2006）。引朵美辛與葡萄糖胺調控人類軟骨瘤細胞Aggrecan 和MMP-3表現之研究〔碩士論文，臺北醫學大學〕。華藝線上圖書館。https://www.airitilibrary.com/Article/Detail?DocID=U0007-1704200715040010
- Chao, M. W. (2015). 探討 vincristine-vorinostat 合併使用與微管抑制劑 MPT0B392 之抗癌機轉及eIF4E binding protein 1 在癌症中的重要性 [doctoral dissertation, National Taiwan University]. Airiti Library. https://doi.org/10.6342/NTU.2015.02393
- Wang, C. Y., Lin, J. H., Wang, W. J., Cheng, M. H., & Lin, M. H. (2019). Glomerulonephritis and Anti-TNF Therapy in Patients with Rheumatoid Arthritis: A Case Report and Literature Review. 醫學與健康期刊, 8(1), 131-136. https://www.airitilibrary.com/Article/Detail?DocID=23046856-201903-201903260017-201903260017-131-136
- Lin, H. K., Lan, J. L., Chen, D. Y., Chen, Y. H., Huang, W. N., Hsieh, T. Y., Hsieh, C. W., & Chen, H. H. (2008). The Diagnostic Value of anti-cyclic Citrullinated Peptide Antibodies and Rheumatoid Factor in Patients with Rheumatoid Arthritis. Formosan Journal of Rheumatology, 22(1&2), 68-73. https://doi.org/10.6313/FJR.2008.22(1-2).10