Please use this identifier to cite or link to this item:
標題: 探討IL-19在類風濕性關節炎患者接受腫瘤壞死因子拮抗劑發生相關發炎性皮疹之病理角色
The pathogenic role of IL-19 in the occurrence of anti-TNF-α-associated inflammatory skin rash in rheumatoid arthritis patients
作者: 何瑋立
Wei-Li Ho
關鍵字: 腫瘤壞死因子拮抗劑;皮疹;致病機轉;介白素-19 (IL-19);類風溼性關節;Anti-tumor necrosis factor (anti-TNF), skin rash, pathogenesis, interleukin-19 (IL-19), rheumatoid arthritis (RA)
引用: Breedveld, F.C. and B.A. Dijkmans, Differential therapy in early and late stages of rheumatoid arthritis. Curr Opin Rheumatol, 1996. 8(3): p. 226-9. 2. Christodoulou, C. and E.H. Choy, Joint inflammation and cytokine inhibition in rheumatoid arthritis. Clin Exp Med, 2006. 6(1): p. 13-9. 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. Choy, E.H. and G.S. Panayi, Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med, 2001. 344(12): p. 907-16. 5. Scheinecker, C., K. Redlich, and J.S. Smolen, Cytokines as therapeutic targets: advances and limitations. Immunity, 2008. 28(4): p. 440-4. 6. Braun, J. and J. Sieper, Biological therapies in the spondyloarthritides--the current state. Rheumatology (Oxford), 2004. 43(9): p. 1072-84. 7. Mease, P.J. and C.E. Antoni, Psoriatic arthritis treatment: biological response modifiers. Ann Rheum Dis, 2005. 64 Suppl 2: p. ii78-82. 8. Mease, P.J., et al., Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet, 2000. 356(9227): p. 385-90. 9. Ford, A.C., et al., Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol, 2011. 106(4): p. 644-59, quiz 660. 10. Brion, P.H., A. Mittal-Henkle, and K.C. Kalunian, Autoimmune skin rashes associated with etanercept for rheumatoid arthritis. Ann Intern Med, 1999. 131(8): p. 634. 11. Bleumink, G.S., et al., Etanercept-induced subacute cutaneous lupus erythematosus. Rheumatology (Oxford), 2001. 40(11): p. 1317-9. 12. Kent, P.D., et al., Bullous skin lesions following infliximab infusion in a patient with rheumatoid arthritis. Arthritis Rheum, 2002. 46(8): p. 2257-8; author reply 2259. 13. Misery, L., et al., Dermatological complications of etanercept therapy for rheumatoid arthritis. Br J Dermatol, 2002. 146(2): p. 334-5. 14. Vergara, G., et al., Cutaneous drug eruption to infliximab: report of 4 cases with an interface dermatitis pattern. Arch Dermatol, 2002. 138(9): p. 1258-9. 15. Wright, R.C., Atopic dermatitis-like eruption precipitated by infliximab. J Am Acad Dermatol, 2003. 49(1): p. 160-1. 16. Williams, V.L. and P.R. Cohen, TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists. Int J Dermatol, 2011. 50(5): p. 619-25. 17. Puxeddu, I., et al., Hypersensitivity reactions during treatment with infliximab, etanercept, and adalimumab. Ann Allergy Asthma Immunol, 2012. 108(2): p. 123-4. 18. Lee, H.H., et al., Cutaneous side-effects in patients with rheumatic diseases during application of tumour necrosis factor-alpha antagonists. Br J Dermatol, 2007. 156(3): p. 486-91. 19. Joyau, C., et al., Anti-tumour necrosis factor alpha therapy and increased risk of de novo psoriasis: is it really a paradoxical side effect? Clin Exp Rheumatol, 2012. 20. Gallagher, G., et al., Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun, 2000. 1(7): p. 442-50. 21. Sakurai, N., et al., Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation. Rheumatology (Oxford), 2008. 47(6): p. 815-20. 22. Alanara, T., et al., Expression of IL-10 family cytokines in rheumatoid arthritis: elevated levels of IL-19 in the joints. Scand J Rheumatol, 2010. 39(2): p. 118-26. 23. Huang, F., et al., Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma. J Allergy Clin Immunol, 2008. 121(6): p. 1415-21, 1421 e1-3. 24. Oral, H.B., et al., Regulation of T cells and cytokines by the interleukin-10 (IL-10)-family cytokines IL-19, IL-20, IL-22, IL-24 and IL-26. Eur J Immunol, 2006. 36(2): p. 380-8. 25. Zhong, H., et al., A2B adenosine receptors induce IL-19 from bronchial epithelial cells, resulting in TNF-alpha increase. Am J Respir Cell Mol Biol, 2006. 35(5): p. 587-92. 26. Curtin, N.M., K.H. Mills, and T.J. Connor, Psychological stress increases expression of IL-10 and its homolog IL-19 via beta-adrenoceptor activation: reversal by the anxiolytic chlordiazepoxide. Brain Behav Immun, 2009. 23(3): p. 371-9. 27. Li, H.H., et al., Interleukin-19 upregulates keratinocyte growth factor and is associated with psoriasis. Br J Dermatol, 2005. 153(3): p. 591-5. 28. Kunz, S., et al., Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol, 2006. 15(12): p. 991-1004. 29. Nestle, F.O., et al., Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med, 2005. 202(1): p. 135-43. 30. Palucka, A.K., et al., Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci U S A, 2005. 102(9): p. 3372-7. 31. de Gannes, G.C., et al., Psoriasis and pustular dermatitis triggered by TNF-{alpha} inhibitors in patients with rheumatologic conditions. Arch Dermatol, 2007. 143(2): p. 223-31. 32. Ma, H.L., et al., Tumor necrosis factor alpha blockade exacerbates murine psoriasis-like disease by enhancing Th17 function and decreasing expansion of Treg cells. Arthritis Rheum, 2010. 62(2): p. 430-40. 33. 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. 34. Prevoo, M.L., et al., Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum, 1995. 38(1): p. 44-8. 35. Ledingham, J. and C. Deighton, Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford), 2005. 44(2): p. 157-63. 36. Fransen, J. and P.L. van Riel, The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol, 2005. 23(5 Suppl 39): p. S93-9. 37. Flendrie, M., et al., Dermatological conditions during TNF-alpha-blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther, 2005. 7(3): p. R666-76. 38. Nagy, G., et al., [Adverse events during biological therapy -- focusing on dermatological side-effects]. Orv Hetil, 2011. 152(6): p. 212-20. 39. Gaffen, S.L., The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep, 2009. 11(5): p. 365-70. 40. Hartung, A.D., et al., Th2-mediated atopic disease protection in Th1-mediated rheumatoid arthritis. Clin Exp Rheumatol, 2003. 21(4): p. 481-4. 41. Hilliquin, P., et al., Reduced incidence and prevalence of atopy in rheumatoid arthritis. Results of a case-control study. Rheumatology (Oxford), 2000. 39(9): p. 1020-6. 42. Rudwaleit, M., et al., Atopic disorders in ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis, 2002. 61(11): p. 968-74. 43. Olsson, A.R., et al., Allergic manifestations in patients with rheumatoid arthritis. APMIS, 2003. 111(10): p. 940-4. 44. Wang, F., et al., Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of interleukin (IL)-19, IL-20 and IL-24. Br J Dermatol, 2012. 167(1): p. 92-102. 45. Harrison, M.J., et al., Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis, 2009. 68(2): p. 209-15.
背景: 類風濕性關節炎(Rheumatoid arthritis, 簡稱RA)為一種慢性關節發炎之自體免疫疾病,會造成關節的變形與失能。發炎性的細胞激素在RA關節的發炎與破壞中扮演重要的角色,其中腫瘤壞死因子(tumor necrosis factor-alpha, 簡稱TNF-α) 是RA關節炎發炎致病過程裡主要的細胞激素。腫瘤壞死因子拮抗劑(TNF-αantagonist)是以TNF-alpha為標靶之生物製劑。有些患者接受TNF-α拮抗劑治療時,會產生與治療相關的非感染性皮疹,機轉目前仍不清楚。介白素-19 (interleukin-19, 簡稱IL-19)在RA患者接受TNF-α拮抗劑治療前後的變化,以及與治療相關的非感染的發炎性皮疹副作用的相關性仍是未知的。

方法: 以RA患者接受TNF-α拮抗劑治療時,產生與治療相關皮疹的患者血漿作IL-19分析。收集在接受TNF-α拮抗劑治療前及治療後3個月的血漿,以酵素免疫分析法enzyme-linked immunosorbent assay (ELISA) 來偵測IL-19值的變化。我們將患者分為有或無TNF-α拮抗劑治療相關皮疹來分析之。

結果: 在RA接受TNF-α拮抗劑治療後產生治療相關皮疹患者的血漿IL-19值,於治療後顯著上升 (p < 0.001)。在RA接受TNF-α拮抗劑治療後無產生治療相關皮疹患者的血漿IL-19值,無顯著變化。比較在RA患者接受TNF-α拮抗劑治療後和健康對照組的血漿IL-19值,顯示顯著差異 (p<0.05)。皮疹嚴重度和患者血漿IL-19於治療前後之差異值(△ IL-19)及治療後IL-19值有顯著相關性 (分別是r=0.618, p<0.001; r=0.467, p<0.05)。TNF-α拮抗劑治療前的血漿IL-19值則與皮疹嚴重度無明顯相關。血漿IL-19值與免疫球蛋白E (IgE)及嗜伊紅性白血球陽離子蛋白質(ECP)數值亦有顯著相關性。

結論: 結果顯示血漿IL-19在RA患者接受TNF-α拮抗劑治療時產生治療相關的皮疹的變化可能是類似IgE及ECP的第2型輔助T細胞(Th2)標記,而且有潛力成為相關的皮疹嚴重度的指標。但是IL-19不能作為預測相關的皮疹發生的預測因子。然而仍需大規模研究來證實以上發現。另外,也需要進一步全國性資料分析來確定TNF-α拮抗劑治療相關的發炎性皮疹發生率。

Background: Rheumatoid arthritis (RA), a chronic articular inflammation and autoimmune disease, may result in joint deformities and disability. Proinflammatory cytokines play an important role in the inflammation and destruction of joints in RA. Tumor necrosis factor-alpha (TNF-α) is one of the major pathogenic inflammatory cytokines in RA. The TNF-αantagonists are biologics that target TNF-α. Some patients developed non-infectious inflammatory skin rashes which are associated with anti-TNF-αtreatment. The exact pathogenic mechanism remains unknown. The change in plasma interleukin-19 (IL-19) levels in RA patients who receive anti-TNF-α treatment and develop non-infectious inflammatory skin rashes are needed to be determined.
Methods: We obtained plasma for IL-19 analysis from 48 RA patients at baseline before anti-TNF-αtherapy and 3 months after the anti-TNF-α therapy. Plasma levels of IL-19 were determined by enzyme-linked immunosorbent assay (ELISA). The enrolled patients were stratified according to the presence and absence of biologic-related skin rashes.
Results: There was a significant increase of plasma IL-19 level in patients of rheumatoid arthritis with anti-TNF-α-associated inflammatory skin rash after treatment (p < 0.001). No significant change of plasma IL-19 levels in RA patients without anti-TNF-α-therapy - associated inflammatory skin rash after treatment was noted. Comparing the plasma IL-19 level of RA patients after anti-TNF-αtherapy and the healthy contrasts showed a significant difference (p<0.05). Significant correlations between the rash severity and plasma IL-19 change before and after treatment (△ IL-19 ) and IL-19 levels of patients post anti-TNF-αtherapy (r=0.618, p<0.001; r=0.467, p<0.05, respectively) were noted. There was no significant correlation between rash severity and plasma IL-19 level of patients before anti-TNF-αtherapy. Significant correlations between the baseline immunoglobulin (IgE) and eosinophil cationic protein (ECP) levels and plasma IL-19 levels were also noted.
Our results suggested that plasma IL-19 might play a major role as a T helper 2 (Th2) cells marker similar to IgE and ECP in RA patients with anti-TNF-α therapy-associated skin rashes. Plasma IL-19 could be a potential marker of rash severity. But, it could not served as a predicting factor for anti-TNF-αtherapy-associated skin rash.
其他識別: U0005-2811201416185873
Rights: 不同意授權瀏覽/列印電子全文服務
Appears in Collections:生命科學院碩士在職專班

Files in This Item:
File Description SizeFormat Existing users please Login
nchu-103-5099052009-1.pdf1.38 MBAdobe PDFThis file is only available in the university internal network    Request a copy
Show full item record

Google ScholarTM


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.