細胞激素，發炎反應與免疫生物製劑

Cytokines, Inflammation and Immune Biological Agents

雖然目前對於類風濕性關節炎（RA）是如何由何種特異性抗原所引起的自體免疫反應仍不清楚；但一般認為類風濕性關節炎的致病機轉是由於身體的先天及後天性免疫所引發的發炎反應有密切相關。在類風濕性關節炎引起關節發炎及破壞的主要發炎反應媒介物質為腫瘤壞死因子（TNF），IL-1，IL-6 等細胞激素以及趨化因子（chemokines）與蛋白酶等。由於對這些引起發炎反應的重要免疫細胞與分子的瞭解，使得我們得以免疫細胞所產生的具免疫調節功能的生物分子（主要為細胞激素）作為生物製劑產品用於醫學治療之用。最近所發現一種新的名為Th17 之CD4 T 細胞次群，可分泌IL-17 及IL-22 等細胞激素，已發現可能在引起自體免疫疾病的發炎反應中扮演著重要角色。因此針對著Th17 細胞也成為新的治療上藥物開發之標的。目前，共有五種腫瘤壞死因子的生物製劑經由美國藥物食品管理局（FDA）認可：infliximab, etanercept, adalimumab, golimumab 以及certolizumab pegol 且所有這些生物製劑在臨床上均顯示對於類風濕性關節炎有卓越的療效。許多研究均證實早期使用腫瘤壞死因子的生物製劑於類風濕性關節炎對於臨床上之緩解有顯著的好處。其他經由FDA 認可在治療類風濕性關節炎的生物製劑包括有abatacept, rituximab 及tocilizumab 等。利用生物製劑選擇性的抑制免疫和發炎反應來治療自體免疫及風濕性疾病是最近的新趨勢，也造成這些疾病在治療上的重大突破。

Although the specific trigger of the autoimmune response in rheumatoid arthritis (RA) is not known, it is generally believed the pathogenesis of RA is associated with the induction of inflammation via interactions of innate and the adaptive immune system. The main inflammatory mediators of joint inflammation and destruction in RA are tumor necrosis factor (TNF)-alpha, interleukin-1 (IL-1), IL-6, chemokines, and proteases. Advances in our understanding of the key cells and inflammatory cytokines have led to the development of targeted biologic agents. Recently, TH17 cells were characterized as a novel CD4+subset that preferentially produces IL-17, and IL-22 as the signature cytokines. TH17 cells appear to play a critical role in sustaining the inflammatory response and their presence is closely associated with autoimmune disease, which makes them an attractive therapeutic target. At present, 5 TNF-alpha inhibitors are approved for use by the FDA: infliximab, etanercept, adalimumab, golimumab, and certolizumab pegol, and all of these agents have been shown to be effective in reducing clinical signs of inflammation in RA patients. Multiple studies have demonstrated significant benefits of early treatment with TNF-alpha inhibitors combined with methotrexate. Other FDA-approved biologic agents for treating moderate-to-severe RA include abatacept, rituximab, and tocilizumab. All biologic agents carry an increased risk of infections. Following a greater understanding of the pathogenesis of RA, the treatment of this chronic disease has improved with the availability of biological agents targeting key molecules.