類風濕性關節炎與免疫風濕疾病的生物製劑治療

Biologic Agents for Rheumatoid Arthritis and Other Rheumatic Diseases

吳建陞(Chien-Sheng Wu)

《台灣醫學》 22卷4期 (2018/07) Pp. 388-393

https://doi.org/10.6320/FJM.201807_22(4).0005

摘要

類風濕性關節炎（rheumatoid arthritis）是一種慢性發炎疾病，會造成病人的痛苦與殘疾。從二十世紀開始時缺乏有效藥物，到二十世紀末免疫生物製劑的誕生，類風溼性關節炎是一個基礎研究轉化為臨床突破的重要疾病模式。腫瘤壞死因子抑制劑（TNF-alpha inhibitors）是第一種用於類風溼性關節炎的生物製劑，孕育其誕生的重要分子生物與免疫學知識在1970-80年代逐漸完備，包括生產單株抗體的融合瘤技術、腫瘤壞死因子特性的研究、與基因工程技術的進步，然而產品商業化的過程，不但需要分子生物免疫學的知識，也需要製藥產業的臨床試驗執行力與人類的想像力。抗腫瘤壞死藥物的誕生，進一步推動對於人類疾病致病機轉的了解，包括腫瘤壞死因子在肺結核免疫的角色，有無抗體結晶片段（Fe）分子造成藥物特性的差異，甚至抗藥抗體的相關知識發展。隨著腫瘤壞死因子抑制劑的成功，後續針對B细胞的莫須瘤（ntuonnab）、針對介白素六受25的安挺樂（tocilizumab）、與針對阻斷抗原呈現細胞與T细胞交互作用的恩瑞舒（abatacept）等各種藥物陸續誕生，都適用於類風溼性關節炎。這些藥物的誕生又深化了我們對於各種免疫细胞與分子作用機轉的了解。然而生物製劑的發展與治療也面臨各種挑戰，例如生物製劑在類風溼性關節炎的療效仍然有進步的空間；在各種伺機性感染如B型肝炎與肺結核的防治上，也將台灣醫界未來的挑戰與機會！

關鍵字

生物製劑 ； 類風溼性關節 ； 腫瘤壞死因子抑制劑

並列摘要

Rheumatoid arthritis (RA), a chronic inflammatory disease, is disabling for patients. From a lack of effective treatment in the early twentieth century till the birth of biologic agent in the end of twentieth century, the development of therapy for RA shows how basic science is applied in clinical treatment. The TNF-alpha inhibitor is the first biologic agent for RA. The biotechnology and immunology knowledge for the development of TNF-alpha inhibitors matured in 1970-80s, including the hybridoma technology, the physiologic effect of TNF-alpha, and the molecular biology. However, the commercialization of biologics needs not only the scientific knowledge but also the execution of clinical trials by pharmaceutical industries and the imagination of human beings. The invention of TNF inhibitors improves the understanding of the pathogenesis of RA, the role of TNF in tuberculosis immunity, the Fc portion in pharmacokinetic properties, and the effect of the anti-drug antibody. Following the success of TNF-inhibitors, other biologic agents (including rituximab that depletes B cells, tocilizumab against IL-6 receptor, and abatacept that blocks the interaction between T cells and antigen presenting cells) were invented and marketed. These medications increased our understanding of the role of the immune cells and molecules. However, there are still some challenges in the treatment of RA. For example, the treatment response of RA has its ceiling. The management of opportunistic infections such as tuberculosis and viral hepatitis is both a challenge and a chance for clinicians in Taiwan!

並列關鍵字

biologics ； rheumatoid arthritis ； TNF-inhibitors

參考文獻

Wu CS: Impact of Immune Biological Agents on the Reactivation of Tuberculosis and Viral Hepatitis B and C. Formosan J Med 2013;17: 49-57. doi: 10.6838/YZU.2008.00312

Pennica D, Nedwin GE, Hayflick JS et al: Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature 1984;312:724-9. doi: 10.1038/312724a0

Yamasaki K, Taga T, Hirata Y et al: Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science (New York, NY) 1988;241:825-8. doi: 10.1126/science.3136546

Chu CQ, Field M, Feldmann M et al: Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis. Arthritis and rheumatism 1991;34:1125-32. doi: 10.1002/art.1780340908

Brennan FM, Chantry D, Jackson A et al: Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet (London, England) 1989;2:244-7. doi: 10.1016/S0140-6736(89)90430-3