Shear Neil H
University of Toronto, Toronto, Ontario, Canada.
Drug Saf. 2006;29(1):49-66. doi: 10.2165/00002018-200629010-00004.
Psoriasis is a chronic inflammatory disease of the skin affecting approximately 2% of the world's population. Traditional systemic treatments, including methotrexate, ciclosporin, psoralen plus UVA (PUVA), oral retinoids and fumaric acid esters, are widely used for severe disease and are effective in the short term. Severe psoriasis is a chronic disease and patients and physicians have expressed concerns about possible harm from organ toxicity, such as skin cancer (PUVA), hyperlipidaemia (retinoids), renal (ciclosporin) or hepatotoxicity (methotrexate). Long-term monitoring is required and may not detect early organ damage. The pathophysiology of psoriasis remains to be clarified, but advances toward the understanding of the immunological basis of psoriasis have uncovered the involvement of immunological pathways; for example, the role of tumour necrosis factor (TNF)-alpha, T cell proliferation and T cell activation, and migration to the epidermis. This advancement in knowledge combined with developments in recombinant technologies has led to the development of target-specific therapies. Biological agents are defined as proteins that can be extracted from animal tissue or produced via recombinant DNA technologies and possess pharmacological activity. Adalimumab, alefacept, infliximab, efalizumab and etanercept are examples of biological agents currently used for the treatment of psoriasis. Some of these are also therapy for other autoimmune conditions, such as rheumatoid arthritis and Crohn's disease. These biological agents are effective in psoriasis but raise new safety concerns. Information on the safety of biological agents in conditions such as rheumatoid arthritis and Crohn's disease can not be directly extrapolated to psoriasis. An increased incidence of lymphomas has been postulated to be associated with etanercept, infliximab and adalimumab; serious infections, such as tuberculosis, have also been reported with these three biologicals, all of which target TNF-alpha. Demyelinating disorders, such as multiple sclerosis, have been reported with some biologicals as has congestive heart failure. Alefacept, because of its mechanism of action of lowering the number of active T cells, is associated with low T cell counts. Efalizumab has been associated with thrombocytopenia and haemolytic anaemia. Data on the safety of >2.5 years' continuous treatment with efalizumab are reassuring and a valuable beginning to understanding the role and risk of harm of long-term therapy for a chronic disease. Longer follow-up studies and safety databases, for each of the biologicals used in psoriasis, are needed to ensure both prolonged efficacy and minimal risk of harm.
银屑病是一种慢性皮肤炎症性疾病，影响着全球约2%的人口。传统的全身性治疗方法，包括甲氨蝶呤、环孢素、补骨脂素加紫外线A（PUVA）、口服维甲酸和富马酸酯，广泛用于治疗严重银屑病，且短期内有效。严重银屑病是一种慢性病，患者和医生对器官毒性可能造成的危害表示担忧，如皮肤癌（PUVA）、高脂血症（维甲酸）、肾毒性（环孢素）或肝毒性（甲氨蝶呤）。需要进行长期监测，且可能无法检测到早期器官损伤。银屑病的病理生理学仍有待阐明，但在理解银屑病免疫基础方面的进展揭示了免疫途径的参与；例如，肿瘤坏死因子（TNF）-α的作用、T细胞增殖和T细胞活化以及向表皮的迁移。这一知识进展与重组技术的发展共同促成了靶向特异性疗法的开发。生物制剂被定义为可从动物组织中提取或通过重组DNA技术生产并具有药理活性的蛋白质。阿达木单抗、阿法西普、英夫利昔单抗、依法利珠单抗和依那西普是目前用于治疗银屑病的生物制剂的例子。其中一些也是治疗其他自身免疫性疾病的药物，如类风湿性关节炎和克罗恩病。这些生物制剂对银屑病有效，但引发了新的安全问题。类风湿性关节炎和克罗恩病等疾病中生物制剂的安全性信息不能直接外推至银屑病。据推测，淋巴瘤发病率的增加与依那西普、英夫利昔单抗和阿达木单抗有关；这三种针对TNF-α的生物制剂也报告了严重感染，如结核病。一些生物制剂还报告了脱髓鞘疾病，如多发性硬化症，以及充血性心力衰竭。阿法西普因其降低活性T细胞数量的作用机制，与低T细胞计数有关。依法利珠单抗与血小板减少症和溶血性贫血有关。依法利珠单抗连续治疗超过2.5年的安全性数据令人放心，是理解慢性病长期治疗的作用和危害风险的一个有价值的开端。需要对用于银屑病治疗的每种生物制剂进行更长时间的随访研究和建立安全数据库，以确保疗效持久且危害风险最小。
