Novel treatments for systemic lupus erythematosus.
Novel treatments for systemic lupus erythematosus.
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发表时间：
2010-11
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通讯作者：
M. Gayed;C. Gordon
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作者：
M. Gayed;C. Gordon
系统性红斑狼疮(SLE)是一种自身免疫性疾病，与自身抗体的产生有关，具有相当高的发病率和死亡率。目前治疗这种疾病的方法是免疫抑制药物，主要是皮质类固醇、硫唑嘌呤、甲氨蝶呤和环磷酰胺，联合使用羟基氯喹。霉酚酸酯已被证明在狼疮性肾炎患者中与环磷酰胺一样有效，尽管没有获得这一适应症的许可，但在临床上的使用越来越多。减少系统性红斑狼疮自身抗体形成的新方法包括使用调节和/或耗尽B细胞的单抗(分别是抗CD22和抗CD20抗体)，或者干扰可溶性因子B淋巴细胞刺激物的刺激作用的单抗(抗BLyS抗体)。替代方法包括使用阿塔西塞普(Merck Serono)，一种跨膜激活剂和钙调节剂配体相互作用(TACI)-Ig融合蛋白，它通过与BLyS和轮廓诱导配体(APRIL)结合来抑制B细胞的刺激，或耐受剂，如Abetimus。阻断共刺激分子的相互作用，如CD40-CD40配体与单抗的相互作用，CD28-B7与可溶性细胞毒性T淋巴细胞抗原4(CTLA-4)-IgG1的相互作用(Abatacept)，也被尝试作为SLE的治疗策略。治疗SLE新药最有希望的策略是Belimumab(人类基因组科学/葛兰素史克)，一种抗BLyS抗体，因为该药物的两个III期临床试验最近达到了主要终点。在这篇综述中，讨论了这些治疗系统性红斑狼疮的新方法，包括靶向参与自身免疫的细胞因子途径的可能性。
Systemic lupus erythematosus (SLE) is an autoimmune disease that is associated with the production of autoantibodies, and with considerable morbidity and mortality. There has been much interest in developing more specific therapies for this disease, which is currently managed with immunosuppressive drugs, predominantly corticosteroids, azathioprine, methotrexate and cyclophosphamide, in combination with hydroxychloroquine. Mycophenolate mofetil has been demonstrated to be as efficacious as cyclophosphamide in patients with lupus nephritis, and is being used increasingly in the clinic despite not being licensed for this indication. Novel methods of reducing autoantibody formation in SLE include the use of mAbs that modulate and/or deplete B-cells (anti-CD22 and anti-CD20 antibodies, respectively), or that interfere with the stimulatory effects of the soluble factor B-lymphocyte stimulator (anti-BLys antibodies). Alternative approaches include the use of atacicept (Merck Serono), a transmembrane activator and calcium modulator ligand interactor (TACI)-Ig fusion protein, which inhibits B-cell stimulation by binding to BLys and a profileration-inducing ligand (APRIL), or toleragens such as abetimus. Blocking costimulatory molecule interactions, such as the CD40-CD40 ligand interaction with mAbs and the CD28-B7 interaction with a soluble cytotoxic T-lymphocyte antigen 4 (CTLA-4)-IgG1 construct (abatacept), has also been attempted as a therapeutic strategy for SLE. The most promising strategy for a new drug for SLE is belimumab (Human Genome Sciences/GlaxoSmithKline), an anti-BLys antibody, as two phase III clinical trials with this drug recently met their primary endpoints. In this review, these novel approaches to the treatment of SLE, including the potential of targeting cytokine pathways involved in autoimmunity, are discussed.