Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis
Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis
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DOI：
10.1136/ard.60.8.729
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发表时间：
2001-08-01
影响因子：
27.4
通讯作者：
Straub, RH
中科院分区：
文献类型：
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作者：
Cutolo, M;Sulli, A;Straub, RH
甲氨蝶呤（MTX）是一种叶酸类似物，最初于20世纪40年代合成，旨在抑制二氢叶酸还原酶。1还原叶酸（四氢叶酸）是细胞增殖所需的DNA和RNA的嘌呤和嘧啶前体从头合成途径中涉及的几种反应中的近端单碳供体。此外，四氢叶酸在第二个重要的生物化学步骤中起作用：甲硫氨酸高半胱氨酸循环，这是为几个下游反应提供甲基所必需的，如DNA，RNA蛋白质的甲基化等。因此，MTX已被广泛用于治疗肿瘤性疾病。1951年，MTX用于治疗类风湿性关节炎（RA）的基本原理是它抑制淋巴细胞和其他引起关节炎症的细胞的增殖。2直到20世纪80年代初，才发表了关于MTX治疗RA临床经验的进一步研究，当时报道了几项非对照试验。3- 8最后，1984年和1985年发表的四项设计良好的盲法安慰剂对照研究介绍了MTX在治疗RA中的应用。9-12 MTX用于风湿性疾病的早期适应症首次在1984年的大型综述中报道。[13]从过去15年获得的大量经验来看，几条证据清楚地表明，MTX并不仅仅是作为RA关节炎症细胞的细胞毒性（抗增殖）剂。事实上，很难理解一种通过防止免疫细胞增殖来减轻炎症的药物如何在有效浓度下仅在很短的时间内和每周一次起作用。此外，在大多数RA患者中使用低剂量MTX给药时观察到的快速临床缓解和对急性期反应物的短期效应，以及停药后疾病的快速发作，表明低剂量MTX的作用机制可能比抗增殖（免疫抑制）更具抗炎性。最近，MTX已被证明具有多种抗炎作用。17尽管很少有研究表明MTX对RA患者的T细胞数量或功能有任何特异性影响，但MTX确实在体内和体外对中性粒细胞，特别是单核细胞/巨噬细胞发挥明显的抑制作用，这些细胞被认为在RA病理生理学和炎性滑膜炎中起核心作用。17-23这些和其他单独的证据支持MTX的抗风湿/抗炎作用的替代机制的观点，这将在这里进行综述。
Methotrexate (MTX) is a folate analogue originally synthesised in the 1940s and designed to inhibit dihydrofolate reductase. 1 Reduced folate (tetrahydrofolate) is the proximal single carbon donor in several reactions involved in the de novo synthetic pathways for purine and pyrimidine precursors of DNA and RNA required for cell proliferation. Furthermore, tetrahydrofolate plays a part in a second important biochemical step: the methioninehomocysteine cycle, which is necessary to provide a methyl group for several downstream reactions such as methylation of DNA, RNA proteins, and others. Therefore, MTX has been used extensively for treatment of neoplastic diseases. In 1951 the rationale for the introduction of MTX for the treatment of rheumatoid arthritis (RA) was that it inhibited proliferation of the lymphocytes and other cells responsible for inflammation in the joint. 2 No further studies on clinical experience with MTX in RA were published until the early 1980s, when several uncontrolled trials were reported. 3–8Finally, four well designed, blinded, placebo controlled studies published in 1984 and 1985 introduced the use of MTX in the treatment of RA. 9–12 The early indications for MTX use in the rheumatic diseases were first reported in a large review in 1984. 13 From the considerable experience obtained over the past 15 years, several lines of evidence clearly suggest that MTX does not act simply as a cytotoxic (antiproliferative) agent for the cells responsible for the joint inflammation in RA. 14 As a matter of fact, it would be diYcult to understand how a drug that diminishes inflammation by preventing proliferation of immune cells might work at eVective concentrations for only a very short time and once a week. In addition, the rapid clinical remission and the short term eVect on the acute phase reactants, as seen with low dose MTX administration in most patients with RA, as well as the fast flare of disease after drug discontinuation, suggest that the mechanism of action of low dose MTX might be more anti-inflammatory than antiproliferative (immunosuppressive). 15 16 Recently, MTX has been shown to possess a variety of anti-inflammatory eVects. 17 Although, few studies suggest any specific eVect of MTX on T cell number or function in patients with RA, MTX does exert clear inhibitory eVects in vivo and in vitro on neutrophils and particularly on monocytes/macrophages that are believed to have a central role in RA pathophysiology and inflammatory synovitis. 17–23 These and other separate lines of evidence support the view that alternative mechanisms are responsible for the antirheumatic/anti-inflammatory eVects of MTX, which will be reviewed here.