dxy

　　Systemic Lupus Erythematosus (SLE)

　　With the incidence of systemic lupus erythematosus (SLE) increasing, anesthesiologists are more likely to be exposed to patients with the disease. Next weeks we'll be discussing various aspects of SLE, and this week, we'll be discussing the future therapies for SLE.

　　1.  What is mycophenolate mofetil, and how may it help SLE?
　　2.  Is immuneablative therapy with or without autologous marrow stem-cell transplantation more effective?
　　3.  Can human intravenous immuglobulin be of benefit in the treatment of SLE?
　　4.  What are some of the new agents on the horizon for the treatment of SLE?

　　本周我们讨论SLE未来的治疗方法：

　　1、麦考酚酸吗乙酯（mycophenolate mofetil）是什么药物？其对SLE的治疗是否有益？
　　2、与单独使用免疫治疗相比，合用自体骨髓造血干细胞治疗是否更有效？
　　3、SLE治疗中，静脉注射人类免疫球蛋白是否有用？
　　4、治疗SLE有哪些新方法？

　　参考答案：

　　1、麦考酚酸吗乙酯（mycophenolate mofetil）是什么药物？其对SLE的治疗是否有益？

　　麦考酚酸吗乙酯是一种次黄嘌呤核苷酸脱氢酶（促进淋巴细胞活性的一种酶）的可逆性抑制剂。该药物治疗可有效地减轻SLE的症状（包括肾脏表现），而副作用轻微且罕见。Chan等[1]通过一个随机对照实验对麦考酚酸吗乙酯与环磷酰胺进行了比较，结果发现，对于42名增生性肾炎患者，两种药物治疗效果相当，但麦考酚酸吗乙酯治疗组的患者副作用更少。

　　2、与单独使用免疫治疗相比，合用自体骨髓造血干细胞治疗是否更有效？

　　20世纪90年代，提出了治疗严重自身免疫性疾病的新方法，即自体干细胞移植的免疫治疗，结果表明有3-5%的死亡率，而同种异体干细胞的死亡率达到了14-35%[2]。对于SLE患者，有为数不多的病例报道和一个I期试验表明有鼓舞人心的结果，这些治疗可迅速的改善血液学，从而改善临床症状[3]。

　　有趣的是，最近Brodsky等[4]通过大剂量的化疗代替放疗行免疫治疗，结果发现，不需要进行干细胞移植。该研究表明，更简单和低廉的治疗方法在未来有望成为可能。

　　3、SLE治疗中，静脉注射人类免疫球蛋白是否有用？

　　静脉注射免疫球蛋白曾作为有多种表现的SLE的治疗。当SLE继发出现关节炎和血小板减少时，这种治疗可产生短期的效果[4]。此外，一些表现如皮肤病对治疗可产生抵抗，并甚至于与该治疗更相关；SLE相关血管炎的矛盾性加重也曾有过报道[5]。

　　4、治疗SLE有哪些新方法？

　　很多尚处于研究中的药物近期用于SLE的治疗[6]。这些药物包括：

　　●2-氯脱氧腺苷和氟达拉滨（血液化疗药物）
　　●他克莫司（免疫抑制剂）
　　●DP-1904（一种选择性血栓素A₂合成酶抑制剂）
　　●CD₄₀抗体
　　●Th₂细胞因子白介素10（一种单克隆抗体）

　　What is mycophenolate mofetil, and how may it help SLE?

　　Mycophenolate mofetil is a reversible inhibitor of inosine monophosphate dehydrogenase, an enzyme which promotes lymphocyte activity. Treatment with this agent has produced a significant reduction in SLE symptoms (including nephrotic symptoms) with only mild and infrequent side effects. Chan et al. (1) in a randomized controlled trial of mycophenolate mofetil versus cyclophosphamide (both with prednisolone) demonstrated the regimens to be equally effective in 42 patients with proliferative nephritis. The patients on mycophenolate mofetil , however, exhibited fewer side effects.

　　Is immunoablative therapy with or without autologous marrow stem-cell transplantation more effective?

　　Proposed as a treatment for severe autoimmune diseases in the early 1990's, immunoablative therapy with autologous stem cell transplantation was noted to have a 3-5% mortality risk, versus 14-35% observed with allogenic stem cells (2). In patients with SLE, several case reports and a single phase I study suggest very encouraging results, with such therapies producing a clinical remission of SLE with rapid hematological recovery (3).

　　Of interest, a recent report from Brodsky et al (4) used immunoablative therapy with high dose chemotherapy (cyclophosphamide) instead of radiation, and noted that stem cell transplantation was not necessary. This experience suggests a more simple and lower cost modality which may be used more frequently in the future, pending further investigation.

　　Can human intravenous immuglobulin be of benefit in the treatment of SLE?

　　Intravenous immunoglobulin has been used in SLE with mixed results. While arthritic and thrombocytopenic signs have responded well, these remissions are generally short lived (4). In addition, some signs such as skin disease remain refractory and even more concerning, paradoxical exacerbations of the vasculitis associated with SLE has been reported (5).

　　What are some of the new agents on the horizon for the treatment of SLE?

　　A number of investigational drugs are currently being evaluated for the treatment of SLE (6). These include:

　　•  cladribine and fludarabine (hematologic chemotherapy agents)
　　•  tacrolimus (immunosuppressant)
　　•  DP-1904 (a selective thromboxane A₂ synthetase inhibitor)
　　•  anti CD₄₀ (a ligand monoclonal antibody which interferes with T and B cell interaction-of note, a recent phase III trial of this agent was halted due to thromboembolic complications)
　　•  Th₂ cytokine interleukin 10 (a monoclonal antibody)

　　References:

　　1.  Chan TM, Li FK, Tang CSO, et al. Efficacy of mycophenolate mofetil in patients with diffuse lupus nephritis. N Engl J Med 2000;343:1156-62.
　　2.  Sherer Y, Shoenfeld Y. Stem cells transplantation--a cure for autoimmune diseases. Lupus. 1998;7(3):137-40.
　　3.  Traynor AE, Schroeder J, Rosa RM, et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet. 2000;356(9231):701-7.
　　4.  Brodsky RA, Fuller AK, Ratner LE, Leffell MS, Jones RJ. Elimination of alloantibodies by immunoablative high-dose cyclophosphamide. Transplantation. 2001;71(3):482-4.
　　5.  Rauova L, Lukac J, Levy Y, Rovensky J, Shoenfeld Y. High-dose intravenous immunoglobulins for lupus nephritis--a salvage immunomodulation. Lupus. 2001;10(3):209-13.
　　6.  Levy Y, Sherer Y, Ahmed A, et al. A study of 20 SLE patients with intravenous immunoglobulin--clinical and serologic response. Lupus. 1999;8(9):705-12.


编辑：ache