他克莫司治疗难治性狼疮肾炎的疗效和安全性

Tacrolimus therapy in refractory lupus nephritis： a prospective study in a single center

目的前瞻性研究环磷酰胺治疗无效的难治性狼疮肾炎患者应用他克莫司（FK506）治疗的临床效果和安全性。方法收集2009年1月至2010年12月门诊或住院的16～60岁的狼疮肾炎患者。入选患者均符合美国风湿病学会（ACR）1997年修订的系统性红斑狼疮（SLE）分类标准；尿蛋白定量（24h）≥1．5g；应用环磷酰胺半年累计剂量超过8g无效。他克莫司起始剂量2-3mg/d（体质量±60kg，3mg／d；体质量〈60kg，2mg／d），2个月后临床症状无好转，可逐渐调整剂量至4mg／d，监测血药浓度，观察期为6个月。疗效评价分为完全缓解、部分缓解和无效，达到完全缓解或部分缓解为有效。统计学处理采用单因素方差分析和Pearson相关分析。结果收集环磷酰胺治疗无效的狼疮肾炎患者14例，其中男性2例，女性12例，平均年龄（30±9）岁，SLE的平均病程（4±3）年；狼疮肾炎的平均病程（2．7±1．9）年。5例患者尿蛋白定量（24h）1．5-2．9g，9例患者尿蛋白定量（24h）±3．0g；9例患者有活动性尿沉渣。应用他克莫司的治疗过程中，尿蛋白定量（24h）水平显著下降，从基线（6．2±5．1）g降至6个月（1．1±0．9）g，差异有统计学意义（F=16．21，P〈0．01）；血清白蛋白水平呈逐渐上升趋势，从基线（27．9±9．7）g，L升至6个月（37．8±2．2）g／L，差异有统计学意义（F=16．71，P〈0．01）。在治疗的第1个月末，8例无效，6例部分缓解；在治疗的第2个月末，3例无效，11例部分缓解；在治疗的第4个月末，2例无效，9例部分缓解，3例完全缓解；在研究6个月时，2例无效，5例完全缓解，7例部分缓解，共12例有效，有效率达86％。他克莫司的起效时间平均（1．7±0．9）个月，其中6例患者1个月内有效，5例患者2个月内有效，1例患者4个月内有效。12例有效患者他克莫司的平均剂量为0．03。0．06rag＆g，所有他克莫司有效患者的药物浓度均低于3ng，ml，完全缓解、部分缓解和无效的他克莫司的平均血药浓度分别为（1．6±0．4），（2．0±0．6）和（2．2±±1．1）ng／ml，他克莫司的疗效和血药浓度之间无相关性。14例患者仅有1例出现新发高血压，1例出现脱发，观察期间未出现其他不良反应。结论他克莫司联合糖皮质激素治疗环磷酰胺无效的狼疮肾炎有效，6个月有效率达86％，是一种快速有效的缓解狼疮肾炎的治疗方法，血药浓度3ng／ml以下即可有效，其治疗狼疮肾炎的最佳剂量可能为0．03-0．06mg·kg-1·d-1。

Objective The purpose of this study was to assess the efficacy, safety and optimal dose of tacrolimus monotherapy in patients with refractory lupus nephritis （LN） who were resistant to cyclophosphamide（CYC）. Methods A total of 14 LN patients （2 men and 12 women） with persistent proteinuria who were resistant to CYC treatment more than 8 g for half a year were enrolled. Taerolimus was initiated at 2 mg/d （patient weight〈60 kg） or 3 mg/d （patient weight≥60 kg） which was administered in two divided doses. Prospective data on daily proteinuria, serum album level and serologic lupus activity were collected and followed for 6 months. ANOVA and Pearson correlation analysis were used for statistical analysis. Results Mean age at baseline was （30±9） years. Mean urinary protein decreased significantly from （6.2±5.1） g atbaseline to （1.1±0.9） g at 6 months （F=16.21, P〈0.01 ）. Mean serum album level increased significantly from （27.9±9.7） g/L at baseline to （37.8±2.2） g/L at 6 months （F=16.71, P〈0.01）. Complete or partial response was observed in 86% of patients receiving tacrolimus therapy. The effective dosage in this study was 0.03-0.06 mg.kg-1.d-1 of the patients who had complete response or partial response to tacrolimus. The tacrolimus level in partially and completely responding patients was less than 3 ng/ml. There was no significant difference among blood tacrolimns levels of complete, partial, and no response patients [ （1.6±0.4）, （2.0±0.6） and （2.2±1.1） ng/ml], respectively）. No definite correlation was found between efficacy and tacrolimus level. Tacrolimus was well tolerated at current dose, besides one with new onset hypertension and one with alopecia. Conclusion Our results suggest that tacrolimus at low dosage and serum level is potentially effective and safe for the treatment of patients with LN and persistent proteinuria resistant to CYC. The optimal dosage of tacrolimus for LN may be 0.03-0.06 mg.k.-1.d-1.