Benenson E, Fries J W U, Heilig B, Pollok M, Rubbert A
Medical Department I, University of Cologne, Cologne, 50924, Germany.
Clin Rheumatol. 2005 Jun;24(3):251-7. doi: 10.1007/s10067-004-1002-8. Epub 2004 Nov 26.
The objective of this study was to evaluate the feasibility and safety of high-dose azathioprine pulse (HAP) therapy in the induction of remission in patients with active Wegener's granulomatosis (WG) or progressive lupus nephritis (LN) refractory to or intolerant of cyclophosphamide. Four patients with antineutrophil cytoplasmic antibody (ANCA)-associated WG and two patients with progressive LN were treated with HAP (1200-1800 mg) applied monthly as continuous intravenous infusions at 50 mg/h. Patients received a total of 50 courses of intravenous azathioprine (AZA) therapy. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) and the Systemic Lupus Erythematosus Activity Index (SLEDAI). As only partial remission was induced in patients with progressive LN on this regimen, an additional 18 cycles were applied in these patients in which oral AZA at 100 mg/day in weeks 2 and 3 was added between two intravenous courses. A hereditary defect in thiopurine methyltransferase activity was excluded before initiation of treatment. High-dose azathioprine pulse and the intensified HAP treatment were well tolerated. Complete remission was achieved in two patients with WG suffering from three relapses of disease on application of 2-6 courses of HAP. Remission was maintained for 16-24 months. The remaining two patients with WG were withdrawn after 2-3 courses due to unchanged disease activity. In two patients with LN, partial remission was noted on 6-9 courses of HAP; however, the patients relapsed despite therapy with methotrexate and mycophenolate mofetil. The intensified HAP regimen led to partial or complete remission in both LN patients which was confirmed by sequential renal biopsies. Our results suggest that HAP therapy represents a well-tolerated regimen in patients with active WG and LN intolerant of or refractory to cyclophosphamide. As partial or complete remission was observed in four of six patients, further studies seem warranted to assess clinical efficacy in these patients.
本研究的目的是评估大剂量硫唑嘌呤冲击（HAP）疗法诱导对环磷酰胺耐药或不耐受的活动性韦格纳肉芽肿（WG）或进行性狼疮性肾炎（LN）患者缓解的可行性和安全性。4例抗中性粒细胞胞浆抗体（ANCA）相关的WG患者和2例进行性LN患者接受了HAP（1200 - 1800 mg）治疗，每月以50 mg/h的速度持续静脉输注。患者共接受了50个疗程的静脉硫唑嘌呤（AZA）治疗。使用伯明翰血管炎活动评分（BVAS）和系统性红斑狼疮疾病活动指数（SLEDAI）评估疾病活动度。由于在此方案下进行性LN患者仅诱导出部分缓解，因此在这些患者中额外应用了18个周期，即在两个静脉疗程之间的第2周和第3周加用100 mg/天的口服AZA。在开始治疗前排除了硫嘌呤甲基转移酶活性的遗传性缺陷。大剂量硫唑嘌呤冲击和强化HAP治疗耐受性良好。2例患有3次疾病复发的WG患者在应用2 - 6个疗程的HAP后实现了完全缓解。缓解维持了16 - 24个月。其余2例WG患者在2 - 3个疗程后因疾病活动度未改善而退出。2例LN患者在6 - 9个疗程的HAP治疗后出现部分缓解；然而，尽管接受了甲氨蝶呤和霉酚酸酯治疗，患者仍复发。强化HAP方案导致2例LN患者部分或完全缓解，这通过连续肾活检得到证实。我们的结果表明，HAP疗法对于对环磷酰胺不耐受或耐药的活动性WG和LN患者是一种耐受性良好的方案。由于6例患者中有4例观察到部分或完全缓解，似乎有必要进一步研究以评估这些患者的临床疗效。
