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Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis

  • Review
  • Intervention

Authors

  • Patricia M Fortin,

    Corresponding author
    1. University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver, BC, Canada
    • Patricia M Fortin, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. patricia@ti.ubc.ca.

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  • Aaron M Tejani,

    1. Fraser Health Authority, Clinical Research and Drug Information, Burnaby, BC, Canada
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  • Ken Bassett,

    1. University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver, BC, Canada
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  • Vijaya M Musini

    1. University of British Columbia, Department of Anesthesiology, Pharmacology and Therapeutics, Vancouver, BC, Canada
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Abstract

Background

Wegener's granulomatosis (WG) is a necrotizing small-vessel vasculitis that can affect any organ in the body but mainly affects the upper and lower respiratory tract, the kidneys, joints, skin and eyes. The current mainstay of remission induction therapy is systemic corticosteroids in combination with oral daily cyclophosphamide (CYC) which induces remission in 75% to 100% of cases. Although standard therapy is effective in inducing partial or complete remission, 50% of complete remissions are followed by at least one relapse.

Objectives

To determine if intravenous immunoglobulin (IVIg) adjuvant therapy provides a therapeutic advantage over and above treatment with systemic corticosteroids in combination with immunosuppressants for the treatment of WG.

Search methods

The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Trials Register (last searched 8 May) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched 2009, Issue 2). We searched MEDLINE (1966 to May 2009) and EMBASE (1980 to May 2009).

Selection criteria

Randomized controlled trials (RCTs), or quasi RCTs, or randomized cross-over trials. Participants had to be adults with a confirmed diagnosis of WG.

Data collection and analysis

Two authors independently extracted data and assessed trial quality. Relative risk was used to analyze dichotomous variables, and mean difference (MD) was used to analyze continuous variables.

Main results

We included one RCT with 34 participants who were randomly assigned to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. There were no significant differences between adjuvant IVIg and adjuvant placebo in mortality, serious adverse events, time to relapse, open-label rescue therapy, and infection rates. The fall in disease activity score, derived from patient-reported symptoms, was slightly greater in the IVIg group than in the placebo group at one month (MD 2.30; 95% Confidence interval (CI) 1.12 to 3.48, P < 0.01) and three months (MD 1.80; 95% CI 0.35 to 3.25, P = 0.01). There was a significant increase in total adverse events in the IVIg group (relative risk (RR) 3.50; 95% CI 1.44 to 8.48, P < 0.01).

Authors' conclusions

There is insufficient evidence from one RCT that IVIg adjuvant therapy provides a therapeutic advantage compared with the combination of steroids and immunosuppressants for patients with WG. Given the high cost of IVIg (one dose at 2g/kg for a 70kg patient = $8,400), it should be limited to treat WG in the context of a well conducted RCT powered to detect patient-relevant outcomes.

摘要

背景

靜脈注射免疫球蛋白(immunoglobulin)作為韋格納肉芽腫病輔助治療

韋格納肉芽腫病(WG)是小血管壞死性血管炎影響體內所有器官,但主要影響上及下呼吸道、腎臟、關節、皮膚與眼睛。目前主要誘導緩解治療是系統性皮質類固醇激素加上每天口服cyclophosphamide (CYC)達到75%至100%患者誘導症狀緩解。雖然標準治療能有效誘導部分或完全緩解,50%完全緩解患者會有至少一次的復發。

目標

確定靜脈注射免疫球蛋白輔助療法是否能提供韋格納肉芽腫病患者比施與系統性皮質類固醇激素合併免疫抑制劑更有利的治療。

搜尋策略

搜尋Cochrane Peripheral Vascular Diseases (PVD) Group Trials Register (至2008年5月)及Cochrane Library的Cochrane Central Register of Controlled Trials (CENTRAL)(至2009年,第2期).也搜尋 MEDLINE (1966年至2009年5月)與EMBASE (1980年至2009年5月).

選擇標準

隨機或小型隨機對照型研究,或隨機交叉型研究。參與研究對象必須是確定韋格納肉芽腫病的成人患者。

資料收集與分析

兩位作者獨立擷取資料與評估試驗品質。二分變量以相對風險(Relative risk)分析,連續變數以平均差(mean difference, MD) 分析。

主要結論

收納一項隨機對照試驗包括34患者參與分派接受一天一次的靜脈注射免疫球蛋白(IVIg)或安慰劑加上硫唑嘌呤(azathioprine)與prednisolone為維持緩解治療。在死亡率、嚴重不良反應、復發時間、開放標示挽救治療、與感染率,IVIg與安慰劑兩者無顯著差異。患者報告症狀的疾病活動評分,IVIg組比安慰劑組有些許較大的下降程度。第一個月MD 2.30; 95%信賴區間1.12至3.48, P < 0.01與第三個月MD 1.80; 95%信賴區間0.35至3.25, P = 0.01。 IVIg組在整體不良反應有顯著增加(相對風險 3.50; 95%信賴區間1.44至8.48, P < 0.01)。

作者結論

由單一對韋格納肉芽腫病病患比較IVIg與皮質類固醇激素合併免疫抑制劑療效的隨機對照試驗結果,沒有足夠的證據證實IVIg有較好的療效。因IVIg的高成本(以一70公斤患者每公斤 2公克劑量算要美金8,400元),他必須經完善設計執行的隨機對照試驗支持有助患者的結果後才用於韋格納肉芽腫病治療。

翻譯人

本摘要由臺中榮民總醫院葉惠英翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

韋格納肉芽腫病是引起血管發炎的罕見疾病。發炎侷限不同器官的血流中製造成器官受損。最常見受損的器官有肺、上呼吸道、腎、關節、皮膚與眼睛。韋格納肉芽腫同時形成肉芽腫(炎症組織的結節塊)圍繞血管毀損周邊組織。形成韋格納肉芽腫病的原因不明。治療是常用來化學治療的皮質類固醇激素及抗癌藥物。大部分病患經這些藥物治療後會改善。然而大約有一半患者會復發。 靜脈注射免疫球蛋白(IVIg)是一曾用來治療韋格納肉芽腫病昂貴且相當稀有的血液製品。但它效果未知。我們想知道IVIg做為輔助治療是否有助於標準治療。我們發現一項有34 位患者的小型隨機試驗,在azathioprine與prednisolone治療下將患者隨機分派接受一天一劑IVIg或安慰劑維持病況緩解。該試驗未提供足夠證據確定在治療韋格納肉芽腫病優於皮質類固醇與免疫抑制劑。

Plain language summary

Intravenous immunoglobulin in addition to standard treatments for Wegener's granulomatosis

Wegener's granulomatosis is a rare disorder that causes inflammation of the blood vessels. This inflammation restricts blood flow to various organs which can eventually damage the organs. Organs most affected by Wegener's include the lungs, upper respiratory tract, kidneys, joints, skin and eyes. Wegener's granulomatosis also produces a granuloma (a mass or nodule of inflammatory tissue) which is found around the blood vessels and which can also damage surrounding tissue. The cause of Wegener's granulomatosis is unknown. Treatment is with corticosteroids and cytotoxic drugs which are often used for chemotherapy. Most patients get better with these drugs. However, the disorder returns in approximately half of patients. Intravenous immunoglobulin (IVIg) is an expensive and fairly rare blood product that has been used to treat Wegener's granulomatosis but its effects on the disorder are unknown. We asked if IVIg provided an advantage as an additive to standard treatments. We found one small randomized trial in which 34 particpants were randomized to receive IVIg or placebo once daily in addition to azathioprine and prednisolone for remission maintenance. This trial did not provide enough evidence to determine if IVIg has an advantage over corticosteroids and immunosuppressants for the treatment of Wegener's granulomatosis.

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