Tocilizumab for rheumatoid arthritis

  • Review
  • Intervention

Authors


Abstract

Background

Tocilizumab, a new biologic that inhibits interleukin-6, is approved for treatment of rheumatoid arthritis (RA) in Europe, Japan and the US.

Objectives

To assess the efficacy and safety of tocilizumab in patients with RA using the data from published randomized or quasi-randomized controlled trials (RCTs).

Search methods

We performed a search of the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL) up to issue 3, 2009; OVID MEDLINE(1966 to 1 October 2009); CINAHL(1982 to 2009); EMBASE (1980 to week 39, 2009); Science Citation Index (Web of Science) (1945 to 2009) and Current Controlled Trials.

Selection criteria

Tocilizumab alone or in combination with disease-modifying anti-rheumatic drugs (DMARDs) or biologics compared to placebo or other DMARDs or biologics.

Data collection and analysis

Two review authors independently extracted all data including major (ACR50, adverse events, serious adverse events, withdrawals, specific adverse events) and secondary outcomes. We calculated the risk ratio for dichotomous outcomes and mean difference for continuous outcomes.

Main results

Eight RCTs were included in this systematic review with 3334 participants; 2233 treated with tocilizumab and 1101 controls. Of the 2233, 1561 were treated with tocilizumab 8 mg/kg every four weeks, which is the approved dose. In patients taking concomitant methotrexate, compared to placebo, tocilizumab-treated patients were four times more likely to achieve ACR50 (absolute %, 38.8% versus 9.6%), 11 times more likely to achieve Disease Activity Score (DAS) remission (absolute %, 30.5% versus 2.7%), 1.8 times more likely to achieve clinically meaningful decrease in Health Assessment Questionnaire (HAQ/mHAQ) scores (absolute %, 60.5% versus 34%), 1.2 times more likely to have any adverse event (absolute %, 74% versus 65%) and 0.6 times less likely to withdraw from therapy for any reason (absolute %, 8.1% versus 14.9%). With the limitation that none of the studies were powered for safety as primary outcome, there were no statistically significant differences in serious adverse effects, or withdrawals due to adverse events. A significant increase in total, HDL and LDL cholesterol and triglyceride level was seen in the tocilizumab treated patients.

Authors' conclusions

Tocilizumab is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with significant increase in cholesterol levels and in total adverse events. Larger safety studies are needed to address these safety concerns.

Resumen

Antecedentes

Tocilizumab para la artritis reumatoide

El tocilizumab, un nuevo fármaco biológico que inhibe la interleucina6, está aprobado para el tratamiento de la artritis reumatoide (AR) en Europa, Japón y EE.UU.

Objetivos

Evaluar la eficacia y la seguridad del tocilizumab en los pacientes con AR utilizando los datos de ensayos controlados aleatorios (ECA) o cuasialeatorios publicados.

Estrategia de búsqueda

Se realizó una búsqueda en las siguientes bases de datos: Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL) hasta el número 3, 2009; OVID MEDLINE (1966 hasta el 1 octubre 2009); CINAHL (1982 hasta 2009); EMBASE (1980 hasta la semana 39, 2009); Science Citation Index (Web of Science) (1945 hasta 2009) y en Current Controlled Trials.

Criterios de selección

Tocilizumab solo o en combinación con fármacos antirreumáticos modificadores de la enfermedad (FARME) o con fármacos biológicos en comparación con placebo u otros FARME o fármacos biológicos.

Obtención y análisis de los datos

Dos revisores extrajeron de forma independiente todos los datos principales incluidos (ACR50, eventos adversos, eventos adversos graves, retiros, eventos adversos específicos) y los resultados secundarios. Se calculó el riesgo relativo para los resultados dicotómicos y la diferencia de medias para los resultados continuos.

Resultados principales

En esta revisión sistemática, se incluyeron ocho ECA con 3334 participantes; 2233 se trataron con tocilizumab y 1101 fueron controles. De los 2233, 1561 fueron tratados con tocilizumab en dosis de 8 mg/kg cada cuatro semanas, que es la dosis aprobada. En los pacientes a los que se les administró también metotrexato, en comparación con el placebo, la probabilidad de lograr ACR50 fue cuatro veces mayor para los pacientes tratados con tocilizumab (% absoluto, 38,8% versus 9,6%), la posibilidad de lograr la remisión según la Disease Activity Score (DAS) (Puntuación de la Actividad de la Enfermedad) fue 11 veces mayor (% absoluto, 30,5% versus 2,7%), la posibilidad de lograr una disminución clínicamente significativa según las puntuaciones del Health Assessment Questionnaire (HAQ/mHAQ) (Cuestionario de Evaluación de la Salud) fue 1,8 veces mayor (% absoluto, 60,5% versus 34%), la probabilidad de eventos adversos fue 1,2 veces mayor (% absoluto, 74% versus 65%) y la probabilidad de retirarse del tratamiento por algún motivo fue 0,6 veces menor (% absoluto, 8,1% versus 14,9%). Con la limitación de que ninguno de los estudios tuvo un poder estadístico suficiente para establecer la seguridad como resultado primario, no hubo diferencias estadísticamente significativas en los efectos adversos graves. Se observó un aumento significativo en los niveles de colesterol total, LDL y HDL, y en los triglicéridos en los pacientes tratados con tocilizumab.

Conclusiones de los autores

El tocilizumab es beneficioso ya que reduce la actividad de la AR y produce mejoría funcional. El tratamiento con tocilizumab se asoció con un aumento significativo en los niveles de colesterol y en los eventos adversos totales. Se requieren más estudios que aborden los aspectos de la seguridad.

Traducción

Traducción realizada por el Centro Cochrane Iberoamericano

摘要

背景

以Tocilizumab 治療風濕性關節炎

Tocilizumab是一種新的、可抑制interleukin6的生物製劑,在美國、歐洲和日本已被許可用於治療風濕性關節炎(rheumatoid arthritis,RA)。

目標

為了評估Tocilizumab 治療風濕性關節炎病人的有效性和安全性,我們使用已發表的隨機或半隨機對照試驗(quasirandomized controlled trials;RCTs)的數據資料。

搜尋策略

我們完成了對下列資料庫的搜尋:Cochrane Central Register of Controlled Trials (CENTRAL) up to issue 3, 2009; OVID MEDLINE (1966 to 1 October 2009); CINAHL (1982 to 2009); EMBASE (1980 to week 39, 2009); Science Citation Index (Web of Science) (1945 to 2009) and Current Controlled Trials。

選擇標準

單獨使用Tocilizumab 、或併用修飾疾病的抗風濕藥物(diseasemodifying antirheumatic drugs;DMARDs)或生物製劑(biologics),和安慰劑或其他併用修飾疾病的抗風濕藥物或生物製劑來比較。

資料收集與分析

二位審查作者獨立的提取包括主要 (ACR50、不良事件、嚴重不良事件、提前退出研究、特殊的不良事件) 及次要結果的所有數據資料。我們為二分法成果(dichotomous outcomes)和平均差連續成果(mean difference for continuous outcomes)計算風險比率(risk ratio)。

主要結論

我們納入了8個隨機對照試驗進行系統性的評估,共有3334位受試對象。其中有2233位是以tocilizumab治療,而1101位為對照組。在以tocilizumab治療的2233位病人當中,有1561位是使用被核准的每4週1次8 mg/kg的劑量。比較同時併用methotrexate或安慰劑的病人,以tocilizumab治療的病人達到ACR50約為使用安慰劑病人的4倍(絕對百分比為38.8% 比9.6%);達到疾病活動分數(Disease Activity Score;DAS)緩解的,約為11倍(絕對百分比為30.5% 比2.7%);達到臨床有意義降低健康評估問卷(Health Assessment Questionnaire;HAQ/mHAQ)分數的,約為1.8倍(絕對百分比為60.5% 比34%);導致任何不良事件的,約為1.2倍(絕對百分比為74% 比65%);而無論原因為何,較不易退出治療的,約為0.6倍(絕對百分比為8.1% 比14.9%)。受限於沒有任何一個研究將安全性定為主要結果,因此,在嚴重不良反應或因不良事件而退出治療方面,都沒有統計上有意義的差異。另外,以tocilizumab治療的病人,其總膽固醇(total cholesterol)、高密度膽固醇(HDL cholesterol)、低密度膽固醇(LDL cholesterol)、及三酸甘油脂(triglyceride)的血中濃度,都有明顯的增加。

作者結論

Tocilizumab對於降低風濕性關節炎的疾病活動程度和增進功能是有益處的。Tocilizumab的治療,和血中膽固醇濃度的明顯增加、以及不良事件的發生數量是有關連性的。需要更多有關安全性的研究,來解決我們對於Tocilizumab安全性的考量。

翻譯人

本摘要由門諾醫院鄭珮文翻譯。

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

總結

以Tocilizumab治療風濕性關節炎:這個Cochrane評估的總結,呈現出我們從研究中得知的有關tocilizumab治療風濕性關節炎的效果。這個評估告訴我們,在患有風濕性關節炎的人,我們對於副作用及併發症通常沒有明確的資訊,尤其對較罕見但嚴重的副作用。可能的副作用包括:腹部問題(stomach problems)、肝臟問題(liver problems)、貧血(anemia)或感染(infection)。究竟什麼是風濕性關節炎,什麼是tocilizumab? 當你罹患風濕性關節炎後,你的免疫系統(正常情況下這個系統是用來對抗感染的)會攻擊你關節的內層(lining of your joints)。這會讓你的關節水腫(swollen)、僵硬(stiff)及疼痛(painful)。最初被侵犯的,通常是你手部和腳部的小關節。目前沒有可以完全治癒風濕性關節炎的方法,因此治療的目的是為了緩解疼痛及僵硬,並改善你活動的能力。像tocilizumab這類的藥物,有助於預防因不治療風濕性關節炎而導致關節的永久性損傷。Tocilizumab 是一種生物製劑的藥物,對於關節炎的病人,它可以讓一種稱為interleukin6的蛋白對身體造成的發炎反應停止。這種生物製劑包含一群的藥物,可抑制免疫系統並降低關節發炎的情形。雖然降低免疫系統的反應可能使它對抗感染的困難度有些微的增加,但它有助於安定體內過度反應的免疫系統。藉由降低發炎反應,有助於達到預防關節損傷的目的。對於單獨使用methotrexate沒有獲得改善,再以tocilizumab來治療的風濕性關節炎病人,最好的評估方法就是: 一、ACR50(發生疼痛或腫脹關節的數目,和其他醫師或病人評估風濕性關節炎的觀感):100位使用tocilizumab的病人當中,有31位風濕性關節炎的症狀獲得改善; −100位使用安慰劑的病人當中,有10位風濕性關節炎的症狀獲得改善;  超過11位使用tocilizumab的病人獲得改善。 二、副作用: −100位使用tocilizumab的病人當中,有5位因無法忍受副作用而退出研究; −100位使用安慰劑的病人當中,有3位因無法忍受副作用而退出研究;  超過2位使用tocilizumab的病人發生副作用。

Plain language summary

Tocilizumab for rheumatoid arthritis

This summary of a Cochrane Review presents what we know from research about the effect of tocilizumab for rheumatoid arthritis (RA).

The review shows that in people with RA:

We often do not have precise information about side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include stomach problems, liver problems, anemia or infection.

What is RA and what is tocilizumab?

When you have rheumatoid arthritis your immune system, which normally fights infection, attacks the lining of your joints. This makes your joints swollen, stiff and painful. The small joints of your hands and feet are usually affected first. There is no cure for RA at present, so the treatments aim to relieve pain and stiffness and improve your ability to move. Drugs such as tocilizumab also aim to help prevent permanent damage to your joints that can happen if RA is not treated. 

Tocilizumab is one of the biologic medicines for arthritis that stops the inflammation caused by a protein in the body called interleukin-6. Biologics are a group of medications that suppress the immune system and reduce the inflammation in the joints. Even though suppressing the immune system can make it slightly harder to fight off infections, it also helps to stabilize an overactive immune system. By reducing the inflammation, the aim is to help prevent damage to the joints.

Best estimate of what happens to people with RA who have not improved with methotrexate alone, who take tocilizumab for rheumatoid arthritis:

ACR50 (number of tender or swollen joints and other doctor or patient-assessed aspects of rheumatoid arthritis)

- 31 people out of 100 who took tocilizumab experienced improvement in the symptoms of their rheumatoid arthritis.

- 10 people out of 100 who took placebo experienced improvement.

- 11 more people experienced improvement with tocilizumab.

Side effects

- 5 people out of 100 dropped out of studies of tocilizumab because of the side effects.

- 3 people out of 100 who took placebo dropped out of the studies.

- 2 more people had side effects with tocilizumab.

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