Adverse effects of biologics: a network meta-analysis and Cochrane overview

  • Review
  • Overview

Authors


Abstract

Background

Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since important risks such as lymphomas, serious infections and tuberculosis (TB) reactivation may be more common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain  much needed risk estimates.

Objectives

To compare the potential adverse effects of tumor necrosis factor inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS).

Methods

Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes (serious adverse events (SAEs), withdrawals due to adverse events (AEs), total AEs, serious infections; specific AEs, namely, tuberculosis (TB) reactivation, lymphoma and congestive heart failure) were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed both Bayesian mixed-treatment comparison models and arm-based generalized linear mixed models.

Main results

We included 160 RCTs with 48,676 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for TB reactivation, lymphoma, and congestive heart failure. Using standard dose, compared with control, biologics as a group were associated with a statistically significant higher rate of total AEs (odds ratio (OR) 1.28, 95% credible interval (CI) 1.09 to 1.50; number needed to treat to harm (NNTH) = 22, 95% confidence interval (CI) 14 to 60), withdrawals due to AEs (OR 1.47, 95% CI 1.20 to 1.86; NNTH = 26, 95% CI 15 to 58), serious infections (OR, 1.37, 95% CI 1.04 to 1.82, NNTH = 108 95% CI, 50 to 989) and TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706).

The rate of SAEs, lymphoma and congestive heart failure were not statistically significantly different between biologics and control treatment. 

Certolizumab pegol (OR 4.75, 95% CI 1.52 to 18.65; NNTH = 12, 95% CI 4 to 79) and anakinra (OR 4.05, 95% CI 1.22 to 16.84; NNTH = 14, 95% CI 4 to 181) were associated with a statistically significantly higher risk of serious infections compared with control treatment. Compared with control, certolizumab was associated with a statistically significantly higher risk of SAEs (as defined in included studies: OR 1.57, 95% CI 1.06 to 2.32; NNTH = 18, 95% CI 9 to 162). Infliximab was associated with a statistically significantly higher risk of total AEs OR 1.55, 95% CI 1.01 to 2.35; NNTH = 13, 95% CI 8 to 505) and withdrawals due to AEs compared with control (OR 2.34, 95% CI 1.40 to 4.14; NNTH = 10, 95% CI 5 to 30). 

The overall numbers were relatively small for indirect comparisons. Indirect comparisons revealed that certolizumab pegol was associated with a statistically significantly higher odds of serious infections compared with abatacept, adalimumab, etanercept, golimumab and rituximab; and anakinra was statistically significantly more likely than rituximab to be associated with serious infections. Certolizumab pegol was associated with a statistically significant higher odds of SAEs compared with adalimumab and abatacept. No statistically significant differences were noted between biologics in total AEs or withdrawals due to AEs in indirect comparisons.

Authors' conclusions

Overall, in the short term biologics were associated with statistically significantly higher rates of serious infections, TB reactivation, total AEs and withdrawals due to AEs. Serious infections included opportunistic infections as well as bacterial infections in most studies. Some biologics had a statistically higher association with certain adverse outcomes compared with control, but there was no consistency across the outcomes so caution is needed in interpreting these results.

There is a need for more research regarding the long-term safety of biologics and an urgent need for comparative safety reports of different biologics; preferably without industry involvement. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics. 

摘要

生物製劑之不良作用:網絡統合分析與Cochrane總覽

背景

生物製劑可為類風濕性關節炎與許多其他病症的治療藥物。雖然生物製劑的療效已獲證實,但對於此類療法的不良作用則仍不確定。因為生物製劑雖然可能較常有重大的風險存在(例如淋巴瘤、嚴重感染與肺結核[TB]再活動),但用於各種適應症時皆僅有少數病患發生,因此我們就許多病症之生物製劑用藥的治療結果進行合併評量,以取得目前最迫切需要的風險估計。

目的

針對任何疾病狀況(人類免疫缺乏症[HIV/AIDS]除外)的病患,比較腫瘤壞死因子抑制劑(adalimumab、certolizumab、etanercept、golimumab、infliximab)、介白素-1(interleukin-1, IL-1)拮抗劑(anakinra)、IL-6拮抗劑(tocilizumab)、抗-CD28抗體(abatacept)與抗-B細胞抗體(rituximab)療法可能出現的不良作用。

方法

針對任何適應症(HIV/AIDS除外)之九種生物製劑用藥之一進行研究,且有我們預先指定之不良評估指標事件(嚴重不良事件[SAE]、因不良事件[AE]退出試驗、整體不良事件、嚴重感染症、特定不良事件[亦即結核病再活動、淋巴瘤與充血性心臟衰竭])報告的隨機分組對照試驗(randomized controlled trials, RCT)、有對照之臨床試驗(controlled clinical trials, CCT)與開放標示延伸(open-label extension, OLE)試驗,皆為我們考量其是否符合納入條件的對象。我們對The Cochrane Library、MEDLINE與EMBASE進行搜尋(截止日期2010年1月)。我們獨立地進行兩次搜尋結果確認與資料萃取。在網絡綜合分析方面,我們同時以Bayesian交錯療法比較模型(Bayesian mixed-treatment comparison models)與分組廣義線性混合模式(arm-based generalized linear mixed models)進行分析。

主要結果

我們總共納入共有48,676名受試者參與的160項隨機分組對照試驗(RCT),以及共有11,954名受試者參與的46項延伸試驗。隨機分組對照試驗的持續時間中位數為6個月,開放標示延伸試驗則為13個月。結核病再活動、淋巴瘤與充血性心臟衰竭方面的資料極少。使用標準劑量時,相較於對照組,生物製劑組的整體不良事件(勝算比[OR] 1.28,95%可信區間[credible interval,CI]:1.09至1.50;發生一例有害事件所需治療病患人數[NNTH] = 22,95%信賴區間[CI]:14至60)、因不良事件而退出試驗(OR 1.47,95% CI:1.20至1.86;NNTH = 26,95% CI:15至58)、嚴重感染(OR 1.37,95% CI:1.04至1.82;NNTH = 108,95% CI:50至989)與結核病復發(OR 4.68,95% CI:1.18至18.60;NNTH = 168,95% CI:143至14706)的發生率皆顯著較高。

在嚴重不良事件、淋巴瘤與充血性心臟衰竭方面,生物製劑與對照療法之間並無具統計顯著性的差異存在。

相較於對照療法,certolizumab pegol(OR 4.75,95% CI:1.52至18.65;NNTH = 12,95% CI:4至79)與anakinra(OR 4.05,95% CI:1.22至16.84;NNTH = 14,95% CI:4至181)的嚴重感染症風險顯著較高。相較於對照療法,certolizumab的嚴重不良事件風險顯著較高(根據所納入的試驗中的定義:OR 1.57,95% CI:1.06至2.32;NNTH = 18,95% CI:9至162)。相較於對照療法,infliximab的整體不良事件風險(OR 1.55,95% CI:1.01至2.35; NNTH = 13,95% CI:8至505)與因不良事件退出試驗(OR 2.34,95% CI:1.40至4.14; NNTH = 10,95% CI:5至30)風險皆顯著較高。

可用於間接比較的整體數目相當小。間接比較的結果顯示,相較於abatacept、adalimumab、etanercept、golimumab與rituximab,certolizumab pegol的嚴重感染症風險顯著較高;anakinra的嚴重感染症風險顯著高於rituximab。Certolizumab pegol的嚴重不良事件風險顯著高於adalimumab 與abatacept。進行間接比較時,在整體不良事件或因不良事件而退出試驗的風險方面,各種生物製劑之間並無具統計顯著性的差異存在。

作者結論

整體而言,在嚴重感染症、結核病再活動、整體不良事件與因不良事件而退出試驗方面,短期使用的生物製劑皆有具統計顯著性的較高發生率。嚴重感染症包括大部分試驗中報告的伺機性感染症與細菌感染。相較於對照組,有些生物製劑與某些不良評估指標事件的相關性顯著較高,但各評估指標事件並無一致的結果,因此必須謹慎解讀這些結果。

我們仍需要更多探討生物製劑之長期安全性的研究,亦急需不同生物製劑的安全性比較報告,且最好無業者介入。全國性與國際性的登記系統與其他類型的大型資料庫皆為提供生物製劑之短期與長期安全性之相關補充證據的重要來源。

譯註

Translated by: East Asian Cochrane Alliance

Translation supported by: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Plain language summary

Side effects of nine commonly used biologics

This summary of a Cochrane review presents what we know from research about the side effects of biologics used for many conditions including inflammatory arthritis and other inflammatory conditions, cancer, and neurological conditions. We did not include studies on HIV/AIDS. The nine biologics we studied were: abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliximab (Remicade®), rituximab (Rituxan or Mabthera®) and tocilizumab (Actmera®).

The review shows that people using these biologics in the short term:

- will probably be a little more likely to experience more serious infections or tuberculosis than people who take placebo (fake drug);

- will probably be a little more likely to experience side effects or drop out of the study due to side effects than people who take placebo;

- will probably not experience more serious side effects* (other than serious infections), cancer, or congestive heart failure than people who take placebo.

(*A serious side effect is a life threatening adverse event that can result in death or hospitalization and disability or permanent damage).

We do not have precise information about other possible side effects and complications, including rare or long-term side effects.

What are biologics?

Biologics are a group of medications that suppress the immune system and reduce the inflammation, even though suppressing the immune system can make it slightly harder to fight off infections.

Best estimate of what happens to people who take biologics in the short term (range: 1 to 63 months)

Serious side effects

Among people who took any biologic, 127 out of 1,000 had serious side effects compared with 118 people out of 1,000 who took placebo (1% absolute harm).

All side effects reported

Among people who took any biologic, 770 out of 1,000 had side effects compared with 724 people out of 1,000 who took placebo (5% absolute harm).

Drop-out of study due to side effects

Among people who took any biologic, 137 out of 1,000 dropped out of the study due to side effects compared with 98 people out of 1,000 who took placebo (4% absolute harm).

Serious infections

Among people who took any biologic, 35 people out of 1000 experienced serious infections compared with 26 people out of 1000 who took placebo (1% absolute harm).

Tuberculosis

Among people who took any biologic, 20 out of 10,000 had tuberculosis compared with 4 people out of 10,000 who took placebo (0.16% absolute harm). However, there were not many cases of tuberculosis so our confidence in this result is low.

Lymphoma (Cancer of the blood)

Over the short time frame of these trials, there may be little or no difference in the number of people who experienced cancer while taking any biologic compared with people who took placebo. However, there were not many cases of cancer so our confidence in this result is low.

Congestive heart failure

There may be little or no difference in the number of people who experienced heart failure taking any biologic compared with people who took placebo. However, there were not many cases of congestive heart failure so our confidence in this result is low.

淺顯易懂的口語結論

9種常用的生物製劑的副作用

本Cochrane文獻回顧針對從用於治療許多病症(包括發炎性關節炎與其它發炎病症、癌症與神經病症)之生物製劑的副作用相關試驗所取得的資訊進行摘要報告。我們並未納入針對HIV/AIDS所進行的試驗。我們所研究的9種生物製劑為:abatacept (Orencia®)、adalimumab (Humira®)、anakinra (Kineret®)、certolizumab pegol (Cimzia®)、etanercept (Enbrel®)、golimumab (Simponi®)、infliximab (Remicade®)、rituximab (Rituxan或Mabthera®)與tocilizumab (Actmera®)。

本文獻回顧顯示,短期使用這些生物製劑的病患:

- 可能稍微比安慰劑(模擬的藥物)服用者較常出現較嚴重的感染症或結核病。

- 可能稍微比安慰劑服用者較常出現副作用或因副作用而退出試驗。

- 可能不會比安慰劑服用者較常出現嚴重的副作用*(嚴重感染症以外)、癌症或充血性心臟衰竭。

(*嚴重副作用為可能導致死亡或住院以及失能或永久傷害的可能致命性不良事件)。

我們沒有與其他可能副作用及併發症(包括罕見或長期副作用)相關的精確資訊。

何謂生物製劑?

生物製劑為可抑制免疫系統與減輕發炎作用的一類藥物,雖然抑制免疫系統會讓身體對抗感染的能力稍微降低。

生物製劑短期(範圍:1至63個月)服用者可能發生之事件的最佳評估

嚴重副作用

在任何生物製劑的服用者中,每1,000人有127人出現嚴重的副作用,安慰劑服用者則為每1,000人有118人(1%絕對傷害)。

所報告的所有副作用

在任何生物製劑的服用者中,每1,000人有770人出現副作用,安慰劑服用者則為每1,000人有724人(5%絕對傷害)。

因副作用退出試驗

在任何生物製劑的服用者中,每1,000人有137人因副作用退出試驗,安慰劑服用者則為每1,000人有98人(4%絕對傷害)。

嚴重感染症

在任何生物製劑的服用者中,每1,000人有35人出現嚴重感染症,安慰劑服用者則為每1,000人有26人(1%絕對傷害)。

結核病

在任何生物製劑的服用者中,每1,000人有20人出現結核病,安慰劑服用者則為每1,000人有4人(0.16%絕對傷害)。不過,因為結核病病例不多,因此我們對此結果不具信心。

淋巴瘤(血液癌症)

在這些試驗的短期進行期間,生物製劑服用者與安慰劑服用者發生癌症的人數差異極小或無差異。不過,因為癌症病例不多,因此我們對此結果不具信心。

充血性心臟衰竭

生物製劑服用者與安慰劑服用者發生充血性心臟衰竭的人數差異極小或無差異。不過,因為充血性心臟衰竭病例不多,因此我們對此結果不具信心。

譯註

Translated by: East Asian Cochrane Alliance

Translation supported by: 台灣衛生福利部/台北醫學大學實證醫學研究中心

Laički sažetak

Štetni učinci devet vrsta lijekova biologika koji se često koriste: prikaz svih Cochrane sustavnih pregleda

Sažetak ovog Cochrane sustavnog pregleda prestavlja cjelokupno trenutno znanje o štetnim učincima lijekova biologika, koji se primjenjuju u liječenju brojnih stanja kao što su upalni artritis i druge upalne bolesti, karcinom i neurološki poremećaji. Nisu uključene studije u kojima su sudjelovali pacijenti oboljeli od HIV/AIDS-a. Uključeno je devet biologika: abatacept (Orencia®), adalimumab (Humira®), anakinra (Kineret®), certolizumab pegol (Cimzia®), etanercept (Enbrel®), golimumab (Simponi®), infliksimab (Remicade®), rituksimab (Rituxan ili Mabthera®) i tocilizumab (Actmera®).

Sustavni pregled pokazuje da osobe koje uzimaju te biologike kroz kratko vrijeme:

- vjerojatno imaju nešto veći rizik od ozbiljnih infekcija ili tuberkuloze u odnosu na osobe koje uzimaju placebo (lažni lijek);

- vjerojatno imaju nešto veći rizik od razvoja nuspojava ili ranijeg odustajanja od sudjelovanja u istraživanju zbog nuspojava nego osobe koje uzimaju placebo;

- vjerojatno neće razviti više ozbiljnih nuspojava* (ako se isključe ozbiljne infekcije), karcinoma ili kongestivnih zatajenja srca nego osobe koje uzimaju placebo.

(*Ozbiljna nuspojava je štetni učinak lijeka opasan po život koji može uzrokovati smrt ili hospitalizaciju te onesposobljenost i trajnu štetu).

Nemamo precizne informacije o drugim mogućim nuspojavama i komplikacijama, uključujući rijetke i dugoročne štetne učinke.

Što su biologici?

Biologici su skupina lijekova koji potiskuju imunološki sustav i smanjuju upalu, iako potiskivanje imunološkog sustava otežava tijelu borbu protiv infekcija.

Najbolja procjena što se događa osobama koje uzimaju biologike kroz kratko vrijeme (1-63 mjeseca)

Ozbiljne nuspojave

Među ljudima koji su uzeli bilo koji biologik,127 od 1000 imat će ozbiljne nuspojave u usporedbi sa 118 od 1000 koji su uzeli placebo (1% apsolutne štete).

Sve prijavljene nuspojave

Među ljudima koji su uzeli bilo koji biologik,770 od 1000 imat će nuspojave u usporedbi sa 724 od 1000 koji su uzeli placebo (5% apsolutne štete).

Odustajanje od sudjelovanja u istraživanju zbog nuspojava

Među ljudima koji su uzeli bilo koji biologik,137 od 1000 odustat će od sudjelovanja u istraživanju u usporedbi s 98 od 1000 koji su uzeli placebo (4% apsolutne štete).

Ozbiljne infekcije

Među ljudima koji su uzeli bilo koji biologik, 35 osoba od 1000 razvit će ozbiljne infekcije u usporedbi sa 26 od 1000 koji su uzeli placebo (1% apsolutne štete).

Tuberkuloza

Među ljudima koji su uzeli bilo koji biologik, 20 od 1000 razvit će tuberkulozu u usporedbi sa 4 od 1000 koji su uzeli placebo (0,16% apsolutne štete). Međutim, zabilježeno je vrlo malo slučajeva tuberkuloze pa ne možemo vjerovati tim rezultatima.

Limfom

Tijekom kratkog roka može biti mala ili nikakva razlika u broju osoba koje su razvile karcinom tijekom uzimanja biologika u usporedbi s onima koje su uzimale placebo. Međutim, broj karcinoma bio je malen pa ne možemo vjerovati tim rezultatima.

Kongestivno zatajenje srca

Razlika između broja osoba koje su doživjele zatajenje srca uzimajući bilo koji biologik i osoba koje su uzimale placebo može biti mala ili nikakva. Međutim, broj zabilježenih kongestivnih zatajenja srca bio je malen pa ne možemo vjerovati tim rezultatima.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Резюме на простом языке

Побочные эффекты девяти наиболее часто используемых биологических лекарств (биопрепаратов)

Это резюме Кокрейновского обзора представляет наши знания из исследований о побочных эффектах биологических лекарств, используемых при многих состояниях, включая воспалительный артрит и другие воспалительные состояния, рак и неврологические состояния. Мы не включили исследования по вопросам ВИЧ / СПИДа. Девять биологических лекарств, которые мы изучали: абатацепт (Оренсия ® ), адалимумаб (Хумира ® ), анакинра (Кинерет ® ), цертолизумаб пегилированный (Симзия ® ), этанерцепт (Энбрел ® ), голимумаб (Симпони ® ), инфликсимаб (Ремикейд ® ), ритуксимаб (Ритуксан или Мабтера ® ) и тоцилизумаб (Актемра ® ).

Обзор показывает, что люди, использующие эти биопрепараты в краткосрочной перспективе:

-  вероятно, будут немного более склонны к развитию серьезных инфекций или туберкулеза, чем люди, принимающие плацебо (поддельные лекарства);

- вероятно, будут немного более склонны к развитию побочных эффектов или выбыванию из исследования из-за побочных эффектов, чем люди, принимающие плацебо;

-  Вероятно, не будут более склонны к развитию серьезных побочных эффектов* (кроме серьезных инфекций), рака или застойной сердечной недостаточности, чем люди, принимающие плацебо.

(*Серьезный побочный эффект является опасным для жизни неблагоприятным событием, которое может привести к смерти или госпитализации и инвалидности или непоправимому ущербу).

У нас нет точной информации о других возможных побочных эффектах и осложнениях, в том числе редких или долгосрочных побочных эффектах.

Что такое биопрепараты (биологические лекарства)?

Биопрепараты представляют собой группу лекарств, которые подавляют иммунную систему и уменьшают воспаление, даже подавляя иммунную систему, могут немного затруднить борьбу с инфекциями.

Лучшая оценка того, что происходит с людьми, которые принимают биопрепараты в краткосрочной перспективе (диапазон: от 1 до 63 месяцев)

Серьезные побочные эффекты

Среди людей, принимавших любые биологические лекарства, 127 из 1000 имели серьезные побочные эффекты по сравнению с 118 из 1000, принимавших плацебо (1% абсолютного вреда).

Сообщения обо всех побочных эффектах

Среди людей, которые принимали любое биологическое лекарство, у 770 из 1000 были побочные эффекты по сравнению с 724 из 1000 принимавших плацебо (5% абсолютного вреда).

Выбывания из исследования из-за побочных эффектов

Среди людей, принимавших любые биологические лекарства, 137 из 1000 выбыли из исследования из-за побочных эффектов, по сравнению с 98 из 1000, принимавших плацебо (4% абсолютного вреда).

Серьезные инфекции

Среди людей, принимавших любые биологические лекарства, у 35 человек из 1000 развились серьезные инфекции по сравнению с 26 из 1000, принимавших плацебо (1% абсолютного вреда).

Туберкулез

Среди людей, которые принимали любое биологическое лекарство, у 20 из 10000 был туберкулез по сравнению с 4-мя лицами из 10000, принимавших плацебо (0,16% абсолютного вреда). Однако, случаев туберкулеза было не много, так что наша уверенность в этом результате низка.

Лимфома (рак крови)

За короткий период времени этих испытаний, может быть мало разницы или вообще не быть разницы в числе людей с развитием рака при приёме любых биологических лекарств по сравнению с принимавшими плацебо. Однако, случаев рака было не много, поэтому наша уверенность в этом результате низка.

Хроническая сердечная недостаточность

За короткий период времени этих испытаний, может быть мало разницы или вообще не быть разницы в числе людей с развитием сердечной недостаточности при приёме любых биологических лекарств по сравнению с принимавшими плацебо. Однако, было не много случаев застойной сердечной недостаточности, так что наша уверенность в этом результате низка.

Заметки по переводу

Перевод: Зиганшина Лилия Евгеньевна. Редактирование: Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

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