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Etanercept for the treatment of rheumatoid arthritis

  1. Anne Lethaby1,†,
  2. Maria Angeles Lopez-Olivo2,‡,
  3. Lara J Maxwell3,
  4. Amanda Burls4,
  5. Peter Tugwell5,6,7,*,
  6. George A Wells8

Editorial Group: Cochrane Musculoskeletal Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 13 JUN 2012

DOI: 10.1002/14651858.CD004525.pub2


How to Cite

Lethaby A, Lopez-Olivo MA, Maxwell LJ, Burls A, Tugwell P, Wells GA. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD004525. DOI: 10.1002/14651858.CD004525.pub2.

Author Information

  1. 1

    University of Auckland, Department of Obstetrics and Gynaecology, Auckland, New Zealand

  2. 2

    The University of Texas, M.D. Anderson Cancer Center, Department of General Internal Medicine, Houston, Texas, USA

  3. 3

    University of Ottawa, Centre for Global Health, Institute of Population Health, Ottawa, Ontario, Canada

  4. 4

    City University London, School of Health Sciences, London, UK

  5. 5

    Faculty of Medicine, University of Ottawa, Department of Medicine, Ottawa, Ontario, Canada

  6. 6

    Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

  7. 7

    University of Ottawa, Institute of Population Health & Department of Epidemiology and Community Medicine, Ottawa, Ontario, Canada

  8. 8

    University of Ottawa, Department of Epidemiology and Community Medicine, Ottawa, Ontario, Canada

  1. Joint first author

  2. Joint first author

*Peter Tugwell, Department of Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, K1H 8M5, Canada. tugwell.bb@uottawa.ca. kerry.obrien@uottawa.ca.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

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Abstract

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. Laički sažetak

Background

Etanercept is a soluble tumour necrosis factor alpha-receptor disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA).

Objectives

The purpose of this review was to update the previous Cochrane systematic review published in 2003 assessing the benefits and harms of etanercept for the treatment of RA. In addition, we also evaluated the benefits and harms of etanercept plus DMARD compared with DMARD monotherapy in those people with RA who are partial responders to methotrexate (MTX) or any other traditional DMARD.

Search methods

Five electronic databases were searched from 1966 to February 2003 with no language restriction. The search was updated to January 2012. Attempts were made to identify other studies by contact with experts, searching reference lists and searching trial registers.

Selection criteria

All controlled trials (minimum 24 weeks' duration) comparing four possible combinations: 1) etanercept (10 mg or 25 mg twice weekly) plus a traditional DMARD (either MTX or sulphasalazine) versus a DMARD, 2) etanercept plus DMARD versus etanercept alone, 3) etanercept alone versus a DMARD or 4) etanercept versus placebo.

Data collection and analysis

Two review authors independently extracted data and assessed the risk of bias of the trials.

Main results

Three trials were included in the original version of the review. An additional six trials, giving a total of 2842 participants, were added to the 2012 update of the review. The trials were generally of moderate to low risk of bias, the majority funded by pharmaceutical companies. Follow-up ranged from six months to 36 months.

Benefit

At six to 36 months the American College of Rheumatology (ACR) 50 response rate was statistically significantly improved with etanercept plus DMARD treatment when compared with a DMARD in those people who had an inadequate response to any traditional DMARD (risk ratio (RR) 2.0; 95% confidence interval (CI) 1.3 to 2.9, absolute treatment benefit (ATB) 38%; 95% CI 13% to 59%) and in those people who were partial responders to MTX (RR 11.7; 95% CI 1.7 to 82.5, ATB 36%). Similar results were observed when pooling data from all participants (responders or not) (ACR 50 response rates at 24 months: RR 1.9; 95% CI 1.3 to 2.8, ATB 29%; 36 months: RR 1.6; 95% CI 1.3 to 1.9, ATB 24%). Statistically significant improvement in physical function and a higher proportion of disease remission were observed in combination-treated participants compared with DMARDs alone ((mean difference (MD) -0.36; 95% CI -0.43 to -0.28 in a 0-3 scale) and (RR 1.92; 95% CI 1.60 to 2.31), respectively) in those people who had an inadequate response to any traditional DMARD. All changes in radiographic scores were statistically significantly less with combination treatment (etanercept plus DMARD) compared with MTX alone for all participants (responders or not) (Total Sharp Score (TSS) (scale = 0 to 448): MD -2.2, 95% CI -3.0 to -1.4; Erosion Score (ES) (scale = 0 to 280): MD -1.6; 95% CI -2.4 to -0.9; Joint Space Narrowing Score (JSNS) (scale = 0 to 168): MD -0.7; 95% CI -1.1 to -0.2), and with combination treatment compared with etanercept alone (TSS: MD -1.1; 95% CI -1.8 to -0.5; ES: MD -0.7; 95% CI -1.1 to -0.2; JSNS: MD -0.5, 95% CI -0.7 to -0.2). The estimate of irreversible physical disability over 10 years given the radiographic findings was 0.45 out of 3.0.

When etanercept monotherapy was compared with DMARD monotherapy, there was generally no evidence of a difference in ACR50 response rates when etanercept 10 mg or 25 mg was used; at six months etanercept 25 mg was significantly more likely to achieve ACR50 than DMARD monotherapy but this difference was not found at 12, 24 or 36 months. TSS and ES radiographic scores were statistically significantly improved with etanercept 25 mg monotherapy compared with DMARD (TSS: MD -0.7; 95% CI -1.4 to 0.1; ES: MD -0.7; 95% CI -1.0 to -0.3) but there was no evidence of a statistically significant difference between etanercept 10 mg monotherapy and MTX.

Harms

There was no evidence of statistically significant differences in infections or serious infections between etanercept plus DMARD and DMARD alone at any point in time. Infection rates were higher in people receiving etanercept monotherapy compared with DMARD; however, there were no differences regarding serious infections. For those participants who had an inadequate response to DMARDs, the rate of total withdrawals was lower for the etanercept plus DMARD group compared with DMARD alone (RR 0.53; 95% CI 0.36 to 0.77, ATB 18%). No other statistically significant differences were observed in any of the assessed comparisons.

Authors' conclusions

Etanercept 25 mg administered subcutaneously twice weekly together with MTX was more efficacious than either etanercept or MTX monotherapy for ACR50 and it slowed joint radiographic progression after up to three years of treatment for all participants (responders or not). There was no evidence of a difference in the rates of infections between groups.

 

Plain language summary

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. Laički sažetak

Etanercept for the treatment of rheumatoid arthritis

Researchers in The Cochrane Collaboration conducted a review of the effect of etanercept (Enbrel) for people with rheumatoid arthritis. After searching for all relevant studies, they found nine studies with over 2800 people.  Their findings are summarised below.

In people with rheumatoid arthritis who have NOT improved with a traditional disease-modifying anti-rheumatic drug (DMARD):

- Etanercept plus DMARDs probably improves pain, function and other symptoms of rheumatoid arthritis;

- Etanercept plus DMARDs reduces disease activity and disability;

- Showing a small difference needs a larger number of participants – when all the data from the different types of participants are combined, etanercept reduces permanent joint damage as seen on x-ray.

We often do not have precise information about side effects and complications. This is particularly true for rare, but serious, side effects. Side effects such as injection site reactions, headache, common colds, nausea, dizziness and infections may occur with etanercept on its own or combined with a DMARD. Another Cochrane Review (Singh 2011) has shown that there is a small risk of tuberculosis reactivation and serious infections.  Rare complications may include certain types of cancer.

What is etanercept and why is it prescribed?
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. Etanercept is a "biologic" that is prescribed to decrease pain and swelling and slow the progress of rheumatoid arthritis. A biologic is a medical product not chemically synthesized, that is derived from living material. This medical product is injected beneath the skin in the same way as insulin in treating diabetes. It is usually prescribed when other DMARDs do not work well, but it can be expensive.

What happens to people with rheumatoid arthritis who take etanercept plus traditional DMARDs (methotrexate or sulphasalazine) after they have NOT improved with traditional DMARDs alone

ACR 50 (number of tender or swollen joints and other outcomes such as pain and disability)

38 more people out of 100 had a 50% improvement in symptoms after six months to three years compared with people taking a DMARD alone (38% absolute improvement).
79 people out of 100 on etanercept plus DMARDs had a 50% improvement in symptoms.
41 people out of 100 on DMARDs alone had a 50% improvement in symptoms

Disease activity

22 more people out of 100 were considered to have low disease activity of their rheumatoid arthritis from six months to three years on etanercept with DMARDs (22% absolute improvement).
46 people out of 100 on etanercept plus DMARDs were considered to have low disease activity of their rheumatoid arthritis.
24 people out of 100 on DMARDs alone were considered to have low disease activity of their rheumatoid arthritis.

Disability

People who took etanercept plus a DMARD rated the change in their disability to be 0.36 points lower on a scale of 0 to 3 after six months to three years compared with people who took a DMARD alone (12% absolute improvement).
People who took etanercept plus a DMARD rated the change in their disability to be between 0.51 and 1.08 on a scale of 0 to 3 after six months to three years.
People who took a DMARD alone rated the change in their disability to be between 0.15 and 0.72 on a scale of 0 to 3 after six months to three years.

X-rays of the joints

When all people in all the studies were considered, joint damage improved slightly in those who received combined treatment with etanercept plus DMARD compared with DMARD or etanercept alone after 12 to 36 months. Joint damage in people whom DMARDs were not working and received combined treatment with etanercept plus DMARD was similar to those given a DMARD alone, but this result might be due to low numbers of people in this group.

 

Laički sažetak

  1. Top of page
  2. Abstract
  3. Plain language summary
  4. Laički sažetak

Etanercept za liječenje reumatoidnog artritisa

Istraživači Cochrane kolaboracije napravili su sustavni pregled učinaka etanercepta (Enbrel) u pacijenata s reumatoidnim artritisom. Nakon pretrage usmjerene na sve odgovarajuće studije, našli su ih devet, s ukupno 2800 ispitanika.  Njihova otkrića su sažeto prikazana.

U ljudi koji se NISU oporavili s pomoću tradicionalnih lijekova koji modificiraju bolest (engl. disease-modifying anti-rheumatic drug, DMARD) kao što su metotreksat ili sulfasalazin:

- Kombinacija etanercepta i metotreksata ili sulfasalazina vjerojatno ublažava bol, funkciju i druge simptome reumatoidnog artritisa;

- Kombinacija etanercepta i metotreksata ili sulfasalazina smanjuje aktivnost bolesti i onesposobljenost;

- Da bi se pokazale male razlike trebalo bi imati veći broj sudionika – kada se združe podatci svih različitih vrsta pacijenata etenercept smanjuje trajno oštećenje zglobova koje se vidi na rentgenu.

Često nemamo točne informacije o štetnim popratnim pojavama i komplikacijama. To osobito vrijedi za rijetke, ali ozbiljne štetne učinke. Nuspojave poput reakcije na mjestu injiciranja, glavobolja, obična prehlada, mučnina, vrtoglavica i infekcije mogu se dogoditi sa samim etanerceptom ili kad se daje s DMARD.Jedan je Cochrane sustavni pregled (Singh, 2011.) pokazao da postoji mali rizik od reaktivacije tuberkuloze i ozbiljnih infekcija. Rijetke komplikacije odnose se i na neke tipove raka.

Što je etanercept i zašto se propisuje?
Kod reumatoidnoga artritisa imuni sustav, koji se normalno suprotstavlja infekciji, napada zglobne ovojnice. To izaziva otok zglobova, njihovu ukočenosti i bolnost. Mali zglobovi šake obično su prvi zahvaćeni. Etanercept je „biološka tvar“ koju se propisuje da se smanji bol i i oteklina i uspori napredovanje reumatoidnoga artritisa. „Biološka tvar“ znači da je to medicinski proizvod koji nije kemijski sintetiziran, nego je dobiven iz živoga tkiva. Uštrcava ga se pod kožu, jednako kao inzulin u liječenju šećerne bolesti. Obično ga se propisuje kada drugi DMARD ne djeluju dovoljno dobro, ali može biti skup.

Što se događa ljudima s reumatoidnim artritisom koji uzimaju etanercept i tradicionalne DMARD (metotreksat ili sulfasalazin) nakon što nisu postigli poboljšanje samo s klasičnim DMARD

ACR 50 (broj osjetljivih ili otečenih zglobova i drugi ishodi, poput boli i onesposobljenosti)

Od sto osoba 38 osoba više ima 50%-tno poboljšanje simptoma šest mjeseci do tri godine nakon početka liječenja u usporedbi s osobama koji uzimaju samo DMARD (38% apsolutno poboljšanje).
Sedamdeset i devet od sto osoba koje uzimaju kombinaciju etanercepta i metotreksata ili sulfasalazina pokaže 50%-tno poboljšanje simptoma.
Četrdeset i jedna od sto osoba koje uzimaju samo DMARD pokaže 50%-tno poboljšanje simptoma.

Aktivnost bolesti

Od 100 osoba 22 osobe više prešlo je u dijagnozu osoba s nisko-aktivnim reumatoidnim artritisom nakon što su liječene kombinacijom etanerecepta i metotreksata ili sulfasalazina od 6 mjeseci do tri godine, u usporedbi s onima koji su primali samo DMARD (22%-tno apsolutno poboljšanje).
Četrdeset i šest od sto osoba liječenih kombinacijom etanerecepta i metotreksata ili sulfasalazina proglašene su osobama s niskom aktivnošću reumatoidnoga artritisa.
Dvadeset i četiri od sto osoba liječenih samo metotreksatom ili sulfasalazinom proglašene su osobama s niskom aktivnošću reumatoidnoga artritisa.

Onesposobljenost

Šest mjeseci do tri godine nakon početka liječenja, osobe koje su primale kombinaciju etanercepta i metotreksata ili sulfasalazina procijenile su promjenu svoje onesposobljenosti 0,36 bodova niže na ljestvici od 0 do 3 nego osobe koje su primale samo metotreksat ili sulfasalazin (12%- tno apsolutno poboljšanje).
Osobe koje su primale kombinaciju etanercepta i metotreksata ili sulfasalazina procijenile su promjenu svoje onesposobljenosti da je između 0,51 i 1,08 na ljestvici od 0 do 3.
Osobe koje su primale samo metotreksat ili sulfasalazin procijenile su promjenu svoje onesposobljenosti nakon liječenja od šest mjeseci do tri godine da je između 0,15 i 0,72 na ljestvici od 0 do 3.

Rendgenska slika zglobova

Kad su zajedno analizirani rezultati svih ispitanika iz svih spomenutih studija, nakon liječenja koje je trajalo od šest mjeseci do tri godine, zaključuje se da je oštećenje zglobova blago smanjeno u onih koji su istodobno primali kombinaciju etanercepta i metotreksata ili sulfasalazina – u usporedbi s onima koji su primali samo metotreksat ili sulfasalazin, ili samo etanercept. Oštećenja zglobova u ljudi u kojih meotreksat ili sulfasalazin nisu djelovali pa su prebačeni na liječenje etanerceptom i metotreksatom ili sulfasalazinom bilo je slično onom u ljudi koji su primali samo metotreksat ili sulfasalazin, ali je to možda posljedica malog broja ispitanika u toj skupini.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Matko Marušić
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