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.

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.

Read the full abstract...
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 strategy: 

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.

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