Certolizumab pegol for treating adults with rheumatoid arthritis

We conducted an updated review of the benefits and harms of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA). We searched for all relevant studies until September 2016 and found 14 trials with 5499 people.

The length of follow-up in most of the trials was 24 weeks; most participants were women.

What is rheumatoid arthritis and what is certolizumab pegol?

When you have RA, your immune system becomes overactive and attacks the lining of your joints. This makes your joints swollen, stiff and painful.

Certolizumab pegol is a biologic medication for the treatment of RA. It works by blocking a substance produced by the body known as tumour necrosis factor alpha (TNFα). Certolizumab pegol is given by injections under the skin. The approved dose is 200 mg.

What happens to people with rheumatoid arthritis who take certolizumab pegol 200 mg every other week after six months?

ACR50 (standard: a 50% improvement in the number of tender or swollen joints and other outcomes such as pain and disability):

- 25 more people out of 100 experienced improvements in the symptoms of their rheumatoid arthritis after six months with certolizumab pegol (absolute improvement 25%).

- 36 people out of 100 who took certolizumab pegol experienced improvements compared to nine people out of 100 who took a placebo (a fake injection).

We rate the quality of evidence for ACR50 as high.

Health-related quality of life (Health Assessment Questionnaire, HAQ: 0 to 3 scale, where a lower score means improvement):

- people who took certolizumab pegol scored 0.35 points lower than people who took placebo (absolute improvement 12%).

- people on certolizumab pegol scored 0.48 points lower compared to 0.13 points lower for people who took a placebo.

We rate the quality of evidence for the HAQ as moderate, downgraded, due to concerns about the high number of people dropping out of the studies.

Remission (absence of clinical signs of inflammation):

- 10 people out of 100 experienced remission with certolizumab pegol (absolute improvement 10%).

- 22 people out of 100 who took certolizumab pegol experienced remission compared to 12 people out of 100 who took a placebo.

We rate the quality of evidence for the remission as high.

Radiological changes (x-rays of the joints, measured on a 0 to 230 unit scale):

- the joint damage in people who took certolizumab pegol was 0.67 units less (absolute improvement -0.29%).

- the damage to joints in people who took certolizumab pegol was 0.04 units less compared to people who took a placebo, whose joint damage was 0.7 units more.

We rate the quality of evidence for the findings in the radiological changes as moderate, downgraded, due to concerns about the high number of people dropping out of the studies.

Serious adverse events:

- three more people out of 100 experienced serious adverse events with certolizumab pegol (3% absolute harm).

- nine people out of 100 who took certolizumab pegol experienced serious adverse events compared to six people out of 100 who took a placebo.

We rate the quality of evidence for serious adverse events as high.

All Withdrawals

- 29 fewer people out of 100 experienced withdrawals with certolizumab pegol (absolute harm 29%).

- 23 people out of 100 who took certolizumab pegol experienced withdrawals compared to 52 people out of 100 who took a placebo.

We rate the quality of evidence for all withdrawals as moderate.

Withdrawals due to adverse events

- two more people out of 100 stopped treatment because of SAEs with certolizumab pegol (2% absolute harm).

- five people out of 100 who took certolizumab pegol estopped treatment because of SAEs compared to three people out of 100 who took a placebo.

We rate the quality of evidence for the withdrawals due to adverse events as high.

In summary:

- certolizumab pegol improves ACR50, health-related quality of life, and remission of RA.

- certolizumab pegol probably reduces joint damage as seen on x-ray.

- certolizumab pegol increases serious adverse events.

- with certolizumab pegol, fewer people stop taking their treatment, but those who stop do so because of serious adverse events.

Authors' conclusions: 

The results and conclusions did not change from the previous review. There is a moderate to high certainty of evidence from randomised controlled trials that certolizumab pegol, alone or combined with methotrexate, is beneficial in the treatment of RA for improved ACR50 and health-related quality of life, an increased chance of remission of RA, and reduced joint damage as seen on x-ray. Fewer people stopped taking their treatment, but most of these who did stopped due to serious adverse events. Adverse events were more frequent with active treatment. We found a clinically but not statistically significant risk of serious adverse events.

Read the full abstract...
Background: 

Tumour necrosis factor (TNF)-alpha inhibitors are beneficial for the treatment of rheumatoid arthritis (RA) for reducing the risk of joint damage, improving physical function and improving the quality of life. This review is an update of the 2014 Cochrane Review of the treatment of RA with certolizumab pegol.

Objectives: 

To assess the clinical benefits and harms of certolizumab pegol (CZP) in people with RA who have not responded well to conventional disease-modifying anti-rheumatic drugs (DMARDs).

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL: Cochrane Library 2016, Issue 9), MEDLINE, Embase, Web of Knowledge, reference lists of articles, clinicaltrials.gov and ICTRP of WHO. The searches were updated from 2014 (date of the last search for the previous version) to 26 September 2016.

Selection criteria: 

Randomised controlled trials that compared certolizumab pegol with any other agent, including placebo or methotrexate (MTX), in adults with active RA, regardless of current or prior treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs), such as MTX.

Data collection and analysis: 

Two review authors independently checked search results, extracted data and assessed trial quality. We resolved disagreements by discussion or referral to a third review author.

Main results: 

We included 14 trials in this update, three more than previously. Twelve trials (5422 participants) included measures of benefit. We pooled 11 of them, two more than previously. Thirteen trials included information on harms, (5273 participants). The duration of follow-up varied from 12 to 52 weeks and the range of doses of certolizumab pegol varied from 50 to 400 mg given subcutaneously. In Phase III trials, the comparator was placebo plus MTX in seven trials and placebo in five. In the two Phase II trials the comparator was only placebo.

The approved dose of certolizumab pegol, 200 mg every other week, produced clinically important improvements at 24 weeks for the following outcomes:

- American College of Rheumatology (ACR) 50% improvement (pain, function and other symptoms of RA): 25% absolute improvement (95% confidence interval (CI) 20% to 33%); number need to treat for an additional beneficial outcome (NNTB) of 4 (95% CI 3 to 5); risk ratio (RR) 3.80 (95% CI 2.42 to 5.95), 1445 participants, 5 studies.

- The Health Assessment Questionnaire (HAQ): -12% absolute improvement (95% CI -9% to -14%); NNTB of 8 (95% CI 7 to 11); mean difference (MD) - 0.35 (95% CI -0.43 to -0.26; 1268 participants, 4 studies) (scale 0 to 3; lower scores mean better function).

- Proportion of participants achieving remission (Disease Activity Score (DAS) < 2.6) absolute improvement 10% (95% CI 8% to 16%); NNTB of 8 (95% CI 6 to 12); risk ratio (RR) 2.94 (95% CI 1.64 to 5.28), 2420 participants, six studies.

- Radiological changes: erosion score (ES) absolute improvement -0.29% (95% CI -0.42% to -0.17%); NNTB of 6 (95% CI 4 to 10); MD -0.67 (95% CI -0.96 to -0.38); 714 participants, two studies (scale 0 to 230), but not a clinically important difference.

-Serious adverse events (SAEs) were statistically but not clinically significantly more frequent for certolizumab pegol (200 mg every other week) with an absolute rate difference of 3% (95% CI 1% to 4%); number needed to treat for an additional harmful outcome (NNTH) of 33 (95% CI 25 to 100); Peto odds ratio (OR) 1.47 (95% CI 1.13 to 1.91); 3927 participants, nine studies.

There was a clinically significant increase in all withdrawals in the placebo groups (for all doses and at all follow-ups) with an absolute rate difference of -29% (95% CI -16% to -42%), NNTH of 3 (95% CI 2 to 6), RR 0.47 (95% CI 0.39 to 0.56); and there was a clinically significant increase in withdrawals due to adverse events in the certolizumab groups (for all doses and at all follow-ups) with an absolute rate difference of 2% (95% CI 0% to 3%); NNTH of 58 (95% CI 28 to 329); Peto OR 1.45 (95% CI 1.09 to 1.94) 5236 participants Twelve studies.

We judged the quality of evidence to be high for ACR50, DAS remission, SAEs and withdrawals due to adverse events, and moderate for HAQ and radiological changes, due to concerns about attrition bias. For all withdrawals we judged the quality of evidence to be moderate, due to inconsistency.

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