Interleukin-1 inhibitors for acute gout

Background: what is an acute gout flare and what are interleukin-1 inhibitors?

Gout results from the deposition of crystals of uric acid in and around joints. The main treatments for gout are drugs that lower uric acid blood levels and resolve the crystal deposits. Acute gout flares result in significant pain and disability and treatment aims at reducing the pain and resolving the arthritis quickly.

Interleukin-1 inhibitors (canakinumab, rilonacept and anakinra) modify the immune system and reduce inflammation. They can be injected in a single dose or repeated doses.

Study characteristics

This summary of a Cochrane review presents what we know from research about the effect of interleukin-1 inhibitors for treating acute gout flares. After searching for all relevant studies to 19 June 2013, we included four studies (806 participants, mean age 52 years, 92% men). Three studies assessed the use of a single injection of canakinumab (10 to 150 mg) compared with a single suboptimal 40 mg intramuscular injection of triamcinolone acetonide (steroid injection) and one study assessed the use of a single subcutaneous injection of rilonacept 320 mg compared with maximum doses of oral indomethacin (50 mg three times a day for three days) (a non-steroidal anti-inflammatory drug (NSAID)) in people with acute gout.

Key results: what happens to people with an acute gout flare who are injected with canakinumab compared with triamcinolone acetonide

Pain on a scale of 0 to 100 points (lower scores mean reduced pain)

- People who took canakinumab rated their pain to be 11 points lower at three days compared with people who had an injection of triamcinolone acetonide.

- People who had a subcutaneous injection of canakinumab rated their pain to be 25 on a scale of 0 to 100.

- People who had an injection of triamcinolone acetonide rated their pain to be 36 on a scale of 0 to 100.

Swelling of the joint

- 12 more people out of 100 reported no swelling in their joint three days after treatment with canakinumab compared with people who had an injection of triamcinolone acetonide.

- 44 people out of 100 who had canakinumab reported no swelling.

- 32 people out of 100 who had triamcinolone reported no swelling.

Participant assessment of good or excellent treatment response

- 17 more people out of 100 rated their treatment as good or excellent after three days' treatment with canakinumab compared with people who had an injection of triamcinolone.

- 64 people out of 100 who had canakinumab reported a good or excellent treatment response.

- 47 people out of 100 who had triamcinolone reported a good or excellent treatment response.

Withdrawal from the study due to side effects

Participant withdrawal due to side effects

- 1 out of 100 people withdrew due to side effects after treatment with canakinumab or injection of triamcinolone.

Side effects

- 10 more people out of 100 had a side effect after treatment with canakinumab compared with people who had an injection of triamcinolone.

- 61 people out of 100 who had canakinumab had a side effect.

- 51 people out of 100 who had triamcinolone had a side effect.

Quality of the evidence

We found moderate-quality evidence that, compared with a single intramuscular injection of the steroid, triamcinolone acetonide, canakinumab injection probably improves pain, swelling and the number of good or excellent treatment responses, but probably results in more side effects. Possible side effects included back pain, headache, high blood pressure, joint pain and a rise in the liver enzyme gamma-glutamyl transpeptidase. Function or quality of life were not measured. Further research may change the estimates.

There was low-quality evidence from one study that rilonacept injection may improve pain less than indomethacin and may not be associated with an increase in side effects. Inflammation, disability, quality of life and participant assessment of treatment success were not measured. Further research is likely to change these estimates.

We found no studies comparing canakinumab with more commonly used therapies for acute gout flares such as NSAIDs or colchicine.

Authors' conclusions: 

Moderate-quality evidence indicated that compared with a single suboptimal 40-mg dose of intramuscular injection of triamcinolone acetonide, a single subcutaneous dose of 150 mg of canakinumab probably results in better pain relief, joint swelling and participant-assessed global assessment of treatment response in people with an acute gout flare but is probably associated with an increased risk of adverse events. The cost of canakinumab is over 5000 times higher than triamcinolone acetonide; however, there are no data on the cost-effectiveness of this approach. We found no studies comparing canakinumab with more commonly used first-line therapies for acute gout flares such as NSAIDs or colchicine. Low-quality evidence indicated that compared with maximum doses of indomethacin (50 mg three times a day), 320 mg of rilonacept may provide less pain relief with a similar rate of adverse events.

Read the full abstract...
Background: 

Acute gout flares cause significant pain and disability and it is important to provide quick and effective pain relief. Traditional options for managing acute flares include colchicine, non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids.

Objectives: 

To assess the benefits and harms of interleukin-1 inhibitors (anakinra, canakinumab, rilonacept) in acute gout.

Search strategy: 

We searched The Cochrane Library, MEDLINE and EMBASE on 19 June 2013. We applied no date or language restrictions. We performed a handsearch of the abstracts from the European League Against Rheumatism (EULAR) (2009 to 2012) and American College of Rheumatology (ACR) (2009 to 2011) conferences and of the references of all included trials. We also screened the Clinical Trials Registry Platform of the World Health Organization and Clinical Trials Registry Platform of the US National Institutes of Health.

Selection criteria: 

We included randomised controlled trials (RCTs) and quasi-randomised clinical trials (controlled clinical trials (CCTs)) assessing an interleukin-1 inhibitor (anakinra, canakinumab or rilonacept) against placebo or another active treatment (colchicine, paracetamol, NSAIDs, glucocorticoids (systemic or intra-articular), adrenocorticotropin hormone, a different interleukin-1 blocking agent or a combination of any of the above) in adults with acute gout.

Data collection and analysis: 

Two review authors independently selected trials for inclusion, assessed the risk of bias and extracted the data. If appropriate, we pooled data in a meta-analysis. We assessed the quality of the evidence using the GRADE approach.

Main results: 

We included four studies (806 participants) in the review. The studies had an unclear risk of selection bias and low risk of performance and attrition biases. One study each had an unclear risk of detection and selection bias.

Three studies (654 participants) compared subcutaneous canakinumab compared with intramuscular triamcinolone acetonide 40 mg in the treatment of acute gout flares of no more than five days' duration. Doses of canakinumab were varied (10 to 150 mg), but most people (255/368) were treated with canakinumab 150 mg. None of the studies provided data on participant-reported pain relief of 30% or greater. Moderate-quality evidence indicated that canakinumab 150 mg was probably superior to triamcinolone acetonide 40 mg in terms of pain relief, resolution of joint swelling and in achieving a good treatment response at 72 hours following treatment, but was probably associated with an increased risk of adverse events.

Mean pain (0- to 100-mm visual analogue scale (VAS), where 0 mm was no pain) was 36 mm after triamcinolone acetonide treatment; pain was further reduced by a mean of 11 mm with canakinumab treatment (mean difference (MD) -10.6 mm, 95% confidence interval (CI) -15.2 to -5.9). Forty-four per cent of participants treated with canakinumab had resolution of joint swelling at 72 hours compared with 32% of participants treated with triamcinolone (risk ratio (RR) 1.39, 95% CI 1.11 to 1.74, number needed to treat for an addition beneficial outcome (NNTB) 9); 65% of participants treated with canakinumab assessed their response to treatment as good or excellent compare with 47% of participants treated with triamcinolone acetonide (RR 1.37, 95% CI 1.16 to 1.61, NNTB 6). Function or health-related quality of life were not measured. In both groups, 0.7% of participants withdrew from treatment (RR 1.1, 95% CI 0.2 to 7.2); there was one death and one alteration of laboratory results in each of the treatment groups. Adverse events were more frequent in participants receiving canakinumab (61%) compared with triamcinolone acetonide (51%; RR 1.2, 95% CI 1.1 to 1.4, number needed to treat for an addition harmful outcome (NNTH) 10).

Low-quality evidence from one study (152 participants with an acute gout flare of no more than 48 hours' duration and affecting fewer than four joints) comparing rilonacept 320 mg with indomethacin (50 mg three times a day for three days followed by 25 mg three times a day for up to nine days) indicated that indomethacin may improve pain more than rilonacept at 24 to 72 hours, and there may be no evidence of a difference in withdrawal rates or adverse events. The mean change (improvement) in pain from baseline with indomethacin was 4.3 points (measured on a 0 to 10 numerical rating scale, where 0 was no pain); pain was improved by a mean of only 2.5 points with rilonacept (MD 2.52, 95% CI 0.29 to 4.75, 25% less improvement in absolute pain with rilonacept). Inflammation, function health-related quality of life and participant global assessment of treatment success were not measured. Rates of study withdrawals due to adverse events were low in both groups: 1/75 (1%) participants in the rilonacept group compared with 2/76 (3%) participants in the indomethacin group (RR 0.5, 95% CI 0.05 to 5.5). Adverse events were reported in 27/75 (36%) participants in the rilonacept group and 23/76 (30%) in the indomethacin group (RR 1.2, 95% CI 0.8 to 1.9).

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