title: Interleukin-1 inhibitors for acute gout.
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.
  
  
  OBJECTIVE
  To assess the benefits and harms of interleukin-1 inhibitors (anakinra, canakinumab, rilonacept) in acute gout.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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).
  
  
  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.
authors.affiliation: Servicio de Reumatologia, Hospital de Elda, Ctra. Elda-Sax, PTDA. La Torreta, S/N, Elda (Alicante), Spain, 03600.
authors.forename: Francisca
authors.initials: F
authors.lastname: Sivera
authors.forename: Mihir D
authors.initials: MD
authors.lastname: Wechalekar
authors.forename: Mariano
authors.initials: M
authors.lastname: Andrés
authors.forename: Rachelle
authors.initials: R
authors.lastname: Buchbinder
authors.forename: Loreto
authors.initials: L
authors.lastname: Carmona
mesh_terms: D000208:Acute Disease; D000328:Adult; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D006073:Gout / Q000188:drug therapy*; D006801:Humans; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D016032:Randomized Controlled Trials as Topic; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D014221:Triamcinolone / Q000008:administration & dosage
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007375:Interleukin-1; D011993:Recombinant Fusion Proteins; D014221:Triamcinolone; C541220:canakinumab; C531377:rilonacept