Quality of the evidence Level III
Question 1: How accurate is clinical
C H A P T E R 1 1 Gouty Arthritis American Rheumatism Association (ARA) criteria to diag- nose gout, rather than joint fluid aspiration.
Finding the evidence
• Cochrane Database, with search term “gout diagnostic criteria”
• PubMed (www.ncbi.nlm.nih.gov/PubMed/) clinical queries search/ systematic reviews: “gout AND diagnostic criteria”
• PubMed (www.ncbi.nlm.nih.gov/PubMed/) -sensitiv- ity search using keywords “gout” AND “diagnostic crite- ria” as well as “gout” AND “classification criteria”
Quality of the evidence
• PubMed (www.ncbi.nlm.nih.gov/PubMed/)—sensitivity search using keywords “gout,” “colchicine,” “randomized”
Quality of the evidence
Level I• 1 systematic review/meta-analysis
• 2 randomized trials
Findings
A Cochrane systematic review found only one randomized study comparing colchicine to placebo for the treatment of acute gout.9 The single study included in this review by Ahern et al.10 is discussed in detail in the following para- graph. Since the publication of the review, another much larger randomized placebo-controlled trial has been pub- lished. Therefore, instead of presenting results from the Cochrane review, we provide updated forest plots (Figure 11.1 and Figure 11.2).
Two studies (n = 229 patients) provide data regarding the use of colchicine for treatment of acute gout. In a ran- domized study of 45 patients, 22 patients with gout were randomized to colchicine 1 g followed by 0.5 mg every 2 hours until complete response or toxicity occurred, and 21 patients received placebo;10 2 patients were excluded because they were unable to understand the visual analog scale used for reporting pain. A significantly higher propor- tion of patients had at least a 50% reduction in pain score (73%) in the colchicine group compared to the placebo group (36%) (p < 0.01). Terkeltaub et al. compared low- dose (1.8 mg total over 1 hour) and high-dose colchicine Question 2: What is the role of oral colchicine
in treatment of acute gout?
Case clarification
The patient has a history of gastrointestinal bleeding, con- traindicating the use of NSAIDs.
Relevance
Selecting the appropriate treatment for acute gout is impor- tant, since adverse events sometimes occur even with short-term medication use. The onset of pain relief may be rapid with NSAIDs or corticosteroids; however, one must be aware of potential adverse events and drug inter- actions of these medications. The pain relief achieved with colchicine may take longer to occur and one must be aware of associated gastrointestinal adverse events, including diarrhea, with this drug.
Current opinion
Current practice patterns suggest that the majority of practitioners avoid NSAIDs for treatment in such a patient and may use oral colchicine or oral or intra-articular corticosteroids.
Finding the evidence
• Cochrane Database, with search terms “gout,” “colchi- cine,” “randomized”
• PubMed (www.ncbi.nlm.nih.gov/PubMed/) clinical queries search/ systematic reviews: “gout colchicine randomized”
Figure 11.1 Efficacy of colchicine vs. placebo in 50% pain reduction.
Study or Subgroup
1.2.2 High dose Colchicine versus placebo Ahern 1987
Terkeltaub 2010 Subtotal (95% Cl)
16 17 33
28 28
61 16
4 4 74 74
29 29
148 79 100.0%
23.4%
23.4%
2.74 [1.05, 7.13]
2.74 [1.05, 7.13]
2.22 [1.40, 3.52]
22 52 74
21 29 50
49.5%
27.1%
76.6%
2.18 [1.13, 4.21]
1.90 [0.78, 4.61]
2.08 [1.22, 3.52]
7 5 12
Total (95% CI) Total events
Heterogeneity: Tau2 = 0.00; Chi2 = 0.32, df = 2 (P = 0.85); I2 = 0%
Test for overall effect: Z = 3.37 (P = 0.0007) 1.2.3 Low Dose Colchicine versus placebo Terkeltaub 2010
Subtotal (95% Cl) Total events
Heterogeneity: Tau2 = 0.00; Chi2 = 0.06, df = 1 (P = 0.80); I2 = 0%
Test for overall effect: Z = 3.71 (P = 0.007)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 2.07 (P = 0.04) Events
Colchicine Placebo
Total Events Total Weight
Risk Ratio M-H, Random, 95% CI
Risk Ratio M-H, Random, 95% CI
0.2 0.5 1 2 5
Favours Placebo Favours Colchicine
C H A P T E R 1 1 Gouty Arthritis
dose colchicine did not lead to more gastrointestinal adverse effects compared to placebo with relative risk of 1.28 (95% CI 0.57–2.90). The number needed to treat to harm (NNT-H) for gastrointestinal toxicity was 2 (95% CI 2–3) for high-dose colchicine and not applicable for low- dose colchicine (no significant differences compared to placebo). Any adverse event (RR 2.79; 95% CI, 1.52–5.12) and diarrhea (RR 5.58; 95% CI, 2.22–14.02) were reported by significantly more patients in the high-dose colchicine vs. placebo group. The low-dose colchicine group did not differ significantly compared to placebo for any adverse event (RR 1.37; 95% CI 0.70–2.66) or diarrhea (RR 1.72; 95%
CI 0.63–4.70). For any adverse event, the NNT-H for high- dose colchicine was 3 (95% CI 2–4) and for diarrhea the NNT-H was 2 (95% CI 2–3).
Recommendations
In patients with acute gout, evidence suggests:
• Colchicine is better than placebo in improving pain in the first 24–48 hours [overall quality: high]
• Low-dose colchicine is as effective as high-dose colchi- cine for treatment of acute gout, which are both better than placebo [overall quality: moderate]
• Colchicine is associated with significantly more gastroin- testinal adverse events than placebo; high-dose colchicine is associated with more gastrointestinal adverse events than placebo; and low-dose colchicine was not statistically significantly different than placebo [overall quality:
moderate]
(4.8 mg total over 6 hours) to placebo in 575 patients with acute gout.11 Of these, 185 patients had a qualifying acute gout flare (52 in high-dose colchicine, 74 in low-dose col- chicine, and 59 in placebo group), of whom 184 were included in the efficacy analyses (1 patient in placebo group did not provide data/flare confirmation) and all 185 were included in safety analyses. A 50% reduction in joint pain at 24 hours was noted in a significantly greater propor- tion of patients in the high-dose colchicine group (17/52, 32.7%) and the low-dose colchicine group (28/74, 37.8%) compared to the placebo group (9/58, 15.5%; p = 0.034 and 0.005, respectively).
A combined analysis of the two randomized controlled trials showed that high-dose colchicine was significantly more likely than placebo to be associated with 50% pain relief at 24–36 hours with a relative risk of 2.08 favoring colchicine (95% CI 1.22–3.52). The absolute risk reduction was 25% (95% CI 2–28%), relative risk reduction was 108% (95% CI 22–252%) and number needed to treat to benefit (NNT-B) was 4 (95% CI 2–50). Low-dose colchicine was significantly more likely than placebo (RR 2.74; 95%
CI 1.05–7.13) to provide 50% pain relief at 24–36 hours.
The absolute risk reduction was 24% (95% CI 7–41%), relative risk reduction was and NNT-B was 4 (95% CI 2–14).
Two studies provided data for gastrointestinal toxicity of colchicine. Compared to placebo, gastrointestinal adverse events were significantly more common in high-dose col- chicine with relative risk of 3.81 (95% CI 2.28–6.38). Low- Figure 11.2 Gastrointestinal adverse events in colchicine vs. placebo.
Study or Subgroup
1.2.1 High dose Colchicine versus placebo Ahern 1987
Terkeltaub 2010 Subtotal (95% Cl)
22 40 62
19 19
81 17
6 6 74 74
30 30
148 80 100.0%
31.3%
31.3%
1.28 [0.57, 2.90]
1.28 [0.57, 2.90]
2.71 [1.37, 5.38]
22 52 74
21 29 50
34.4%
34.3%
68.7%
3.91 [1.89, 8.09]
3.72 [1.80, 7.70]
3.81 [2.28, 6.38]
6 6 11
Total (95% CI) Total events
Heterogeneity: Tau2 = 0.22; Chi2 = 4.93, df = 2 (P = 0.09); I2 = 59%
Test for overall effect: Z = 2.86 (P = 0.004) 1.2.2 Low Dose Colchicine versus placebo Terkeltaub 2010
Subtotal (95% Cl) Total events
Heterogeneity: Tau2 = 0.00; Chi2 = 0.01, df = 1 (P = 0.92); I2 = 0%
Test for overall effect: Z = 5.10 (P = 0.00001)
Total events
Heterogeneity: Not applicable
Test for overall effect: Z = 0.60 (P = 0.55) Events
Colchicine Placebo
Total Events Total Weight
Risk Ratio M-H, Random, 95% CI
Risk Ratio M-H, Random, 95% CI
0.2 0.5 1 2 5
Favours Colchicine Favours Placebo
Two studies compared NSAIDs to prednisone in patients with acute gout, but there are no studies comparing colchi- cine or ACTH to NSAIDs or prednisone. In one study of 90 patients, an oral prednisolone/acetaminophen combina- tion was found to be as effective as oral indomethacin/
acetaminophen combination in relieving pain and was associated with fewer adverse effects.18 In an equivalence study of prednisolone and naproxen for acute gout, no significant differences were noted between treatment arms for pain reduction at 90 hours.19 Adverse events were similar between groups.
Recommendations
• NSAIDs may relieve symptoms of acute gout including pain and a variety of NSAIDs have similar efficacy in this regard [overall quality: low].
• Corticosteroids can also relieve pain during acute gouty arthritis [overall quality: low]
Question 4: What is the role of colchicine in