Interventions for tophi in gout

Background

Gout is caused by urate crystals forming within or around joints.

Inflammation can lead to pain, redness, warmth and swelling of the affected joints, making it difficult to touch or move. Some of the reasons why people develop gout include their genetic makeup, being overweight, ingesting certain medications (e.g. cyclosporine), impaired kidney function and lifestyle habits such as drinking excessive amounts of alcohol and sugar sweetened drinks.

Tophi are nodules that develop in people with uncontrolled chronic gout. Tophi can become infected, cause pain and lead to reduced function. Tophi can be treated with urate-lowering drugs (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase, lesinurad), surgical removal or other interventions.

Study characteristics

This is a summary of a Cochrane Review on interventions for the management of tophi. The literature was searched up to 28 August 2020. We reported five studies on pharmacological interventions. Participants were from a wide range of countries, including the USA, Canada, Mexico, South Africa, Australia, New Zealand, and locations in Europe. All studies were funded by pharmaceutical companies.

Key results

Comparing biweekly pegloticase to placebo (fake treatment) (1 study; 79 participants)

Resolution of tophi

34 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase biweekly (every 2 weeks) compared with placebo (16% better to 50% better).

40 out of 100 people had tophi resolution with pegloticase.

74 out of 100 people had tophi resolution with placebo.

Total adverse events:

1 more person out of 100 had an adverse event with pegloticase compared with placebo (9% fewer to 7% more).

94 out of 100 people had an adverse event with pegloticase.

95 out of 100 people had an adverse event with placebo.

Comparing monthly pegloticase to placebo (1 study; 79 participants)

Resolution of tophi

14 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase monthly compared with placebo (1% worse to 29% better).

21 out of 100 people had tophi resolution with pegloticase.

7 out of 100 people had tophi resolution with placebo.

Total adverse events

5 more people out of 100 had an adverse event with pegloticase compared with placebo (20% fewer to 12% more).

100 out of 100 people had an adverse event with pegloticase.

95 out of 100 people had an adverse event with placebo.

Comparing lesinurad plus allopurinol to allopurinol (2 studies; 103 participants)

Resolution of tophi

11 fewer people out of 100 had complete resolution of target tophus after 12 month's treatment with lesinurad 200 mg plus allopurinol versus alopurinol alone (28% worse to 6% better).

21 out of 100 people had tophi resolution with lesinurad 200 mg plus allopurinol.

32 out of 100 people had tophi resolution with allopurinol.

7 fewer people out of 100 had complete resolution of target tophus after 12 month's treatment with lesinurad 400 mg combination versus allopurinol alone (25% worse to 11% better).

25 out of 100 people had tophi resolution with lesinurad 400 mg plus allopurinol.

32 out of 100 people had tophi resolution with allopurinol.

Comparing lesinurad 400 mg plus febuxostat to lesinurad 200 mg plus febuxostat (1 study; 129 participants)

Resolution of tophi

7 more people out of 100 had complete resolution of target tophus after 12 month's treatment with lesinurad 400 mg versus lesinurad 200 mg, both in combination with febuxostat (10% fewer to 23% more).

63 out of 100 people had tophi resolution with lesinurad 400 mg plus febuxostat.

59 out of 100 people had tophi resolution with lesinurad 200 mg plus febuxostat.

Number of participant withdrawals due to adverse events

Only one study reported on adverse events separately in participants with tophi. 

9 more people out of 100 withdrew due to adverse events after 12 month's treatment with lesinurad 400 mg versus lesinurad 200 mg, both in combination with febuxostat (3% less to 43% better).

70 out of 100 people with lesinurad 400 mg plus febuxostat withdrew from the study.

61 out of 100 people with lesinurad 200 mg plus febuxostat withdrew from the study.

Total adverse events

15 more people out of 100 had one or more adverse event after 12 month's treatment with lesinurad 400 mg versus lesinurad 200 mg, both in combination with febuxostat (3% less to 18% better).

97 out of 100 people had an adverse event with lesinurad 400 mg plus febuxostat.

82 out of 100 people had an adverse event with lesinurad 200 mg plus febuxostat.

Certainty of evidence

Moderate-certainty evidence indicated that pegloticase biweekly or monthly probably resolves one or more tophi. Moderate-certainty evidence showed that lesinurad (400 mg or 200 mg) in combination with allopurinol is probably not beneficial for resolution of tophi in gout. Low-certainty evidence indicated that lesinurad 400 mg compared to lesinurad 200 mg (both in combination with febuxostat) may resolve tophi and may result in no difference in adverse events or withdrawals due to adverse events. However, this study did not have a placebo arm. 

Authors' conclusions: 

Moderate-certainty evidence showed that pegloticase is probably beneficial for resolution of tophi in gout. Although there was little difference in adverse events when compared to placebo, participants on pegloticase had more withdrawals due to adverse events. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution compared with lesinurad 200 mg plus febuxostat; there was no difference in adverse events between these groups. We were unable to determine whether lesinurad plus febuxostat is more effective than placebo. Lesinurad (400 mg or 200 mg) plus allopurinol is probably not beneficial for tophi resolution, and there was no difference in adverse events between these groups. RCTs on interventions for managing tophi in gout are needed, and the lack of trial data is surprising given that allopurinol is a well-established treatment for gout.

Read the full abstract...
Background: 

Tophi develop in untreated or uncontrolled gout. This is an update of a Cochrane Review first published in 2014. 

Objectives: 

To assess the benefits and harms of non-surgical and surgical treatments for the management of tophi in gout.

Search strategy: 

We updated the search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 28 August 2020.

Selection criteria: 

We included all published randomised controlled trials (RCTs) or controlled clinical trials examining interventions for tophi in gout in adults.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included one trial in our original review. We added four more trials (1796 participants) in this update. One had three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Two studies looked at lesinurad 200 mg or 400 mg in combination with allopurinol. One trial studied lesinurad 200 mg or 400 mg in combination with febuxostat. One trial compared febuxostat 80 mg and 120 mg to allopurinol.

Two trials were at unclear risk of performance and detection bias due to lack of information on blinding of participants and personnel. All other trials were at low risk of bias.

Moderate-certainty evidence (downgraded for imprecision; one study; 79 participants) showed that biweekly pegloticase resolved tophi in 21/52 participants compared with 2/27 on placebo (risk ratio (RR) 5.45, 95% confidence interval (CI) 1.38 to 21.54; number needed to treat for a benefit (NNTB) 3, 95% CI 2 to 6). Similar proportions of participants receiving biweekly pegloticase (80/85) had an adverse event compared to placebo (41/43) (RR 0.99, 95% CI 0.91 to 1.07). However, more participants on biweekly pegloticase (15/85) withdrew due to an adverse event compared to placebo (1/43) (RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for a harm (NNTH) 7, 95% CI 4 to 16).

More participants on monthly pegloticase (11/52) showed complete resolution of tophi compared with placebo (2/27) (RR 2.86, 95% CI 0.68 to 11.97; NNTB 8, 95% CI 4 to 91). Similar numbers of participants on monthly pegloticase (84/84) had an adverse event compared to placebo (41/43) (RR 1.05, 95% CI 0.98 to 1.14). More participants on monthly pegloticase (16/84) withdrew due to adverse events compared to placebo (1/43) (RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Infusion reaction was the most common reason for withdrawal.

Moderate-certainty evidence (2 studies; 103 participants; downgraded for imprecision) showed no clinically significant difference for complete resolution of target tophus in the lesinurad 200 mg plus allopurinol arm (11/53) compared to the placebo plus allopurinol arm (16/50) (RR 0.40, 95% CI 0.04 to 4.57), or in the lesinurad 400 mg plus allopurinol arm (12/48) compared to the placebo plus allopurinol arm (16/50) (RR 0.79, 95% CI 0.42 to 1.49).

An extension study examined lesinurad 200 mg or 400 mg in combination with febuxostat, or placebo (low-certainty evidence, downgraded for indirectness and imprecision). Participants on lesinurad in the original study continued (CONT) on the same dose. Lesinurad 400 mg plus febuxostat may be beneficial for tophi resolution; 43/65 in the lesinurad 400 mg CONT arm compared to 38/64 in the lesinurad 200 mg CONT arm had tophi resolution (RR 1.11, 95% CI 0.85 to 1.46). Lesinurad 400 mg plus febuxostat may result in no difference in adverse events; 57/65 in the lesinurad 400 mg CONT arm had an adverse event compared to 50/64 in lesinurad 200 mg CONT arm (RR 1.12, 95% CI 0.96 to 1.32). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events; 10/65 participants in the lesinurad 400 mg CONT arm withdrew due to an adverse event compared to 10/64 participants in the lesinurad 200 mg CONT arm (RR 0.98, 95% CI 0.44 to 2.20). Lesinurad 400 mg plus febuxostat may result in no difference in mean serum uric acid (sUA), which was 3 mg/dl in the lesinurad 400 mg CONT group compared to 3.9 mg/dl in the lesinurad 200 mg CONT group (mean difference -0.90, 95% CI -1.51 to -0.29).

Participants who were not on lesinurad in the original study were randomised (CROSS) to lesinurad 200 mg or 400 mg, both in combination with febuxostat. Low-certainty evidence downgraded for indirectness and imprecision showed that lesinurad 400 mg (CROSS) may result in tophi resolution (17/34) compared to lesinurad 200 mg (CROSS) (14/33) (RR 1.18, 95% CI 0.70 to 1.98). Lesinurad 400 mg in combination with febuxostat may result in no difference in adverse events (33/34 in the lesinurad 400 mg CROSS arm compared to 27/33 in the lesinurad 200 mg (CROSS); RR 1.19, 95% CI 1.00 to 1.41). Lesinurad 400 mg plus febuxostat may result in no difference in withdrawals due to adverse events, 5/34 in the lesinurad 400 mg CROSS arm withdrew compared to 2/33 in the lesinurad 200 mg CROSS arm (RR 2.43, 95% CI 0.51 to 11.64). Lesinurad 400 mg plus febuxostat results in no difference in sUA (4.2 mg/dl in lesinurad 400 mg CROSS) compared to lesinurad 200 mg (3.8 mg/dl in lesinurad 200 mg CROSS), mean difference 0.40 mg/dl, 95% CI -0.75 to 1.55.

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