Interventions for tophi in gout
Abstract
Background
Tophi develop in untreated or uncontrolled gout. Their presence can lead to severe and potentially fatal complications. To date there have been no systematic reviews focused on the management of tophi in gout.
Objectives
To assess the benefits and harms of non‐surgical and surgical treatments for the management of tophi in gout.
Search methods
We searched three databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE. We handsearched American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts from 2010 to 2011, references from included studies and trial registries. We completed the most recent search on 20 May 2013.
Selection criteria
All published randomised controlled trials (RCTs) or controlled clinical trials with quasi‐randomised methods of allocating participants to treatment examining interventions for tophi in gout in adults. Possible interventions included urate‐lowering pharmacological treatment (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis.
Data collection and analysis
Two review authors extracted data from titles, abstracts and selected studies for detailed review, and extracted data and risk of bias independently. Major outcomes were number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, joint pain reduction, function, quality of life, serum urate normalisation and total adverse events.
Main results
Only one study, at low risk of all biases, met the inclusion criteria. This was the pooled results from two RCTs (225 participants, 145 with tophi at baseline) randomised to one of three arms; pegloticase infusion every two weeks (biweekly), monthly pegloticase infusion (pegloticase infusion alternating with placebo infusion every two weeks) and placebo. Moderate‐quality evidence from one study indicated that biweekly pegloticase 8 mg infusion reduced tophi in the subset of participants with tophi, but increased withdrawals due to adverse events in all participants, and monthly infusion appeared to result in less benefit.
Biweekly pegloticase treatment resulted in resolution of tophi in 21/52 participants compared with 2/27 who received placebo (risk ratio (RR) 5.45, 95% confidence intervals (CI) 1.38 to 21.54; number needed to treat for an additional beneficial outcome (NNTB) 3 (95% CI 2 to 6).
Eleven of 52 participants with monthly pegloticase treatment had complete resolution of one or more tophi compared with 2/27 who received placebo (RR 2.86, 95% CI 0.68 to 11.97).
Participant‐reported pain relief of 30% or greater, function, quality of life, serum urate normalisation, were reported for all participants but not separately for those with tophi; therefore, we did not include the results.
Pegloticase administered biweekly resulted in more withdrawals due to adverse events compared with placebo (15/85 participants with pegloticase versus 1/43 participants with placebo; RR 7.59, 95% CI 1.04 to 55.55; number needed to treat for an additional harmful outcome (NNTH) 7, 95% CI 4 to 17). Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 participants with pegloticase versus 1/43 participants with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14). Most withdrawals were due to infusion reactions.
Total adverse events were high in all treatment groups: 80/85 participants administered pegloticase biweekly reported an adverse event compared with 41/43 from the placebo group (RR 0.99, 95% CI 0.91 to 1.07); 84/84 participants administered pegloticase monthly reported an adverse event versus 41/43 in the placebo group (RR 1.05, 95% CI 0.98 to 1.14). As 80% of adverse events were due to flares of gout, probably unrelated to the drug treatment per se, this may explain the high rate of adverse events in the placebo group ‐ who were essentially untreated.
Authors' conclusions
This study showed pegloticase is probably beneficial in the management of tophi in gout, in terms of resolution of tophi, but with a high risk of adverse infusion reactions. However, there is a need for more RCT data considering other interventions, including surgical removal of tophi.
PICOs
Plain language summary
Interventions for tophi in gout
Background: what are tophi and what interventions are used?
Gout is caused by urate crystals forming either within or around joints. Inflammation can lead to pain, redness, warmth and swelling of the affected joints, making the area difficult to touch or move. Some of the reasons why people get gout include their genetic make‐up, 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 poorly treated or uncontrolled chronic gout. Tophi can become infected, cause pain and lead to a decrease in function. Tophi can be treated with urate‐lowering drugs (e.g. benzbromarone, probenecid, allopurinol, febuxostat, pegloticase), surgical removal or other interventions such as haemodialysis. Surgical interventions can be used where urgent removal is required, for example, for relief of nerve compression.
Study characteristics
This is a summary of a Cochrane review that shows interventions for the management of tophi. After searching for all relevant studies in May 2013, we found only one study (pooled results from two randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups)) that randomised 225 people to pegloticase (every two weeks (biweekly) or monthly) or placebo, in the management of chronic gout; 145 participants had tophi and 131 contributed outcome data.
Key results: what happens to people with tophi who are treated with biweekly or monthly pegloticase versus placebo
Resolution of tophi
‐ 33 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase biweekly compared with placebo (33% absolute improvement).
‐ 14 more people out of 100 had resolution of one or more tophi after six months' treatment with pegloticase monthly compared with placebo (14% absolute improvement).
‐ 40 people out of 100 in the biweekly pegloticase group had resolution of one or more tophi.
‐ 21 people out of 100 in the monthly pegloticase group had resolution of one or more tophi.
‐ 7 people out of 100 in the placebo group had resolution of one or more tophi.
Other outcomes were for all participants, and not separated out for those people with tophi. Therefore, we have not reported them in this review. However, we reported on withdrawal due to adverse events for the total population. Most withdrawals were due to adverse reactions to drug infusion.
Withdrawal due to adverse events
‐ 16 more people out of 100 withdrew from treatment with biweekly pegloticase compared with placebo (16% more withdrawals).
‐ 17 more people out of 100 withdrew from treatment with monthly pegloticase compared to placebo (17% more withdrawals).
‐ 18 people out of 100 withdrew from treatment with biweekly pegloticase due to adverse events.
‐ 19 people out of 100 withdrew from treatment with monthly pegloticase due to adverse events.
‐ 2 people out of 100 withdrew from treatment with placebo due to adverse events.
Quality of evidence
Moderate‐quality evidence indicated that pegloticase biweekly or monthly probably resolves one or more tophi. However, this has to be weighed up against high withdrawal rates from treatment due to adverse events, mostly due to an increase in infusion reactions. Pain reduction, quality of life, serum urate normalisation and function were not reported separately in people with tophi. The evidence was downgraded due to imprecise results. Further research may change these results.
We do not know if other interventions, including surgery, are effective, as we found no randomised controlled trials that assessed other interventions.
Authors' conclusions
Summary of findings
| Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi | ||||||
| Patient or population: participants with tophi in gout | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Biweekly pegloticase | |||||
| Regression of tophi | 74 per 1000 | 404 per 1000 | RR 5.45 | 79 | ⊕⊕⊕⊝ | Absolute improvement with pegloticase 33% (16% to 50%) Relative change 445% (40% to 2060%) NNTB 3 (2 to 6)2 |
| Joint pain reduction ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Quality of life ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Serum urate normalisation ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Function ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Number of participant withdrawals due to adverse events Follow‐up: median 6 months | 23 per 1000 | 177 per 1000 | RR 7.59 | 128 | ⊕⊕⊕⊝ | Absolute increase in withdrawals with pegloticase 16% (8% to 28%) Relative increase in withdrawals 660% (4% to 5455%) NNTH 7 (4 to 16) (Reported for all participants but not separately for those with tophi) |
| Total adverse events ‐ not reported | 953 per 1000 | 941 per 1000 (851 to 1000) | RR 0.99 (0.91 to 1.07) | 128 (1 study) | ⊕⊕⊕⊝ | Absolute decrease in adverse events with pegloticase 1% (9% decrease to 7% increase) Relative decrease 1% (‐9% to 7%) NNTH ‐ not applicable |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Estimates are from a single study, and wide confidence intervals indicate imprecision. | ||||||
| Monthly pegloticase compared with placebo for tophi | ||||||
| Patient or population: participants with tophi in gout | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Monthly pegloticase | |||||
| Regression of tophi | 74 per 1000 | 212 per 1000 | RR 2.86 | 79 | ⊕⊕⊕⊝ | Absolute improvement with pegloticase: 14% (1% worse to 29% improvement) Relative change: 190% improvement (30% worse to 1100% improvement) NNTB ‐ not applicable2 |
| Joint pain reduction ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Quality of life ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Serum urate normalisation ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Function ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Number of participant withdrawals due to adverse events Follow‐up: mean 6 months | 23 per 1000 | 190 per 1000 | RR 8.19 | 127 | ⊕⊕⊕⊝ | Absolute increase in withdrawals with pegloticase: 17% (7% to 26%) Relative change: 719% more withdrawals (12% to 5870% more) NNTH 6 (4 to 14)2 (Reported for all participants but not separately for people with tophi) |
| Total adverse events | 953 per 1000 | 1000 per 1000 (980 to 1000) | RR 1.05 (0.98 to 1.14) | 127 (1 study) | ⊕⊕⊕⊝ | Absolute increase with pegloticase: 5% (20% decrease to 12% increase) Relative increase 5% (‐20% to 14%) NNTH ‐ not applicable2 |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Estimates are from a single study, and wide confidence intervals indicate imprecision. 2 NNTB or NNTH not applicable when result is not statistically significant. Number needed to treat for dichotomous outcomes calculated using 1/risk difference | ||||||
Background
Description of the condition
Gout is the most common type of inflammatory arthritis in men; it affects at least 1% of the population in western countries (Terkeltaub 2003). It is characterised by the formation of monosodium urate crystals in joints and other tissues. The crystals trigger release of pro‐inflammatory cytokines leading to inflammation causing gouty arthritis. Gouty arthritis can progress to chronic, deforming and physically disabling disease through the development of disfiguring tophi, joint destruction and persistent pain (Schlesinger 2011).
Tophi are nodular masses of monosodium urate. The presence of tophi is common in people with untreated or inadequately controlled gout. Tophi can become infected, cause pain and lead to a decrease in function. Complications may also occur when tophi develop in unusual sites such as heart valves, carpal tunnel, larynx and spine.
Description of the intervention
The mainstay of management of tophi is through pharmacological interventions (i.e. urate‐lowering therapy including purine and non‐purine xanthine oxidase inhibitors (such as allopurinol and febuxostat), uricosuric agents (e.g. probenecid and benzbromarone) and uricases (e.g. pegloticase)). However, other interventions, such as surgical management, are also used in practice.
How the intervention might work
Tophi develop in people with poorly treated or uncontrolled gout. This is postulated to be due to persistently raised serum uric acid levels. Pharmacotherapy aims to reduce serum uric acid levels and thus leads to a reduction in tophi.
Surgical therapy may be used for direct removal of tophi, for example, where the presence of tophi have led to a decrease in function, or where there is urgent need for removal, for example, as a cause of spinal cord compression.
Other interventions may work by also reducing serum uric acid (e.g. haemodialysis).
Why it is important to do this review
The presence of tophi can lead to significant morbidity, and even mortality through potential complications. Despite this, there have been no systematic reviews to date determining the management of tophi separately from the management of gout.
Objectives
To assess the benefits and harms of non‐surgical and surgical treatments for the management of tophi in gout.
Methods
Criteria for considering studies for this review
Types of studies
All published, randomised controlled trials (RCTs) or controlled clinical trials (CCTs) with pseudo‐randomised methods of allocating people to treatment considering the management of tophi in gout. Although our original search included other types of studies, for the purpose of this review we will only include trials and pseudo‐RCTs for assessment of treatment benefit.
Types of participants
All adults (aged 18 years or older) with a diagnosis of gout and the presence of one or more tophi. Where trials included gout with a subset of people with tophi, we reported on the people with tophi only.
Types of interventions
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Pharmacotherapy (i.e. urate‐lowering therapy including purine and non‐purine xanthine oxidase inhibitors, uricosuric agents and uricases).
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Any form of surgical removal (e.g. debridement, shaving, arthroscopic removal).
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Other interventions.
Comparators were:
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placebo;
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no surgical or pharmacological intervention;
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one pharmacological or surgical intervention versus another;
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combination versus single intervention or another combination therapy.
Types of outcome measures
Major outcomes
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Proportion of people with complete resolution.
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Pain reduction.
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Health‐related quality of life.
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Serum urate normalisation.
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Function (i.e. activity limitation).
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Study participant withdrawals due to adverse events (e.g. wound infection, failure to close or surgical complications, infusion reactions).
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Total adverse events.
Minor outcomes
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Proportion of people with recurrence.
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Time to recurrence.
Search methods for identification of studies
Electronic searches
We searched the following databases using the search strategies detailed in the appendices. We completed the search in May 2013:
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the Cochrane Central Register of Controlled Trials (CENTRAL, via The Cochrane Library) on 20 May 2013 (Appendix 1);
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Ovid MEDLINE 1948 to May 2013 (Appendix 2);
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EMBASE 1980 to May 2013 (Appendix 3);
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trial registries: Clinical Trials.gov (www.clinicaltrials.gov, accessed 20 May 2013); the Australian & New Zealand Clinical Trial Registry (www.anzctr.org.au, accessed 20 May 2013); and the World Health Organization (WHO) Clinical Trials Registry Platform (www.who.int/ictrp/en/, accessed 20 May 2013) to identify potential ongoing studies.
We did not exclude studies based on language.
Searching other resources
We searched the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) conference abstracts from 2010 and 2011. We also conducted handsearches of references from included articles and relevant reviews to identify any additional studies not retrieved by the search strategies.
Data collection and analysis
Selection of studies
Two review authors (MS, OV) independently reviewed all retrieved trials to identify the ones that fulfilled the criteria for inclusion in this systematic review. We retrieved all relevant articles in full‐text for closer examination. We resolved disagreements about study inclusion or exclusion by consensus or by discussion with a third review author (CE) if needed. We translated studies into English where necessary.
Data extraction and management
Two independent review authors (MS, OV) extracted the following information from included trials using pre‐determined data extraction forms:
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study design;
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characteristics of the study population (age, gender, number and distribution of tophi);
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intervention used;
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control interventions;
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outcome measures;
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timing of outcome assessment; and
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methodological domains relevant to risk of bias assessment.
We resolved any differences in data extraction by referring back to the original articles and establishing consensus. We consulted a third review author (CE) to help resolve differences if necessary.
Assessment of risk of bias in included studies
We assessed the potential for bias in included studies using a 'Risk of bias' table (Higgins 2011). Two review authors (MS, OV) independently assessed the risk of bias for all included trials, and resolved any disagreements by consensus. We consulted a third review author (CE) to help resolve differences if necessary. We assessed the following methodological domains in conformity with The Cochrane Collaboration's recommendations.
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Random sequence generation: to determine if the method of generating the randomisation sequence was adequate to prevent biased allocation to interventions.
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Allocation concealment: to determine if adequate methods were used to conceal allocation to interventions.
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Blinding of participants, personnel and outcome assessors for each outcome measure.
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Incomplete outcome data.
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Selective outcome reporting.
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Other potential sources of bias, such as inappropriate administration of an intervention or insensitive instrument to measure outcome.
To determine the risk of bias of an included study, for each criterion we evaluated the presence of sufficient information and the likelihood of potential bias. We rated each criterion as 'low risk' of bias, 'high risk' of bias or 'unclear risk' of bias (either lack of information or uncertainty over the potential for bias).
We planned to compare the fixed‐effect estimate against the random effects model. In the event of the possible presence of small sample bias in the published literature (i.e. in which the intervention effect was more beneficial in smaller studies), the random‐effects estimate of the intervention is more beneficial than the fixed‐effect estimate (Sterne 2011).
Measures of treatment effect
For dichotomous outcomes, we calculated the risk ratio (RR) with corresponding 95% confidence intervals (CIs) and numbers needed to treat for an additional beneficial (NNTB) or harmful (NNTH) outcome. We had planned to calculate mean difference and 95% CI for continuous outcomes measured on the same scale, or standardised mean difference and 95% CI for continuous outcomes reported on different scales. However, the included trials only reported dichotomous outcomes.
Unit of analysis issues
For the included study, we compared each treatment arm (i.e. pegloticase every two weeks (biweekly) and monthly pegloticase) with placebo in separate analyses. We also compared biweekly pegloticase with monthly pegloticase.
Dealing with missing data
We did not need to deal with missing data.
Assessment of heterogeneity
We planned to assess heterogeneity using subgroup analyses on effect of serum urate levels on tophus regression, or rate of tophi recurrence following surgical treatment. We included only one study in the review, hence we did not assess for heterogeneity.
Assessment of reporting biases
In order to determine whether reporting bias was present, we determined whether the protocol of the RCT was published before recruitment of participants of the study was started by searching trial registries for trial protocols. We evaluated whether selective reporting of outcomes was present (outcome reporting bias).
We were unable to explore the potential for reporting bias by funnel plots further due to lack of data.
Data synthesis
We planned to perform meta‐analyses using a random‐effects model, regardless of the results of the I2 statistic. We were unable to analyse the data in meta‐analyses since we only included one study. We have presented analyses of outcomes for three comparisons from a single study in forest plots.
Presentation of key results
We produced a 'Summary of findings' tables using GRADEpro software. This table provides key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the most important participant‐relevant outcomes (number of participants with complete resolution of tophi, number of study participant withdrawals due to adverse events, total adverse events, health‐related quality of life, serum urate normalisation and function) as recommended by The Cochrane Collaboration (Schünemann 2011a).
The 'Summary of findings' table includes an overall grading of the evidence related to each of the main outcomes using the GRADE approach (Schünemann 2011b). In addition to the absolute and relative magnitude of effect provided in the 'Summary of findings' table, we calculated the NNTB or NNTH.
We were only able to extract data for dichotomous outcomes (proportion with tophi resolution; proportion who withdrew due to adverse events).
For dichotomous outcomes, we calculated the absolute risk difference using the risk difference statistic in Review Manager (RevMan 2011) and the result expressed as a percentage. The relative per cent change for dichotomous data was calculated as the RR ‐ 1 and expressed as a percentage. The number needed to treat was calculated from the RR using 1/risk difference (RD).
Subgroup analysis and investigation of heterogeneity
There were insufficient studies to do planned subgroup analyses.
Sensitivity analysis
There were insufficient studies to do planned sensitivity analysis.
Results
Description of studies
Results of the search
Our preliminary searches found no RCTs examining interventions for tophi. Based on this, we extended the search to include systematic literature reviews, RCTs, CCTs, observational studies, case series and case reports. We have reported on other studies that we identified in our discussion.
We carried out the initial search on 22 October 2011 (Figure 1). This recovered 3206 articles. We excluded 3116 articles on review of title and abstract and 90 following full‐text review.
Study selection flow chart.
Only one article met the inclusion criteria for this review. We performed an updated search on 20 May 2013; we recovered 416 additional articles, none of which were RCTs that met the inclusion criteria.
Included studies
We included only one study in this systematic review (Sundy 2011). A total of 262 participants participated in the study and 225 participants were randomised. The primary efficacy end point was normalisation of plasma uric acid, and secondary efficacy end points included reduction in tophi, gout flares, and improvement in physical function and quality of life. One hundred and thirty‐one participants had tophi at baseline; 52 in the pegloticase every two weeks (biweekly) group, 52 in the monthly pegloticase group and 27 in the placebo group.
Sundy 2011 reported on the pooled results of two replicate randomised, double‐blind placebo‐controlled trials. The aim of the study was to report on the efficacy and tolerability of pegloticase in people with chronic gout that was refractory to traditional urate‐lowering therapy.
Participants were recruited from rheumatology practices across the USA, Canada and Mexico between June 2006 and October 2007. They were aged 18 years or older and met criteria for refractory gout:
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baseline serum uric acid 8.0 mg/dL or greater;
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contraindication to treatment with allopurinol or history of failure to normalise uric acid despite three months or more with maximal medically appropriate allopurinol dose (determined by the participant's physician);
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at least one of the following:
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three or more self reported gout flares during previous 12 to 18 months;
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one or more tophi;
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gouty arthropathy defined clinically or radiographically as joint damage due to gout.
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Participants who were on urate‐lowering therapy at the time of screening underwent a one‐week washout period prior to entering study.
Two hundred and twenty‐five participants were randomised to one of three arms: biweekly pegloticase infusion, monthly pegloticase infusion ‐ pegloticase infusion alternating with placebo infusion every two weeks or placebo (also an infusion). Two hundred and twelve participants were included in primary analysis; 85 participants in biweekly pegloticase group, 84 in monthly pegloticase group and 43 in placebo group. Participants were analysed according to the group they were randomised to. Randomisation was performed by an automated interactive voice response system. Participants were given infusions of 250‐mL 0.9% sodium chloride containing either pegloticase 8 mg or placebo every two weeks.
The primary efficacy point was proportion of uric acid responders; this was defined as maintaining a plasma uric acid level of less than 6.0 mg/dL for over 80% of the time during both months three and six. Secondary efficacy points included tophus regression. For this, standardised photographs of hands and feet and two other sites with tophi were taken. These were compared by a central reader who was unaware of treatment allocation.
Excluded studies
We assessed 90 articles in full text and excluded them based on population (Rozenberg 1995), study type (Chen 1999; Feher 2003; Flugel 1978; Hulsmeyer 2000; Kaarela 2009; Kitazawa 2006; Klotz 1981; Kropelin 1972; Kumar 2005; Kung 1991; Martin 1982; Marwaha 2010; McLean 2004; Piza‐Katzer 1997; Ribeiro 2009; Richette 2007; Zuber 1996; Abrahamsson 1987; Abrams 2006; Baraf 2008; Barrett 2001; Baxter 2009; Becker 2009; Caldas 2007; Chang 2005; Chatterjee 2008; Dhote 1997; El Sandid 2004; Ertugrul 2000; Fiehn 2006; Frankel 1984; Funck‐Brentano 2011; Graefen 1991; Griffin 2009; Hughes 2005;Johnson 1979; Kao 2000; Kemp 2010; Kerman 1993; Ko 1996; Kobayashi 2005; Kuo 2007; Landry 1986; Lapidus 1963; Lee 2003; Lee 2010; Li 2006; Lin 2009; Lui 2008; Mahmud 2005; Martínez‐Villen 2007; Marwaha 2010; McGonagle 2007; Melloni 2004; Mockford 2003; Moolenburgh 2006; Morino 2007; Mrabet 2010; Nakazawa 2004; Niva 2006; Ntsiba 2010; Pai 1993; Pankhania 2006; Paquette 2000; Perez‐Ruiz 2002; Pledger 1976; Raman 1981; Reineke 2009; Richette 2006; Schuind 2003; Sekiya 2010; Sener 2000; Shimizu 2008; Staub‐Zahner 2007; Tan 2003; Tashiro 2002; Tausche 2011; Thavarajah 2011; Tran 2011; Uh 2011; Vetter 2008; Vogt 2005; Wakabayashi 1998; Weniger 2003; Woughter 1959; Yen 2002; Yetkin 1999; Migita 2001, and no intervention (Pouye 2006).
Risk of bias in included studies
Allocation
There was no selection bias; participants were randomly allocated to groups via an automated interactive voice response system. Numbers were stratified to get comparable numbers of participants with tophi within the groups.
Blinding
There was adequate blinding of outcome data (e.g. the use of a blinded central reader for tophi outcomes), and thus a low risk of detection bias. There was also blinding in terms of treatment (ensuring same number of infusions for all participants); however, blinding of staff during treatment, and thus the risk of performance bias, was unclear.
Incomplete outcome data
Incomplete outcome data were addressed where possible. Three participants were lost to follow‐up. A total of 145 participants had tophi at baseline, of these, 131 were reported on in terms of complete resolution of tophi. The proportion of participants with tophi who dropped out was evenly distributed across treatment groups.
Selective reporting
The study protocol was registered with ClinicalTrials.gov in 2006. There were minimal changes made to the protocol. No selective reporting was noted. The work was funded by Savient Pharmaceuticals. The author‐employees were responsible for study concept and design, and sponsor‐employees were responsible for data collection and storage. However, we have no evidence to suggest there was selective reporting of data.
Other potential sources of bias
We noted no other potential sources of bias, such as inappropriate administration of an intervention or insensitive instrument to measure outcome.
Effects of interventions
See: Summary of findings for the main comparison Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi; Summary of findings 2 Monthly pegloticase compared with placebo for tophi
We present only the outcomes that were reported separately for the subgroup of participants with tophi at baseline (resolution of tophi). All other outcomes were reported for total participants with no separate reporting for people with tophi. Thus, we were unable to report the effect of pegloticase on other outcomes in the participants with tophi. However, we have reported on withdrawal due to adverse events and total adverse events for the total participants.
Resolution of tophi
More participants in the pegloticase every two weeks (biweekly) group had complete resolution of one or more tophi compared with participants in the placebo group (21/52 with biweekly pegloticase versus 2/27 with placebo; RR 5.45, 95% CI 1 to 22; NNTB 3, 95% CI 2 to 6; Analysis 1.1) (summary of findings Table for the main comparison).
More participants in the monthly pegloticase group had complete resolution of one or more tophi compared with participants in the placebo group (11/52 with monthly pegloticase versus 2/27 with placebo; RR 2.86, 95% CI 0.7 to 12.0; NNTB 8, 95% CI 4 to 91; Analysis 2.1) (summary of findings Table 2).
In addition, comparison of the two pegloticase group found that more participants in the biweekly pegloticase arm had complete resolution of one or more tophi compared with participants in the monthly pegloticase group (RR 1.91, 95% CI 1.03 to 3.55; Analysis 3.1).
Other outcomes
As pain, function, serum acid normalisation and quality of life data were only presented for the total population in the trial, and not for the subgroup with tophi at baseline, we could not report these outcomes.
Withdrawal due to adverse events
Pegloticase administered biweekly resulted in more withdrawals due to adverse events than placebo (15/85 with biweekly pegloticase versus 1/43 with placebo; RR 7.59, 95% CI 1.04 to 55.55; NNTH 5, 4 to 17; Analysis 1.2) (summary of findings Table for the main comparison).
Pegloticase administered monthly also resulted in more withdrawals due to adverse events than placebo (16/84 with monthly pegloticase versus 1/43 with placebo; RR 8.19, 95% CI 1.12 to 59.71; NNTH 6, 95% CI 4 to 14; Analysis 2.2) (summary of findings Table 2).
A similar proportion of participants in the biweekly and monthly pegloticase arms withdrew due to adverse events (RR 0.93, 95% CI 0.49 to 1.75; Analysis 3.2).
Infusion reactions were the most common reason for study discontinuation with both biweekly and monthly pegloticase (22/85 with biweekly pegloticase versus 2/43 with placebo; RR 5.56, 95% CI 1.37 to 22.57; NNTH 2; 35/84 with monthly pegloticase group versus 2/43 with placebo; RR 8.96, 95% CI 2.26 to 35.49; NNTH 2).
Of note, one ACR hotline update advised measurement of routine serum uric acid level prior to each pegloticase infusion in order to identify people at increased risk of infusion reaction. This study noted that 79% of participants who had an infusion reaction in the development of pegloticase antibody, did so after loss of urate‐lowering response (i.e. rising uric acid levels). Two deaths during the treatment period were attributed to cardiovascular adverse events (cardiac arrest, arrhythmia) in the biweekly group. The third death was due to renal failure in the monthly pegloticase group.
Adverse events
Pegloticase administered biweekly resulted in similar numbers of participants with any adverse event to placebo (80/85 with biweekly pegloticase treatment versus 41/43 with placebo; RR 0.99, 95% CI 0.91 to 1.07) (summary of findings Table for the main comparison).
Pegloticase administered monthly also resulted in similar numbers of participants with any adverse event to placebo (84/84 with monthly pegloticase versus 41/43 with placebo; RR 1.05, 95% CI 0.98 to 1.14) (summary of findings Table 2).
The top three most common adverse events were gout flares, infusion reactions and headaches; 80% of adverse events were due to flares of gout. This may explain the high rate of adverse events in the placebo groups that were essentially untreated.
More participants in the biweekly and monthly pegloticase group had infusion reactions compared with participants in the placebo group (22/85 with biweekly pegloticase versus 2/43 with placebo; RR 5.56, 95% CI 1.37 to 22.57; NNTH 2; 35/84 with monthly pegloticase group versus 2/43 with placebo; RR 8.96, 95% CI 2.26 to 35.49; NNTH 2).
We were unable to perform the subgroup or sensitivity analyses as only one study met the inclusion criteria for this review.
Discussion
Summary of main results
Only one study met our inclusion criteria for this review for interventions for tophi in gout. The study showed that the pegloticase every two weeks (biweekly) dose of 8 mg was beneficial in reduction of tophi. Monthly pegloticase was also beneficial but to a lesser degree. Relative risk of withdrawals due to adverse events appeared to be similar in the biweekly and monthly pegloticase groups. Our review also shows that further RCT data are needed to examine specifically interventions for tophi.
Overall completeness and applicability of evidence
We have included the only RCT evidence for interventions for tophi that is published at present. We found no RCT data for other interventions or for non‐pharmacological interventions such as surgery.
We extended our search to include studies other than RCTs for management of tophi. We will discuss them here.
Pharmacotherapy
Becker 2009 reported the results of fEbuXostat/allopurinol Comparative Extension Long‐term study (EXCEL). This was an open‐label extension of two phase III double‐blind trials. These compared febuxostat (80 and 120 mg) versus allopurinol (100 or 300 daily, higher dose used if serum creatinine less than 1.5 mg/dL). Outcome was measured by percentage reduction in number of tophi and reduction in size or disappearance of index tophus. At baseline, 214 participants had palpable tophi. The high‐dose febuxostat (120mg) group appeared to fare better in terms of complete resolution of primary tophi. The study also noted that overall, long‐term maintenance of goal serum uric acid led to a reduction in tophi.
Perez‐Ruiz 2002 reported on a prospective observational study comparing allopurinol alone, benzbromarone alone and allopurinol plus benzbromarone on tophi resolution. All participants had one or more tophi at baseline. There was no placebo arm to act as comparator. Outcome was reduction in size of target tophus. The participants in the combination group appeared to fare best with a mean rate of reduction until tophus resolution of 1.53 mm/month (standard deviation 0.45). However, the mean time to resolution in this group was the longest at 27.8 months (standard deviation 1.21). Participants with more severe tophaceous gout were given combination therapy, which may explain this finding (Table 1).
| Study | Study type | No of participants (no of drop‐outs) | Duration | Intervention | Comparator | Overall risk of bias |
| USA Canada | Open‐label extension | 1086 (168) | 3 years | Febuxostat 80 or 120 mg | Allopurinol | High |
| Spain | Cohort (prospective observational) | 70 (7) | 6 months | Allopurinol 200 mg daily plus benzbromarone 50 mg daily | Allopurinol maximum 300 mg daily alone or benzbromarone maximum 200 mg daily alone | High |
No: number.
We retrieved 14 case‐series and reports that compared pharmacological interventions. There were few negative outcomes reported. Objective measures of outcome included pictoral (photographs taken before and after intervention) and size/physical measurement. Not all of the studies reported objective measures of outcome (Table 2).
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Interleukin‐1 inhibitor (anakinra) | 2 | 4 | Pain reduction sUA reduction | 0 | Pictoral resolution of tophi (2) |
| Febuxostat | 2 | 2 | sUA reduction Improved QoL Reduction in tophi | 0 | Pictoral |
| Allopurinol | 4 | 4 | Improved function Reduction in tophi sUA reduction | No resolution of tophi (1 case) | Pictoral (1) CT image (1) |
| Probenecid and steroid injections | 1 | 1 | Improved function Pain reduction | ‐ | None |
| Rasburicase | 3 | 12 | Improved function Reduction in tophi sUA reduction | Acute attacks of arthritis (1) | Physical measurement (12 participants) |
| Pegloticase | 1 | 2 | sUA reduction Resolution of tophi | ‐ | Size of tophi |
| Infliximab | 1 | 1 | Pain reduction | ‐ | None |
CT: computed tomography; No: number; QoL: quality of life; sUA: serum uric acid.
Surgical interventions
We found 40 case‐series and reports for surgical interventions for tophi. These compared decompression/laminectomy, excision/debridement and soft‐tissue shaving. All reported positive outcomes. However, none of the studies employed objective outcome measures (Table 3).
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Decompression/laminectomy Barrett 2001; Chang 2005; Dhote 1997; El Sandid 2004; Kao 2000; Ko 1996; Kuo 2007; Lin 2009; Mahmud 2005; Martínez‐Villen 2007; Ntsiba 2010; Pankhania 2006; Pledger 1976; Tan 2003; Thavarajah 2011; Yen 2002 | 16 | 21 | Improved function Reduction in pain | Postoperative flare of gout in 2 cases | None |
| Excision/amputation/debridement Abrams 2006; Ertugrul 2000; Kerman 1993; Kobayashi 2005; Lapidus 1963; Sener 2000; Yetkin 1999; Lee 2010; Li 2006; Lui 2008; Martin 1982; Melloni 2004; Mockford 2003; Morino 2007; Pai 1993; Paquette 2000; Reineke 2009; Schuind 2003; Tashiro 2002; Vetter 2008; Wakabayashi 1998; Weniger 2003; Woughter 1959 | 23 | 27 | Pain reduction Improved function No evidence of local recurrence | Superficial wound dehiscence in 1 case | None |
| Soft‐tissue shaving procedure | 1 | 17 | Improved function Pain reduction | Skin loss (2 cases) Gastrointestinal bleed leading to death (1 case) | none |
No: number.
Other interventions
The only other single intervention found in our literature search was haemodialysis. This was in one participant with chronic renal failure who was started on haemodialysis for congestive heart failure, and incidentally was noted to have a reduction of tophi. No objective measure of outcome was noted.Migita 2001
Combination therapies
There were 13 studies which reported on combination therapies. These also had few negative outcomes.
Although there are some objective measures of outcome in this group, we could not determine whether combination was superior to single surgical, pharmacological or other therapy due to lack of head to head trials (Table 4).
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Rasburicase plus allopurinol | 1 | 1 | Reduction in tophi sUA reduction | Flare after each infusion | Size |
| Benzbromarone plus allopurinol | 1 | 1 | Resolution of tophi Improved function | 0 | Pictoral |
| Anakinra plus haemodialysis | 1 | 1 | Resolution of tophi Improved function | 0 | Pictoral |
| Benzbromarone plus allopurinol, arthroscopic removal | 1 | 1 | Improved function | 0 | None |
| Debridement, vacuum‐assisted dressing and allopurinol | 1 | 1 | No recurrence of tophi | 0 | None |
| Excision/debridement/joint replacement and allopurinol Abrahamsson 1987; Frankel 1984; Graefen 1991; Griffin 2009; Hughes 2005; Landry 1986; Nakazawa 2004; Sekiya 2010 | 8 | 8 | Reduction in pain Improved function | Postoperative ischaemic ulceration (1) Recurrence of tophi (1) | None |
No: number; sUA: serum uric acid.
Quality of the evidence
The overall quality of evidence was moderate for resolution of tophi, withdrawals due to adverse events and total adverse events after treatment with pegloticase. We assessed study limitations, indirectness, consistency and publication bias. The results were based on one study, and we downgraded the evidence because of imprecision. Other important outcomes were not measured in participants with tophi: pain, quality of life, serum urate normalisation and function, thus we do not know the effect of treatment on these outcomes. The quality of evidence is summarised in summary of findings Table for the main comparison and summary of findings Table 2.
Savient Pharmaceuticals, as the manufacturer of pegloticase, sponsored the study. However, there was no evidence that this has led to selective data reporting.
Other pharmacological or surgical interventions have not been assessed in RCTs.
Potential biases in the review process
We used a sensitive search strategy and included searching of grey literature to identify as many studies as possible. However, we acknowledge that the time lag between the completion of the search and the publication of the review may be a potential source of bias.
Two review authors independently extracted titles, abstracts and data, minimising errors and bias in the review process.
We did not report data on pain, function, serum acid normalisation and quality of life as these were only presented for the total population in the trial, and not for the subgroup with tophi at baseline.
Agreements and disagreements with other studies or reviews
To our knowledge there has been no published systematic literature reviews or meta‐analyses examining interventions for tophi in gout in isolation. There is one previous Cochrane systematic review on pegloticase in chronic gout (Anderson 2010). However, the study did not report on tophi outcomes.
Study selection flow chart.
Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 1 Proportion with tophi resolution.
Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 2 Withdrawal due to adverse events.
Comparison 1 Pegloticase every two weeks (biweekly) versus placebo, Outcome 3 Total adverse events.
Comparison 2 Pegloticase monthly versus placebo, Outcome 1 Proportion with tophi resolution.
Comparison 2 Pegloticase monthly versus placebo, Outcome 2 Withdrawal due to adverse events.
Comparison 2 Pegloticase monthly versus placebo, Outcome 3 Total adverse events.
Comparison 3 Pegloticase every two weeks (biweekly) versus pegloticase monthly, Outcome 1 Proportion with tophi resolution.
Comparison 3 Pegloticase every two weeks (biweekly) versus pegloticase monthly, Outcome 2 Withdrawals due to adverse events.
| Pegloticase every two weeks (biweekly) compared with placebo for participants with tophi | ||||||
| Patient or population: participants with tophi in gout | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Biweekly pegloticase | |||||
| Regression of tophi | 74 per 1000 | 404 per 1000 | RR 5.45 | 79 | ⊕⊕⊕⊝ | Absolute improvement with pegloticase 33% (16% to 50%) Relative change 445% (40% to 2060%) NNTB 3 (2 to 6)2 |
| Joint pain reduction ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Quality of life ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Serum urate normalisation ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Function ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Number of participant withdrawals due to adverse events Follow‐up: median 6 months | 23 per 1000 | 177 per 1000 | RR 7.59 | 128 | ⊕⊕⊕⊝ | Absolute increase in withdrawals with pegloticase 16% (8% to 28%) Relative increase in withdrawals 660% (4% to 5455%) NNTH 7 (4 to 16) (Reported for all participants but not separately for those with tophi) |
| Total adverse events ‐ not reported | 953 per 1000 | 941 per 1000 (851 to 1000) | RR 0.99 (0.91 to 1.07) | 128 (1 study) | ⊕⊕⊕⊝ | Absolute decrease in adverse events with pegloticase 1% (9% decrease to 7% increase) Relative decrease 1% (‐9% to 7%) NNTH ‐ not applicable |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Estimates are from a single study, and wide confidence intervals indicate imprecision. | ||||||
| Monthly pegloticase compared with placebo for tophi | ||||||
| Patient or population: participants with tophi in gout | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Monthly pegloticase | |||||
| Regression of tophi | 74 per 1000 | 212 per 1000 | RR 2.86 | 79 | ⊕⊕⊕⊝ | Absolute improvement with pegloticase: 14% (1% worse to 29% improvement) Relative change: 190% improvement (30% worse to 1100% improvement) NNTB ‐ not applicable2 |
| Joint pain reduction ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Quality of life ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Serum urate normalisation ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Function ‐ not reported | See comment | See comment | Not estimable | ‐ | See comment | Reported for all participants but not separately for people with tophi |
| Number of participant withdrawals due to adverse events Follow‐up: mean 6 months | 23 per 1000 | 190 per 1000 | RR 8.19 | 127 | ⊕⊕⊕⊝ | Absolute increase in withdrawals with pegloticase: 17% (7% to 26%) Relative change: 719% more withdrawals (12% to 5870% more) NNTH 6 (4 to 14)2 (Reported for all participants but not separately for people with tophi) |
| Total adverse events | 953 per 1000 | 1000 per 1000 (980 to 1000) | RR 1.05 (0.98 to 1.14) | 127 (1 study) | ⊕⊕⊕⊝ | Absolute increase with pegloticase: 5% (20% decrease to 12% increase) Relative increase 5% (‐20% to 14%) NNTH ‐ not applicable2 |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1 Estimates are from a single study, and wide confidence intervals indicate imprecision. 2 NNTB or NNTH not applicable when result is not statistically significant. Number needed to treat for dichotomous outcomes calculated using 1/risk difference | ||||||
| Study | Study type | No of participants (no of drop‐outs) | Duration | Intervention | Comparator | Overall risk of bias |
| USA Canada | Open‐label extension | 1086 (168) | 3 years | Febuxostat 80 or 120 mg | Allopurinol | High |
| Spain | Cohort (prospective observational) | 70 (7) | 6 months | Allopurinol 200 mg daily plus benzbromarone 50 mg daily | Allopurinol maximum 300 mg daily alone or benzbromarone maximum 200 mg daily alone | High |
| No: number. | ||||||
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Interleukin‐1 inhibitor (anakinra) | 2 | 4 | Pain reduction sUA reduction | 0 | Pictoral resolution of tophi (2) |
| Febuxostat | 2 | 2 | sUA reduction Improved QoL Reduction in tophi | 0 | Pictoral |
| Allopurinol | 4 | 4 | Improved function Reduction in tophi sUA reduction | No resolution of tophi (1 case) | Pictoral (1) CT image (1) |
| Probenecid and steroid injections | 1 | 1 | Improved function Pain reduction | ‐ | None |
| Rasburicase | 3 | 12 | Improved function Reduction in tophi sUA reduction | Acute attacks of arthritis (1) | Physical measurement (12 participants) |
| Pegloticase | 1 | 2 | sUA reduction Resolution of tophi | ‐ | Size of tophi |
| Infliximab | 1 | 1 | Pain reduction | ‐ | None |
| CT: computed tomography; No: number; QoL: quality of life; sUA: serum uric acid. | |||||
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Decompression/laminectomy Barrett 2001; Chang 2005; Dhote 1997; El Sandid 2004; Kao 2000; Ko 1996; Kuo 2007; Lin 2009; Mahmud 2005; Martínez‐Villen 2007; Ntsiba 2010; Pankhania 2006; Pledger 1976; Tan 2003; Thavarajah 2011; Yen 2002 | 16 | 21 | Improved function Reduction in pain | Postoperative flare of gout in 2 cases | None |
| Excision/amputation/debridement Abrams 2006; Ertugrul 2000; Kerman 1993; Kobayashi 2005; Lapidus 1963; Sener 2000; Yetkin 1999; Lee 2010; Li 2006; Lui 2008; Martin 1982; Melloni 2004; Mockford 2003; Morino 2007; Pai 1993; Paquette 2000; Reineke 2009; Schuind 2003; Tashiro 2002; Vetter 2008; Wakabayashi 1998; Weniger 2003; Woughter 1959 | 23 | 27 | Pain reduction Improved function No evidence of local recurrence | Superficial wound dehiscence in 1 case | None |
| Soft‐tissue shaving procedure | 1 | 17 | Improved function Pain reduction | Skin loss (2 cases) Gastrointestinal bleed leading to death (1 case) | none |
| No: number. | |||||
| Intervention | No of case‐series/reports | Total no of participants | Positive outcomes | Negative outcomes | Objective measure of outcome? |
| Rasburicase plus allopurinol | 1 | 1 | Reduction in tophi sUA reduction | Flare after each infusion | Size |
| Benzbromarone plus allopurinol | 1 | 1 | Resolution of tophi Improved function | 0 | Pictoral |
| Anakinra plus haemodialysis | 1 | 1 | Resolution of tophi Improved function | 0 | Pictoral |
| Benzbromarone plus allopurinol, arthroscopic removal | 1 | 1 | Improved function | 0 | None |
| Debridement, vacuum‐assisted dressing and allopurinol | 1 | 1 | No recurrence of tophi | 0 | None |
| Excision/debridement/joint replacement and allopurinol Abrahamsson 1987; Frankel 1984; Graefen 1991; Griffin 2009; Hughes 2005; Landry 1986; Nakazawa 2004; Sekiya 2010 | 8 | 8 | Reduction in pain Improved function | Postoperative ischaemic ulceration (1) Recurrence of tophi (1) | None |
| No: number; sUA: serum uric acid. | |||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion with tophi resolution Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Total adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion with tophi resolution Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Withdrawal due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 3 Total adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Proportion with tophi resolution Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Withdrawals due to adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
