Description of the condition
Gout is an inflammatory arthritis that is characterised by the deposition of monosodium urate crystals in synovial fluid and other tissues. The natural history of articular gout is generally composed of three periods, of asymptomatic hyperuricaemia, episodes of acute gout and chronic gouty arthritis (Richette 2010). Gout often heralds its presence by an exquisitely painful, acute monoarthritic attack of sudden onset; polyarticular initial attacks, though less common (3% to 14%), are well recognised (Richette 2010). Gout occurs with the backdrop of hyperuricaemia, which is necessary but not sufficient to cause gout (Neogi 2011). Hyperuricaemia itself is contributed to rarely by over-production or more commonly under-excretion of uric acid, or both (Neogi 2011). Lower limb joints, particularly the big toe, are the most commonly involved followed by the mid-tarsi, ankles, knees and upper limb joints. Subsequent acute attacks tend to be longer lasting, polyarticular and to affect the upper limbs joints, such as the wrist or elbow (Richette 2010).
Description of the intervention
Intra-articular glucocorticoids have a well established diagnostic and therapeutic place in the repertoire of available options for several rheumatological conditions, including acute inflammatory arthritis, tenosynovitis, enthesitis and bursitis (Jacobs 2008; Kim 2002). In gout, they can be used as stand-alone, single-dose therapy administered into the involved joint for relieving the pain of an acute attack; this is of particular value in situations where other standard therapies recommended for acute gout, such as non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine, are contraindicated (for example in renal failure) (Zhang 2006). Several preparations of intra-articular glucocorticoids are available and are generally classified as soluble (for example phosphate salts, betamethasone phosphate) or insoluble (for example methylprednisolone acetate and triamcinolone hexacetonide). Soluble salts have a shorter duration of action compared to insoluble preparations (Courtney 2005; Courtney 2009; Jacobs 2008). The side effects of intra-articular glucocorticoids include facial flushing (12%), post-injection flare (15%) and sepsis (< 1:78,000); subcutaneous atrophy is a rare complication (Courtney 2009).
How the intervention might work
Intra-articular glucocorticoids may have a direct anti-inflammatory effect, as suggested by the rapidity of the clinical response. These drugs act on intracellular steroid receptors to control the rate of synthesis of messenger ribonucleic acid (RNA) and proteins, thus inducing alterations in white blood cell trafficking, levels of enzymes and phospholipase A2 inhibition that result in reduction of pro-inflammatory mediators (Creamer 1997; Stahn 2008). Reduction of inflammation in turn reduces pain by decreasing stimulation of primary afferent nociceptive fibres by inflammatory and mechanical stimuli (Creamer 1997).
Why it is important to do this review
Intra-articular glucocorticoids are an attractive alternative for treatment of patients with mono or oligoarticular (≤ four joints) acute gout in which concomitant serious illness or comorbidities preclude use of other established therapies such as NSAIDs or colchicine. While intra-articular corticosteroids are commonly used in acute gout, they are deemed to be highly effective (Richette 2010) and rheumatological guidelines have espoused their use in this situation (Jordan 2007; Zhang 2006), evidence for their benefit and safety remains sparse. Hence there exists an unmet need to do a systematic review on this topic.
To assess the benefit and safety of intra-articular glucocorticoids for treatment of acute gout.
Criteria for considering studies for this review
Types of studies
All published randomised controlled trials (RCTs) or controlled clinical trials that use quasi-randomisation methods (CCTs) that compared intra-articular glucocorticoids to another therapy (placebo or active, including non-pharmacological therapies) for acute gout were considered for inclusion.
Studies of intra-articular glucocorticoids in acute gout that did not have the outcome measures of interest were excluded. Only trials that were published as full articles or were available as a full trial report were considered for inclusion.
Types of participants
Adult patients (aged 18 years or older) with a diagnosis of acute gout (author-defined or presence of monosodium crystals in joint aspirate, or patients fulfilling American College of Rheumatology (Wallace 1977) or the 1963 Rome (O'Sullivan 1972) or 1966 New York (O'Sullivan 1972) criteria for gout). Populations that included a mix of people with acute gout and other musculoskeletal pain were excluded unless results for the acute gout population could be separated out for the analysis.
Types of interventions
All trials that evaluated intra-articular glucocorticoids were considered for inclusion.
Comparators could be:
- no treatment,
- systemic glucocorticoids,
- interleukin-1 (IL-1) inhibitors,
- intra-articular glucocorticoid via a different formulation or dosing interval,
- non-pharmacological treatments,
- combination therapy (any of the above in combination).
Types of outcome measures
There is considerable variation in the outcome measures reported in clinical trials of interventions for acute gout. For the purpose of this review, we aimed to include outcome measures that are considered to be of greatest importance to patients with acute gout and the clinicians who care for them.
Outcome Measures in Rheumatology Clinical Trials (OMERACT) has proposed outcome measures to be used in the evaluation of resolution of acute attacks (Grainger 2009; Schumacher 2005). Intense pain is the hallmark of an acute gout attack and hence pain has been proposed as an OMERACT outcome measure; it has also been a consistent outcome measure in clinical trials involving acute gouty arthritis, though the instruments and time intervals used to measure pain vary (Grainger 2009). The other proposed OMERACT outcome measures include joint swelling and tenderness, patient global assessment and safety (Grainger 2009; Schumacher 2005).
- Benefit: pain
- Safety: study participant withdrawal due to adverse events (AEs)
- Reduction of inflammation (joint swelling, erythema, tenderness)
- Function of target joint
- Patient global assessment of treatment success
- Health-related quality of life (HRQoL)
- Proportion of participants with serious adverse events (SAEs)
We considered inclusion of all end points as measured in the trials for inclusion and considered combining data into short (up to two weeks), medium (two to six weeks) and long (> six weeks) term outcomes depending on the feasibility of doing so from the available data.
Search methods for identification of studies
We searched the following databases for RCTs and CCTs using the search strategies detailed in the appendices:
- Ovid MEDLINE (1948 to 16 October 2012) (Appendix 1),
- Ovid EMBASE (1980 to 16 October 2012) (Appendix 2),
- Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Library (on 16 October 2012) (Appendix 3).
No language restrictions were applied.
Searching other resources
Abstracts from the two major international rheumatology scientific meetings, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), were searched (for the years 2010 and 2011). The reference lists of articles considered for inclusion were inspected for additional trials, as was the trial registry clinicaltrials.gov for ongoing trials.
Data collection and analysis
Selection of studies
All identified studies were assessed independently by two review authors (MW, OV) to identify trials that fulfilled the inclusion criteria. All possibly relevant articles were retrieved in full text and any disagreement in study selection was resolved by consensus or by discussion with a third review author (RB) if needed. We planned to translate studies into English, where necessary.
Data extraction and management
Two independent review authors (MW and OV) planned to extract relevant information from the trials considered for inclusion, including study design, characteristics of study population, treatment regimen and duration, outcomes and timing of outcome assessment using pre-determined forms. The raw data (means and standard deviations for continuous outcomes and number of events or participants for dichotomous outcomes) were planned to be extracted for outcomes of interest. Differences in data extraction were planned to be resolved by referring back to the original articles and establishing consensus. A third review author (RB) was to be consulted, if necessary, to help resolve differences.
Assessment of risk of bias in included studies
The potential for bias in included studies would have been assessed using a 'Risk of bias' table. Two review authors (MW, OV) would have independently assessed risk of bias for all included studies for the following items: random sequence generation, allocation concealment, blinding of participants and care provider and outcome assessor for each outcome measure (see Types of outcome measures), incomplete outcome data and other biases, conforming to the methods recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). To determine the risk of bias of a study, for each criterion, the presence of sufficient information and the likelihood of potential bias would have been evaluated. Each criterion would have been rated 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). Disagreements among the review authors would have been discussed and resolved in a consensus meeting. If consensus could not be reached, a third review author (RB) would have made the final decision.
Measures of treatment effect
For continuous data, results would have been analysed as mean differences (MDs) between the intervention and comparator group, with corresponding 95% confidence intervals (95% CI). The MD between the treated group and control group would have been weighted by the inverse of the variance in the pooled treatment estimate. When different scales were used to measure the same conceptual outcome (for example functional status or pain), standardised mean differences (SMDs) would have been calculated instead, with corresponding 95% CIs. SMDs would have been calculated by dividing the MD by the standard deviation, resulting in a unitless measure of treatment effect. For dichotomous data, a risk ratio (RR) with corresponding 95% CI would have been calculated.
For studies containing more than two intervention groups, making multiple pair-wise comparisons between all pairs of intervention groups possible, we would have included the same group of participants only once in the meta-analysis.
Unit of analysis issues
Unit of analysis problems were not expected in this review. In the event that cross-over trials had been identified in which the reporting of continuous outcome data precluded paired analysis, these data would not have been included in a meta-analysis in order to avoid unit of analysis error. Where carry-over effects were thought to have existed, and where sufficient data existed, only data from the first period would have been included in the analysis (Higgins 2011b). We would have extracted data from all time points and combined them into short term (up to two weeks), medium term (> two to six weeks) and long term (> six weeks) outcomes, though this would have depended on the feasibility of doing so from the available data. If more than one time point had been reported within the subgroup (for example at one-week and two-week follow-up), we would have extract the later time point (that is two weeks) only.
Dealing with missing data
Where data were missing or incomplete, further information would have been sought from the study authors. In cases where individuals were missing from the reported results and no further information was forthcoming from the study authors, we would have assumed the missing values to have a poor outcome.
For dichotomous outcomes that measured AEs (for example number of withdrawals due to AEs), the withdrawal rate would have been calculated using the number of patients that received treatment as the denominator (worst case analysis). For dichotomous outcomes that measured benefits, the worst case analysis would have been calculated using the number of randomised participants as the denominator.
For continuous outcomes (for example pain), we would have calculated the MD or SMD based on the number of patients analysed at the time point. If the number of patients analysed had not been presented for each time point, the number of randomised patients in each group at baseline would have been used.
Where possible, missing standard deviations would have been computed from other statistics such as standard errors, CIs or P values, according to the methods recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011c). If calculation of standard deviations was not possible, they would have been imputed (for example from other studies in the meta-analysis) (Higgins 2011b).
Assessment of heterogeneity
Prior to meta-analysis, we would have assessed studies for clinical homogeneity with respect to type of therapy, control group and the outcomes. For any studies judged as clinically homogeneous, statistical heterogeneity would have been assessed using the I
Assessment of reporting biases
In order to determine whether reporting bias was present, we would have determined whether the protocol of the RCT was published before recruitment of patients into the study was started. For studies published after 1 July 2005, we would have screened the Clinical Trial Register at the International Clinical Trials Registry Platform of the World Health Organization (apps.who.int/trialssearch; DeAngelis 2004).
We would have evaluated whether selective reporting of outcomes was present (outcome reporting bias). We would have compared the fixed-effect model estimate against the random-effects model to assess the possible presence of small sample bias in the published literature (that is the intervention effect is more beneficial in smaller studies). In the presence of small sample bias, the random-effects model estimate of the intervention would have been more beneficial than the fixed-effect model estimate (Sterne 2011).
The potential for reporting bias would have been further explored by funnel plots if more than 10 studies were available.
Where studies were sufficiently homogeneous, so that it remained clinically meaningful for them to be pooled, meta-analysis would have been performed using a random-effects model regardless of the I
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
- number of joints involved (monoarticular versus polyarticular acute gout);
- type of glucocorticoid used (soluble versus insoluble), as the insoluble preparations are longer acting and hence potentially more effective;
- presence or absence of other concomitant arthritis (e.g. osteoarthritis, rheumatoid arthritis), as these may possibly affect baseline and post-therapy pain scores.
We would have liked to present, for the main benefit outcome, the above subgroups within each trial (for example monoarticular versus polyarticular gout) and informally compare the magnitudes of effect to assess possible differences in response to treatment between the subgroups. However, we anticipated that the outcomes may not be reported by subgroups within the trials, which would preclude the planned analyses.
Where sufficient studies existed, sensitivity analyses were planned to assess the impact of any bias attributable to inadequate or unclear treatment allocation (including studies with quasi-randomised designs) or lack of blinding.
Presentation of key results
A 'Summary of findings' table would have been produced using GRADEpro software. Summary of findings tables provide key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcomes. They are recommended by The Cochrane Collaboration (Schünemann 2011a) and include 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, for dichotomous outcomes the number needed to treat to benefit (NNTB) or the number needed to treat to harm (NNTH) would have been calculated from the control group event rate (unless the population event rate was known) and the risk ratio (RR) using the Visual Rx NNT calculator (Cates 2008).
For continuous outcomes, the NNTB or NNTH would have been calculated using the Wells calculator software available at the Cochrane Musculoskeletal Group (CMSG) editorial office. The minimal clinically important difference (MCID) for each outcome would have been determined for input into the calculator.
For the 'Summary of findings' table, the outcomes included would have been:
- study participant withdrawal due to adverse events,
- reduction of inflammation (joint swelling, erythema, tenderness),
- function of target joint,
- patient global assessment of treatment success,
- quality of life,
- proportion of participants with serious adverse events.
Description of studies
Results of the search
The search strategy yielded 182 references (see Figure 1). After excluding 32 duplicate references, 101 references that were not RCTs or CCTs, 28 non-acute gout-related references and 19 articles that used other forms of glucocorticoids, two studies (Fernandez 1999; Komatsu 1969) were retrieved for full assessment.
|Figure 1. Study flow diagram.|
No studies were found that met our inclusion criteria.
Risk of bias in included studies
No studies were found that met our inclusion criteria.
Effects of interventions
No studies were found that met our inclusion criteria.
Summary of main results
Despite their perceived effectiveness (Richette 2010) and endorsement by various guidelines and literature reviews (Hamburger 2011; Jordan 2007; Khanna 2012; Zhang 2006), there are no published RCTs or CCTs that have assessed the efficacy and safety of intra-articular glucocorticoid therapy versus placebo in people with acute gout. There were also no trials that compared the effects of intra-articular glucocorticoid therapy to other active interventions.
Overall completeness and applicability of evidence
We identified two studies (one an open single arm trial, the other a case series) related to the use of local glucocorticoids in acute gout. The first (Fernandez 1999) involved 19 patients all of whom received a single dose of intra-articular triamcinolone acetonide (10 mg in the knee or 8 mg in small joints). This resulted in a reduction in pain, from 88 (range 82 to 93) on a 0 to 100 mm visual analogue scale (VAS) at baseline to 0 (range 0 to 21) at 48 hours; the treatment was safe and free of side effects with no rebound attacks or need for additional therapy. The second study (Komatsu 1969) involved 10 people with gout (full details of this Japanese study are awaiting translation); they were treated with 10 mg of triamcinolone acetonide infiltrated into the most painful part of the periarticular soft tissue and had complete resolution of symptoms.
In the absence of RCTs of intra-articular glucocorticoid injection for the treatment of people with acute gout, findings from systematic reviews and randomised controlled trials of intra-articular glucocorticoid injection for other acutely inflamed joints might also be informative. Intra-articular glucocorticoid therapy has previously been shown to be effective for the treatment of knee osteoarthritis in the short term in RCTs (Dieppe 1980; Friedman 1980; Godwin 2004) and in a Cochrane systematic review (Bellamy 2006), particularly in the presence of chondrocalcinosis (Bellamy 2006; Dieppe 1980). Another Cochrane review investigated intra-articular glucocorticoids for rheumatoid arthritis and included five RCTs of intra-articular glucocorticoids versus placebo (Wallen 2006). Pain relief was evident on day one and improvement in joint function and swelling continued over the ensuing weeks, with a suggestion that this might be dose-related.
These Cochrane reviews (Bellamy 2006; Wallen 2006) also addressed safety. No adverse events were reported in the trials of intra-articular glucocorticoids for rheumatoid arthritis (Wallen 2006) while very few adverse events were reported in the trials included in the osteoarthritis Cochrane review (Bellamy 2006). Potential adverse events of intra-articular glucocorticoid therapy include local effects such as post-injection flare, glucocorticoid crystal-induced synovitis, tissue atrophy, sepsis, avascular necrosis, haematoma and fat necrosis; systemic effects include hot flush, fluid retention, hyperglycaemia and hypertension. Risk of infection is minimised by adherence to an appropriate sterile technique.
In the context of acute gout, systemic (oral and intramuscular) glucocorticoids have been the subject of a Cochrane systematic review (Janssens 2008a) and a subsequent randomised placebo-controlled trial (Janssens 2008b). The Cochrane review included three very low to moderate quality trials and was unable to draw conclusions about the efficacy of systemic glucocorticoids, although no adverse events were reported (Janssens 2008a). The RCT included 120 participants randomised to receive either oral prednisolone or naproxen and found no difference in benefit or adverse events (abdominal pain, itching or dizziness, dyspnoea, palpitations or other) between the two treatments (Janssens 2008b).
Potential biases in the review process
We are confident that the broad literature search used in this review has captured relevant literature and minimised the likelihood that we missed any relevant trials.
Agreements and disagreements with other studies or reviews
Recommendations for the management of gout have been published by the European League Against Rheumatism (EULAR) in 2006 (Zhang 2006) and by Hamburger et al in 2011 (Hamburger 2011). While both acknowledged a paucity of evidence, both noted that intra-articular glucocorticoid therapy may be useful for an acute attack of gout (Hamburger 2011; Zhang 2006) and may have particular relevance in a severe, acute monoarticular attack in those in whom NSAIDs and colchicine were contraindicated (Zhang 2006). Very recent (Khanna 2012) guidelines by the American College of Rheumatology (ACR) recommended the option of using intra-articular glucocorticoids for acute gout involving one or two large joints, with the dosing based on the size of the involved joint, and that this therapy could be used in combination with oral corticosteroids, NSAIDs or colchicine. The basis for these guidelines was the previously quoted open-label single arm study (Fernandez 1999).
In addition, where joint sepsis is a concern, joint aspiration for confirmation of diagnosis and exclusion of infection is critical.
Implications for practice
There is a presently a lack of evidence from RCTs and CCTs to establish the efficacy and safety of intra-articular glucocorticoid therapy for the treatment of people with acute gout. However, extrapolated evidence from data on its use in osteoarthritis and rheumatoid arthritis and from the effectiveness of systemic glucocorticoids in acute gout suggest that it may be a useful alternative treatment for those in whom NSAIDs or colchicine are contraindicated.
Implications for research
Randomised placebo-controlled trials and trials comparing intra-articular glucocorticoids to treatments of known benefit are needed before definitive conclusions can be drawn about the role of intra-articular glucocorticoids in people with acute gout.
Planned trials might include participants with comorbidities that influence the pharmacotherapy choice for acute gout treatment (for example renal impairment, cardiovascular disease) and assess outcomes recommended by OMERACT for studies of acute gout (Grainger 2009; Schumacher 2005), including reduction in joint swelling and tenderness, patient global assessment and safety. The CONSORT statement (Moher 2012) should be used as a guide for both designing and reporting trials.
Trial reporting should include the method of randomisation and treatment allocation concealment; blinding of study participants, study personnel and outcome assessment; follow-up of all participants who entered the trial; and complete reporting of outcomes. Sample sizes should be reported and have adequate power to answer the research question; and ideally trials should assess both the benefits and risks of intra-articular glucocorticoids for acute gout. To enable comparison and pooling of the results of RCTs, we suggest that future trials report means with standard deviations for continuous measures, or number of events and total numbers analysed for dichotomous measures, and use standardised measurement tools for reporting relevant outcomes.
The authors thank Louise Falzon, former Trials Search Coordinator of the Cochrane Musculoskeletal Group, for assisting with the design of the search strategy.
Data and analyses
This review has no analyses.
Appendix 1. MEDLINE search strategy
1. exp gout/
3. Acute Disease/
5. 1 or 2
6. 3 or 4
7. 5 and 6
8. exp Glucocorticoids/
9. Adrenocorticotropic Hormone/
10. exp Adrenal Cortex Hormones/
28. 7 and 27
29. randomized controlled trial.pt.
30. controlled clinical trial.pt.
33. drug therapy.fs.
38. (animals not (humans and animals)).sh.
39. 37 not 38
40. 28 and 39
Appendix 2. EMBASE search strategy
1. exp gout/
3. acute disease/
5. 1 or 2
6. 3 or 4
7. 5 and 6
8. exp glucocorticoid/
9. exp corticotropin/
10. exp corticosteroid/
13. triamcinolone acetate/ or triamcinolone hexacetonide/ or triamcinolone/ or triamcinolone diacetate/ or triamcinolone acetonide/
29. 7 and 28
30. (random$ or placebo$).ti,ab.
31. ((single$ or double$ or triple$ or treble$) and (blind$ or mask$)).ti,ab.
32. controlled clinical trial$.ti,ab.
33. RETRACTED ARTICLE/
35. (animal$ not human$).sh,hw.
36. 34 not 35
37. 29 and 36
Appendix 3. CENTRAL search strategy
#1 MeSH descriptor Gout explode all trees
#3 MeSH descriptor Acute Disease, this term only
#5 (#1 OR #2)
#6 (#3 OR #4)
#7 (#5 AND #6)
#8 MeSH descriptor Glucocorticoids explode all trees
#9 MeSH descriptor Adrenocorticotropic Hormone explode all trees
#10 MeSH descriptor Adrenal Cortex Hormones explode all trees
#11 (glucocortic* or prednison* or betamet?asone or triamcinolone or cortison* beclomet?asone or hydrocort* or paramet?asone or dexamet?asone or fluocortolone or corticotropin or budesonide or desonide or fluprednidene or fluocinomide or methylpred*):ti,ab,kw
#12 (#8 OR #9 OR #10 OR #11)
#13 (#7 AND #12)
Last assessed as up-to-date: 16 October 2012.
Contributions of authors
MW wrote the current version of the review. RB, OV and NS provided comments and suggestions on draft versions of the protocol, and all authors approved the final version.
Declarations of interest
Sources of support
- Flinders University, Australia.In kind support
- University of Toronto, Canada.In kind support
- University of Medicine & Dentistry of New Jersey/ Robert Wood Johnson Medical School, USA.In kind support
- Cabrini Hospital, Australia.In kind support
- Monash University, Australia.In kind support
- No sources of support supplied
Medical Subject Headings (MeSH)
MeSH check words