Abstract
Introduction
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of treatments to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2008 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, corticotrophin (ACTH), non-steroidal anti-inflammatory drugs (NSAIDs), sulfinpyrazone, xanthine oxidase inhibitors, advice to lose weight, advice to reduce alcohol intake, advice to reduce dietary intake of purines.
Key Points
Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi) in the skin.
Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Diagnosis is usually clinical, supported by signs of hyperuricaemia.
Risk factors are those associated with increased serum urate concentrations, including: older age; non-white ethnicity; obesity; consumption of alcohol, meat, and fish; and use of diuretics.
Hyperuricaemia may be associated with an increased risk of cardiovascular events; we don't know whether it is an independent risk factor.
We don't know whether NSAIDs reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects.
Indometacin is widely used to treat acute gout despite the absence of RCT evidence of benefit. Etoricoxib is as effective as indometacin with reduced risks of gastrointestinal adverse effects.
Although it has been widely used for many years, we don't know whether oral colchicine improves symptoms in acute gout. Its use is limited by the high incidence of adverse effects.
We don't know whether intra-articular, parenteral or oral corticosteroids, or corticotropin (ACTH), improve symptoms in acute gout.
We don't know whether colchicine prevents attacks of gout in people with prior episodes, but it may reduce the risk of an attack in a person starting allopurinol treatment.
We don't know whether advice to lose weight or reduce alcohol or dietary purine intake prevents further attacks of gout.
We don't know whether allopurinol or febuxostat, orsulfinpyrazone reduce the risk of recurrent attacks compared with placebo or other treatments.
About this condition
Definition
Gout is a syndrome caused by deposition of urate crystals. It typically presents as an acute monoarthritis of rapid onset. The first metatarsophalangeal joint is the most commonly affected joint (podagra). Gout also affects other joints; joints in the foot, ankle, knee, wrist, finger, and elbow are the most frequently affected. Crystal deposits (tophi) may develop around hands, feet, elbows, and ears. Diagnosis: This is usually made clinically. The American College of Rheumatology (ACR) criteria for diagnosing gout are as follows: (1) characteristic urate crystals in joint fluid; (2) a tophus proved to contain urate crystals; or (3) the presence of six or more defined clinical laboratory and x ray phenomena (see table 1 ). We have included studies of people meeting the ACR criteria, studies in which the diagnosis was made clinically, and studies that used other criteria.
Table 1.
American College of Rheumatology criteria for acute gout (people must fulfill at least 6 criteria).
| 1 | More than 1 attack of acute arthritis |
| 2 | Maximum inflammation developed within 1 day |
| 3 | Monoarthritis attack |
| 4 | Redness observed over joints |
| 5 | First metatarsophalangeal joint painful or swollen |
| 6 | Unilateral first metatarsophalangeal joint attack |
| 7 | Unilateral tarsal joint attack |
| 8 | Tophus (proved or suspected) |
| 9 | Hyperuricaemia |
| 10 | Asymmetric swelling within a joint on x ray film |
| 11 | Subcortical cysts without erosions on x ray film |
| 12 | Joint culture negative for organism during attack |
Incidence/ Prevalence
Gout is more common in older people and men. In people aged 65-74 years in the UK, the prevalence is about 50/1000 in men and about 9/1000 in women. The annual incidence of gout in people aged over 50 years in the USA is 1.6/1000 in men and 0.3/1000 in women. One 12-year longitudinal study of 47,150 male health professionals with no previous history of gout estimated that annual incidence of gout ranged from 1.0/1000 for those aged 40-44 years to 1.8/1000 for those aged 55-64 years. Gout may become more common because of increasing longevity, obesity, meat and fish consumption, and use of diuretics. Gout may be more common in some non-white ethnic groups. A pooled analysis of two cohort studies of former medical students found the annual incidence of gout to be 3.1/1000 in black men and 1.8/1000 in white men. After correcting for the higher prevalence of hypertension among black men, which is a risk factor for gout, the relative risk of gout in black men compared with white men was 1.30 (95% CI 0.77 to 2.19). A cross-sectional survey of 657 people aged 15 years and over in New Zealand found a higher prevalence of gout in Maoris than in people of a European background (6.4% in Maoris v 2.9% in people with European background; age-adjusted RR 3.2, 95% CI 1.6 to 6.6).
Aetiology/ Risk factors
Urate crystals form when serum urate concentration exceeds 0.42 mmol/L. Serum urate concentration is the principal risk factor for a first attack of gout, although 40% of people have normal serum urate concentration during an attack of gout. A cohort study of 2046 men followed up for about 15 years found that the annual incidence was about 0.4% in men with a urate concentration of 0.42-0.47 mmol/L, rising to 4.3% when serum urate concentration was 0.45-0.59 mmol/L. One 5-year longitudinal study of 223 asymptomatic men with hyperuricaemia estimated the 5-year cumulative incidence of gout to be 10.8% for those with baseline serum urate of 0.42-0.47 mmol/L, 27.7% for baseline urate of 0.48-0.53 mmol/L, and 61.1% for baseline urate levels of 0.54 mmol/L or more. The study found that a 0.6 mmol/L difference in baseline serum urate increased the odds of an attack of gout by a factor of 1.8 (OR adjusted for other risk factors for gout: 1.84, 95% CI 1.24 to 2.72). One 12-year longitudinal study (47,150 male health professionals with no history of gout) estimated that the relative risks of gout associated with one additional daily serving of various foods (weekly for seafood) were as follows: meat 1.21 (95% CI 1.04 to 1.41), seafood (fish, lobster, and shellfish) 1.07 (95% CI 1.01 to 1.12), purine-rich vegetables 0.97 (95% CI 0.79 to 1.19), low-fat dairy products 0.79 (95% CI 0.71 to 0.87), and high-fat dairy products 0.99 (95% CI 0.89 to 1.10). Alcohol consumption of greater than 14.9 g daily significantly increased the risk of gout compared with no alcohol consumption (RR for 15.0-29.9 g/day: 1.49, 95% CI 1.14 to 1.94; RR for 30.0-49.9 g/day: 1.96, 95% CI 1.48 to 2.60; RR for at least 50 g/day: 2.53, 95% CI 1.73 to 3.70). The longitudinal study also estimated the relative risk of gout associated with an additional serving of beer (355 mL, 12.8 g alcohol), wine (118 mL, 11.0 g alcohol), and spirits (44 mL, 14.0 g alcohol). It found that an extra daily serving of beer or spirits was significantly associated with gout, but an extra daily serving of wine was not (RR for 355 mL/day beer: 1.49, 95% CI 1.32 to 1.70; RR for 44 mL/day spirits: 1.15, 95% CI 1.04 to 1.28; RR for 118 mL/day wine: 1.04, 95% CI 0.88 to 1.22). Other suggested risk factors for gout include obesity, insulin resistance, dyslipidaemia, hypertension, dietary fructose intake and cardiovascular disorders.
Prognosis
We found few reliable data about prognosis or complications of gout. One study found that 3/11 (27%) people with untreated gout of the first metatarsophalangeal joint had spontaneous resolution after 7 days. A case series of 614 people with gout who had not received treatment to reduce urate levels, and who could recall the interval between first and second attacks, reported recurrence rates of 62% after 1 year, 78% after 2 years, and 84% after 3 years. An analysis of two prospective cohort studies of 371 black and 1181 white male former medical students followed up for about 30 years found no significant difference in risk of CHD in men who had developed gout compared with men who had not (RR 0.85, 95% CI 0.40 to 1.81).
Aims of intervention
For treating gout: to reduce the severity and duration of pain and loss of function, with minimal adverse effects of treatment. For preventing recurrence: to reduce the frequency and severity of recurrent attacks, and minimise the adverse effects of interventions.
Outcomes
For treating gout: severity of symptoms (pain scores, proportion of people with improved symptoms), adverse effects of treatment. For preventing recurrence (over 6 months): number of recurrent episodes a year, severity of recurrent episodes a year, adverse effects of treatment.
Methods
Clinical Evidence search and appraisal June 2008. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2008, Embase 1980 to May 2008, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2008, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded and containing more than 20 people of whom more than 80% were followed up. For question 1 on treatment of acute gout there was no minimum length of follow-up required to include studies. For question 2 on prevention of recurrent gout the minimum length of follow-up is 6 months or longer, except for xanthine oxidase inhibitors plus prophylactic drugs where the minimum length of follow-up is 3 months. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as RRs and ORs. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
Table.
GRADE evaluation of interventions for gout
| Important outcomes | Symptom severity, recurrence of gout, adverse effects | ||||||||
| Number of studies (participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for acute gout? | |||||||||
| 1 (43) | Symptom severity | Colchicine v placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for narrow inclusion criteria |
| 1 (90) | Symptom severity | Corticosteroids v NSAIDS | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data. Consistency point deducted for different results at different end points |
| 1 (31) | Symptom severity | Corticosteroids v corticotropin | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for sparse data. Directness point deducted for only assessing one corticosteroid |
| 1 (30) | Symptom severity | NSAIDs v placebo | 4 | –2 | –1 | –1 | +1 | Very low | Quality points deducted for sparse data and statistical flaws. Consistency point deducted for conflicting results at different end points. Directness point deducted for assessing only one drug. Effect-size point added for RR greater than 2 |
| 6 (548) | Symptom severity | NSAIDs v each other | 4 | 0 | 0 | –1 | 0 | Moderate | Directness point deducted for assessment of only some NSAIDs |
| What are the effects of treatments to prevent gout in people with prior acute episodes? | |||||||||
| 1 RCT | Recurrence of gout | Sulfinpyrazone plus colchicine v colchicine plus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and incomplete reporting of results |
| 1 (760) | Recurrence of gout | Xanthine oxidase inhibitors v each other | 4 | 0 | –1 | 0 | 0 | Moderate | Consistency point deducted for conflicting results at different end points and with different doses |
| 1 (43) | Recurrence of gout | Xanthine oxidase inhibitors alone v xanthine oxidase inhibitors plus prophylactic drugs | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and for uncertainty about basis of statistical analysis |
Type of evidence: 4 = RCT; 2 = Observational; Consistency: similarity of results across studies. Directness: generalisability of population or outcomes.Effect size: based on relative risk or odds ratio.
Glossary
- Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
- Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
- Very low-quality evidence
Any estimate of effect is very uncertain.
Disclaimer
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
References
- 1.Emmerson BT. The management of gout. N Engl J Med 1996;334:445–451. [DOI] [PubMed] [Google Scholar]
- 2.Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 1977;20:895–900. [DOI] [PubMed] [Google Scholar]
- 3.Kim KY, Schumacher HR, Hunsche E, et al. A literature review of the epidemiology and treatment of acute gout. Clin Ther 2003;25:1593–1616. [DOI] [PubMed] [Google Scholar]
- 4.Harris CM, Lloyd DC, Lewis J. The prevalence and prophylaxis of gout in England. J Clin Epidemiol 1995;48:1153–1158. [DOI] [PubMed] [Google Scholar]
- 5.Abbott RD, Brand FN, Kannel WB, et al. Gout and coronary heart disease: the Framingham Study. J Clin Epidemiol 1988;41:237–242. [DOI] [PubMed] [Google Scholar]
- 6.Choi HK, Atkinson K, Karlson EW, et al. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med 2004;350:1093–1103. [DOI] [PubMed] [Google Scholar]
- 7.Bieber JD, Terkeltaub RA. Gout: on the brink of novel therapeutic options for an ancient disease. Arthritis Rheum 2004;50:2400–2414. [DOI] [PubMed] [Google Scholar]
- 8.Hochberg MC, Thomas J, Thomas DJ, et al. Racial differences in the incidence of gout. The role of hypertension. Arthritis Rheum 1995;38:628–632. [DOI] [PubMed] [Google Scholar]
- 9.Klemp P, Stansfield SA, Castle B, et al. Gout is on the increase in New Zealand. Ann Rheum Dis 1997;56:22–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.McGill NW. Gout and other crystal-associated arthropathies. Baillieres Best Pract Res Clin Rheumatol 2000;14:445–460. [DOI] [PubMed] [Google Scholar]
- 11.Lin KC, Lin HY, Chou P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J Rheumatol 2000;27:1501–1505. [PubMed] [Google Scholar]
- 12.Schlesinger N, Baker DG, Schumacher HR Jr. Serum urate during bouts of acute gouty arthritis. J Rheumatol 1997;24:2265–2266. [PubMed] [Google Scholar]
- 13.Logan JA, Morrison E, McGill PE. Serum uric acid in acute gout. Ann Rheum Dis 1997;56:696–697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Stewart OJ, Silman AJ. Review of UK data on the rheumatic diseases –4. Gout. Br J Rheumatol 1990;29:485–488. [DOI] [PubMed] [Google Scholar]
- 15.Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med 1987;82:421–426. [DOI] [PubMed] [Google Scholar]
- 16.Choi HK, Atkinson K, Karlson EW, et al. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363:1277–1281. [DOI] [PubMed] [Google Scholar]
- 17.Culleton BF. Uric acid and cardiovascular disease: a renal-cardiac relationship? Curr Opin Nephrol Hypertens 2001;10:371–375. [DOI] [PubMed] [Google Scholar]
- 18.Bryan E. Are gout and increased uric acid levels risk factors for cardiac disease? Centre for Clinical Effectiveness, Monash University. 2002. Available online at: http://www.mihsr.monash.org/cce/res/pdf/b/805.pdf (last accessed 7 November 2008). [Google Scholar]
- 19.Choi HK, Curhan G, Choi HyonK, et al. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008;336:309–312. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Bellamy N, Downie WW, Buchanan WW. Observations on spontaneous improvement in patients with podagra: implications for therapeutic trials of non-steroidal anti-inflammatory drugs. Br J Clin Pharmacol 1987;24:33–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Yu TF, Gutman AB. Efficacy of colchicine prophylaxis in gout. Ann Intern Med 1961;55:179–192. [DOI] [PubMed] [Google Scholar]
- 22.Gelber AC, Klag MJ, Mead LA, et al. Gout and risk for subsequent coronary heart disease. The Meharry-Hopkins Study. Arch Intern Med 1997;157:1436–1440. [PubMed] [Google Scholar]
- 23.Schlesinger N, Schumacher R, Catton M, et al. Colchicine for acute gout. In: The Cochrane Library, Issue 2, 2008. Chichester, UK: John Wiley & Sons, Ltd. Search date 2006. 17054279 [Google Scholar]
- 24.Ahern MJ, Reid C, Gordon TP, et al. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med 1987;17:301–304. [DOI] [PubMed] [Google Scholar]
- 25.Schlesinger N, Schumacher HR Jr. Gout: can management be improved? Curr Opin Rheumatol 2001;13:240–244. [DOI] [PubMed] [Google Scholar]
- 26.Underwood M. Diagnosis and management of gout. BMJ 2006;332:1315–1319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Janssens HJ, Lucassen PL, Van de Laar FA, et al. Systemic corticosteroids for acute gout. In: The Cochrane Library, Issue 2, 2008. Chichester, UK: John Wiley & Sons, Ltd. Search date 2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Man CY, Cheung IT, Cameron PA, et al. Comparison of oral prednisolone/paracetamol and oral indomethacin/paracetamol combination therapy in the treatment of acute goutlike arthritis: a double-blind, randomized, controlled trial. Ann Emerg Med 2007;49:670–677. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Taylor CT, Brookes NC, Kelley KW. Corticotropin for acute management of gout. Ann Pharmacother 2001:35:365–368. [DOI] [PubMed] [Google Scholar]
- 30.Sutaria, S, Katbamna, R, Underwood M. Effectiveness of interventions for the treatment of acute and prevention of recurrent gout: a systematic review. Rheumatology 2006;45:1422–1431. Search date 2005; primary sources Medline, Pubmed, Cochrane Controlled Trials Register, ISI Web of Science, Embase, Amed, and hand searches of identified trials and reviews. [DOI] [PubMed] [Google Scholar]
- 31.Garcia de la Torre I. Double-blind parallel study comparing tenoxicam and placebo in acute gouty arthritis. Invet Med Int 1987;14:92–97. [In Spanish] [Google Scholar]
- 32.Rubin BR, Burton R, Navarra S, et al. Efficacy and safety profile of treatment with etoricoxib 120 mg once daily compared with indomethacin 50 mg three times daily in acute gout: a randomized controlled trial. Arthritis Rheum 2004;50:598–606. [DOI] [PubMed] [Google Scholar]
- 33.Schumacher HR Jr, Boice JA, Daikh DI, et al. Randomised double blind trial of etoricoxib and indometacin in treatment of acute gouty arthritis. BMJ 2002;324:1488–1492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Maccagno A, Di Giorgio E, Romanowicz A. Effectiveness of etodolac ("Lodine") compared with naproxen in patients with acute gout. Curr Med Res Opin 1991;12:423–429. [DOI] [PubMed] [Google Scholar]
- 35.Lederman R. A double-blind comparison of etodolac (Lodine) and high doses of naproxen in the treatment of acute gout. Adv Ther 1990;7:344–354. [Google Scholar]
- 36.Altman RD, Honig S, Levin JM, et al. Ketoprofen versus indomethacin in patients with acute gouty arthritis: a multicenter, double blind comparative study. J Rheumatol 1988;15:1422–1426. [PubMed] [Google Scholar]
- 37.Lomen PL, Turner LF, Lamborn KR, et al. Flurbiprofen in the treatment of acute gout. A comparison with indomethacin. Am J Med 1986;80:134–139. [DOI] [PubMed] [Google Scholar]
- 38.Fraser RC, Davis RH, Walker FS. Comparative trial of azapropazone and indomethacin plus allopurinol in acute gout and hyperuricaemia. J R Coll Gen Pract 1987;37:409–411. [PMC free article] [PubMed] [Google Scholar]
- 39.Non-steroidal anti-inflammatory drugs. In: Royal Pharmaceutical Society of Great Britain, eds. British National Formulary. Wallingford: Pharmaceutical Press, 2008:543–552. [Google Scholar]
- 40.Cheng TT, Lai HM, Chiu CK, et al. A single-blind, randomized, controlled trial to assess the efficacy and tolerability of rofecoxib, diclofenac sodium, and meloxicam in patients with acute gouty arthritis. Clin Ther 2004;26:399–406. [DOI] [PubMed] [Google Scholar]
- 41.Willburger RE, Mysler E, Derbot J, et al. Lumiracoxib 400 mg once daily is comparable to indomethacin 50 mg three times daily for the treatment of acute flares of gout. Rheumatology 2007;46:1126–1132. [DOI] [PubMed] [Google Scholar]
- 42.Anon. Gout in primary care. Drug Ther Bull 2004;42:37–40. [DOI] [PubMed] [Google Scholar]
- 43.National Institute for Clinical Excellence. Osteoarthritis. The care and management of osteoarthritis in adults. NICE Clinical Guideline CG 59. 2008. Available at http://www.nice.org.uk/CG59 (last accessed 7 November 2008). [Google Scholar]
- 44.Becker MA, Schumacher, HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 2005;353:2450–2461. [DOI] [PubMed] [Google Scholar]
- 45.Borstad GC, Bryant LR, Abel MP, et al. Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis. J Rheumatol 2004;31:2429–244. [PubMed] [Google Scholar]
- 46.Gibson T, Rodgers V, Potter C, et al. Allopurinol treatment and its effect on renal function in gout: a controlled study. Ann Rheum Dis 1982;41:59–65. [DOI] [PMC free article] [PubMed] [Google Scholar]