Clinical Topic A-Z Clinical Speciality

Gout

Gout
D006073Gout
Endocrine and metabolicMusculoskeletal
2012-08-01Last revised in August 2012

Gout - Summary

Gout is a disorder of purine metabolism characterized by a raised uric acid level in the blood (hyperuricaemia) and the deposition of urate crystals in joints and other tissues.

The natural history of gout can occur in three distinct phases:

A long period of asymptomatic hyperuricaemia.

A period during which acute attacks of gouty arthritis are followed by variable intervals (months to years) when there are no symptoms.

The final period of chronic tophaceous gout where people have nodules affecting joints.

Hyperuricaemia is the single most important risk factor for developing gout.

Gout is more common in men and in older people. Only 3–6% of people with gout have onset of the disease before 25 years of age.

Hyperuricaemia-induced renal disease is a possible complication of gout. Also, tophi may become inflamed, exude tophaceous material, or develop secondary infection.

First acute attacks of gout usually completely subside in 3–10 days. However, attacks may recur.

The diagnosis of gout is based on the clinical history and examination. There is no single examination which confirms a diagnosis of gout.

To manage an acute attack of gout:

A nonsteroidal anti-inflammatory drug (NSAID) e.g. diclofenac, should be prescribed as soon as possible and continued until 48 hours after the attack has resolved (a proton pump inhibitor or misoprostol can be co-prescribed for gastric protection, if necessary).

If NSAIDs are unsuitable, colchicine is an option.

If colchicine is unsuitable, systemic corticosteroids can be considered.

Paracetamol (with or without codeine) should be used if NSAIDs, colchicine, and corticosteroids are all unsuitable.

Appropriate self-care advice should be given (e.g. rest and keeping the joint in a cool environment by avoiding clothing and using an ice pack).

Appropriate life-style advice should be provided (e.g. weight loss and smoking cessation).

If there is no improvement in symptoms after 2–3 days:

The diagnosis should be reviewed.

Compliance with medications and self-care strategies should be checked.

Medication can be increased to the maximum dose.

To prevent an attack of gout:

Allopurinol should be prescribed — after two or more attacks of gout within a year or after the first attack in people at higher risk with one or more tophi, X-ray features of gouty arthritis, renal impairment, known uric acid stones, or on long-term diuretic medication.

Febuxostat can be considered as second-line therapy if allopurinol is not tolerated or contraindicated.

Co-prescription of a low dose of an NSAID or low-dose colchicine may prevent acute attacks of gout during urate lowering treatment with allopurinol or febuxostat.

Allopurinol or febuxostat should be started 1-2 weeks after the inflammation has settled, as the drug may precipitate further attacks.

Advice should be sought from a specialist if:

The diagnosis is uncertain.

Gout occurs during pregnancy or in a person under 25 years of age.

Complications are present.

The person is at risk of adverse effects of drug treatment.

Have I got the right topic?

192months3060monthsBoth

This CKS topic covers gouty arthritis and asymptomatic hyperuricaemia.

This CKS topic does not cover the management of other crystal-related arthropathies (e.g. pseudogout), gout in children, uric acid renal stones, urate nephropathy, or the prevention of hyperuricaemia in people who are being treated for haematological malignancies.

There are separate CKS topics on NSAIDs - prescribing issues, Osteoarthritis and Rheumatoid arthritis.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in August 2012

February 2014 — minor update to the prescribing information section for allopurinol.

July 2013 — minor update. The text has been updated to reflect recent guidance from the MRHA regarding diclofenac [MHRA, 2013].

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

January 2013 — minor update. Black triangle status removed from febuxostat, and advice from the Medicines and Healthcare products Regulatory Agency regarding hypersensitivity reactions of febuxostat has been inserted.

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

August 2012 — reviewed. A literature search was conducted in August 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made.

Previous changes

February 2012 — minor update. Updated to include the recommendation from the House of Commons Science and Technology Committee that people should have at least two alcohol-free days per week [House of Commons, 2011]. Issued in March 2012.

July 2011 — minor update. Updated adverse effects of febuxostat to include post marketing reports of skin rashes and hypersensitivity reactions highlighted in the updated Summary of Product Characteristics. Issued in September 2011.

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.

October 2010 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

June 2010 — updated to include the option of using febuxostat for the management of chronic gout for people who are intolerant of allopurinol, or for whom allopurinol is contraindicated. This is in line with National Institute for Health and Clinical Excellence technology appraisal guidance Febuxostat for the management of hyperuricaemia in people with gout [NICE, 2008a]. In addition, in people at risk of cardiovascular adverse events, ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line NSAIDs. Issued in July 2010.

December 2009 — minor update. Triamcinolone acetonide (Kenalog®) pre-filled syringes have been discontinued. Prescription replaced with triamcinolone acetonide 40 mg/1 mL vials. Issued in December 2009.

July to November 2007 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

The recommendations have been revised to be in-line with the British Society for Rheumatology and the British Health Professionals guidelines for the management of gout published in 2007. The dose and duration of recommended drug treatments have been updated to be in-line with current practice, in particular, for oral prednisolone.

November 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reminded prescribers that colchicine has a narrow therapeutic window and is extremely toxic in overdose [MHRA, 2009]. Issued in November 2009.

June 2009 — minor update. The intra-articular corticosteroid prescriptions have been updated. Issued in June 2009.

January 2009 — minor typographical correction. Issued in February 2009.

July 2005 — update to text discussing nonsteroidal anti-inflammatory drugs (NSAIDs) in the Prescribing information section. Issued in July 2005.

January 2005 — reviewed. Validated in March 2005 and issued in April 2005.

August 2001 — reviewed. Validated in November 2001 and issued in April 2002.

April 1999 — written. Validated in July 1999 and issued in August 1999.

Update

New evidence

Evidence-based guidelines

Guidelines published since the last revision of this topic:

Khanna, D., Fitzgerald, J.D., Khanna, P.P., et al. (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care & Research 64(10), 1431-1446.

Khanna, D., Khanna, P.P., Fitzgerald, J.D. et al. (2012) 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care & Research 64(10), 1447-1461.

Manara, M., Bortoluzzi, A., Favero, M., et al. (2013) Italian Society of Rheumatology recommendations for the management of gout. Reumatismo 65(1), 4-21. [Abstract]

HTAs (Health Technology Assessments)

Technology appraisals published since the last revision of this topic:

NICE (2013) Pegloticase for treating severe debilitating chronic tophaceous gout. NICE technology appraisal 291. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Economic appraisals

No new economic appraisals relevant to England since 1 August 2012.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Khanna, P.P., Gladue, H.S., Singh, M.K., et al. (2014) Treatment of acute gout: a systematic review. Seminars in Arthritis and Rheumatism epub ahead of print. [Abstract]

Li, X.X., Han, M., Wang, Y.T., and Liu, J.P. (2013) Chinese herbal medicine for gout: a systematic review of randomized clinical trials. Clinical Rheumatology 32(7), 943-959. [Abstract]

Moi, J.H.Y., Sriranganathan, M.K., Edwards, C.J., and Buchbinder, R. (2013) Lifestyle interventions for chronic gout (Cochrane Review). The Cochrane Library. Issue 5. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Moi, J.H.Y., Sriranganathan, M.K., Edwards, C.J., and Buchbinder, R. (2013) Lifestyle interventions for acute gout (Cochrane Review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Tayar, J.J., Lopez-Olivo, M.A., and Suarez-Almazor, M.E. (2012) Febuxostat for treating chronic gout (Cochrane review). The Cochrane Library. Issue 11. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Wang, M., Jiang, C., Wu, W. and Zhang, D. (2013) A meta-analysis of alcohol consumption and the risk of gout. Clinical Rheumatology 32(11), 1641-1648. [Abstract]

Wechalekar, M.D., Vinik, O., Schlesinger, and Buchbinder, R. (2013) Intra-articular glucocortoids for acute gout (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Ye, P., Yang, S., Zhang, W., et al. (2013) Efficacy and tolerability of febuxostat in hyperuricemic patients with or without gout: a systematic review and meta-analysis. Clinical Therapeutics 35(2), 180-189. [Abstract]

Primary evidence

No new randomized controlled trials published in the major journals since 1 August 2012.

New policies

No new national policies or guidelines since 1 August 2012.

New safety alerts

No new safety alerts since 1 August 2012.

Changes in product availability

No changes in product availability since 1 August 2012.

Goals and outcome measures

Goals

To enable the person to understand the nature of gout, and the risks and benefits of the various drug and dietary treatment options

To relieve the pain and inflammation of an acute attack of gout promptly

To reduce the risk of recurrent attacks of gout — if not outweighed by the risks of treatment

To minimize the risks of developing new tophi, and to resolve existing tophi

To minimize the risks of developing complications of gout, such as joint damage, renal stones, and urate nephropathy

To identify and modify risk factors for gout that may have other adverse effects on the person's health

Outcome measures

The British Society of Rheumatology recommend assessing the impact of the following for audit purposes:

The frequency and duration of gout flares

The achievement of target reduction in plasma urate levels

Lifestyle modification (weight reduction, alcohol intake, and dietary adjustment)

The assessment and treatment of comorbid disorders (diabetes mellitus, hypertension, cardiovascular risk factors)

The time to accurate diagnosis and treatment of gout in primary care

QIPP - options for local implementation

QIPP - options for local implementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).

If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008b].

Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008b; NICE, 2009a; NICE, 2009b].

Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.

[NICE, 2013]

Background information

Definition

What is it?

Gout is a disorder of purine metabolism characterized by a raised uric acid level in the blood (hyperuricaemia) and the deposition of urate crystals in joints and other tissues, such as soft connective tissues or the urinary tract.

Gouty arthritis is arthritis due to urate crystals in joints.

The natural history of gout can occur in three distinct phases:

A long period of asymptomatic hyperuricaemia before gout manifests.

A period during which acute attacks of gouty arthritis are followed by variable intervals (months to years) when there are no symptoms, so-called 'interval gout', or 'intercritical gout'.

The final period of chronic tophaceous gout, where people have nodules affecting joints.

Gout may present without hyperuricaemia, and hyperuricaemia may occur without gout.

[Roddy and Doherty, 2010]

Causes and risk factors

What are the causes and risk factors for gout?

Uric acid is the end-product of the breakdown of purines (adenine and guanine), and exists as sodium urate in extracellular fluid.

Two-thirds of urate is excreted by the kidneys and a third by the gastrointestinal tract.

Hyperuricaemia is the single most important risk factor for developing gout (see Table 1) [Jordan et al, 2007; DTB, 2010].

The duration and magnitude of hyperuricaemia is directly correlated with the likelihood of subsequent development of gouty arthritis, uric acid kidney stones, and age of onset of initial clinical gouty manifestations. However, gout can occur in people with normal plasma urate levels and many people with hyperuricaemia never develop gout.

Hyperuricaemia is usually due to impaired renal excretion of urate. About 90% of people with hyperuricaemia are under-excretors of urate, about 10% are over-producers of urate, and some people are both under-excretors and over-producers of urate [DynaMed, 2007].

In many people with hyperuricaemia, the cause is multifactorial — suggested risk factors include cardiovascular disease, renal disease, diabetes mellitus, obesity, metabolic syndrome, dyslipidaemia, severe psoriasis, alcoholism, lead toxicity, and use of certain drugs (for example diuretics) [Underwood, 2006b; Singh et al, 2011].

Gout tends to attack joints in the extremities because temperatures in the feet and hands can be low enough to precipitate urate from plasma. Thus tophi typically form in the helix of the ear, finger tips, olecranon bursae, and other cool anatomical sites.

Table 1 . Five-year cumulative incidence of gout categorized by plasma urate level or serum uric acid level (SUA).
Plasma urate level (micromol/L) 5-year cumulative incidence of gout (per 1000)
< 420 5
420–470 20
480–530 41
540–590 198
>= 600 305
Note: plasma urate level is interchangeable with serum uric acid level (SUA). Data from: [Campion et al, 1987]

[Cohen and Emmerson, 1998; Rott and Agudelo, 2003; Terkeltaub, 2003; Choi et al, 2005b; DynaMed, 2007]

Prevalence

How common is it?

Gout is more common in men (30–60 years of age) and in older people. Only 3–6% of people with gout have onset of the disease before 25 years of age [Kim et al, 2003].

A study of UK general practice found that [Mikuls et al, 2005]:

The prevalence of gout in people registered in the General Practice Research Database (GPRD) was 1.4%.

The overall ratio of men to women was 3.6:1.

The annual incidence of gout ranged from 1.19–1.80 cases per 1000 person-years.

One 12-year longitudinal study of 47,150 male health professionals in the US estimated that annual incidence of gout ranged from 1.0/1000 for those 40–44 years of age, to 1.8/1000 for those 55–64 years of age [Choi et al, 2004b].

Gout may be more common in some non-white ethnic groups [Kim et al, 2003]:

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.

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 versus 2.9% in Europeans; age adjusted RR 3.2, 95% CI 1.6 to 6.6).

Complications and prognosis

Complications

Tophi may create problems with activities of daily living (preparing food, dressing), become inflamed, exude tophaceous material [Schumacher et al, 2009], or develop secondary infection.

Hyperuricaemia-induced renal disease may occur, such as acute and chronic urate nephropathy. Urinary stones are found in 10–25% of people with gout, the incidence being strongly correlated with plasma urate level; in people with levels higher than 780 micromol/L, the incidence increases by up to 50% [DynaMed, 2007].

Prognosis

First acute attacks usually completely subside in 3–10 days [Underwood, 2006b].

Attacks have been reported to recur in 62% of people within a year — recurrent acute episodes and the development of chronic gout lead to progressive joint damage, pain, and disability [DynaMed, 2007].

Serum uric acid levels greater than 360 micromol/L are associated with increased risk for recurrent gout attacks [Li-Yu et al, 2001].

Diagnosis

Diagnosis of gout

Diagnosis

How do I know my patient has it?

The diagnosis of gout is based on the clinical history and examination.

Investigations are of limited use initially because serum uric acid level can be normal during an acute attack, especially if the person is taking urate-lowering drugs, high-dose aspirin, or corticosteroids.

Specific diagnostic criteria are not generally used in UK primary care.

History

What history should I take?

Ask about:

Previous attacks:

Which joints are (and have been) involved? Gout typically affects the first metatarsophalangeal joint (big toe) — this is the case in 70% of people at first presentation, and in 90% of people at some time during the disease.

Rapidity of onset — severe pain with associated swelling and redness, usually reaches maximum intensity within 24 hours.

The frequency and duration of attacks.

Any previous drug interventions tried.

Age of onset:

Onset of gout in a person younger than 30 years of age suggests renal disease or enzymatic disorders, is often associated with genetic causes, and may require more aggressive investigation and drug treatment.

In older people gout is more likely to be polyarticular, the upper limb is more likely to be involved, and tophi can occur early in the disease (sometimes without previous attacks of gout), and may be found in atypical sites.

Possible risk factors for developing gout:

Alcohol intake.

Dietary intake of purines, particularly from red meat and seafood.

Use of drugs that can raise plasma urate levels, such as aspirin (low-dose), ciclosporin, cytotoxic drugs, diuretics (thiazide and loop), ethambutol, nicotinic acid, pyrazinamide, tacrolimus, and lead exposure.

Family history — 20% of people with gout have a family history.

Associated comorbidity which can increase the risk of developing gout, including the following:

Obesity, hypertension, renal impairment, diabetes mellitus, myeloproliferative disease, hyperlipidaemia (especially hypertriglyceridaemia), vascular disease, severe psoriasis,and enzyme defects such as hypoxanthine guanine phosphoribosyltransferase (HGPRT) deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Basis for recommendation

Basis for recommendation

The recommendations on what to ask when taking a history in a person with suspected gout are based on expert opinion from a Dutch guideline [Dutch College of General Practitioners, 2004], review articles [Nuki, 2002; Terkeltaub, 2003; DynaMed, 2007], and text books [Cohen and Emmerson, 1998; Schlesinger and Schumacher, 2004].

Examination

What examination should I perform?

There is no single examination which confirms a diagnosis of gout. Look for evidence of:

Arthritis (swelling, redness, warmth, and pain on passive movement).

The big toe (first metatarsophalangeal joint) is most frequently affected by gout.

Other affected areas include the mid foot ('boot-lace' area of the foot), heel, ankle, knee, finger, wrist, and elbow (listed in order of decreasing frequency).

Lower limb joints are affected more frequently than upper limb joints.

Tophi (firm, white, translucent nodules).

It usually takes at least 10 years after the first attack of acute gout for tophi to develop.

Tophi are most commonly found on fingers, toes, ulnar side of forearms, olecranon bursae, prepatellar bursae, Achilles tendons, and the helix of the ears, but they can occur anywhere (for example the spinal canal and vocal cords), especially in older people.

The pattern of tophi and joint involvement is characteristically asymmetric.

In postmenopausal women who are taking diuretics, tophi can form over Heberden's nodes.

Basis for recommendation

Basis for recommendation

The recommendations on performing an examination in a person with suspected gout are based on expert opinion from a Dutch guideline [Dutch College of General Practitioners, 2004], review articles [O'Dell, 1983; Nuki, 2002], and text books [Cohen and Emmerson, 1998; Schlesinger and Schumacher, 2004].

Investigations

What investigations should I consider?

No initial investigations are required when managing people with gout-like symptoms.

However, the following tests may be considered as part of ongoing follow up of people with gout-like symptoms:

Joint fluid microscopy and culture:

Aspiration of joint fluid is not indicated unless the diagnosis of gout is in doubt or septic arthritis is suspected.

Presence of urate crystals confirms a diagnosis of gout.

Absence of evidence of infection rules out septic arthritis.

Serum uric acid (SUA) or plasma urate is usually measured 4–6 weeks after an acute attack of gout to confirm hyperuricaemia:

In the UK the upper limit of the reference range for SUA is usually taken as 420 micromol/L for males, and 360 micromol/L for premenopausal females.

Hyperuricaemia may be present without gout. The presence of hyperuricaemia does not equate with a diagnosis of gout as most people with hyperuricaemia do not develop gout.

Gout may be present without hyperuricaemia — this is particularly common during the acute attack when plasma urate levels may fall.

Joint X-ray:

Consider X-ray of an affected joint (especially wrist or knee) to look for chondrocalcinosis (calcification of cartilage within joints) which can be associated with gout.

Blood tests such as renal function, cholesterol level, and fasting blood glucose may be appropriate if clinically indicated.

Basis for recommendation

Basis for recommendation

The recommendations on investigations to consider in a person with suspected gout are based on expert opinion from a Dutch guideline [Dutch College of General Practitioners, 2004], review articles [Nuki, 2002; Bencardino and Hassankhani, 2003], and text books [Cohen and Emmerson, 1998; Schlesinger and Schumacher, 2004].

Fluid microscopy

A review rated the quality of evidence supporting the use of microscopy to detect urate crystals as 'bronze'. No randomized controlled trial (RCT) has studied the effect on clinical outcomes of testing for urate crystals in synovial fluid or tophi. The test can have false positives and false negatives, and the quality of the test depends on the quality of both the laboratory providing the test and the specimen sent for testing [Schlesinger and Schumacher, 2004].

Serum uric acid levels

Gout may be present without hyperuricaemia — this is particularly common during the acute attack when plasma urate levels may fall. A Dutch national guideline suggested that a serum uric acid level below 330 micromol/L during an acute attack may be a safe cut-off to exclude gout [Dutch College of General Practitioners, 2004]; however this value is not universally accepted.

Diagnostic criteria

What are the American College of Rheumatology criteria for the diagnosis of acute gouty arthritis?

The 'gold standard' for diagnosing gout is demonstration by microscopy of urate crystals in synovial fluid or tophi. However, testing for urate crystals in joint fluid or tophi is often not practical.

In 1977, the American College of Rheumatology (ACR) published classification criteria for the diagnosis of acute gouty arthritis. These criteria were designed for research purposes and not specifically for use in clinical practice. The criteria supported a diagnosis of acute gouty arthritis if six or more of the following were met:

More than one attack of acute arthritis.

Maximal inflammation developing within 1 day of onset.

Monoarthritis attack (90% of initial attacks are monoarticular).

Redness over affected joint.

Unilateral attack on the first metatarsophalangeal (big toe) joint.

Unilateral attack on the tarsal joint.

Tophus (proven or suspected).

Hyperuricaemia.

Asymmetric swelling within a joint on X-ray. Asymmetric swelling can also be found on examination, but the data from which the ACR criteria were derived did not include this.

Subcortical cysts without erosions on X-ray.

No organisms found on culture of synovial fluid.

Basis for recommendation

Basis for recommendation

The American College of Rheumatology (ACR) classification criteria for the diagnosis of acute gouty arthritis are described in a review article [Wallace et al, 1977].

Differential diagnosis

What else might it be?

Septic arthritis:

Septic arthritis must be considered in any person who is systemically unwell (with or without a temperature) and an acutely painful, hot, swollen joint. It is important to diagnose septic arthritis promptly, as late recognition can be fatal. If suspected, refer for emergency joint aspiration and culture.

Non-urate crystal-induced arthropathy, such as:

Pseudogout; calcium pyrophosphate deposition disease (CPPD).

Hydroxyapatite crystal deposition disease (basic calcium phosphate crystallopathy).

Combined CPPD and hydroxyapatite crystallopathy.

Osteoarthritis

Psoriatic arthritis

Reactive arthritis

Rheumatoid arthritis

Seronegative spondyloarthropathy

Haemochromatosis

Basis for recommendation

Basis for recommendation

Information on the differential diagnosis of gout is described in a text book [Roddy and Doherty, 2010].

Management

Management

Scenario: Acute gout : covers the management of an acute attack of gout and includes advice on what to do if treatment fails and what follow-up is recommended.

Scenario: Preventing gout : covers the management of recurrent attacks of gout and includes information for prescribing prophylactic drug treatment.

Scenario: Acute gout

Scenario: Acute gout

192months3060monthsBoth

Assessment

How do I assess someone with gout?

Confirm the diagnosis of gout and exclude alternative diagnoses, especially septic arthritis.

If septic arthritis is suspected, refer urgently or aspirate the joint and arrange urgent microscopy and culture.

Assess the severity of the attack (number of joints affected, the person's ability to mobilize, impact on work and functioning).

Ask about previous attacks and which drugs (if any) the person is taking or has tried (including nonsteroidal anti-inflammatory drugs [NSAIDs] such as diclofenac, or urate-lowering drugs such as allopurinol).

Assess risk factors such as medication (for example diuretics), alcohol, diet, and obesity.

Identify any associated conditions (for example hypertension, diabetes, and cardiovascular disease), and arrange follow up to manage these as appropriate.

Assess the person's cardiovascular risk (usually after the attack has settled). Provide lifestyle advice and manage any associated conditions (see Follow up).

Measure the person's serum uric acid level 4–6 weeks after the acute attack.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice, and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of available literature [Jordan et al, 2007].

Treatment

What treatment is recommended in acute gout?

For people with mild symptoms and a high risk of adverse effects, consider self care rather than any specific drug treatment.

If drug treatment is necessary:

Prescribe a nonsteroidal anti-inflammatory drug (NSAID) (diclofenac, indometacin, or naproxen) as soon as possible, and continue the treatment until 48 hours after the attack has resolved.

Co-prescribe a proton pump inhibitor (PPI) for gastric protection in people at risk of peptic ulcers, gastric bleeds, or perforations. For more information, see the section on Preventing and managing gastrointestinal adverse effects in the CKS topic on NSAIDs - prescribing issues.

If NSAIDs are contraindicated, not tolerated, or have been ineffective in previous attacks, prescribe oral colchicine.

If NSAIDs and colchicine are contraindicated, consider systemic corticosteroids (given orally, intramuscularly, or intravenously).

Intra-articular corticosteroids are an option if the diagnosis is certain and only one or two (particularly large) joints are affected, and they are suitable for injecting, and the expertise to inject the joint is available. For more information, see the section on intra-articular corticosteroids.

Give paracetamol, with or without codeine, in addition to other drug treatment, or alone, if NSAIDs, colchicine, and corticosteroids are all contraindicated.

Do not stop allopurinol or febuxostat during an acute attack of gout if the person is already established on these drugs.

Irrespective of the treatment used, advise the person to return if symptoms get worse, or if there is no improvement after 3–4 days. See Treatment failure for more information.

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. There is little good quality evidence on the treatment of acute gout. Treatment needs to be based on patient preference and a balance of risk and benefits.

Nonsteroidal anti-inflammatory drugs (NSAIDs): the evidence comes mainly from non-randomized controlled trials (non-RCTs) using indometacin. All NSAIDs appear equally effective and there is normally symptomatic relief within 24 hours [Underwood, 2006b]. CKS could find no head-to-head comparisons of NSAIDs with colchicine.

Of the cyclo-oxygenase-2 selective NSAIDs, only etoricoxib is licensed for the treatment of gout and there are trial data to support its effect [Schumacher et al, 2002; Rubin et al, 2004], but it may have a small increased risk of cardiovascular thrombotic events associated with its use [Aldington et al, 2005]. As people with gout may be at higher risk of cardiovascular disease, etoricoxib is best avoided.

NSAID choices — CKS recommends diclofenac, naproxen, and indometacin as the NSAIDs of choice in acute gout because:

Diclofenac and naproxen are widely considered to have acceptable adverse effect profiles [CSM, 2002].

Indometacin has been studied more in gout than any other NSAID, and its safety profile is classed as intermediate risk of causing serious gastrointestinal (GI) adverse effects, although it is associated with more GI adverse events than naproxen or diclofenac.

Diclofenac, indometacin, and naproxen are all fast acting NSAIDs with short half-lives, so clinical benefit will often be seen within a couple of days [BNF 63, 2012].

Ketoprofen, piroxicam, and sulindac are other standard NSAIDs that are licensed for the treatment of gout, but they are less frequently used and their adverse effect profiles are probably less favourable than diclofenac or naproxen.

Ibuprofen and other standard NSAIDs not listed here are not licensed for the treatment of acute gout.

Modified-release NSAIDs offer no additional benefit in terms of efficacy compared with standard preparations.

Colchicine: the evidence comes from one small RCT (n = 43) showing colchicine to be more effective than placebo, and more effective if taken in the first 24 hours. However, all the participants treated with colchicine suffered gastrointestinal adverse effects (diarrhoea and/or vomiting) [Schlesinger et al, 2006a; Underwood, 2006b].

The BSR recommend lower doses of colchicine than those advised in the British National Formulary, to minimize the risk of adverse effects [Jordan et al, 2007].

Systemic corticosteroids: the evidence from one small RCT (n = 90) shows that oral prednisolone (30 mg for 5 days) may be equally as effective as indometacin with fewer adverse effects [Man et al, 2007; Janssens et al, 2008]. CKS could find no studies on the optimum dose and duration of corticosteroids but a short course of prednisolone 40 mg or less is relatively safe. Most people in case series reports respond in 24 hours with no adverse effects or rebound symptoms after stopping corticosteroids. In people with monoarthritis, an intra-articular corticosteroid injection is highly effective in terminating an attack [Jordan et al, 2007].

Analgesia: there is no trial evidence supporting the role of paracetamol or codeine in acute gout, but expert opinion and best practice suggests a role when symptoms are inadequately controlled using conventional measures.

Self care

What self care is recommended during an acute attack of gout?

Advise the person to:

Rest and elevate the limb.

Avoid trauma to the affected joint.

Keep the joint in a cool environment by not covering (with a sock, shoe, or bed clothing) and using an ice pack.

A pack of frozen peas can be used as an ice pack as it moulds to fit the affected area.

The pack should be wrapped in a towel to avoid ice-burn, and applied for about 20 minutes.

This can be repeated as often as required. However, advise the person to make sure the temperature of the affected part has returned to normal before repeating the application.

Discuss lifestyle issues such as weight loss, exercise, diet, alcohol consumption, and fluid intake. See Lifestyle advice for more information.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion, pragmatic advice, and the guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007].

CKS could only find one small randomized controlled trial (n = 19) and a survey looking at the role of ice and cooling of the affected joint in acute gout.

Ice: pain was reduced in 48% (95% CI 8 to 67) of people who used an ice pack (NNT was 3, 95% CI 2 to 13) [Schlesinger et al, 2002].

Cooling: people with gout prefer cooling the affected joint compared with heat, and this can help to distinguish gout from other forms of inflammatory arthritis [Schlesinger, 2006].

Lifestyle advice

What lifestyle advice is recommended for someone with gout?

Advise people with gout to:

Aim for an ideal body weight — but avoid crash dieting and high protein/low carbohydrate diets.

Eat sensibly — by restricting the amount of red meat and avoiding a high protein intake. Avoid excessive consumption of foods rich in purines (such as liver, kidneys, and seafood).

Drink alcohol sensibly — by avoiding binge drinking and restricting alcohol consumption to 21 units per week for men and 14 units per week for women, with at least two alcohol-free days a week.

Avoid dehydration by drinking water (up to 2 litres/day unless there is a medical contraindication).

Drink skimmed milk or consume low-fat dairy products (up to 2 servings daily).

Limit consumption of sugary drinks and snacks.

Take regular exercise — but avoid intense muscular exercise and trauma to joints.

Stop smoking — see CKS topic on Smoking cessation.

Consider taking vitamin C supplements.

Provide written information and patient support via the UK Gout Society. For more information, see www.ukgoutsociety.org.

Basis for recommendation

Basis for recommendation

There are no controlled trials (mainly observational studies and case studies) on the effect or lifestyle changes on the incidence of gout, but expert opinion is that lifestyle changes can be beneficial [Saag and Choi, 2006; Sutaria et al, 2006; Choi, 2010].

Weight loss and exercise: there is evidence suggesting that obesity is linked with gout. Daily exercise and gradual weight loss may improve uric acid levels, reduce the frequency of gout attacks, and have a beneficial effect on associated cardiovascular and/or metabolic comorbidities (such as insulin resistance, type 2 diabetes, and hypertension) [Choi, 2010].

Weight loss should not involve diets that increase urate levels, such as high-protein diets or starvation regimens [Saag and Choi, 2006].

Swimming and walking should be encouraged, but strenuous exercise or trauma to joints may precipitate attacks of gout.

Diet: there is evidence that restricting dietary purines can improve serum uric acid levels. A low-purine diet may have some clinical benefit in reducing attacks of gout, and this is especially important in people with renal impairment [Choi, 2005]. There is also some evidence (mostly from observational studies) that high consumption of low fat dairy products [Choi, 2010; Dalbeth and Palmano, 2011], limiting sugary drinks and snacks [Choi and Curhan, 2008; Choi et al, 2010; Choi, 2010], and taking vitamin C supplements (500 mg daily or more) [Choi et al, 2009; Choi, 2010] may reduce the risk of gout. Although good quality randomized controlled trials are needed to support or refute these recommendations, they are safe and have multiple health benefits [Choi, 2010].

The diet should be nutritionally balanced, but purine intake limited. Excessive consumption of foods which are very rich in purines such as liver, kidneys, red meat, yeast extracts, seafood (herring, sardines, and shellfish), and certain vegetables (asparagus, beans, cauliflower, lentils, mushrooms, and spinach), should be avoided [Choi et al, 2004b; Choi, 2005; Choi, 2010].

Soya foods are also high in purines but are less likely to lead to gout than meats and seafood.

It is the quantity of purine-rich food consumed that is more important than the absolute purine content in each food. However, if the person is keen to measure quantities of food, they should aim for a maximum total daily purine intake of around 200 mg [Jordan et al, 2007; DTB, 2010].

Vitamin C supplements (500 mg/day or more) may reduce serum uric acid levels and the future risk of gout. The potential benefits of lower intake of vitamin C are unclear [Choi et al, 2009].

Fructose contained in sugary drinks and snacks may increase serum uric acid levels and the risk of gout. In addition, fructose intake is linked to increased insulin resistance and weight gain which are risk factors for developing gout [Choi et al, 2010].

People with diabetes should continue with their diabetic diet as this will help with lowering urate levels.

Alcohol: the evidence suggests that drinking alcohol above the recommended limit (especially beer, stout, port, and fortified wines) is associated with a higher incidence of gout. Moderate consumption of wine (two glasses per day) was not associated with a significant increased risk [Choi, 2005].

Recommendations for limiting alcohol consumption are in line with advice on sensible drinking from the Department of Health. The recommendation to advise all people to have at least two alcohol-free days is based on alcohol guidelines from the House of Commons Science and Technology Committee [House of Commons, 2011].

The aim of lifestyle advice is not only to reduce episodes of gout but to reduce overall cardiovascular risk, which is higher in people with gout. For more information, see the CKS topic on CVD risk assessment and management.

Treatment failure

What if treatment fails in acute gout?

If there is no improvement in symptoms after 2–3 days:

Review the diagnosis, check compliance with medication, and encourage self care strategies.

Increase the dose of medication to maximum and add paracetamol, with or without codeine.

If there is still no improvement in symptoms in a confirmed case of gout, either:

Try an alternative drug or consider combining treatment, or

Seek specialist advice, especially if the person may be at risk of adverse effects.

Additional information

Additional information

Most people with gout will respond within 2–3 days to a nonsteroidal anti-inflammatory drug (NSAID), colchicine, or oral prednisolone. If there is no improvement after this time, reviewing the diagnosis is necessary to exclude any other underlying pathology. See Differential diagnosis for more information.

People should ideally be started on the maximum dose of medication, but if colchicine has been prescribed at a lower dose (to avoid adverse effects), consider increasing to the maximum tolerated dose.

Always seek specialist advice if unsure about the next step if someone fails to respond to standard treatment. Switching to an alternative NSAID or colchicine may be worth trying, provided there are no contraindications.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice and the guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007].

There is no evidence regarding switching medication or combining treatment when first-line drugs fail in acute gout. Nevertheless, if there are no contraindications, this may be an option. A survey of American Rheumatologists found that combining medication is common practice [Schlesinger et al, 2006b].

People with gout are more likely to be elderly and have comorbidities, so are generally more vulnerable to drug adverse effects. If considering combining treatment, make a decision based on the risks and benefits.

Management of tophi

How should I manage people with gouty tophi?

The principles of management of people with tophi (and other complications of gout) are similar to those for managing people with frequent recurrences of gout.

The natural history of tophi may vary from individual to individual. Tophi can remain static, enlarge, or dissolve with urate-lowering therapy. As tophi dissolve they may ulcerate through the skin. This can be misinterpreted as evidence of local infection. Reassure the person that the ulcer should heal as the tophaceous material completely resolves or discharges.

Rarely, tophi may be so large or painful that referral is indicated. Occasionally surgical excision may be considered.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion from a review article [Gibson, 2005].

A case report describes successful surgical removal of a large painful tophaceous nodule on the plantar aspect of the first metatarsophalangeal joint. Surgery relieved the pain and restored the ability to wear shoes and walk without discomfort [Naas and Sanders, 1998].

Follow up

What follow up is recommended after an acute attack of gout?

Follow up the person 4–6 weeks after an acute attack of gout has resolved, and:

Check their Serum uric acid level.

Measure their blood pressure and take blood for fasting glucose, renal function, and lipid profile.

Identify and manage underlying conditions such as hypertension, diabetes, or renal impairment, and assess the person's overall cardiovascular risk.

Provide advice on risk factors such as obesity, diet, excessive alcohol consumption, and exercise.

Consider prophylactic medication if a person is having two or more attacks of gout in a year.

Consider providing an advance prescription of effective treatment for future attacks of gout.

Serum uric acid level

Serum uric acid level

Measuring the baseline serum uric acid (SUA) level 4–6 weeks after an acute attack of gout will help confirm the diagnosis of gout. If the person has no further symptoms, then urate-lowering therapy is not recommended, even if the SUA level is above the target value of 360 micromol/L. However, certain people who are at a higher risk of subsequent attacks (for example people with a SUA level of 600 micromol/L or more, or who have other risk factors), or those developing end-organ damage (affecting joints and kidneys) should be considered for prophylactic treatment earlier, such as after the first attack of gout.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007].

An overall cardiovascular risk assessment should be made and lifestyle advice should be given [Saag and Choi, 2006; Underwood, 2006a; Stamp et al, 2007]. For more information, see the CKS topic on CVD risk assessment and management.

When to refer

When is referral recommended in someone with gout?

Admit the person if septic arthritis is suspected.

Seek specialist advice when:

The diagnosis is uncertain, there is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 25 years of age).

Allopurinol or febuxostat is at maximum dose but a person is still having recurrent attacks of gout.

A person has persistent symptoms during an acute attack despite maximum doses of anti-inflammatory medication (alone or in combination).

An intra-articular steroid injection is indicated but the facilities or expertise are not available.

Complications are present, including urate kidney stones, urate nephropathy, or troublesome tophi.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. The recommendation regarding febuxostat is based on the Summary of Product Characteristics [ABPI Medicines Compendium, 2012c].

Many people with gout have comorbidities, so close monitoring for adverse effects and deteriorating renal function is needed. A referral to secondary care or further specialist advice may be advisable if the person is inadequately controlled on routine medication or there are contraindications to starting treatment.

Scenario: Preventing gout

Scenario: Preventing gout

192months3060monthsBoth

Assessment

How do I assess someone with gout?

Confirm the diagnosis of gout and exclude alternative diagnoses, especially septic arthritis.

If septic arthritis is suspected, refer urgently or aspirate the joint and arrange urgent microscopy and culture.

Assess the severity of the attack (number of joints affected, the person's ability to mobilize, impact on work and functioning).

Ask about previous attacks and which drugs (if any) the person is taking or has tried (including nonsteroidal anti-inflammatory drugs [NSAIDs] such as diclofenac, or urate-lowering drugs such as allopurinol).

Assess risk factors such as medication (for example diuretics), alcohol, diet, and obesity.

Identify any associated conditions (for example hypertension, diabetes, cardiovascular disease), and arrange follow up to manage these as appropriate.

Assess the person's cardiovascular risk (usually after the attack has settled). Provide lifestyle advice and manage any associated conditions (see Follow up).

Measure the person's serum uric acid level 4–6 weeks after the acute attack.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice, and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007].

Drug treatment

What drug treatment is recommended to prevent recurrent attacks of gout?

Start allopurinol after two or more attacks of gout within a year or after the first attack in people at higher risk with one or more tophi, X-ray features of gouty arthritis, renal impairment, known uric acid stones, or on long-term diuretic medication:

Start allopurinol 1–2 weeks after the inflammation has settled and titrate the dose every few weeks until the serum uric acid (SUA) level is below 300 micromol/L.

When starting allopurinol, co-prescribe a low dose of a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, naproxen, or diclofenac; or low-dose colchicine, for at least 1 month to prevent acute attacks of gout.

Prescribe NSAIDs for up to 6 weeks and consider the need for gastroprotective medication.

Prescribe colchicine for up to 6 months (usually 3 months).

If NSAIDs and colchicine are contraindicated, consider low-dose oral prednisolone once a day for 4 to 12 weeks.

Consider febuxostat as second-line therapy if allopurinol is not tolerated or is contraindicated.

Start febuxostat 1–2 weeks after the inflammation has settled. The dose may be increased after 2–4 weeks if the SUA level remains above 360 micromol/L.

When starting febuxostat, co-prescribe a low dose of a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, naproxen, or diclofenac; or low-dose colchicine, to prevent acute attacks of gout.

Prescribe NSAIDs for up to 6 weeks and consider the need for gastroprotective medication.

Prescribe colchicine for at least 6 months.

If NSAIDs and colchicine are contraindicated, consider low-dose oral prednisolone once a day for 4 to 12 weeks.

Note: a prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.

Advise the person that:

Urate-lowering medication is normally lifelong and regular monitoring is needed.

Allopurinol or febuxostat may cause acute attacks of gout just after initiating treatment, and for some weeks afterwards. Explain that they should start their anti-inflammatory treatment as soon as possible and not to stop their allopurinol or febuxostat during acute attacks.

Basis for recommendation

Basis for recommendation

The recommendations regarding allopurinol are based mainly on published expert opinion, pragmatic advice, and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. The quality of the evidence on allopurinol is poor and CKS could not find any prospective randomized controlled trials (RCTs) comparing different treatments.

The recommendations regarding febuxostat are based on a NICE technology appraisal: Febuxostat for the management of hyperuricaemia in people with gout [NICE, 2008a] and the Summary of Product Characteristics [ABPI Medicines Compendium, 2012c].

In the UK, allopurinol is the first-line urate-lowering drug. Probenecid, sulfinpyrazone, or benzbromarone are not commonly used and have limitations to their use [Jordan et al, 2007].

Starting a urate-lowering drug is usually recommended after a second attack of gout in a year, as 40% of people will not experience another attack within the first year and lifestyle modifications can be effective. People with very high serum uric acid levels, renal impairment, previous uric acid stones, visible tophi, or people taking diuretic medication may be vulnerable to repeated attacks of gout and end organ damage (kidneys and joints), so treatment may be advisable after the first attack [Jordan et al, 2007].

Urate-lowering drugs: the evidence suggests that the use of a urate-lowering drug is effective at reducing recurrent acute attacks of gout. Clinical observation suggests that starting prophylactic treatment too early after an attack (before 1–2 weeks after the inflammation has settled) can lead to a prolonged flare up of gout.

Evidence for using nonsteroidal anti-inflammatory drugs (NSAIDs) or colchicine for gout flare prophylaxis: there is no evidence base for prophylactic low-dose NSAIDs, although these are routinely used in practice. One small RCT (n = 43) showed that colchicine (0.6 mg) twice daily for 6 months reduced the number of flares when starting allopurinol, compared with placebo. At least one flare occurred in 33% of the colchicine group compared with 77% of the placebo group (NNT = 3) [Borstad et al, 2004].

Duration of NSAIDs or colchicine for gout flare prophylaxis:

For allopurinol, the manufacturer and the British National Formulary (BNF) recommends that a prophylactic NSAID or colchicine is co-prescribed for at least 1 month when starting allopurinol [ABPI Medicines Compendium, 2012a; BNF 63, 2012].

The BNF states that gout flare prophylaxis treatment is usually given for up to 3 months when using allopurinol [BNF 63, 2012]. However, the BSR advises that prophylaxis with colchicine can be given for up to 6 months but prophylaxis with NSAIDs should be limited to 6 weeks [Jordan et al, 2007].

When starting febuxostat, the manufacturer and the BNF recommend that a prophylactic NSAID or colchicine is co-prescribed for at least 6 months [ABPI Medicines Compendium, 2012c; BNF 63, 2012]. The recommendation to limit prophylaxis with NSAIDs to 6 weeks is extrapolated from the BSR recommendation on gout flare prophylaxis with allopurinol [Jordan et al, 2007].

NSAID choices — CKS recommends ibuprofen, diclofenac, or naproxen as the NSAIDs of choice because they have favourable adverse-effect profiles and they are widely co-prescribed (in lower doses) by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease. Similar regimes should be considered if starting febuxostat urate-lowering therapy.

Oral prednisolone — if the use of NSAIDs and colchicine are contraindicated, the recommendation to use oral prednisolone for up to 3 months is based on the expert opinion of reviewers of this CKS topic.

Lifestyle advice

What lifestyle advice is recommended in someone with gout?

Advise people with gout to:

Aim for an ideal body weight — but avoid crash dieting and high protein/low carbohydrate diets.

Eat sensibly — by restricting the amount of red meat and avoiding a high protein intake. Avoid excessive consumption of foods rich in purines (such as liver, kidneys, and seafood).

Drink alcohol sensibly — by avoiding binge drinking and restricting alcohol consumption to 21 units per week for men and 14 units per week for women, with at least two alcohol-free days a week.

Avoid dehydration by drinking water (up to 2 litres/day unless there is a medical contraindication).

Drink skimmed milk or consume low-fat dairy products (up to 2 servings daily).

Limit consumption of sugary drinks and snacks.

Take regular exercise — but avoid intense muscular exercise and trauma to joints.

Stop smoking — see CKS topic on Smoking cessation.

Consider taking vitamin c supplements.

Provide written information and patient support via the UK Gout Society. For more information, see www.ukgoutsociety.org.

Basis for recommendation

Basis for recommendation

There are no controlled trials (mainly observational studies and case studies) on the effect on lifestyle changes on the incidence of gout, but expert opinion is that lifestyle changes can be beneficial [Saag and Choi, 2006; Sutaria et al, 2006; Choi, 2010].

Weight loss and exercise: there is evidence suggesting obesity is linked with gout. Daily exercise and gradual weight loss may improve uric acid levels, reduce the frequency of gout attacks, and have a beneficial effect on associated cardiovascular and/or metabolic comorbidities (such as insulin resistance, type 2 diabetes, and hypertension) [Choi, 2010].

Weight loss should not involve diets that increase urate levels, such as high-protein diets or starvation regimens [Saag and Choi, 2006].

Swimming and walking should be encouraged, but strenuous exercise or trauma to joints may precipitate attacks of gout.

Diet: there is evidence that restricting dietary purines can improve serum uric acid levels. A low-purine diet may have some clinical benefit in reducing attacks of gout, and this is especially important in people with renal impairment [Choi, 2005]. There is also some evidence (mostly from observational studies) that high consumption of low fat dairy products [Choi, 2010; Dalbeth and Palmano, 2011], limiting sugary drinks and snacks [Choi and Curhan, 2008; Choi et al, 2010; Choi, 2010], and taking vitamin C supplements (500 mg daily or more) [Choi et al, 2009; Choi, 2010]may reduce the risk of gout. Although good quality randomized controlled trials are needed to support or refute these recommendations, they are safe and have multiple health benefits [Choi, 2010].

The diet should be nutritionally balanced, but purine intake limited. Excessive consumption of foods which are very rich in purines such as liver, kidneys, red meat, yeast extracts, seafood (herring, sardines, and shellfish), and certain vegetables (asparagus, beans, cauliflower, lentils, mushrooms, and spinach), should be avoided [Choi et al, 2004b; Choi, 2005; Choi, 2010].

Soya foods are also high in purines but are less likely to lead to gout than meats and seafood.

It is the quantity of purine-rich food consumed that is more important than the absolute purine content in each food. However, if the person is keen to measure quantities of food, they should aim for a maximum total daily purine intake of around 200 mg [Jordan et al, 2007; DTB, 2010].

Vitamin C supplements (500 mg/day or more) may reduce serum uric acid levels and the future risk of gout. The potential benefits of lower intake of vitamin C are unclear [Choi et al, 2009].

Fructose contained in sugary drinks and snacks may increase serum uric acid levels and the risk of gout. In addition, fructose intake is linked to increased insulin resistance and weight gain which are risk factors for developing gout [Choi et al, 2010].

People with diabetes should continue with their diabetic diet as this will help with lowering urate levels.

Alcohol: the evidence suggests that drinking alcohol above the recommended limit (especially beer, stout, port, and fortified wines) is associated with a higher incidence of gout. Moderate consumption of wine (two glasses per day) was not associated with a significant increased risk [Choi, 2005].

Recommendations for limiting alcohol consumption are in line with advice on sensible drinking from the Department of Health. The recommendation to advise all people to have at least two alcohol-free days is based on alcohol guidelines from the House of Commons Science and Technology Committee [House of Commons, 2011].

The aim of lifestyle advice is not only to reduce episodes of gout but to reduce overall cardiovascular risk, which is higher in people with gout. For more information, see the CKS topic on CVD risk assessment and management.

Stopping urate-lowering treatment

Can urate-lowering treatment be stopped in chronic gout?

Once allopurinol or febuxostat is started, treatment is usually lifelong, especially in people at higher risk:

Who have renal impairment, gouty tophi, uric acid stones, or those taking long-term diuretics.

Who have recurrent attacks of gout when trying to stop urate-lowering treatment.

Consider stopping allopurinol or febuxostat in people who have had a normal serum uric acid level for many years with no acute attacks of gout.

Lifelong treatment

Lifelong treatment

If considering discontinuing urate-lowering medication, explain that there is no certainty that a further episode of gout will not recur.

Make sure they have a supply of home medication to use in an acute attack, but advise them not to start allopurinol or febuxostat immediately if an acute attack develops, and to seek medical advice.

Stress the importance of a healthy lifestyle and avoidance of trigger factors.

Provide early and close follow up as needed.

It is likely that gout attacks will not recur until urate load has become excessive again, so after a long period with a low serum uric acid level, it may be several years till they need to restart.

Allopurinol or febuxostat may be stopped if a person is unable to tolerate adverse effects.

For more information see adverse effects of allopurinol, and adverse effects of febuxostat.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. The evidence in this area is limited and comes from small observational studies.

The evidence from one study shows that people with milder gout may be able to stop treatment without any attacks of gout for over 3 years.

Another observational study (n = 109) suggested that the lower the serum uric acid level prior to stopping urate-lowering therapy, the longer the person will remain free of gout [Perez-Ruiz et al, 2006].

Discontinuing allopurinol or febuxostat is not common practice but a trial free period may be a pragmatic approach in an elderly person who has remained symptom-free from gout for years, but who takes multiple medications for comorbidities.

Follow up

What follow up is needed in someone with recurrent episodes of gout?

If taking allopurinol, check the serum uric acid (SUA) level and renal function every 3 months in the first year, then annually thereafter, and aim for a SUA level below 300 micromol/L.

If taking febuxostat, use clinical judgement to decide if liver function tests need to be retested periodically.

If the person is still having frequent attacks of gout:

Assess compliance with prophylactic medication or increase the dose if appropriate.

Review any trigger factors such as medication (for example diuretics), trauma, diet, weight gain, and excess alcohol consumption.

Provide a home supply of medication to be used during an acute attack in order to minimize the impact on the person's functioning.

Review cardiovascular risk factors and provide ongoing lifestyle advice. For more information, see the CKS topic on CVD risk assessment and management.

In a person with hypertension, stop diuretics during an acute attack and change to an alternative antihypertensive. For more information, see the CKS topic on Hypertension - not diabetic.

In a person with heart failure, continue diuretics during an acute attack. If using a nonsteroidal anti-inflammatory drug (NSAID) for pain relief, monitor renal function closely. For more information, see the CKS topic on Heart failure - chronic.

Consider referral to secondary care, if the person is still having attacks despite all these measures.

Basis for recommendation

Basis for recommendation

The recommendations regarding allopurinol recommendations are based on the best available evidence and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. The recommendations regarding febuxostat are based on the Summary of Product Characteristics [ABPI Medicines Compendium, 2012c].

If a person is still symptomatic despite optimum management in primary care, refer for specialist assessment as other urate-lowering agents (sulfinpyrazone, benzbromarone, or probenecid) may be tried or combined by a specialist.

When to refer

When is referral recommended in someone with gout?

Admit the person if septic arthritis is suspected.

Seek specialist advice when:

The diagnosis is uncertain, there is a suspicion of an underlying systemic illness (for example rheumatoid arthritis or connective tissue disorder), or gout occurs during pregnancy or in a young person (under 25 years of age).

Allopurinol or febuxostat is at maximum dose but a person is still having recurrent attacks of gout.

A person has persistent symptoms during an acute attack despite maximum doses of anti-inflammatory medication (alone or in combination).

An intra-articular steroid injection is indicated but the facilities or expertise are not available.

Complications are present, including urate kidney stones, urate nephropathy, or troublesome tophi.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion, pragmatic advice and a guideline produced by expert representatives of the British Society for Rheumatology (BSR). The evidence supporting the BSR recommendations is based on a systematic review of literature [Jordan et al, 2007]. The recommendation regarding febuxostat is based on the Summary of Product Characteristics [ABPI Medicines Compendium, 2012c].

Many people with gout have comorbidities, so close monitoring for adverse effects and deteriorating renal function is needed. A referral to secondary care or further specialist advice may be advisable if the person is inadequately controlled on routine medication or there are contraindications to starting treatment.

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

NSAIDs

Nonsteroidal anti-inflammatory drugs

Choosing a dosing regimen

What dosing regimen of nonsteroidal anti-inflammatory drug should I use?

For the treatment of an acute attack of gout, prescribe diclofenac, indometacin, or naproxen.

Doses recommended are:

Diclofenac 50 mg three times a day.

Note: diclofenac is now contraindicated in people with ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, mild, moderate, or severe heart failure. For information on other contraindications of nonsteroidal anti-inflammatory drugs (NSAIDs) see the CKS topic NSAIDs - prescribing issues.

Indometacin 50 mg three or four times a day.

Naproxen initially 750 mg (initial dose), then 250 mg every 8 hours.

If effective, continue the NSAID until 48 hours after the attack has finished (up to 1–2 weeks). As the pain resolves, reduce the dose of the NSAID.

For the prevention of gout (while urate-lowering therapy is initiated), prescribe ibuprofen, diclofenac, or naproxen.

Doses recommended are:

Ibuprofen 400 mg three times a day.

Diclofenac 25–50 mg three times a day.

Naproxen 250 mg three times a day.

For detail prescribing information on NSAIDs see the CKS topic NSAIDs - prescribing issues.

Basis for recommendation

For the treatment of acute gout, CKS recommends diclofenac, naproxen, and indometacin as the NSAIDs of choice in acute gout because:

Diclofenac and naproxen are widely considered to have acceptable adverse effect profiles [CSM, 2002].

Indometacin has been studied more in gout than any other NSAID, and its safety profile is classed as intermediate risk of causing serious gastrointestinal (GI) adverse effects, although it is associated with more GI adverse events than naproxen or diclofenac.

Diclofenac, indometacin, and naproxen are all fast acting NSAIDs with short half-lives, so clinical benefit will often be seen within a couple of days [BNF 63, 2012].

Oral diclofenac — The MHRA now recommend that like coxibs, diclofenac is now contraindicated for people with ischaemic heart disease, peripheral arterial disease, cerebrovascular disease, and, congestive heart failure (New York Heart Association [NYHA] classification II–IV [MHRA, 2013]. The MHRA based this recommendation on a recently published meta-analysis which found evidence that the arterial thrombotic risk with oral diclofenac is similar to that for the selective COX-2 inhibitors.

Ketoprofen, piroxicam, and sulindac are other standard NSAIDs that are licensed for the treatment of gout, but they are less frequently used and their adverse effect profiles are probably less favourable than diclofenac or naproxen.

Ibuprofen and other standard NSAIDs not listed here are not licensed for the treatment of acute gout.

Modified-release NSAIDs offer no additional benefit in terms of efficacy compared with standard preparations.

Of the cyclooxygenase-2 selective NSAIDs, only etoricoxib is licensed for the treatment of gout and there are trial data to support its effect [Schumacher et al, 2002; Rubin et al, 2004]. Etoricoxib may be associated with a slightly lower rate of gastrointestinal events compared with standard NSAIDs, but there may be a small increased risk of cardiovascular thrombotic events associated with its use [Aldington et al, 2005]. As people with gout may be at higher risk of cardiovascular disease, etoricoxib is best avoided.

For the prevention of gout (while urate-lowering therapy is initiated), CKS recommends ibuprofen, diclofenac, or naproxen as the NSAIDs of choice because they have favourable adverse-effect profiles and they are widely co-prescribed (in lower doses) by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease.

Similar regimes should be considered if starting febuxostat urate-lowering therapy.

The recommended doses of the NSAIDs are pragmatic, based on current practice by physicians.

Naproxen (up to 1000 mg per day) is associated with a lower thrombotic risk, and low doses of ibuprofen (up to 1200 mg per day) have not been associated with an increased risk of myocardial infarction [BNF 63, 2012].

Colchicine

Contraindications

Who should avoid taking colchicine?

Avoid colchicine in people with blood dyscrasias and bone marrow disease.

Ideally colchicine should also be avoided in:

The elderly.

People with poor renal function, poor liver function, gastrointestinal disease, or cardiac disease.

Pregnant or breastfeeding women.

In the rare event of a pregnant or breastfeeding woman presenting with gout, colchicine should be avoided, and the woman should be referred to a specialist if she requires treatment.

Basis for recommendation

Colchicine has a narrow therapeutic index and is extremely toxic in overdose. Elderly people, and people with renal or hepatic impairment, gastrointestinal, or cardiac disease are at particular risk of colchicine toxicity [MHRA, 2009].

Colchicine is excreted by the kidneys and, in people with renal impairment, there is the potential for accumulation and toxicity [ABPI Medicines Compendium, 2010].

In overdose, colchicine can cause confusion, reduced cardiac output, cardiac arrhythmias, renal damage, liver damage, respiratory distress, hyperpyrexia, and bone-marrow depression [MHRA, 2009].

Colchicine is also best avoided in people with severe heart failure as it constricts blood vessels [ABPI Medicines Compendium, 2010].

In elderly people, who are more prone to dehydration, colchicine is also best avoided because of its relatively high risk of causing diarrhoea [Jordan et al, 2007].

The use of colchicine during pregnancy is not advised [ABPI Medicines Compendium, 2010].

Choosing a dosing regimen

What dosing regimen of colchicine should I use?

For acute gout:

Prescribe a colchicine dose of 500 micrograms, two to four times a day, until pain relief is achieved, or diarrhoea or vomiting occurs.

Do not exceed a total dose of 6 mg of colchicine (i.e. up to 6 days with colchicine 500 micrograms twice a day, or up to 3 days with colchicine 500 micrograms four times a day), and

Do not repeat treatment within three days.

In people with moderate renal impairment, consider using a low starting dose of 500 micrograms twice a day.

For prophylaxis of gout (during urate-lowering treatment):

Prescribe a colchicine dose of 500 micrograms twice a day (low-dose) following initiation of long-term treatment with allopurinol or febuxostat. For more information, see the sections on allopurinol and febuxostat.

In elderly people, and in people with moderate renal impairment, use colchicine 500 micrograms once a day for prophylaxis of gout.

Basis for recommendation

For acute gout, a guideline from the British Society for Rheumatology (BSR) recommends that colchicine should be used in doses of 500 micrograms, two to four times a day, until relief of pain is achieved, or diarrhoea or vomiting occurs [Jordan et al, 2007].

In people with moderate renal impairment, a low starting dose of 500 micrograms twice a day should be considered [ABPI Medicines Compendium, 2010].

The licensed daily dose of colchicine (1 mg followed by 500 micrograms every 2–3 hours, up to a maximum of 6 mg) [ABPI Medicines Compendium, 2010] has been found to commonly cause gastrointestinal adverse effects [Morris et al, 2003], although there may be a faster clinical response than with the dose recommended by the BSR [Jordan et al, 2007].

The information on the maximum treatment dose and the duration of treatment is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010].

For prophylaxis of gout (during urate-lowering treatment), the BSR recommends that colchicine 500 micrograms twice a day (low-dose) should be given following initiation of long-term treatment with allopurinol (or uricosuric drugs) [Jordan et al, 2007]. Colchicine 500 micrograms two to three times a day is the licensed dose for prophylaxis. Doses varying from colchicine 500 micrograms once a day to colchicine 500 micrograms three times a day have historically been commonly used [Jordan et al, 2007; ABPI Medicines Compendium, 2010].

In elderly people, and in people with moderate renal impairment, use colchicine 500 micrograms once a day for prophylaxis of gout [ABPI Medicines Compendium, 2010].

Adverse effects

What are the adverse effects of colchicine?

Gastrointestinal adverse effects, such as nausea and vomiting, diarrhoea, and abdominal pain, are common with colchicine use, and can be severe enough to limit treatment.

The severity of adverse effects of colchicine is dose dependent.

Colchicine has a narrow therapeutic index and is extremely toxic in overdose.

Basis for recommendation

These recommendations are based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010] and a drug safety update published by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2009].

Corticosteroids

Prescribing issues

What issues do I need to consider when prescribing a corticosteroid?

Oral prednisolone should normally be taken as a single dose in the morning to reduce the disturbance to circadian cortisol secretion.

People using corticosteroids should be given a 'steroid card' which gives guidance on minimizing risk and provides details of prescriber, drug, dosage, and duration of treatment, if steroids are needed for more than 3 weeks duration. Adverse effects are uncommon with occasional short courses of oral corticosteroids. For more information, see the CKS topic on Corticosteroids - oral.

People that require oral prednisolone for prevention of an acute attack of gout when starting long-term urate-lowering therapy need monitoring for:

High blood pressure.

Diabetes mellitus.

Osteoporosis.

Administration of an intra-articular corticosteroid may cause atrophy of subcutaneous tissues and local skin depigmentation as a result of corticosteroid peri-articular leakage. The risk is greatest if large or repeated doses of a long-acting, potent corticosteroid are given. See the section on Intra-articular injections for more information.

Basis for recommendation

This information is based on the British National Formulary [BNF 63, 2012].

Dosing regimen of oral prednisolone

What dosing regimen of oral prednisolone should I use?

For acute gout:

A short course of a moderately high dose of oral prednisolone is recommended (for example prednisolone 20–40 mg once a day for 5 days).

For prophylaxis of gout (during urate-lowering treatment):

Prednisolone 5–10 mg orally once a day for 4 to 12 weeks is recommended.

Basis for recommendation

Acute gout

CKS could find no studies on the optimum dose and duration of oral corticosteroids for gout. The suggested dose of 20–40 mg once a day for 5 days is based on expert opinion.

A short course of prednisolone 40 mg or less is relatively safe and is likely to have a rapid response in acute gout flare ups [Man et al, 2007; BNF 63, 2012].

Historically, lower doses of prednisolone have been used for the treatment of acute gout in UK clinical practice.

Prophylaxis of gout (during urate-lowering treatment)

The recommended dose and duration of prednisolone is based on the professional opinion of expert reviewers of this CKS topic.

Dosing regimen of IM corticosteroid

What dosing regimen of intramuscular corticosteroid should I use?

Intramuscular corticosteroids are not specifically licensed for the treatment of gout.

Triamcinolone acetonide or methylprednisolone can be given as a one-off deep intramuscular injection to relieve the symptoms of gout. In order to avoid the danger of subcutaneous fat atrophy, the corticosteroid should be deeply injected into the gluteal muscle.

The dose will depend on the size of the joint and the severity of the condition.

For methylprednisolone, doses ranging from 40–120 mg are licensed (although not specifically for use in people with gout).

For triamcinolone, doses ranging from 40–80 mg are licensed (although not specifically for use in people with gout).

Basis for recommendation

This information is based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2012b].

Intra-articular injections

Which corticosteroids are recommended for intra-articular injection?

Intra-articular corticosteroids are not specifically licensed for the treatment of gout.

Specific corticosteroids are recommended for different joints according to their size. Atrophy of subcutaneous tissues and local skin depigmentation may occur from peri-articular leakage of corticosteroid. The risk is greatest if large or repeated doses of a long-acting, potent corticosteroid are given. In general, for:

Smaller joints: methylprednisolone or hydrocortisone is recommended.

Larger joints: methylprednisolone or triamcinolone is recommended.

When to avoid intra-articular corticosteroids

When should I avoid administering an intra-articular corticosteroid injection?

Avoid administering intra-articular injections unless the necessary training has been fulfilled and the person feels confident in carrying out the procedure.

Avoid injecting:

Prosthetic joints.

When there is any possibility of sepsis.

Joints within 3 months of a previous injection.

Inject with caution if the person is taking anticoagulant medication.

Dosing regimen of intra-articular steroid

What dosing regimen of intra-articular corticosteroid should I use?

Intra-articular corticosteroids are not specifically licensed in the treatment of gout.

The licensed dose of intra-articular injection depends upon the steroid chosen, size of the joint, and the severity of the condition.

Methylprednisolone: 40–80 mg (1–2 mL) for large joints, 20–40 mg (0.5–1 mL) for medium joints, 10–20 mg (0.25–0.5 mL) for small joints.

Triamcinolone acetonide: 40 mg (1 mL) for large joints, 20–40 mg (0.5–1 mL) for medium joints.

Hydrocortisone acetate: 12.5–25 mg (0.5–1 mL) for small joints.

Basis for recommendation

This information is based on the manufacturers' Summaries of Product Characteristics [ABPI Medicines Compendium, 2009a; ABPI Medicines Compendium, 2009b; ABPI Medicines Compendium, 2012b].

Allopurinol

Prescribing allopurinol

How should I prescribe allopurinol?

Start allopurinol 1–2 weeks after the inflammation has settled, as the drug may precipitate further attacks.

The usual starting dose of allopurinol is 100 mg once a day (preferably taken with food), increased by 50–100 mg increments approximately every 2–3 weeks until a dose of 300 mg is reached. Check the person's serum uric acid (SUA) level and renal function at 3 months.

Increase doses further to achieve SUA level below 300 micromol/L. The maintenance dose of allopurinol is often in the region of 300 mg a day but may vary between 100–900 mg a day depending on the severity of the gout, and the dose required to maintain the SUA at an appropriate level.

Allopurinol is usually given once a day. However, doses of over 300 mg per day should be taken in divided doses to help minimize any gastrointestinal adverse effects.

In elderly people, those with frequent attacks, those with renal impairment (glomerular filtration rate less than 60 mL/min), and in those with hepatic impairment:

Prescribe an allopurinol starting dose of 50 mg once a day (allopurinol 50 mg tablets are not available, so when providing a 50 mg dose check that the 100 mg tablets are scored).

See Managing renal impairment for more information on managing people with renal impairment.

When starting allopurinol, co-prescribe a low dose of a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, naproxen, or diclofenac; or low-dose colchicine, for at least 1 month to prevent acute attacks of gout.

Prescribe NSAIDs for up to 6 weeks and consider the need for gastroprotective medication.

Prescribe colchicine for up to 6 months (usually 3 months).

If NSAIDs and colchicine are contraindicated, consider low-dose oral prednisolone once a day for 4 to 12 weeks.

If a gout flare occurs during treatment with allopurinol:

Advise that allopurinol should not be discontinued.

Manage the flare as appropriate for the person.

Reassure the person that continuous treatment with allopurinol will decrease the frequency and intensity of further gout flares.

Adjust the dose of allopurinol according to:

SUA levels.

Renal function.

Clinical response and how well the allopurinol is tolerated.

Basis for recommendation

Information on prescribing allopurinol is based mainly on a guideline produced by expert representatives of the British Society for Rheumatology (BSR) [Jordan et al, 2007] and the Manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2012a].

The manufacturers of allopurinol and the British National Formulary (BNF) recommend that a prophylactic NSAID or colchicine is co-prescribed for at least 1 month when starting allopurinol [ABPI Medicines Compendium, 2012a; BNF 63, 2012].

The BNF states that gout flare prophylaxis treatment is usually given for up to 3 months when using allopurinol [BNF 63, 2012]. However, the BSR advises that prophylaxis with colchicine can be given for up to 6 months but prophylaxis with NSAIDs should be limited to 6 weeks [Jordan et al, 2007].

CKS recommends ibuprofen, diclofenac, or naproxen as the NSAIDs of choice because they have favourable adverse-effect profiles and they are widely co-prescribed (in lower doses) by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease.

Adverse effects

How should I manage the adverse effects of allopurinol?

There is a risk of precipitating acute attacks of gout after starting allopurinol.

Advise people who experience acute attacks of gout after initiation of treatment with allopurinol, or during established treatment, to continue taking allopurinol.

Pruritic maculopapular skin rashes may occur in up to 10% of people who take allopurinol.

A rash can be the first sign of a rare hypersensitivity reaction; advise people who experience a rash to stop allopurinol immediately and seek prompt medical advice.

If the rash was mild and subsequently resolved, gradually reintroduce the allopurinol. If the rash recurs, immediately discontinue the allopurinol.

Somnolence, vertigo, and ataxia have been reported with allopurinol use.

Advise that when starting allopurinol, people should be cautious about driving or using machinery until they are reasonably certain that allopurinol does not adversely affect their performance.

Since allopurinol and its metabolites are excreted by the kidney, impaired renal function may lead to retention of the drug and/or its metabolites, with consequent prolongation of plasma half-life.

People with chronic renal impairment who also take allopurinol may be at increased risk of hypersensitivity reactions. Treatment should be stopped immediately if a hypersensitivity reaction occurs.

Overall, adverse effects are rare but their incidence (particularly rashes) is higher in the presence of renal impairment.

Basis for recommendation

These recommendations are based mainly on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2014] and on a guideline produced by expert representatives of the British Society for Rheumatology (BSR), which is based on a systematic review of the literature [Jordan et al, 2007].

Managing renal impairment

How do I manage someone with renal impairment who requires allopurinol?

Acute attacks of gout are relatively rare in people with renal impairment, due to the anti-inflammatory effects of uraemia. However, following a kidney transplant, people are vulnerable to gout (which has an atypical upper limb and polyarticular presentation due to the effects of immunosuppressant drug regimens).

Allopurinol is effective in people with renal impairment and it can be used after transplantation, but interactions with cytotoxic medication (for example azathioprine) need to be considered, and colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs) are best avoided in these people.

Since allopurinol is excreted by the kidney, impaired renal function may lead to retention of allopurinol and/or its metabolites, with consequent prolongation of plasma half-life, therefore the dose should be modified based on the person's creatinine clearance or glomerular filtration rate (GFR) as outlined in Table 1.

Once allopurinol has been started, it is best to check urate levels and renal function every 2–4 weeks for the first 3 months.

See the section on allopurinol for more prescribing information.

Table 1 . Modification of allopurinol dosage with reduced renal function from any cause.
Glomerular Filtration Rate (GFR)* Usual dose of allopurinol
> 80 mL/min 200–300 mg each day
60–80 mL/min 100–200 mg each day
30–60 mL/min 50–100 mg each day
15–30 mL/min 50–100 mg alternate days
On dialysis 50–100 mg each week
* Or based on the creatine clearance. † Most apparently healthy 80-year-olds have this level of renal insufficiency.
Data from: [Jordan et al, 2007]

Febuxostat

Febuxostat

Prescribing febuxostat

How should I prescribe febuxostat?

Prescribe febuxostat as a second-line treatment in people with chronic symptomatic gout who are intolerant of allopurinol, or for whom allopurinol is contraindicated.

Prescribers should be aware that a prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.

Do not start febuxostat until an acute attack of gout has completely subsided, as febuxostat may precipitate further attacks.

Perform liver function tests (LFTs) before starting febuxostat treatment, as mild liver test abnormalities have been observed. Check LFTs periodically thereafter, based on clinical judgement.

Prescribe febuxostat at a starting dose of 80 mg once daily. If the serum uric acid (SUA) level is greater than 6 mg/dl (360 micromol/L) after 2–4 weeks, increase the dose of febuxostat to 120 mg once daily, aiming for a therapeutic target SUA level of below 6 mg/dl (360 micromol/L).

In people with mild hepatic impairment, febuxostat 80 mg is recommended. There is limited information regarding the use of febuxostat in people with more severe hepatic impairment.

No dose adjustment is needed for the elderly, or those with mild or moderate renal impairment. Febuxostat has not been fully evaluated in people with severe renal impairment (creatinine clearance less than 30 ml/min).

When starting febuxostat, co-prescribe a low dose of a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen, naproxen, or diclofenac; or low-dose colchicine, to prevent acute attacks of gout.

Prescribe NSAIDs for up to 6 weeks and consider the need for gastroprotective medication.

Prescribe colchicine for at least 6 months.

If NSAIDs and colchicine are contraindicated, consider low-dose oral prednisolone once a day for 4 to 12 weeks.

If a gout flare occurs during treatment with febuxostat:

Advise that febuxostat should not be discontinued.

Manage the flare as appropriate for the person.

Reassure the person that continuous treatment with febuxostat will decrease the frequency and intensity of further gout flares.

Where possible, avoid febuxostat in people with ischaemic heart disease, heart failure, or malignant disease.

Basis for recommendation

Information on prescribing febuxostat is based mainly on the Technology Appraisal: Febuxostat for the management of hyperuricaemia in people with gout, published by the National Institute for Health and Clinical Excellence [NICE, 2008a] and the Summary of Product Characteristics for Adenuric® film-coated tablets [ABPI Medicines Compendium, 2012c].

The Summary of Product Characteristics for Adenuric® film-coated tablets and the British National Formulary recommend that a prophylactic nonsteroidal anti-inflammatory drug (NSAID) or colchicine is co-prescribed for at least 6 months when starting febuxostat [ABPI Medicines Compendium, 2012c; BNF 63, 2012]. This is to minimize the risk of a flare up of gout when treatment with febuxostat is started, which may occur when changing levels of serum uric acid mobilize urate from tissue deposits.

The recommendation to limit prophylaxis with NSAIDs to 6 weeks is extrapolated from the BSR recommendation on gout flare prophylaxis with allopurinol [Jordan et al, 2007].

Febuxostat is an effective second-line drug for the treatment of gout and may be an alternative for people who are unable to take allopurinol.

There is evidence from a small retrospective study that febuxostat in people with previously documented severe allopurinol adverse effects is largely safe. However, caution, careful dose escalation, and close monitoring is recommended when febuxostat is considered in allopurinol-intolerant people [Chohan, 2011].

NSAID choices — CKS recommends ibuprofen, diclofenac, or naproxen as the NSAIDs of choice because they have favourable adverse-effect profiles and they are widely co-prescribed (in lower doses) by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease.

Hepatic impairment

The manufacturers recommend that a maximum dose of 80 mg once daily is prescribed to people with mild hepatic impairment.

Expert opinion in review articles states that dosage adjustments are not needed in people with mild or moderate hepatic impairment [Fravel and Ernst, 2011; Gray and Walters-Smith, 2011].

Renal impairment and elderly people

Febuxostat does not require dose adjustments in mild to moderate renal disease and may be preferred in older people with gout [Fravel and Ernst, 2011; Gray and Walters-Smith, 2011; ABPI Medicines Compendium, 2012c].

NSAID choices

CKS recommends ibuprofen, diclofenac, or naproxen as the NSAIDs of choice because of their more favourable adverse-effect profiles. In addition, lower doses are widely co-prescribed by physicians when initiating allopurinol treatment, with the aim of preventing a flare of disease.

Adverse effects

How should I manage the adverse effects of febuxostat?

There is a risk of precipitating acute attacks of gout after starting febuxostat.

Advise people who experience acute attacks of gout after initiation of treatment with febuxostat, or during established treatment, to continue taking febuxostat.

The most commonly reported adverse effects in clinical trials of febuxostat have been mostly mild or moderate in severity. The most common adverse effects are liver abnormalities, diarrhoea, headache, nausea, and rash.

There have been post-marketing reports of rare serious rashes, generalised skin rashes, and severe hypersensitivity reactions occurring mostly during the first month of treatment with febuxostat. Some of the people affected reported previous hypersensitivity to allopurinol. Following on from this, the Medicines and Healthcare products Regulatory Agency have advised that:

Febuxostat should be stopped immediately if signs or symptoms of serious hypersensitivity reactions occur; early withdrawal is associated with a better prognosis.

If a hypersensitivity reaction occurs with febuxostat, including Stevens-Johnson syndrome, febuxostat must not be re-started at any time.

Anyone taking febuxostat should be advised of the signs and symptoms of severe hypersensitivity reactions or Stevens-Johnson syndrome.

A prior history of hypersensitivity to allopurinol and/or renal disease may indicate potential hypersensitivity to febuxostat.

Somnolence, dizziness, and paraesthesia have been reported with febuxostat use.

Advise that when starting febuxostat, people should be cautious about driving or using machinery until they are reasonably certain that febuxostat does not adversely affect their performance.

Basis for recommendation

These recommendations are based mainly on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2012c], and advice issued from the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA, 2012].

Evidence

Evidence

Supporting evidence

Abbreviations

Abbreviations used in this section

Abbreviation Definition
CI Confidence interval
NNT Number needed to treat
OR Odds ratio
RCT Randomized controlled trial
SD Standard deviation

Application of an ice pack

Evidence supporting the application of an ice pack during an acute attack of gout

An RCT of 19 subjects found that pain was reduced in 48% of people (95% CI 8 to 67) who used an ice pack; the NNT was 3 (95% CI 2 to 13) [Schlesinger et al, 2002].

NSAIDs

Evidence supporting the use of NSAIDs for an acute attack of gout

Effectiveness of NSAIDs

CKS found 12 clinical trials that compared two different NSAIDs 'head-to-head'.

No study reported any clinical advantage of one NSAID over another in terms of effectiveness.

Evidence on adverse effects was inconsistent, although the largest study reported that indometacin (a traditional non-selective NSAID) was associated with more drug-related adverse events than etoricoxib (a cyclooxygenase-2 selective NSAID).

One placebo-controlled trial of 30 people with acute gout compared the nonsteroidal anti-inflammatory drug (NSAID) tenoxicam with placebo [Garcia de la Torre, 1987; Underwood, 2006b].

After 1 day, tenoxicam significantly increased the proportion of people who reported at least a 50% reduction in pain, compared with placebo.

After 4 days, the response to tenoxicam was rated by the treating physician as 'good or excellent' more often than with placebo.

There are no randomized controlled trials (RCTs) comparing an NSAID with colchicine for the treatment of gout [Schlesinger and Schumacher, 2004; Underwood, 2006b].

A review of RCTs comparing NSAIDs in acute gout reported that, in most reviewed studies, recovery was faster in people treated with an NSAID than in a historical series of untreated people [Schlesinger and Schumacher, 2004].

Effect of aspirin on plasma urate

There is some concern about the use of aspirin in people with hyperuricaemia and/or gout [Schlesinger and Schumacher, 2004].

Much literature on gout refers to aspirin use being a risk factor. However, a review found that results from three observational studies were inconsistent, and concluded that there are no major concerns with the use of aspirin in people with gout [Schlesinger and Schumacher, 2004]. Case series have found that:

Aspirin at more than 3 g/day is uricosuric [Yu and Gutman, 1959].

Aspirin 1–2 g/day causes uric acid retention [Yu and Gutman, 1959].

Aspirin 75–325 mg/day has variable effects on uric acid excretion [Caspi et al, 2000; Harris et al, 2000].

Oral colchicine

Evidence supporting the use of oral colchicine for an acute attack of gout

A review [Schlesinger et al, 2006a] found one randomized controlled trial (RCT) of colchicine treatment for acute gout [Ahern et al, 1987].

Colchicine (1 mg, then 0.5 mg every 2 hours until complete response or toxicity) was given to 22 people with acute gout. A placebo was given to 21 people. Nonsteroidal anti-inflammatory drugs were not given.

After 48 hours, two-thirds of the people treated with colchicine had improved, whereas a third of the people taking placebo had improved.

Colchicine treatment resulted in more rapid improvement.

Colchicine was more effective when taken within 24 hours of the onset of an attack.

All people taking colchicine developed diarrhoea and/or vomiting: median time 24 hours (range 12–36); mean total dose 6.7 mg. People taking placebo did not experience diarrhoea or vomiting, although five of them became nauseous.

Data from uncontrolled trials are consistent with this placebo-controlled RCT [Schlesinger and Schumacher, 2004].

Corticosteroids

Evidence supporting the use of corticosteroids for an acute attack of gout

Oral corticosteroids

More trial data are needed to establish whether the use of oral corticosteroids improves symptoms in people with acute gout.

A randomized controlled trial (RCT) of 90 adults with a clinical diagnosis of gout were allocated (within 3 days of onset of symptoms) to receive oral prednisolone (30 mg for 5 days) or indometacin (50 mg for 5 days) with additional agents. There was no difference in pain scores between the groups, but less adverse effects were seen with prednisolone than indometacin [Man et al, 2007]. A subsequent Cochrane systematic review identified the same study and found no further trials that compared an oral corticosteroid with a nonsteroidal anti-inflammatory drug [Janssens et al, 2008].

A prospective case series compared intravenous methylprednisolone with oral prednisone for treating people with acute gout who had contraindications to the use of nonsteroidal anti-inflammatory drugs [Groff et al, 1990]:

Complete resolution of symptoms occurred within 7 days for 11/13 people, and within 10 days for the remaining two people.

In the nine people who had fewer than six affected joints, doses of corticosteroid ranged from 20 mg/day to 50 mg/day and were tapered over 4–20 days.

No rebound attacks occurred when the steroids were stopped.

Different dosing regimens have not been tested in clinical trials [Schlesinger and Schumacher, 2004].

Intramuscular corticosteroids

A review found one non-randomized clinical trial of treatments for acute gout that compared an intramuscular corticosteroid with a nonsteroidal anti-inflammatory drug [Schlesinger et al, 2006a].

Oral indometacin 50 mg three times a day was compared with intramuscular triamcinolone acetate 50 mg in a clinical trial of 27 people presenting within 5 days of an attack of gouty arthritis [Alloway et al, 1993].

People with contraindications to treatment with indometacin received triamcinolone acetonide.

The mean time to resolution of symptoms was indometacin 8 days; triamcinolone acetate 7 days.

No adverse effects or episodes of rebound gout occurred with the triamcinolone acetonide therapy.

A subsequent Cochrane systematic review identified the same study and found no further trials that compared an intramuscular corticosteroid with a nonsteroidal anti-inflammatory drug [Janssens et al, 2008].

Intra-articular corticosteroids

There are no controlled trials of intra-articular corticosteroids for acute attacks of gout [Schlesinger and Schumacher, 2004; Underwood, 2006b].

The use of intra-articular steroids in acute gouty arthritis is supported by expert opinion, based on clinical experience reported as case series [Gray et al, 1981; Fernandez et al, 1999; Nuki, 2002; Schlesinger and Schumacher, 2004].

Dietary measures

Evidence supporting dietary measures to prevent recurrent attacks of gout

Moderating alcohol intake

CKS could find no studies that specifically looked at the effect of alcohol reduction on recurrence rates in people with gout.

A study that followed 47,150 men over a period of 12 years found that alcohol intake was strongly associated with an increased relative risk of gout. The risk varied according to quantity and type of alcoholic beverage: beer conferred a larger risk than spirits. Moderate wine drinking did not increase the risk of gout [Choi et al, 2004a]. Two subsequent review articles reported similar findings [Choi, 2005; Choi, 2010].

A population survey found alcohol consumption to be predictive of gout in hyperuricaemic people irrespective of the level of plasma uric acid (OR 2.31, 95% CI 1.04 to 5.54) [Lin et al, 2000a].

A prospective observational study of 233 men with raised plasma uric acid found that alcohol consumption was an independent predictor of the onset of gout (OR 3.45, 95% CI 1.58 to 7.56) [Lin et al, 2000b].

Dietary changes

A study that followed 47,150 men over a period of 12 years found increased relative risks (RR) for gout associated with high levels of consumption of meat and seafood respectively (RR 1.41, 95% CI 1.07 to 1.86; RR 1.51, 95% CI 1.17 to 1.95) [Choi et al, 2004b].

The study found no evidence for increased risk of gout from eating vegetables with high purine content (peas, beans, lentils, spinach, mushrooms, oatmeal, and cauliflower), and concluded that moderate intakes of purine-rich vegetables or protein are not associated with an increased risk of gout.

The study also showed that high levels of consumption of dairy products were associated with a decreased risk of gout [Choi et al, 2004b]. A subsequent review article reported similar findings [Choi, 2010].

There is also some evidence (mostly from observational studies) that high level of consumption of low fat dairy products [Choi, 2010; Dalbeth and Palmano, 2011], limiting sugary drinks and snacks [Choi and Curhan, 2008; Choi et al, 2010; Choi, 2010], and taking vitamin C supplements (500 mg/day or more) [Choi et al, 2009; Choi, 2010]may reduce the risk of gout. Although good quality randomized controlled trials are needed to support or refute this, these recommendations are safe and have multiple health benefits [Choi, 2010].

Low-fat dairy foods have been linked to a lower incidence of cardiovascular heart disease, premenopausal breast cancer, colon cancer, type 2 diabetes, and hypertension.

High intake of sugary foods and drinks has been linked to weight gain, obesity, type 2 diabetes, an increased risk of certain cancers, and symptomatic gallstone disease.

Vitamin C is safe, particularly within the recommended ranges (< 2000 mg/day in adults), and has cardioprotective properties.

[Choi, 2010]

A case series of 15 people with gout found that a strict purine-free diet can reduce plasma uric acid by 15–20%, but there was no effect on clinical outcomes [Nicholls and Scott, 1972] (cited in [Schlesinger and Schumacher, 2004]).

Avoiding weight gain, losing weight

A prospective cohort study followed 47,150 men over a period of 12 years and confirmed 730 cases of gout [Choi et al, 2005a]. The authors concluded that higher adiposity and weight gain are strong risk factors for gout in men, while weight loss is protective.

Table 1 and Table 2 outline the multivariate relative risks of gout associated with adiposity and weight gain respectively.

Table 1 . Multivariate relative risks of gout associated with adiposity.
Body Mass Index (BMI) Relative Risk 95% Confidence Interval
21 to 24.9 1
25 to 29.9 1.95 1.44–2.65
30 to 34.9 2.33 1.62–3.36
35 or greater 2.97 1.73–5.10
p < 0.001 for trend
Table 2 . Multivariate relative risks of gout associated with weight gain.
Change in weight Relative Risk 95% Confidence Interval
Lost 10 lb or more since study baseline 0.61 0.40–0.92
Stable within 4 lb since 21 years old 1
Gained 30 lb or more since 21 years old 1.99 1.49–2.66

A population survey found central obesity to be predictive of gout in hyperuricaemic people irrespective of the level of plasma uric acid (OR 2.43, 95% CI 1.14 to 5.29) [Lin et al, 2000a].

A prospective observational study of 233 men with raised plasma uric acid found that excessive weight gain was an independent predictor of the onset of gout (OR 1.91, 95% CI 0.98 to 4.01) [Lin et al, 2000b].

An observational study of a diet with restricted energy content that was high in complex carbohydrates and mono- and poly-unsaturated fats, included 13 non-diabetic obese men with gout. At 16 weeks the mean frequency of gouty attacks reduced from 2.1 to 0.6 per month. The mean uric acid level decreased from 570 micromol/L to 470 micromol/L [Dessein et al, 2000].

Colchicine to prevent recurrent gout

Evidence supporting the use of colchicine to prevent recurrent attacks of gout

Several clinical trials of prophylactic colchicine have been reported, but all have methodological weaknesses [Schlesinger and Schumacher, 2004].

No randomized controlled trial (RCT) has tested the use of colchicine alone for preventing recurrent gout [Schlesinger and Schumacher, 2004].

The best evidence comes from an RCT of 51 people with recurrent gout [Paulus et al, 1974] (cited in [Schlesinger and Schumacher, 2004]).

Subjects were treated either with probenecid 1.5 g/day plus colchicine 1.5 mg/day, or with probenecid 1.5 g/day plus placebo.

Results were reported only for the 38 people who had a sustained reduction in plasma uric acid (on the grounds that the others were unlikely to be compliant).

There were 23 attacks of acute gout during the 109 person-months of therapy with probenecid plus colchicine, and 35 attacks of acute gout during the 94 person-months of therapy with probenecid plus placebo.

Urate-lowering drugs in prevention

Evidence supporting the use of urate-lowering drugs to prevent recurrent attacks of gout

Frequency of acute gout during the first months of urate-lowering therapy

Evidence on frequency of acute gout during urate-lowering therapy

Published evidence to support this comes from case reports in three articles [Thompson et al, 1962; Yu and Gutman, 1964; Delbarre et al, 1966] (cited in [Schlesinger and Schumacher, 2004]). Most of the episodes of acute gout occurred while colchicine was being taken and/or dietary interventions were being applied.

Effects of urate-lowering therapy

Allopurinol

A trial (randomization unclear) of 183 people with gout compared allopurinol with uricosuric treatment [Weinberger et al, 1975] (cited in [Schlesinger and Schumacher, 2004]).

Attacks of gout ceased after at most 4 years in people treated with allopurinol; uricosuric treatment was not as effective.

A clinical quasi-randomized trial in 37 people compared allopurinol with uricosuric treatment [Scott, 1966] (cited in [Schlesinger and Schumacher, 2004]).

The daily dose of allopurinol (300 mg in 12 men, 400 mg in six men, and 600 mg in two men) was determined by the plasma uric acid level.

Probenecid was started at 1 g/day and increased to 2 g/day after 2 weeks.

Sulfinpyrazone was switched for probenecid in five people who had adverse effects.

All people also received colchicine 0.5 mg two to three times a day for the first few months.

Mean plasma uric acid fell to 4.7 mg/dL (range 2.6–5.5 mg/dL) in the allopurinol group and 5.2 mg/dL (range 3.8–7.3 mg/dL) in the uricosuric group.

Clinical response was equivalent in the two groups; half of the people were free of acute gout at the final assessment.

Febuxostat

A NICE technology appraisal summarised the evidence on the clinical effectiveness of febuxostat, primarily from three randomized controlled trials (RCTs) [NICE, 2008a]:

The FACT trial (multi-arm, randomized, double-blind, parallel-group trial) for 52 weeks, compared febuxostat 80 mg daily (257 people), febuxostat 120 mg daily (251 people), and allopurinol 300 mg daily (254 people).

The APEX trial (multi-arm, randomized, double-blind trial) for 28 weeks, compared febuxostat 80 mg daily (267 people), febuxostat 120 mg daily (269 people), febuxostat 240 mg daily (134 people), allopurinol 300 mg daily (258 people) or 100 mg daily (10 people with renal impairment), and placebo (134 people).

The TMX-00-004 study (small dose-response, multi-centre, randomized, double-blind, parallel-group trial) for 4 weeks, compared febuxostat 40 mg daily (37 people), febuxostat 80 mg daily (40 people), febuxostat 120 mg daily (38 people) and placebo (38 people).

The main evidence supporting the effectiveness of febuxostat was from the manufacturer's pooled data analysis from the FACT and APEX trials. This suggested that febuxostat (80 mg and 120 mg daily) was significantly more effective than fixed dose allopurinol (300 mg or 100 mg daily) at lowering serum uric acid (SUA) level to target therapeutic levels of less than 6 mg/100 ml (p <= 0.05). Post-hoc subgroup analysis of the pooled data also confirmed the increased effectiveness of febuxostat compared with allopurinol.

No statistically significant difference was seen between the febuxostat and allopurinol groups in the proportion of people needing treatment for acute flares of gout.

However, NICE identified methodological limitations in the manufacturer's use of fixed-dose allopurinol as a comparator in the pooled data analysis, as current recommendations support the use of dose-titrated allopurinol according to therapeutic targets (up to a maximum of 900 mg daily). Also, pooling of the data did not preserve randomization of the original trial RCT evidence, which may have introduced bias. A subsequent meta-analysis by NICE of the RCT evidence still supported the use of febuxostat compared with fixed-dose allopurinol in lowering SUA level. NICE also identified uncertainty around the cost-effectiveness analyses by the manufacturer.

Subsequent to the NICE technology appraisal, CKS identified 5 further studies and a technology appraisal on the use of febuxostat.

The CONfirmation of Febuxostat in Reducing and Maintaining Serum urate (CONFIRMS) trial (a randomized, double-blind, non-inferiority study) compared febuxostat 80 mg and febuxostat 40 mg with allopurinol 300 mg (or 200 mg for people with an estimated creatinine clearance of 30–59 mL/min) for 6 months in people with gout. The study recruited 2269 participants, 276 of whom were known treatment-responders from previous studies (FOCUS and EXCEL studies). The primary outcome measure was the proportion of participants achieving a final-visit SUA below 360 micromols/L [Becker et al, 2010].

The proportion of participants that achieved a final-visit SUA below 360 micromols/L was greater with febuxostat 80 mg than with febuxostat 40 mg (67.1% compared with 45.2%, p < 0.001) and allopurinol (42.1%, p < 0.001).

Febuxostat 40 mg was considered to be non-inferior to allopurinol.

Compared with allopurinol, it appeared that more participants in the febuxostat group had flares requiring treatment (about 59% with 80 mg febuxostat and 51% with 40 mg febuxostat, compared with 41% with allopurinol).

A 5 year open-label extension study (n = 116) assessed the urate lowering and clinical efficacy and safety of long-term febuxostat treatment in people with gout [Schumacher et al, 2009]. Participants who had previously completed a 28-day phase 2 RCT (the FOCUS study [Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety]) were given febuxosat 80 mg daily. Febuxostat dose could be increased to 120 mg or decreased to 40 mg between weeks 4 and 24 in order to maintain SUA between 3 and 6 mg/100ml, to respond to an adverse event, or at the discretion of the investigator. The primary end-point was reduction to and maintenance of SUA levels less than 6 mg/100 ml. All participants received gout prophylaxis in the first 4 weeks. Gout flares were recorded and treated throughout the study, and SUA, baseline tophi and safety of febuxostat were monitored. Dose adjustments were made for 44 participants. Therefore, 8 participants received febuxostat 40 mg, 79 received febuxostat 80 mg, and 29 received febuxostat 120 mg.

Fifty percent of the participants (58 participants) prematurely discontinued the study. Thirteen participants withdrew because of an adverse effect and eight participants withdrew because of gout flares.

After 5 yrs of taking febuxostat, 93% of the remaining participants (54 out of 58 people) had SUA less 6 mg/100 ml and the number of participants that experienced gout flares declined to zero. Long-term maintenance of SUA at a level less than 6.0 mg/dl also resulted in the resolution of baseline tophi in the majority of subjects.

Limitations of the study include:

High drop out rate (50%) which may skew the results towards a greater reduction in gout flares.

Small sample size.

Method of assessment of flares and tophi. In the study, assessment of flares was subjective (relied on self-reports and confirmation by documentation of treatment) and was determined by individual investigators.

Study design — participants were not randomized to dose groups and dose titration was allowed. In addition, there was no control or comparator group.

The authors concluded that longer term studies comparing various doses of febuxostat with allopurinol are needed to establish the long term benefits of these drugs.

A retrospective study assessed the safety of febuxostat in 13 people with gout with prior documented severe allopurinol reactions [Chohan, 2011].

Febuxostat was well tolerated in 12 of the 13 people.

One person who was previously hospitalized with documented exfoliative erythroderma during allopurinol treatment, developed biopsy-confirmed cutaneous leukocytoclastic vasculitis. However, this was not definitively related to febuxostat use.

None of the other 12 people treated with febuxostat showed rash, worsening hepatic function, blood cytopenia or eosinophilia.

The authors concluded that the use of febuxostat in people with previously documented severe allopurinol adverse effects is largely safe. However, the small risk of development of a hypersensitivity type cutaneous vasculitis early in treatment mandates caution, careful dose escalation, and close monitoring when febuxostat is considered in allopurinol-intolerant people.

A secondary analysis of data from the CONFIRMS trial assessed the safety and efficacy of febuxostat and allopurinol in older people compared with younger people [Becker et al, 2011].

Among 374 older people (65 years or older) with gout, recommended doses of febuxostat or allopurinol were at least comparable to that in 1894 younger participants (younger than 65 years of age).

Febuxostat and allopurinol were also well tolerated despite high rates of renal impairment and cardiovascular comorbidities in the older participants.

A retrospective study compared the characteristics of female compared with male participants with gout. The study also assessed the urate lowering efficacy and safety of febuxostat and allopurinol in women with gout [Chohan et al, 2012]. The study was a retrospective analysis of 4,101 people with gout (SUA level 8.0 mg/dl or more) enrolled in 3 phase III comparative trials and randomized to receive placebo, febuxostat (40 mg, 80 mg, 120 mg, or 240 mg daily), or allopurinol (100 mg, 200 mg, or 300 mg daily, based on renal function). Urate-lowering efficacy, which was defined as the proportion of subjects with SUA levels less than 6.0 mg/dl at final visit, was assessed for all subjects and, among women, according to baseline renal function.

The female participants (n = 226) were older with significantly higher rates of obesity and metabolic and cardiovascular comorbidities than the male participants.

The percentage of female participants with SUA levels less than 6.0 mg/dl at final visit was:

0% in the placebo group.

54.3%, 85.1%, 81.0%, and 100.0% in the febuxostat 40 mg, 80 mg, 120 mg, and 240 mg groups, respectively.

45.9% in the allopurinol group.

Similar patterns of urate-lowering efficacy rates were observed when stratified by renal function.

Results showed that among all the female participants, febuxostat 80 mg was significantly more efficacious than allopurinol (p < 0.001). Rates of adverse events were low, the most frequently reported were upper respiratory tract infections, musculoskeletal/connective tissue disorders, and diarrhoea.

The technology appraisal presented a summary of their evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of febuxostat for the management of hyperuricaemia in people with gout. The ERG report was based upon a review of the manufacturer's submission to NICE [Stevenson and Pandor, 2009]. The authors' conclusions were consistent with the conclusions in the NICE technology appraisal [NICE, 2008a].

Target for lowering plasma urate

Evidence on the target for lowering plasma urate

Urate crystals persist in 58% of asymptomatic knees of people with non-tophaceous gout, despite lowering plasma uric acid to 430 micromol/L (7.1 mg/dL) [Bomalaski et al, 1986].

A case series of 57 people with recurrent gout compared the clinical response to urate-lowering therapy in people whose plasma uric acid remained above (group A) or below (group B) the target of 360 micromol/L (6 mg/dL) [Li-Yu et al, 2001].

Urate crystals in joint aspirates were found in 14/16 people in group A, and in 7/16 people in group B.

The mean number of acute attacks of gout in the last year of follow up was 6 for group A, and 1 for group B.

A cohort study found that attacks diminished once allopurinol was started, even before plasma uric acid levels returned to normal [Beutler et al, 2001] (cited in [Schlesinger and Schumacher, 2004]).

Duration of treatment

Evidence on duration of treatment

Allopurinol

Urate lowering on treatment with allopurinol is dose-dependent, yet many people are maintained on a fixed dose of allopurinol, usually 100 mg/day or 300 mg/day, irrespective of plasma urate levels [Schlesinger and Schumacher, 2004].

When allopurinol is stopped, urate levels rise, and acute attacks and tophi can occur [Levinson and Becker, 1993].

A study of ten people with gout followed for 33 months after stopping urate-lowering therapy found five without a recurrence of gout, and five with recurrent attacks after an average of just under 16 months [DynaMed, 2007].

A randomized controlled trial that followed 50 people with gout for 2–4 years compared the use of continuous allopurinol with allopurinol used for only 2 months each year [Bull and Scott, 1989].

From the third year of treatment, there were no further attacks in the continuously treated group, while gout recurred in people treated intermittently.

Febuxostat

There is no specific recommendation in the Summary of Product Characteristics of febuxostat regarding the optimal duration of treatment [ABPI Medicines Compendium, 2012c]. The NICE technology appraisal of febuxostat noted that gout is a chronic illness requiring life-long therapy, however trial evidence has shown that a higher percentage of people receiving febuxostat discontinued treatment compared with allopurinol, over a 2-year time horizon [NICE, 2008a].

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of gout.

Search dates

2007 – August 2012

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Gout/, gout.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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