Gout

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The short-term treatment goal for acute gout is rapid resolution of pain and preservation of function. Long-term goals are to prevent recurrent attacks and chronic joint destruction. The earlier treatment is initiated, the better the clinical response.

Short-term management

Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or colchicine are recommended first-line treatments for patients experiencing a gout flare.[53][82][83] The treatment course is generally 7 to 14 days. However, NSAIDs should be given for the shortest period possible, at the lowest effective dose.

The choice between treatments should be guided by patient preference, and potential risks and contraindications (e.g., renal impairment in the case of NSAIDs).[53][82]

Initiation of treatment with urate-lowering drugs (e.g., xanthine oxidase inhibitors such as allopurinol and febuxostat; uricosuric agents such as probenecid or pegloticase) is not typically recommended in patients experiencing their first gout flare.[82][84]

NSAIDs

NSAIDs halt the inflammatory cascade of acute gout if they are started early, and are first-line therapy if no contraindications exist. They are also used to suppress gouty attacks when maintenance therapy with uric acid-lowering drugs is started.[82]
It is common to use indomethacin, although there is no evidence to suggest that it is more effective than other NSAIDs.[85] One Cochrane review reported, with moderate certainty, that NSAIDs and selective cyclo-oxygenase-2 (COX-2) inhibitors have similar efficacy for pain, swelling, treatment success, and quality of life in patients with gout.[86] [ ] The review found no difference between groups for function, but this result was based on low-certainty evidence. Higher withdrawal rates due to adverse events (mainly gastrointestinal) were seen with nonselective NSAIDs.[86] [ ] An additional systematic review concluded that although COX-2 inhibitors are equally as effective as nonselective NSAIDs for pain relief in patients with gout, COX-2 inhibitors may be more beneficial overall.[87]
Choice of NSAID should be guided by patient preference.[82]
In patients at high risk of gastrointestinal complications, a proton-pump inhibitor or misoprostol should be co-prescribed. Proton-pump inhibitors should be considered for all patients who are taking an NSAID.[53] COX-2 inhibitors may be safer than traditional NSAIDs in patients with a history of gastrointestinal bleeding or comorbidities.

Corticosteroids

Corticosteroids can be given either as an intra-articular injection for monoarticular acute gout or parenterally for oligoarticular or polyarticular acute gout.[82]
In the UK, off label use of intra-articular or intramuscular injections of corticosteroids are only considered if NSAIDs and colchicine are contraindicated.[53]
Corticosteroids are probably more effective than colchicine for acute gout, although there are no head-to-head trials.[88] Corticosteroids are associated with potentially serious adverse effects.
One Cochrane review reported moderate certainty evidence that corticosteroids had similar efficacy for pain, inflammation, function, and treatment success when compared with NSAIDs for patients with gout.[86]

Aspiration and injection of the knee: animated demonstration

How to aspirate synovial fluid from the knee and administer intra-articular medication using a medial approach.

Aspiration and injection of the shoulder animated demonstration

How to aspirate synovial fluid from the shoulder and administer intra-articular medication. Video demonstrates a posterior approach to the glenohumeral joint and a lateral approach to the subacromial space.

Colchicine

Minimal effective dose should be used because of the narrow benefit to risk index.[82] The conclusion of one Cochrane review, based on low-quality evidence, suggests that low-dose colchicine may be effective for the treatment of gout compared with placebo, and may have similar efficacy compared with NSAIDs.[89]
Common adverse effects are diarrhea, nausea, and vomiting.[90] In rare cases, colchicine treatment has been associated with an increased risk for fetal chromosomal aberrations.[91]

Interleukin-(IL)-1 inhibitors

Anakinra and canakinumab are second-line therapies. They are conditionally recommended over no therapy (beyond supportive/analgesic treatment) for patients experiencing a gout flare who are refractory to, are intolerant of, or have contraindications to other anti-inflammatory therapies.[53][82]

Anakinra

Anakinra, a recombinant IL-1 receptor antagonist, has been found to be noninferior to usual treatment (patient choice of either colchicine, naproxen, or prednisone) for the management of acute gout flare.[92] In patients for whom a NSAID and colchicine was ineffective or contraindicated, treatment with either anakinra or the corticosteroid triamcinolone reduced patient-assessed gout flare pain to a similar extent within 72 hours.[93] Anakinra is off-label for the treatment of gout in the US and Europe.

Canakinumab

An IL-1-beta inhibitor monoclonal antibody. Pooled results from two randomized, double-blind trials indicate that patients who received a single dose of canakinumab during an acute flare experienced rapid and effective pain relief compared with patients receiving triamcinolone (mean 72-hour visual analog scale pain score of 25.0 mm vs. 35.7 mm, respectively; P <0.0001), and a 56% reduction in risk of new flares over a 24-week period (hazard ratio [HR] 0.44; P ≤0.0001).[94]
The US Food and Drug Administration (FDA) panel rejected the approval of canakinumab for the treatment of gout due to the potential risk of infection, hypertriglyceridemia, and elevated uric acid levels.[95]
Canakinumab is approved by the European Medicines Agency for the symptomatic treatment of adult patients with frequent gouty arthritis attacks (at least three attacks in the previous 12 months) in whom NSAIDs and colchicine are contraindicated, are not tolerated, or do not provide an adequate response, and in whom repeated courses of corticosteroids are not appropriate.

Long-term management: dietary modifications

The long-term management of gout includes dietary modifications and weight loss (if indicated).[15][17][53] Limiting the intake of alcohol, purine, and high-fructose corn syrup, in conjunction with weight loss, are conditionally recommended lifestyle changes for people with gout.[82][96][97] Nonetheless, there is a paucity of high-quality evidence to support or refute the use of lifestyle modifications, or dietary supplements for improving outcomes in people with chronic gout.[98][99] [ ]

Initiating urate-lowering drugs

Initiation of treatment with urate-lowering drugs (e.g., xanthine oxidase inhibitors such as allopurinol and febuxostat; uricosuric agents such as probenecid or pegloticase) is recommended for patients with gout with any of the following:[53][82]

≥1 subcutaneous tophi
Evidence of radiographic damage (any modality) attributable to gout
Frequent gout flares (defined as ≥2 annually).

Urate-lowering drugs may also be used to treat patients:[53][82]

Who have experienced at least one previous gout flare but have infrequent flares (<2/year)
Who are experiencing their first flare and have comorbid moderate-to-severe chronic kidney disease (stage ≥3), serum urate concentration >9 mg/ dL, or urolithiasis
Who receive diuretic therapy
Who have chronic gouty arthritis.

Patients experiencing their first gout flare, and those with asymptomatic hyperuricemia, should not be treated with urate-lowering drugs.[53][82]

In the US, treatment can be initiated during a gout flare.[82][Evidence C]What are the effects of urate-lowering therapy (ULT)ᵃ during a gout flare compared with ULT after a gout flare has resolved in people diagnosed with gout?[82] There is evidence to suggest that starting urate-lowering therapy during a flare does not significantly extend flare duration or severity.[100][101] Furthermore, symptoms related to the current flare may motivate patients to take urate-lowering therapy (ULT). However, in the UK, it is recommended that ULT is started at least 2 to 4 weeks after a gout flare has settled, unless the patient is experiencing frequent flares, in which case ULT can be started during a flare.[53]

The decision to initiate urate-lowering treatment should be based on patient preference.[82]

Urate-lowering drugs are typically prescribed to target serum uric acid levels <6 mg/dL, to prevent supersaturation and crystal formation.[53][82] In the UK, a lower target serum urate level below 5 mg/dL should be considered for patients who:[53]

Have tophi or chronic gouty arthritis
Continue to have frequent flares despite having a serum urate level below 6 mg/dL.

One double blind randomized controlled trial demonstrated that more intensive serum urate lowering does not improve bone erosion scores in patients with erosive gout at 2 years.[102]

Pharmacologic anti-inflammatory prophylaxis (e.g., NSAIDs, low-dose colchicine, low dose oral steroid) is recommended for all gout patients during the initiation and titration of a urate-lowering drug.[53][82][85] In the UK, colchicine is preferred form of prophylaxis; off-label use of low dose NSAIDs or oral corticosteroid should only be considered if colchicine is contraindicated, not tolerated or ineffective.[53] Anti-inflammatory prophylaxis should be continued for at least 3 to 6 months after reaching the target level of uric acid.[82]

Patients with a confirmed diagnosis of gout who require urate-lowering drugs should continue urate-lowering therapy indefinitely (unless there is a serious adverse effect).[53][82] Adherence rates should be monitored carefully.[103]

Relapse of gout is common after discontinuation of urate-lowering drug treatment.[104]

Xanthine oxidase inhibitors

Allopurinol is the preferred first-line urate-lowering agent for all patients with gout, including those with moderate-to-severe chronic kidney disease (stage ≥3).[82][105]

In the UK, allopurinol is recommended as joint first line treatment with febuxostat, however, for patients with major cardiovascular disease (e.g., previous myocardial infarction, stroke, or unstable angina) allopurinol should be offered as first line treatment.[53]

Allopurinol can be started at a low dose (e.g., ≤100 mg/day and lower in patients with chronic kidney disease [stage ≥3]) during a gout flare, or once the flare has abated, depending on patient preference.[82]

The allopurinol dose should be increased over several weeks to months, with a serum urate target <6 mg/dL.[82] Evidence from one randomized controlled trial indicates that, in addition to reducing monosodium urate crystal burden, long-term allopurinol can slow the progression of bone erosion using a treat‐to‐serum urate target (<6 mg/dL) strategy.[106]

In the UK, if the target serum urate level is not reached or first line treatment with allopurinol is not tolerated, switching to a second line treatment with febuxostat should be considered, taking into account any comorbidities or preferences.[53]

Allopurinol hypersensitivity

Allopurinol should be initiated at lower doses in patients with renal insufficiency because of the risk of allopurinol hypersensitivity.[82] Gradual allopurinol dose escalation, in conjunction with kidney and liver function monitoring, may be considered in patients with kidney impairment.[107]
Prospective cohort studies suggest that allopurinol therapy is associated with a reduced incidence of renal disease.[108][109]
In populations where HLA-B*5801-positive people are at high risk for severe allopurinol hypersensitivity reaction (e.g., Koreans with renal insufficiency, Han Chinese descent, and Thai descent), HLA-B*5801 screening may be considered.[82] One large retrospective study conducted in Taiwan estimated the annual incidence of hypersensitivity reaction in new users of allopurinol at 4.68 per 1000, with mortality of 0.39 per 1000.[110] The risk of hypersensitivity was statistically significant among patients with renal or cardiovascular disease who were prescribed allopurinol for asymptomatic hyperuricemia.[110] A subsequent Taiwanese cohort study found that allopurinol is associated with a 5.5-fold increased risk of cutaneous adverse reactions compared with febuxostat.[111]

Febuxostat

Febuxostat is a nonpurine selective xanthine oxidase inhibitor that reduces the production of uric acid. [ ]
The FDA recommends that febuxostat should only be prescribed for patients who:[112]
- Have failed treatment with or cannot tolerate allopurinol, and
- Have been counseled regarding the cardiovascular risk.
The American College of Rheumatology guidelines recommend that patients with gout who are taking febuxostat, and have a history of cardiovascular disease or a new cardiovascular event, should switch to another urate-lowering therapy, if available.[82]
The UK Medicines and Healthcare products Regulatory Agency recommends that patients with preexisting major cardiovascular disease (e.g., myocardial infarction, stroke, or unstable angina) should avoid treatment with febuxostat unless no other therapy options are available.[113]
Febuxostat is recommended as joint first line treatment with allopurinol in the UK, once the patient's comorbidities and preferences are noted.[53] If the target serum urate level is not reached or first line treatment with febuxostat is not tolerated, switching to a second line treatment with allopurinol should be considered, taking into account any comorbidities or preferences.[53]
In randomized controlled trials of patients with hyperuricemia or gout, febuxostat reduced serum urate level more effectively than allopurinol.[114][115] Open label-data suggest that this benefit is maintained for up to 40 months.[116] In these studies, however, allopurinol was administered at doses less than the maximum approved dose for this indication. A subsequent double blind noninferiority trial demonstrated comparative efficacy for febuxostat and allopurinol in controlling flares when given at standard doses at 72 weeks.[117]
Commonly reported adverse effects of febuxostat therapy include elevated liver function tests, headache, hypertension, diarrhea, and arthralgia/stiffness.[118][119]
Cardiovascular death and all-cause mortality were significantly more common among patients taking febuxostat than those taking allopurinol (4.3% vs. 3.2%, HR 1.34 [95% CI 1.03 to 1.73]; 7.8% vs. 6.4%, HR 1.22 [95% CI 1.01 to 1.47], respectively) in a multicenter noninferiority trial of patients with gout and cardiovascular disease.[120] Febuxostat was noninferior to allopurinol with respect to a composite primary outcome of cardiovascular events. Conversely, evidence from subsequent systematic reviews suggest that there is no significant association with high blood pressure, all cause mortality, myocardial infarction, or stroke for either febuxostat or allopurinol, and no significant difference between the two treatments for the composite outcome of major adverse cardiovascular events (including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with urgent coronary revascularization) among adult patients with hyperuricemia and/or gout.[121][122][123]

Uricosuric agents

If the patient cannot tolerate allopurinol or febuxostat, starting probenecid at a low dose may be considered.[82][124]

Uricosuric agents increase renal excretion of uric acid. They are contraindicated in known over-producers of uric acid.

A 24-hour urine collection for uric acid should be obtained before prescribing probenecid. If uric acid excretion exceeds 800 mg in 24 hours, probenecid is contraindicated, as it increases the risk of urate nephrolithiasis.

Probenecid is not effective in patients with renal insufficiency. Allopurinol or febuxostat are recommended for patients with moderate-to-severe chronic kidney disease (stage ≥3).[82]

Pegloticase

Intravenous pegloticase (a pegylated recombinant mammalian uricase) is an option for patients with gout who fail to achieve a uric acid level of <6 mg/dL, and who continue to have frequent gout flares (≥2 flares/year), or have nonresolving subcutaneous tophi, with conventional urate-lowering agents.[82][125][126]

Pegloticase is associated with anaphylaxis and serious hypersensitivity reactions. Only administer this drug in a specialized care setting under a clinician who is experienced in managing infusion reactions and anaphylaxis. Monitor serum uric acid levels prior to each infusion. Discontinue pegloticase if serum uric acid level increases to >6 mg/dL, particularly if two consecutive levels are >6 mg/dL; patients who have lost therapeutic response are at an increased risk of developing infusion reactions or anaphylaxis. Other urate-lowering drugs should not be taken concomitantly as they affect serum uric acid levels. Premedicate patients with an antihistamine and corticosteroid prior to administration. Monitor patients closely during and after infusion.

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