Gout

Definition, Etiology, PathogenesisTop

Gout is a type of arthritis that is caused by the deposition of monosodium urate (MSU) crystals in synovial fluid. In addition, MSU can also be found in periarticular tissue, pinnae (as gouty tophi), kidneys (renal interstitium, tubes, and ureters), and at various other body sites.

Hyperuricemia is defined as serum uric acid levels >7 mg/dL (420 micromol/L). It may be either primary (due to an innate cause, such as a genetic abnormality of enzymes involved in purine metabolism) or secondary (due to an identifiable underlying pathology). Pathology involved in secondary hyperuricemia may be associated with:

1) Increased production of urate: Increased dietary purine intake (eg, meat, broth, some types of seafood) and tumor lysis syndrome (a common complication in solid organ transplant patients).

2) Decreased excretion of urate: Impaired renal excretion secondary to comorbid disorders (eg, patients with polycystic kidney disease, lead nephropathy), drugs (eg, diuretics, salicylates, pyrazinamide, ethambutol), and a ketogenic diet.

3) Mixed etiology: Alcohol use disorder (via accelerated adenosine triphosphate [ATP] degradation and increased lactic acid production), high dietary fructose intake (via accelerated ATP degradation and inhibition of uric acid secretion), and starvation (via increased purine conversion and impaired renal excretion).

Ultimately, however, it remains unclear what precise factors are directly responsible for the deposition of MSU crystals in synovial fluid and tissues in persons with hyperuricemia.

Crystal-induced arthritis may be acute or chronic. Recurrent acute episodes of arthritis (gouty attacks) and progression to chronic arthritis usually lead to progressive damage to articular cartilage and bone.

Clinical Features and Natural HistoryTop

Gout is most prevalent in men >40 years of age and postmenopausal women.

The natural history of gout can be divided into the following phases:

1) Asymptomatic hyperuricemia.

2) Episodes of acute gouty arthritis.

3) Periods of remission between attacks.

4) Chronic (tophaceous) gout.

Notably, the majority of patients with hyperuricemia never develop gout.

A different 4-phase classification proposal includes:

1) A high risk of gout (mostly hyperuricemia) without clinical features and without MSU crystal deposition in tissues detected by microscopy or imaging studies.

2) Asymptomatic hyperuricemia with MSU crystal deposition.

3) Acute flares of gout.

4) Tophaceous gout, chronic arthritis, and bone erosions detected by radiography.

Acute gouty arthritis manifests as sudden-onset very severe joint pain and swelling. The skin over the joint is erythematous, taut, and shiny. Epidermal desquamation develops early. Edema of subcutaneous tissue and effusions in large joints are seen. Symptoms most commonly affect the metatarsophalangeal (MTP) joint of the big toe (this is known as podagra; in ~95% of patients the joint is involved in the course of gout) and commonly occur in the early morning. Ankles, knees, and less frequently joints of the upper extremities may also be affected. Untreated acute gouty arthritis lasts from 10 days to 3 weeks and tends to resolve spontaneously. Factors triggering acute gouty arthritis include alcohol intake, fructose intake, consumption of large amounts of purine-rich foods (particularly meat), strenuous exercise, trauma, surgery, infection, low temperatures, and drugs (eg, thiazide or loop diuretics, cyclosporine [INN ciclosporin], low-dose acetylsalicylic acid [ASA]).

In patients with acute gouty arthritis recurrence may be expected after 6 months to 2 years, although the duration of remission varies. With time, gouty attacks may occur more frequently and patients gradually develop chronic polyarthritis (typically after 5-10 years). Urate deposits accumulate near the joints and in other tissues (gouty tophi) and may lead to renal failure. Approximately one-third of patients develop nephrolithiasis, which may manifest as renal colic, and 20% to 40% of patients have proteinuria. Hyperlipidemia, hyperglycemia, obesity, and hypertension often coexist with hyperuricemia, leading to an increased risk of cardiovascular diseases caused by atherosclerosis. Avascular necrosis of the femoral head is another potential complication of gout.

DiagnosisTop

Diagnostic Criteria

The diagnosis of gout can be confirmed only on finding phagocytosed MSU crystals in synovial fluid obtained by joint aspiration or in gouty tophi. The clinical diagnosis of gout is suggested by symptoms of acute monoarthritis, most frequently affecting the first MTP joint, with periarticular erythema, which is most severe in the first 6 to 12 hours. Rapid improvement after the administration of colchicine supports the diagnosis of gout. In patients with chronic arthritis diagnosis is confirmed by joint changes found on radiographs. A more formal set of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria is available at www.mdcalc.com.

Diagnostic Tests

Diagnostic tests include a combination of laboratory measures, synovial fluid analysis, imaging investigations and, at times, biopsies.

In patients with clinical presentations indicative of possible acute gout, synovial fluid analysis should be used as the diagnostic test of choice.

1. Laboratory tests: Elevated serum uric acid levels (although these may be normal during an acute gouty attack), often increased urinary urate excretion, hyperlipidemia, and elevated serum creatinine and glucose levels.

2. Synovial fluid: Inflammatory, containing MSU crystals. Cultures should always be ordered to exclude a coexisting bacterial infection. The American College of Physicians (ACP) recommends that clinicians use synovial fluid analysis when clinical judgment indicates that diagnostic testing is necessary in patients suspected of having acute gout.

3. Imaging studies: In patients with crystal deposits in cartilage and bone, radiographs may reveal narrowing of the joint space and well-defined bone erosions, sometimes with extensive osteolysis. When using ultrasonography, MSU crystals in synovial fluid may give a “snowstorm” appearance, while crystal deposits in articular cartilage may cause a “double outline.” Crystals may also be seen in vessel walls. Ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI) may demonstrate MSU deposits in periarticular tissues (eg, tendons).

4. Biopsy: Histologic examination of periarticular tophi is performed to establish whether they are due to MSU deposition (MSU or uric acid crystal deposits may also be found in renal biopsy specimens). Biopsy material should be fixed in anhydrous ethanol, because all commonly used formaldehyde solutions may dissolve the crystals. Crystals may also be found in discharge from fistulae that can develop near gouty tophi.

Differential Diagnosis

1. Acute gouty arthritis: Acute arthritis caused by calcium pyrophosphate dihydrate (CPP) crystals (also termed pseudogout), arthritis associated with hyperlipidemia, infectious arthritis, reactive arthritis, trauma, hemarthrosis, serum sickness, early symptoms of other types of chronic arthritis and inflammatory osteoarthritis.

2. Chronic gouty arthritis: Rheumatoid arthritis, osteoarthritis.

TreatmentTop

Treatment goals include rapid suppression of pain and inflammation in acute gout, preventing recurrence of gouty episodes, and inhibiting the evolution of chronic synovitis and associated connective tissue destruction.

General Measures

1. Provide patients with information about causes and consequences of gout and hyperuricemia, management of acute flares, lifestyle and dietary factors, activity, alcohol use, and urate-lowering therapies for prophylaxis. Before urate-lowering therapy is initiated, a discussion regarding benefits, harms, cost, values, and preferences should take place.

2. Weight reduction in overweight patients.

3. Low-purine diet: Avoidance of purine-rich products. Consumption of milk and low-fat dairy products is recommended.

4. Avoidance of alcohol (particularly beer), fructose, and tobacco.

5. Asymptomatic hyperuricemia is an indication for pharmacologic treatment in patients with serum uric acid levels >12 mg/dL (720 micromol/L), 24-hour urinary uric acid excretion >1100 mg, or as prevention of tumor lysis syndrome; in such instances, use allopurinol (see below).

6. An individualized management strategy with attention to concurrent comorbidities and medications.

7. Medication changes may be warranted in the presence of gout. For example, as per the 2016 European League Against Rheumatism (EULAR) guidelines, for patients on loop or thiazide diuretics, angiotensin receptor blockers (eg, losartan) or calcium channel blockers may be considered for hypertension, and statins or fibrates may be considered for hyperlipidemia.

Treatment of Acute Gouty Arthritis

1. Oral colchicineEvidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Shekelle PG, Newberry SJ, FitzGerald JD, et al. Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017 Jan 3;166(1):37-51. doi: 10.7326/M16-0461. Epub 2016 Nov 1. Review. PubMed PMID: 27802478. Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010 Apr;62(4):1060-8. doi: 10.1002/art.27327. PubMed PMID: 20131255.Ahern MJ, Reid C, Gordon TP, McCredie M, Brooks PM, Jones M. Does colchicine work? The results of the first controlled study in acute gout. Aust N Z J Med. 1987 Jun;17(3):301-4. PubMed PMID: 3314832.: Moderate-quality evidence has shown that lower doses of colchicine (initially 1.2 mg followed by 0.6 mg after 1 hour) are as effective as higher doses for pain control and have fewer adverse effects. The recommended dose as per the 2016 EULAR guidelines is a loading dose of 1 mg followed 1 hour later by 0.5 mg on day 1.

Adverse effects of colchicine are primarily gastrointestinal (diarrhea, nausea, vomiting, abdominal cramping, and pain). Colchicine should be avoided in patients with severe renal impairment and in those receiving strong P-glycoprotein or CYP3A4 inhibitors (eg, cyclosporine, clarithromycin).

2. Oral nonsteroidal anti-inflammatory drugs (NSAIDs)Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Shekelle PG, Newberry SJ, FitzGerald JD, et al. Management of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2017 Jan 3;166(1):37-51. doi: 10.7326/M16-0461. Epub 2016 Nov 1. Review. PubMed PMID: 27802478.Garcia de la Torre I. A comparative, double-blind, parallel study with tenoxicam vs placebo in acute gouty arthritis. Invest Med Int. 1987;14:92-7.: Low-quality evidence has demonstrated a significant reduction in pain and subsequent gout flares with NSAIDs. NSAIDs at maximum doses have been recommended as the drugs of choice by the British Society for Rheumatology (BSR). Adverse effects are primarily gastrointestinal, ranging from minor (dyspepsia) to major (perforations, ulcers, and bleeding) complications. NSAIDs should be avoided in patients with severe renal impairment.

3. Glucocorticoids: Oral glucocorticoids have been also recommended by the ACP in patients without contraindications. They are a cost-effective alternative, with efficacy comparable with NSAIDs and fewer adverse effects. The recommended dose as per the 2016 EULAR guidelines is 30 to 35 mg daily of equivalent prednisolone dose for 3 to 5 days. Adverse effects include mood disorders, hyperglycemia, immunosuppression, and fluid retention.

Joint aspiration and injection of a glucocorticoid have also been recommended by the BSR as being highly effective in acute monoarticular gout and, potentially, as the treatment of choice for acute flares in patients with comorbidities.

4. Animal-derived corticotropin: Moderate-quality evidence shows pain reduction in patients with acute gout receiving parenteral corticotropin, with outcomes comparable to NSAIDs and glucocorticoids. Adverse effects are assumed to be similar to glucocorticoids.

5. In patients refractory to treatment, a combination of the above anti-inflammatory therapies (colchicine, NSAIDs, glucocorticoids) may be employed.

6. In some jurisdictions interleukin-1 (IL-1) inhibitors (canakinumab or anakinra) are approved for use in specialized settings in patients who are not controlled by usual treatments.

Long-Term Prophylaxis of Recurrent Gouty Attacks

1. Avoidance of triggering factors: As above.

2. Urate-lowering therapies: To reduce uric acid synthesis, the xanthine oxidase inhibitor allopurinol remains the first-line drug of choice, with febuxostat as an alternative. To increase urinary uric acid excretion, the uricosuric agents benzbromarone or probenecid as well as fenofibrate and losartan are used. Uric acid degradation (with pegloticase) is a further option.

As per the 2020 EULAR guidelines, urate-lowering therapy is recommended in all patients with a definite diagnosis of gout who have subcutaneous tophi, evidence of radiographic damage attributable to gout, or ≥2 flares per year. The guidelines suggest against initiating long-term urate-lowering therapy in most patients after a first gouty attack and in patients with infrequent attacks, unless there is urolithiasis, stage ≥G3 chronic kidney disease, or serum uric acid >9 mg/dL (540 micromol/L).

As per the 2020 ACR guidelines, in gouty arthritis the target serum uric acid level is ≤6 mg/dL (360 micromol/L). According to 2016 EULAR guidelines lower levels are recommended in tophaceous gout (≤5 mg/dL [300 micromol/L] but not <3 mg/dL [180 micromol/L]).

Because urate-lowering therapy may precipitate an acute gouty attack, start with low doses and for the first 3 to 6 months of treatment (or longer if there is persistent inflammation) combine this with low-dose colchicine or an NSAID; if these are contraindicated or ineffective, glucocorticoids ≤10 mg/d can be used. The traditional advice was to wait 2 to 4 weeks until an acute gouty attack has resolved before starting uricosuric/urate-lowering treatment; however, there is reasonable clinical suggestion that starting allopurinol immediately is unlikely harmful.Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision.Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med. 2012 Nov;125(11):1126-1134.e7. doi: 10.1016/j.amjmed.2012.05.025. PubMed PMID: 23098865. If an acute attack occurs during uricosuric/urate-lowering treatment, the drug should not be discontinued.

1) Allopurinol: There is moderate-quality evidence that allopurinol probably does not reduce the number of acute gouty attacks but does increase the proportion of individuals achieving target serum uric acid levels without serious adverse events.Evidence 4Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Seth R, Kydd AS, Buchbinder R, Bombardier C, Edwards CJ. Allopurinol for chronic gout. Cochrane Database Syst Rev. 2014 Oct 14;(10):CD006077. doi: 10.1002/14651858.CD006077.pub3. Review. PubMed PMID: 25314636. In patients with normal kidney function, the 2016 EULAR guidelines recommend starting allopurinol at 100 mg daily and increasing by 100 mg every 2 to 4 weeks as needed to reach the target serum uric acid level. In patients with renal impairment, the maximum dosage should be adjusted to creatinine clearance. Potential adverse effects include hypersensitivity reactions (fever, rash, hepatitis, eosinophilia, renal failure).

2) Febuxostat: A second-line drug used in patients not responding to allopurinol. Potential adverse effects include abdominal pain, diarrhea, and musculoskeletal pain. Febuxostat may cause hypersensitivity reactions in patients with prior hypersensitivity reactions to allopurinol; the risk of adverse effects appears to be higher in patients with impaired kidney or liver function. Recent postmarketing trial evidence suggests that febuxostat may be associated with increased cardiovascular and all-cause mortality events compared with allopurinol. The US Food and Drug Administration suggests that it should be used only in patients in whom treatment with allopurinol has failed or is not tolerated and that clinicians should counsel patients about the drug’s cardiovascular risk.Evidence 5Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision, heterogeneity, and inclusion of nonexperimental design. Voelker R. Another Warning for Febuxostat. JAMA. 2019 Apr 2;321(13):1245. doi: 10.1001/jama.2019.3043. PubMed PMID: 30938784. Food and Drug Administration, Center for Drug Evaluation and Research. Transcript for the January 11, 2019 Joint Meeting of the Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management Advisory Committee (DSaRM). http://www.fda.gov. Accessed April 11, 2019.

3) Probenecid and benzbromarone: Uricosurics, recommended in patients without an adequate response to allopurinol alone. Recommended dose ranges according to the 2016 EULAR guidelines are probenecid 1 to 2 g daily and benzbromarone 50 to 200 mg daily. Benzbromarone is more potent than probenecid. These agents are indicated in patients with hyperuricemia caused by impaired renal uric acid excretion (<700 mg/24 h). Contraindications include age >60 years, creatinine clearance <50 mL/min, and nephrolithiasis. Combination therapy with allopurinol and a uricosuric may be more effective than allopurinol alone.

4) Pegloticase: A recombinant uricase (an enzyme that degrades uric acid to easily excreted allantoin). The 2016 EULAR guidelines recommend pegloticase in patients with crystal-proven, severe, debilitating, chronic tophaceous gout and poor quality of life, where other drugs at maximal doses are unable to achieve the target serum uric acid level. Allergic reactions are a common adverse effect.

3. Prophylactic colchicine: In patients with frequent attacks who begin urate-lowering therapy, consider long-term treatment (ie, up to 6 months) with colchicine 0.5 to 1 mg/d (EULAR guidelines) or 0.6 to 1.2 mg/d (ACP guidelines). Other prophylactic treatments (NSAIDs, oral glucocorticoids) may also be used in this setting.