Classic presentation is an acute inflammatory monoarthritis, often in the first metatarsophalangeal joint, in a middle-aged man.
Characterized by recurrent episodes of acute inflammatory arthritis.
It is characterized by low grade inflammation with elevated concentrations of pro-inflammatory cytokines and reactive oxygen species, formation of neutrophil extracellular traps, endothelium dysfunction, and platelet hyperactivity that may precipitate atherothrombosis.
It is a chronic disease of monosodium urate deposition characterized by arthritis flares and disability.
Gout flares are characterized by inflammation due to reactivation of the NLRP3 inflammasome.
Characterized by recurrent attacks of acute inflammatory arthritis and appears as red, swollen, tender joints.
Flares are separated by asymptomatic periods and can increase in frequency and severity over time.
Currently, the most common inflammatory arthritis, affecting 8.3 million US adults.
Prevalence 1-4% in developed countries.
Most recent survey in the US is that gout affects approximately 5% of US adults and hyperuricemia is present in approximately 20% of adults.
The prevalence and incidence have almost doubled between 1990 and 2010 with approximately 8 per 1000 persons affected.
Worldwide burden has grown in recent decades.
Gout burden has been magnified with the Covid-19 virus pandemic and the opioid epidemic.
Patients with gout had a higher risk for infection and death from Covid – 19.
Estimated that 10 million adults in the US have been diagnosed with gout.
Americans of Japanese descent have a higher incidence of gout and they have worse outcomes.
HLA-B*5801 gene increases risk of gout in Asian and Black individuals.
Women with gout are less likely to receive appropriate treatment, more have hypertension and chronic kidney disease, and are more likely to have a typical joint involvement.
Advanced disease develops in approximately 15% of patients: characterized by subcutaneous nodules composed of monosodium urate (tophi), unremitting articular inflammation, and potential joint erosion and deformity.
The prevalence is higher among Black people with an estimated prevalence of 4.8%, and lower among Hispanics at 2%, and estimated 4% among white people.
The increasing trend of gout burden is most likely to continue as the global aging population is on the rise.
Gout and pseudogout can present as monoarticular or polyarticular and asymmetric or symmetric.
Approximately 50% of all cases affect the big toe or the first metatarsal joint, referred to as podagra.
There are four stages of gout: asymptomatic with hyperuricemia, acute flares of crystallization, intervals between flares, and advanced gout.
Most people with hyperuricemia never develop clinical gout.
Hyperuricemia is a necessary but insufficient risk factor.
Hyperuricemia of greater than 6.8 mg/dL is 3 to 5 times as common is gout.
A disease of urate metabolism characterized by inflammatory arthritis, and is associated with a number of cardiovascular processes including coronary artery disease, heart failure, and peripheral vascular disease.
Among individuals with gout, those who experienced a cardiovascular event, compared with those who did not, had significantly higher odds of a recent gout flare in the preceding days: suggesting gout flare is associated with an increase, transiently, in cardiovascular events following the flare (Cipolleta E).
Hyperuricemia can be present decades before the first attack.
Characterized by recurrent attacks and in some patients the presence of tophi.
Recurrent attacks is the main clinical burden and despite urate lowering therapy the risk of recurrent gout is at least one attack a year is 69%.
Psoriatic arthritis is a risk factor.
Tophi consist of large aggregates if uric acid crystals and the surrounding inflammatory reaction.
Biologic basis is urate oversaturation of extracellular fluids with resulting precipitation of urate crystals.
Excess urate precipitates within joints and soft tissues, forming monosodium urate crystals.
Tophi are crystal aggregates which can deposit throughout the body and erode into adjacent joints.
Monosodium urate crystals precipitate in joints as synovial fluid is a poorer solvent than plasma.
A positive result on polarized microscopy yields 100% specificity.
Joint aspiration and other targeted tests are critical to rule out septic arthritis or pseudogout.
The joint fluid becomes supersaturated with monosodium urate, especially in peripheral joints with lowered temperatures.
Prolonged hyperuricemia cause the formation of crystals and microtophi of urates in the synovium and joint cartilage.
The release of crystals into the synovial fluid occurs for unknown reasons, but may be related to trauma, and they cause chemoattraction of leukocytes, activation of complement with generation of C3 and C5a.
Innate immune cells can engulf these crystals and trigger an interleukin 1beta mediated auto inflammatory cascade, resulting in a gout flare.
Flares generally cause swelling, redness, and tenderness in affected joints, and they can cause fevers and chills and mimic septic arthritis.
About 6 1/2% of patients suspected of having gout and pseudogout are initially crystal negative but become crystal positive after24 hours later.
Incubation of fluid at lower than body temperature plays in important role in increasing crystal formation.
Neutrophils and macrophages accumulate in the joints and synovial membranes.
x-rays of symptomatic joints of the feet or hands, may show bone erosion or advanced gout with overhanging edges and sclerotic margins.
Overall prevalence is 6 per 1000 population for men and 1 per 1000 population for women.
Mean age about 51 years.
Rarely occurs before 20-30 years of hyperuricemia.
Occurs in families and follows multifactorial inheritance and is an X linked abnormality in hypoxanthine guanine phosphoribosyl transferase deficiency.
The heritability of the serum your rate concentration may be as high as 60%.
African-Americans have a significantly lower risk for gout and hyperuricemia compared with Caucasians.
Prevalence increasing secondary to increasing longevity, subclinical renal impairment, increased incidence of obesity and increase use of drugs that may increase serum uric acid levels.
Risk factors for hyperuricemia and gout include: male sex, older age, dietary and lifestyle factors, obesity, renal impairment, the use of medications, such as diuretics, that increase urate concentrations.
hypertension, obesity, cardiovascular disease, diabetes, and chronic kidney disease are all more frequent in patients with gout, and collectively help explain the increase mortality accompanying this condition.
Heavy alcohol intake predisposes to attacks of gouty arthritis.
Obesity increases risk.
Increase risk associated with hospitalization which may be due for associated fluid shifts, alterations in pH, tissue hypoxia, change in renal urate handling, and the initiation or the discontinuation of various medications.
Hospitalization associated with more than a fourfold increased risk of recurrent gout attack, suggesting patients should be considered for prevention of gout during hospitalization for patients with preexisting gout (Dubreuil M et al).
Primary causes account for 90% of cases with overproduction of uric acid and normal excretion and in some cases increased excretion of and underexcretion of uric acid.
Secondary causes associated with nucleic acid turnover with overproduction of uric acid and chronic renal disease with reduced excretion of uric acid an normal production, and rarely inborn errors of metabolism with overproduction of uric acid and decreased urinary excretion.
Diagnosis is made by demonstrating monosodium urate crystals in synovial fluid or a tophus.
A fine needle aspiration and examination for negatively birefringment needle shaped crystals confirms the diagnosis.
Synovial fluid white counts are elevated, approximately 60,000 cells/micrL, and synovial fluid cultures should be performed if there is suspicion for the presence of a simultaneous septic arthritis.
Diagnosis includes a synovial fluid analysis, which is considered the gold standard.
Serum urate levels have no influence on gout diagnosis, but measuring baseline levels is helpful.
Serum uric acid levels are commonly elevated in patients without gout and can be normal or even low in gout.
Diagnosis, however can be made solely on clinical presentation without synovial fluid examination.
May be associated with fine deposits, refractile yellow crystals in the corneal epithelium and stroma.
Deposits may occur in the episclera and sclera, manifesting as red eyes
Tophi may be present in the conjunctiva with refractile deposits.
May be associated with subjunctival hemorrhage and tortuous vessels.
Onset before age 35 often is related to an inherited defect in metabolism.
Acute flares of crystallization are often nocturnal.
Symptoms include warmth, swelling, erythema and pain, as well as a possible fever.
Untreated gout lasts for 3-10 days, but can last much longer.
Crystallization occurs in joints, bursa, and tendons.
Intervals between flares, if left untreated, will shorten, and crystals will enter asymptomatic joints and the body urate stores increase.
During flare intervals, silent tissue deposition and hidden damage occur.
Advanced gout is characterized by chronic arthritis and joint damage visible on an x-ray.
The average time from initial attack to chronic gout is 11.6 years.
Tophi are solid urate deposits in tissues, and when more than one tophi is present the patient has stage 4 disease.
Risk factors for tophi include: a long duration of hyperuricemia, high serum urate, and long periods of active, untreated gout.
Gout risk factors include: male or postmenopausal female, advancing age, hypertension, DM, hyperlipidemia, use of diuretics, ASA, cyclosporine, transplant status, alcohol intake which is highest with beer, lowest with whiskey and not influenced with wine, high BMI/obesity, diet high in meat and seafood, and sugar-sweetened drinks.
The most important differential diagnoses include infectious arthritis, calcium pyrophosphate deposition disease (pseudogout) and spondyloarthropathy.
A normal uric acid level does not exclude the diagnosis, as in one study one third of patients with get out initially had a serum uric acid level less than 8mg/dL, and 14% less than 6 mg/dL (Schlesinger N et al).
Levels of uric acid above 7 mg/dL considered elevated because that levels exceeds saturation value for uric acid at normal body temperature and blood pH.
Many patients with chronic gout may develop urate nephropathy.
Approximately 10% of the population has hypouricemic, but gout develops in less than 0.5% of the population suggesting hyperuricemia is not the sole determinate of the development of the disease.
In younger patients overwhelmingly observed in men and over the age of 60 the incidence is equal in women.
Rare in premenopausal women and children.
Women more likely to have coexistent renal disease, hypertension and past history of diuretic treatment than male counterparts.
May be precipitated by dietary excess, trauma, surgery, myocardial infarction, excess alcohol intake, steroid withdrawal.
Periodic episodes can lead to a chronic nonsymmetrical synovitis.
Associated with thiazide diuretics as it competitively inhibits the secretion of uric acid.
Asymptomatic hyperuricemia is much more common than gout and is associated with other disorders.
Most commonly affected sites are the first metatarsal joint, the ankle and the soft tissue of the mid-foot.
Polyarticular arthritis may occur in patients with concomitant hypertension and alcohol abuse.
Typically acute episodes occur at night.
Early in the attack may resemble cellulitis.
Monosodium may be deposited in the Achilles tendon or on the external ear.
Less than 10% of patients have tophi.
Tophi form after many years of having hyperuricemia.
Frequency of associated hypertension about 40-60%.
In elderly is more likely to occur in upper extremities and is more indolent.
During acute episodes of inflammation colchicine, NSAIDs and systemic and intraarticular glucocorticoid injections provide pain relief.
Treatment goals: rapidly ending acute flares, protect against future flares, and reduce the chance of crystal inflammation, prevent disease progression and lower urate serum levels.
Medical considerations include the use of NSAIDs, and colchicine.
Colchicine, is not as affective in the later stages of flare.
Colchicine is the only agent approved to prevent flares.
Recommended colchicine dosage is 0.6 mg q per day or bid for six months.
If patients are not treated the odds of a repeat flare are at 40% versus 3% with the treatment with NSAIDs and colchicine.
In patients with gout, naproxen was associated with similar pain relief, fewer side effects and lower use of other analgesics compared to low-dose colchicine.
Naproxen should be considered ahead of low-dose colchicine in primary care on the grounds of effectiveness, safety and cost.
Corticosteroids may be used for patients who have contraindications to NSAIDs and colchicine.
Protection against future flares, requires at least 6 months of colchicine at 0.6-1.2 mg/day and/or low doses of NSAIDs.
Cherry intake lowers the risk of gout flares by 35%.
Cherry extract intake lowers risk of gout flares by 45%.
Cherries may reduce both the acute and chronic inflammation associated with recurrent gout flares and its chronic destructive arthropathy.
Allopurinol alone reduces the risk of gout flares by 53%, and when combined with cherries, reduces the risk by 75%.
Febuxostat in early gout reduces the incidence of gout flares at 24 months versus placebo.
Uricosurics alone, or in combination with the xanthine oxidase inhibitor may be effective: benzbromalone, probenecid.
Urate-lowering therapy is only to be started 1-2 weeks after an acute attack subsides, and the goal is to lower urate to < 6.0 mg/dl.
Once resolution of the acute attack occurs hypouricemic therapy is utilized to prevent recurrence.
flares may occur as a physiological consequence of rapid lowering of urate levels, so best practices include the use of anti-inflammatory prophylaxis during the initiation and adjustment phases of urate lowering therapy: a stepwise initiation of urate lowering therapy is an alternative approach.
Probenecid increases uric acid excretion is useful to increase uric acid excretion in patients excreting <600 mg/24 hours or patients dependent in thiazide diuretics.
Allopurinol is best to treat uric acid overproduction or under excretion and renal insufficiency.
Standard of care for reduction of serum uric acid is allopurinol.
Uric acid lowering therapy fails in approximately 3% of patients because of refractoriness, contraindication or intolerance.
Ineffective urate lowering management will result in many patients in progressive severe chronic gout with frequent arthritic flares, chronic arthropathy, enlarging tophi, joint deformity, chronic pain, functional impairment and impaired quality of life.
Indications for urate lowering therapy, for the treatment of gout include recurrent flares, the presence of tophi, any evidence of gout related joint damage with erosive changes on x-rays.
Earlier intervention should be taken with patients with marked hyperuricemia, renal stones, or chronic kidney disease.
High rates of cardiovascular, metabolic and renal comorbidities are present in patients with chronic gout.
Associated with the metabolic syndrome.
Flares or treated with rapid pain, resolution and restoration of function methods.
First line therapies include colchicine, nonsteroidal, anti-inflammatory drugs, and glucocorticoids, the latter administered orally, primarily or by intra-articular injection.
Colchicine is used to block NLRP3 oligomerization on the basis that nucleotide binding oligomerization domain like receptor protein 3 plays a role in gout related inflammation.
Of recommended first line treatment options parenteral glucocorticoids may offer the most rapid pain relief.
Allopurinol, a xanthine oxidase inhibitor remains the first line urate lowering therapy.
Other options include feboxostat, probenecid, a uricsuric and less commonly pegloticase.