The deposition of monosodium urate [MSU] crystal is characterized biochemically by extracellular fluid urate saturation, which is reflected in the blood by hyperuricemia, with serum or plasma urate concentrations exceeding 6.8 mg/dL (approximately 400 micromol/L); this level of urate is the approximate limit of urate solubility . This produces the clinical manifestations of gout which may include:
- Recurrent flares of inflammatory arthritis (gout flare)
- A chronic arthropathy
- Accumulation of urate crystals in the form of tophaceous deposits
- Uric acid nephrolithiasis
- A chronic nephropathy that, in gouty patients, is most often due to comorbid states
Hyperuricemia that is caused by the overproduction of urate or, more commonly, by renal urate underexcretion is necessary but not sufficient to cause gout. In one cohort study, gout developed in only 22% of subjects with urate levels of more than 9.0 mg per deciliter (535 μmol per liter) during a 5-year period. Gout tends to occur earlier in life in men, more often in post-menopausal women and is rare in childhood. In children gout occurs in instances of marked hyperuricemia due to urate overproduction, such as inherited defects in enzymes of purine metabolism or diseases with greatly increased rates of cell proliferation i,e glucose-6-phosphatase deficiency (glycogen storage disease, type I, myeloproliferative disorders, lymphoproliferative disorders, hemolytic disorders, psoriasis, obesity, Down’s syndrome, cytotoxic drugs or due to severely impaired renal uric acid clearance, as in familial juvenile hyperuricemic nephropathy.
In men, adult serum urate levels of 5 to 6 mg/dL are usually reached at puberty, with little increase thereafter due to age alone. The corresponding age-related course of serum urate levels differs in women, in whom serum urate concentrations average approximately 1.0 to 1.5 mg/dL lower than men of similar age; the lower levels result from higher urinary fractional excretion of urate during the childbearing period, which is mediated by estrogenic compounds. After menopause, the urate concentrations in women rise to levels comparable to those in adult men. It is usually not necessary to check the uric acid level in a young woman because she has the onset of arthritis. If she does have a high level of uric acid then check out her renal function. She probably has impaired renal function. Pregnant women may have a rise in uric acid levels caused by placental insufficiency. They do not have gout and need their renal function checked as well. Increase in the incidence of gout is detectable in men by the fourth or fifth decades of life and in women by the sixth or seventh decades.
Gout has two clinical phases. The first phase is characterized by intermittent acute attacks that spontaneously resolve, typically over a period of 7 to 10 days, with asymptomatic periods between attacks. With inadequately treated hyperuricemia, transition to the second phase can occur, manifested as chronic tophaceous gout, which often involves polyarticular attacks, symptoms between attacks, and crystal deposition (tophi) in soft tissues or joints. Although the prevalence of tophaceous gout varies among populations, in one study, tophi were detected in three quarters of patients who had had untreated gout for 20 years or more. Recurrent attacks are common.
Who is likely to get gout?
The use of thiazide diuretics, cyclosporine, and low-dose aspirin (<1 g per day) can cause hyperuricemia, whereas high-dose aspirin (≥3 g per day) is uricosuric. Factors that are associated with hyperuricemia and gout include insulin resistance, the metabolic syndrome, obesity, renal insufficiency, hypertension, congestive heart failure, and organ transplantation. The uricosuric effects of glycosuria in diabetes may reduce the risk of gout. The risk of incident gout is increased in persons with an increased intake of dietary purines (particularly meat and seafood), ethanol (particularly beer and spirits), soft drinks, and fructose and is decreased in those with an increased intake of coffee, dairy products, and vitamin C (which lower urate levels). Triggers for recurrent flares include recent diuretic use, alcohol intake, hospitalization, and surgery. Urate-lowering therapy, which reduces the risk of gout attacks in the long term, can trigger attacks in the early period after its initiation, presumably as a result of mobilization of bodily urate stores.
What should we rely on to make a diagnosis of gout?
The diagnostic standard remains synovial fluid or tophus aspiration with identification of negatively birefringent monosodium urate crystals under polarizing microscopy. Crystals are detectable during attacks and also potentially between attacks, primarily in previously inflamed joints in patients with hyperuricemia. However, crystal evaluation is not performed routinely in clinical practice. Hyperuricemia may not be present during acute gout attacks and therefore may not be a helpful criterion for diagnosis.
A typical presentation that is strongly suggestive of the diagnosis includes rapid development of severe pain (i.e., within 24 hours), erythema, and swelling in a characteristic joint distribution — for example, in the first metatarsophalangeal joint (podagra). In a population with a 0.5% prevalence of gout overall, a patient with hyperuricemia and this presentation has an 82% chance of having gout.
What can present as gout?
The differential diagnosis of acute gout includes:
- other crystal-induced arthritides (e.g., calcium pyrophosphate dihydrate)
- septic joint
Joint aspiration with Gram’s staining and culture must be performed if a septic joint is suspected, even if monosodium urate crystals are identified. Older adults, particularly women, may present with polyarticular involvement, which may be mistaken for rheumatoid arthritis; a tophus may be mistaken for a rheumatoid nodule. Tophaceous deposits that are not clinically apparent may be visualized by plain radiography or another imaging method. A diagnosis of gout should prompt evaluation for potentially modifiable risk factors (e.g., dietary habits) and associated coexisting illnesses (e.g., hypertension and hyperlipidemia) that may require intervention.
The American College of rheumatology has updated its recommendations for the management of gout in 2012. Each recommendation is rated as “strong” (supported by moderate- or high-certainty evidence) or “conditional” (benefits and risks are closely balanced, or only low-certainty evidence or no data are available).
(Allan S. Brett, MD reviewing FitzGerald JD et al. Arthritis Rheumatol 2020 June). Sponsoring Organization: American College of Rheumatology (ACR).
- Urate-lowering therapy (ULT) is strongly recommended for patients with two or more gout flares annually, or tophi, or gout-related radiographic damage.
- ULT is conditionally recommended for patients who have had more than one flare but whose flares are infrequent (<2 annually).
- ULT is not recommended routinely after a first gout flare but is conditionally recommended for a patient with a first flare if serum uric acid is >9 mg/dL or if the patient has stage ≥3 chronic kidney disease (CKD) or urolithiasis.
- Allopurinol is the strongly recommended first-line ULT. To minimize adverse drug reactions, the starting dose should be ≤100 mg daily (≤50 mg daily for CKD patients), with titration for weeks to months until serum uric acid level <6 mg/dL is achieved. Indications for use of second-line agents (i.e., febuxostat, pegloticase, probenecid) are discussed in the guideline.
- A 3- to 6-month course of concomitant anti-inflammatory therapy is strongly recommended when ULT is initiated and titrated.
- Colchicine, nonsteroidal anti-inflammatory drugs, and glucocorticoids (systemic or intra-articular) all are appropriate first-line agents for acute gout flares. Adjuvant application of topical ice is also conditionally recommended.
- Limiting intake of alcohol, purine, and high-fructose corn syrup is conditionally recommended.
- For patients with hypertension, avoiding hydrochlorothiazide (which raises serum uric acid) and using losartan (which lowers serum uric acid) are conditionally recommended, if feasible.
Clinical management of gout.
Acute attack of gout.
The main aim of therapy for acute gout is rapid relief of pain and disability caused by intense inflammation. Options for managing acute attacks include the use of nonsteroidal antiinflammatory drugs (NSAIDs), colchicine, glucocorticoids, and possibly corticotropin. The choice of agent, dose, and duration of therapy is guided by consideration of coexisting illnesses that preclude the safe use of a particular regimen, as well as the severity of the gout. Adjunctive measures include applying ice to and resting the affected joint.
In a randomized trial, colchicine (at a dose of 1.2 mg at the onset of a flare, followed by 0.6 mg 1 hour later) was significantly more likely than placebo to result in a reduction in pain of 50% or more 24 hours later (rates, 37.8% and 15.5%, respectively). This regimen had efficacy similar to that of a high-dose regimen (1.2 mg, then 0.6 mg per hour for 6 hours), with fewer gastrointestinal side effects.
Monoarticular attacks are often managed with the use of intraarticular glucocorticoids. In two randomized, placebo-controlled trials of a 5-day course of oral prednisolone (one evaluating a dose of 30 mg daily and the other a dose of 35 mg daily), the efficacy of prednisolone was equivalent to that of standard regimens of indomethacin (vs. the 30-mg dose of prednisolone) and naproxen (vs. the 35-mg dose).
Clinical experience suggests that 7 to 10 days of treatment may be necessary to ensure the resolution of symptoms. Increased doses of antiinflammatory drugs are typically prescribed for the first few days, with a reduction in the dose once symptoms begin to improve. Flares should be treated without interruption of urate-lowering therapy. A “medications in the pocket” strategy should be considered for patients with established gout so that therapy can be started promptly at the onset of symptoms that are consistent with typical attacks.
There is evidence that attacks of gout are caused by the activation of the NLRP3 inflammasome by urate crystals, leading to the release of interleukin-1β33. For this reason, interleukin-1 antagonists are being studied as potential options for patients in whom other treatments are not feasible.34 In a randomized trial, the fully human monoclonal antibody canakinumab significantly reduced pain from acute gout, as compared with 40 mg of intramuscular triamcinolone acetonide, 72 hours after administration of the study drug.35 Anakinra and rilonacept improved acute and chronic gout symptoms, respectively, in two small, uncontrolled pilot studies; however, rilonacept did not significantly reduce pain, as compared with indomethacin, in a randomized trial.34,36,37
Three classes of drugs are approved for lowering urate levels: xanthine oxidase inhibitors, uricosuric agents, and uricase agents. Xanthine oxidase inhibitors block the synthesis of uric acid and can be used regardless of whether there is overproduction of urate. In this class of drugs, the one most commonly prescribed to lower urate levels is allopurinol, which is effective in decreasing flares and tophi, particularly among patients in whom target urate levels are achieved.22,39
Severe allopurinol hypersensitivity is not common but can be life-threatening. Allopurinol desensitization can be attempted in patients with mild cutaneous reactions, but its safety in those with more serious reactions is unknown.44 The majority of patients receive 300 mg of allopurinol daily, but this dose is often inadequate to achieve target urate levels. Daily doses up to 800 mg may be used in patients with normal renal function. The dose is typically reduced in patients with renal impairment, owing to concerns about an increased risk of hypersensitivity in such patients.
n 2009, another xanthine oxidase inhibitor, febuxostat, was approved by the FDA for the treatment of hyperuricemia in patients with gout. As compared with a daily dose of 300 mg of allopurinol, febuxostat at daily doses of 80 mg and 120 mg was 2.5 and 3 times as likely, respectively, to achieve serum urate levels of less than 6 mg per deciliter in a 52-week trial.22
Uricosuric drugs (including probenecid, sulfinpyrazone, and benzbromarone) block renal tubular urate reabsorption. Although these drugs can be used in patients with underexcretion of urate (accounting for up to 90% of patients with gout), they are used less frequently than xanthine oxidase inhibitors and are contraindicated in patients with a history of nephrolithiasis. Benzbromarone may be used in patients with mild-to-moderate renal insufficiency but is potentially hepatotoxic, whereas the other two drugs are generally ineffective in patients with renal impairment.
Uricase converts uric acid into soluble allantoin. Pegloticase, a polyethylene glycolated (pegylated) modified porcine recombinant uricase, was approved by the FDA in 2010 for chronic gout that is refractory to conventional treatments.
Pharmacological treatment of acute gout. Pegloticase must be administered intravenously, and infusion reactions are common.46 Rasburicase, which is approved for use in preventing the tumor lysis syndrome, is not appropriate for use in patients with gout because of its immunogenicity and short half-life.
Lifestyle, nutrition and adjunct therapy.
Patients are advised to avoid alcohol, meat, sea food, fructose containing drinks. The intake of milk and dairy products may help to reduce the uric acid levels in between attacks as does the intake of vitamin C 500mg daily. Losartan and fenofibrate also help lower the uric acid levels. Because rapid lowering of urate levels is associated with gout flares, with an increased risk associated with therapies that more effectively lower urate levels,22,46 prophylaxis against acute flares is advised during the initiation of urate-lowering therapy. Oral colchicine (at a dose of 0.6 mg twice daily for an average of 5.2 months) significantly reduced the likelihood of gout attacks and lessened the severity of flares that did occur, as compared with placebo.21 Diarrhea was common, resulting in a once-daily regimen of colchicine for many patients. Thus, the general recommendation for flare prophylaxis is to use colchicine at a dose of 0.6 mg once or twice daily, with dose adjustments as needed for renal impairment, potential drug interactions, or intolerance. For patients without tophi, prophylaxis should be continued for 6 months.
I have copied the table for the pharma-therapy of gout. I have left the links in from the NEJM review article so that you can look them up yourself.