Overview of Gout
Gout is the most common form of inflammatory arthritis and is caused by the presence of monosodium urate crystals formed during the course of prolonged hyperuricemia. It causes recurrent bouts of arthritis and synovitis and can also lead to tophi and destructive arthropathy. It is a common condition that can be treated by primary care providers and specialists.
It is a condition that will likely be encountered in a sports medicine practice and providers should be comfortable with the diagnosis and management. Many times there are many factors when choosing an agent that include awareness of co-morbidities and sports medicine providers may be uniquely qualified to assist in the treatment and management.
Despite the availability for more than 50 years of safe, effective, relatively inexpensive and potentially ‘curative’ urate-lowering drugs there has been a global increase in its incidence and prevalence. It affects around 4.0% of adults in the US and admissions have also been increasing in recent years . Inadequately treated gouty arthritis leads to structural joint damage, physical disability and chronic impairment of health-related quality of life. In addition, gout is frequently associated with comorbidities such as chronic kidney disease (CKD), obesity, diabetes mellitus, hypertension and cardiovascular disease, and with increased mortality [2-3].
Prolonged elevation of serum urate above its crystallization threshold is a major risk factor for developing gout. Baseline levels have been rising in the adult population due to secular increases in aging, increasing prevalence of comorbidities, drugs that raise serum urate and changes in lifestyle that have led to increased obesity. Current treatment is suboptimal, with as many as 70 percent of patients having recurrent gout attacks. It occurs 3-6 times more often in men.
The vast majority of gout patients are under excretors of urinary urate compared to the normal population. Patients with gout have higher tubular reabsorption of urate. This elevated reabsorption level is driven by genetic variation in urate transporters. The most significant genetic associations are SLC2A9 (GLUT9) and SLC22A12 (URAT1) with a large number of other genes, including numerous transporters, making smaller contributions .
The primary sources of urate are (1) dietary purines and foodstuffs that are converted into urate (eg. fructose), and (2) metabolism, from purine degradation (eg. cellular repair and replacement). Large epidemiological studies have demonstrated that intake of alcohol, sugar sweetened beverages and fructose, organ meat and seafood contribute to hyperuricemia. However, it is worth noting that there is a lack of evidence from education and intervention trials that dietary limitation of these sources of urate makes a clinically meaningful impact on the management of established gout [6-8].
While clinical characteristics can be very helpful, they cannot be relied on exclusively. Clinical symptoms of acute flares are usually characterized by rapid onset of severe pain that may come with redness, warmth, swelling and disability. This can occur within hours and often occurs at night. Early in the course of disease, acute attacks are usually monoarticular and most often affect the great toe. Around 80 percent affect the lower extremities. Maximal severity of the flare is usually reached within 12 to 24 hours. Complete resolution of the earliest flares almost always occurs within a few days to several weeks, even in untreated individuals .
The gold standard for diagnosis is the identification of monosodium urate crystals in the synovial fluid or in a suspected clinically palpable tophus. Any suspected joint can be aspirated, including the first MTP joint. Neutrophilic leukocytosis and/or elevation of the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) are common in gout flares. Serum urate levels can be difficult to interpret during a gout flare. For example, in the early months of urate-lowering drug therapy, gout flares often occur with normal or even low serum urate concentrations at the time of the acute event. The most accurate time to check serum studies is two weeks following a flare .
Subcortical bone cysts apparent on plain radiography or magnetic resonance imaging (MRI) examination can be suggestive of gouty tophi or erosions. Plain radiographs may be the first step and can also rule out stress fractures or other bony lesions. Changes of these types seen in imaging procedures are not usually detectable at the time of the first gout flare. More specific gouty lesions, such as delicate “overhanging edges” of bone associated with bone erosions due to tophi, occur with more chronic disease .
Findings on ultrasound examination can strongly and independently support the diagnosis of gout and may be useful in the early detection and monitoring of therapy. Important diagnostic features include a hyperechoic linear density (double contour sign [DCS]) overlying the surface of joint cartilage. A systematic review of the diagnostic performance of ultrasonographic findings in gout found that the DCS had sensitivities and specificities of 83 and 76 percent, respectively. For HCAs consistent with tophus, the estimate was 65 and 80 percent, respectively [9,11].
Dual energy CT scan, a technique using two X-ray beams with different energies (80 and 140 KV), has had a recent development in its use in gout. The dual-energy configuration allows a distinction between chemical entities, because each compound has a unique signature . In gout patients, DECT can distinguish between urate and calcium deposits, allowing the demonstration of urate deposits both in joints and soft tissues, particularly the frequent deposition in tendons and ligaments [21-22]. Its contribution to the diagnosis of gout is established in difficult cases.
The goal of therapy in a gout flare is prompt and safe termination of pain and disability. Management of acute flares requires treatment with one or more potent anti-inflammatory agents. Four categories are available: NSAIDs, colchicine, corticosteroids, and anti-IL-1β biologics (not FDA-approved in the US). All are effective, and selection should be directed at minimizing individual risk . Despite relative contraindications to agents in one or often several of the anti-inflammatory categories, many gout patients are treated by necessity with drugs that are potentially harmful and require monitoring.
Evidence does not show one NSAID to be superior . By virtue of prostaglandin inhibition, all NSAIDs may reduce renal blood flow, promote salt and water retention, and exacerbate hypertension and the risk of acute heart failure . Whatever NSAID is selected, gout flare treatment generally warrants higher doses (e.g. 500 bid naproxen or 400 bid celecoxib). These are usually started at 3 or 5 days and tailored depending on symptoms.
Some studies suggest that glucocorticoids and NSAIDs are roughly comparable as regards efficacy for treating acute gout flare and a few studies show that they may be superior [15,17]. American College of Rheumatology (ACR) guidelines recommend 0.5 mg/kg of prednisone or equivalent as the initial dose . Prednisone may be continued at this level until the attack is fully resolved. Alternatively, a predefined tapering strategy can be employed. As for NSAIDs, the goal is to use glucocorticoids for the shortest appropriate duration, but not too short, as tapering too quickly may result in flare recurrence.
Colchicine disrupts the assembly of microtubules, with implications for leukocyte activation, vacuolar movement and cell migration . The currently recommended dose of colchicine for acute flare is 1.2 mgs, followed by 0.6 mgs one hour later. However, in one study , the significant majority of patients treated with this dose, despite deriving some benefit, needed additional rescue medication for pain relief. The earlier the start on colchicine after the first symptoms, the better the effect, suggesting that patients should have colchicine at hand (in a nightstand, bag or pocket). Colchicine must be used with caution, and/or dose adjusted, in patients with chronic kidney disease (CKD).
Guidelines suggest the commencement of urate lowering therapy when people have more than one flare per year or have tophi or structural joint damage. Many providers will continue NSAIDs or anti-inflammatory treatment while urate lowering treatment is being started. The prevention of recurrent gout flares, tophi, and progressive structural joint damage generally requires the long-term use of drugs that reduce the serum urate concentration either by enhancing renal excretion of uric acid (uricosuric agents) or by decreasing urate synthesis (xanthine oxidase inhibitors [XOIs]), a combination of both, or by uricolytic medications, such as uricases. The choice of specific drug therapy depends upon several factors .
Upon resolution of a gout flare, the patient is said to have entered an intercritical (between flares) period. In newly diagnosed patients, the following preventive issues should be addressed during this period including risk reduction, comorbid disorders, and urate lowering drug therapy . Urate-lowering therapy is many times started around one to two weeks following a flare if indicated.
In practice, the most widely recommended goal range of urate-lowering therapy is serum urate <6 mg/dL (<357 micromol/L) , which is substantially below the urate solubility limit (serum urate of 6.8 mg/dL [405 micromol/L]). A goal serum urate of <5 mg/dL (<297 micromol/L) should be used in patients with tophi, as lower serum urate levels appear to speed resolution of tophi. The maintenance of sub saturating levels impedes the nucleation of new crystals in tissues and dissolves those already formed. Most expert groups have supported this treat-to-target approach.
Allopurinol is first line therapy for most patients at a low dose. This is typically 100 mg daily in a patient with a weight-adjusted creatinine clearance (CrCl) >60 mL/minute, with dose titration by 100 mg every two to four weeks to reach and maintain the urate-lowering goal range <6 mg/dL or 5 mg/dL.
Most providers have a preference for allopurinol based upon conflicting data regarding concerns with febuxostat regarding cardiovascular adverse effects and the ease of use of allopurinol compared with probenecid, and the reduced effectiveness of probenecid in patients with decreased renal function. Allopurinol, when dosed using a treat to serum urate target approach, has similar clinical efficacy to febuxostat .
For most patients unable to take or intolerant of allopurinol who are not high cardiovascular risk or with a history of a previous cardiovascular adverse event (eg, myocardial infarction), febuxostat can be used. Febuxostat (Uloric), an XOI with different structural and metabolic properties than allopurinol, is easier to use than most uricosurics. It is recommended that the starting dose is 40 mg once daily. Titration to a daily dose of 80 mg is suggested for patients whose serum urate level does not fall to goal levels after two weeks of treatment on 40 mg. Cost and insurance coverage is more of an issue with febuxostat.
Uricosuric drugs increase the renal clearance of UA typically by inhibiting UA reabsorption in the renal proximal tubule. Probenecid can improve the allopurinol SUA-lowering effect, but this favorable interaction is reported to be significant only in patients with eGFR > 50 mL/min . Contrarily, it should be used cautiously in subjects with CrCl < 50 mL/min, due to the lack of long term safety and efficacy data. A large observational study of 38,888 elderly gouty patients has associated probenecid treatment with a modestly decreased risk of cardiovascular events compared to allopurinol, including myocardial infarction, stroke, and heart failure exacerbation . Uricosuric agents should be avoided in patients with urolithiasis and risk of uric acid nephropathy and may be less effective in patients who are overproducers of urate.
Both probenecid and benzbromarone are proposed as monotherapy or in combination with XOIs. Although probenecid has a poor general tolerance profile and requires at least two daily intakes, benzbromarone use was impaired by very rare cases of serious hepatotoxicity, explaining its withdrawal in the US and Europe . Dosing can also be challenging with probenacid starting at 250mg and titrating up to two times a day. Some will require two, three or four tablets per dose depending on the amount of uric acid in the blood or urine. Benzbromarone is usually 100 mg once per day but can be used up to 200 mg.
In summary, gout is characterized by recurrent bouts of arthritis and synovitis and can also lead to tophi and destructive arthropathy. Many factors exist that can affect the diagnosis of gout but sports medicine providers are uniquely qualified to assist in the diagnosis by performing an arthrocentesis or doing a diagnostic ultrasound. The provider may also choose to manage gout, though this does require serial labs and awareness of other comorbidities.
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