Gout is the collective name for several disorders that are characterized by the formation and deposition of monosodium urate (MSUr) crystals. The condition is associated with recurrent episodes of acute joint pain due to the deposition of MSUr crystals in the synovial fluid. In addition to the effects observed in the joints, skin/subcutaneous tissue and kidneys may also be affected by tophaceous deposits, cellulitis, urate nephropathy, and/or kidney stones, respectively. In most cases, no identifiable underlying cause of gout is present, but evident factors are usually present that may contribute to increases in urate (uric acid) levels, such as reduced renal function, obesity, and the use of diuretics. Hyperuricemia may exist for several years to decades before the first symptoms of gout attacks appear; therefore it is a disease associated and correlated with aging.
Gout is one of the most common inflammatory arthritis affecting the elderly; however in general it appears to be poorly managed.1
Partly this is due to an absence of sufficient treatment strategies and guidelines. In 2006, the European League against Rheumatism (EULAR) published the first international recommendations for the diagnosis and treatment of gout.4
The development of these EULAR and British Society of Rheumatology (BSR) guidelines coincided with improved professional and patient education as well as the urge for improved professional performance. Until recently, allopurinol was the only antihyperuricemic drug worldwide available. Two uricosurics with barriers regarding availability (benzbromarone and probenecid) have been available for years, but their exact place in treatment strategy is not clear. In 2008 and 2009 respectively, European Medicines Agency (EMEA) and Food and Drug Administration (FDA) have approved febuxostat, a novel selective xanthine inhibitor, for the treatment of hyperuricemia in gout patients, respectively. Febuxostat greatly expands the treatment options for refractory or allopurinol-intolerant gout, given the huge prevalence of the disorder and good worldwide availability of only one antihyperuricemic drug.
The incidence and prevalence of gout in the elderly is increasing.1
This appears related to improved lifespan leading to similar increases in age-related diseases (eg, cardiovascular diseases) and their associated adverse effects of treatment (eg, diuretics and low-dose salicylates) which can increase the risk of gout. “Elderly onset gout” differs from “classical” gout found in middle-aged men in several respects: no male predominance but an equal gender distribution, polyarticular presentation with upper-extremity-joint involvement, fewer acute gouty episodes, indolent clinical course, and an increased incidence of tophi.1
Several reviews have addressed the specific challenges of gout treatment in the elderly.1
This review will focus on febuxostat for the management of gout in the elderly.
Uric acid is formed from nucleic acid either endogenously from cell breakdown or exogenously from metabolism of food. Cooling and acidification of the microenvironment, which can result in acute formation of urate crystals, reduce the solubility of MSUr. The gut excretes one-third of urate and two-thirds are excreted renally. Renal urate transport is typically explained by a 4-component model: glomerular filtration, a near-complete reabsorption of filtered urate, subsequent secretion, and postsecretory reabsorption in the remaining proximal tubule.12
Recently, several new urate transporters have been identified as playing key roles in urate homeostasis, including URAT-1, and Glut9.12
The regulation of serum uric acid levels is under a strong genetic control. A recent meta-analysis of genome-wide association scans shows that common DNA variants at 9 different loci are associated with uric acid concentrations.14
Excessive consumption of alcohol (particularly beer), sweetened soft drinks, fructose, meat, and seafood can also increase levels of serum urate (sUr).12
Inhibition of urate transporters can be achieved by uricosurics, and production of uric acid can be inhibited using xanthine oxidase inhibitors, such as allopurinol. Febuxostat is a new selective inhibitor of xanthine oxidase. Uric acid deposits can also be lysed by the enzyme uricase, the coding gene for which became defective in humans in the Miocene because of an evolutionary mutation. The combined absence of uricase and almost total reabsorption of filtered urate explains that humans (and the greater apes) have 10-fold higher sUr levels than other mammals.
Chronic diuretic therapy is associated with reduced excretion of uric acid. Mechanisms are increased uric acid reabsorption in the proximal tubule secondary to volume depletion, and competition between the diuretic and uric acid for the organic acid secretory mechanism in the proximal tubule.15
Low-dose diuretic therapy in hypertensive patients does not seem to alter serum urate levels significantly.15
Indeed, the requirement for anti-gout therapy in hypertensive patients is doubled for thiazide doses of ≥25 mg/day (in hydrochlorothiazide equivalents); no significant increase in risk is seen for lower doses.15
Similarly, low-dose therapy with a loop diuretic is not associated with hyperuricemia.15
However, low-dose diuretic therapy may be effective in hypertension but insufficient in patients with chronic heart failure who often additionally suffer from chronic renal failure.
Salicylates are known to interact with renal urate handling and low doses inhibit urate excretion. In one study it was found that even mini-dose aspirin (75 mg/day) was associated with a 15% decrease of urate excretion in elderly patients.19
Thus, in elderly people with cardiovascular diseases not only diuretics, but also mini-dose aspirin is of importance.
Characteristics of gout presentation
Gout can be diagnosed with certainty only by identification of urate (MSUr) crystals, present in joints during acute attacks of gout, or in tophi. The clinical practitioner can confirm the presence and type of crystals by polarization microscopy.4
The characteristic profile of gout is that of severe monoarthritis occurring within several hours. The first metatarsophalangeal joint is affected in 50% of gout attacks, and this is known as podagra. Gout may be localized in other joints, but shoulders, hips, and the vertebral column are rarely affected. The initial gout attack usually involves monoarthritis, but long-term gout over several years may become polyarticular and could lead to increasing joint damage. Similarly, a positive uric acid balance over a number of years can cause tophaceous deposits, possibly with periodic arthritis.
Primary gout tends to involve low urate excretion, which is primarily originated in the proximal tubule. Only a minority of cases involves overproduction of urate. In some treatments of cancer (particularly lymphomas and leukemias), patients can develop tumour lysis syndrome including severe hyperuricemia with risk of urate nephropathy.
Urate nephropathy in gout
Aggressive chemotherapy among patients with chronic leukemia or malignant lymphoma could cause an excessive supply of uric acid resulting in acute urate nephropathy due to the deposition of urate crystals in collection ducts and ureters. Several kinds of urate crystals can be found, including uric acid crystals, amorphous urate, monosodium urate, and ammonium urate crystals.
In chronic hyperuricemia, the risk of developing renal crystals increases as serum urate concentrations rise. The risk is about 10% with serum urate 0.42 to 0.48 mmol/L, but can rise to 50% with serum urate concentrations >0.70 mmol/L. In the absence of stones or other risk factors (such as hypertension), the risk of urate nephropathy has generally been considered low.22
Radiographic presentations of gout
X-ray examination at the initial onset of gout has revealed no abnormalities except for possible pre-existing arthrosis and soft tissue edema. Cartilage and bone might be affected by chronic and/or recurring arthritis, and subsequently exhibit narrowing of the joint cavity because of the disappearance of cartilage, and erosions or cysts because of contact with juxta-articular bone. These abnormalities and the appearance of the erosions may raise suspicions of gout, but erosions are a secondary manifestation and non-diagnostic characteristic of early gout. In chronic gout, however, some of these characteristic changes can help with diagnosis.