Continuing Education Activity

Gout is one of the most common causes of chronic inflammatory arthritis in the United States, characterized by monosodium urate (MSU) monohydrate crystals deposition in the tissues. Gout was first recognized even before the common era. Hence, it is arguably the most understood and manageable disease among other rheumatic diseases. This activity reviews the evaluation and management of gout and highlights the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.

Objectives:

• Identify the clinical and biochemical markers of gout, including hyperuricemia and monosodium urate crystals, for accurate diagnosis.

• Screen for gout risk factors, hyperuricemia, and associated comorbidities, especially in at-risk patients.

• Select appropriate urate-lowering therapies, anti-inflammatory agents, and pain management strategies tailored to individual patient profiles.

• Collaborate with healthcare providers to facilitate comprehensive care, ensuring consistent messaging and therapy coordination.

Introduction

Gout, once known as the "disease of kings and king of diseases," is among the most prevalent etiologies of chronic inflammatory arthritis in the United States, characterized by monosodium urate (MSU) monohydrate crystals deposition within tissues.[1][2] Hippocrates first described gout in ancient Greece; hence, it is the most understood and manageable disease among all rheumatic diseases.[3][4]

Gout is characterized biochemically by extracellular fluid urate saturation, which is reflected by hyperuricemia in the blood, with plasma or serum urate concentrations exceeding 6.8 mg/dL (approximately 400 µmol/L); this level is the approximate limit of urate solubility.[5] The clinical manifestations of gout may include:

• Acute gout flare (recurrent flares of inflammatory arthritis)
• Chronic gouty arthropathy
• Accumulation of urate crystals in the form of tophaceous deposits
• Uric acid nephrolithiasis
• Chronic nephropathy

Etiology

The etiology of gout is usually multifactorial, including genetic predisposition, medical comorbidities, and dietary factors. In rare cases, a single genetic defect may be responsible for causing gout, usually associated with other medical complications. Irrespective of the underlying trigger, the result involves elevated serum uric acid, which can manifest as clinical gout in certain individuals.

Genes Associated with Gout

The heritability of hyperuricemia and gout is about 73% and about 40% to 50% of patients have a family history of gout.[6] Genes associated with gout fall into 4 categories (see Table. Genes Associated With Gout).[6][7]

Table 1. Genes Associated With Gout

Risk Factors

The final step of purine metabolism is the conversion of hypoxanthine to xanthine and then uric acid by xanthine oxidase, which then transforms allantoin by uricase. Allantoin has a much higher solubility than uric acid. Humans, other primates, giraffes, and Dalmatians possess gene mutations that result in the absence of uricase production,[8][9] a genetic mutation resulting in the inactivation of the uricase gene occurred about 25 million years ago. Simultaneously, there was an increase in URAT1 activity, responsible for uric acid excretion. About 20 million years ago, humans and other primates lost the ability to produce vitamin C,[9] leading to the emergence of the antioxidant theory in which uric acid replaced ascorbic acid as the main antioxidant.

One unique aspect of this evolutionary process is the development of hyperuricemia in humans, making them the only known mammals to develop spontaneous gout. Hyperuricemia is the leading cause of gout,[1][10] a condition where uric acid crystals accumulate in joints, causing inflammation and pain. Research has shown that individuals with higher serum urate levels face an increased risk of developing gout and experiencing more frequent flare-ups over time.[11][12] In a study involving over 2000 older adults with gout, those with serum urate levels exceeding 9 mg/dL were 3 times more likely to experience a flare over the next 12 months than those with levels below 6 mg/dL (see Table. Relationship Between Serum Uric Acid Concentration and Incident Gout).[13]

Table 2. Relationship Between Serum Uric Acid Concentration and Incident Gout [12]

Hyperuricemia, while a significant risk factor, does not singularly account for the development of gout (see Table. Risk Factors of Hyperuricemia and Gout); only a minority of individuals with elevated uric acid levels actually develop the condition. To assess the impact of diet on uric acid levels, examining the lower physiological uric acid range in species that do not produce uricase becomes essential. Dietary sources that can contribute to hyperuricemia and gout include the consumption of animal food such as seafood (eg, shrimp and lobster), organs (eg, liver and kidney), and red meat (eg, pork and beef). Additionally, beverages like alcohol, sweetened beverages, sodas, and those containing high-fructose corn syrup may also contribute to the onset of this disease.[1][14][15]

Epidemiological studies have reported a rising burden of gout, primarily attributed to lifestyle changes like increased protein consumption and a sedentary lifestyle. These shifts in habits underscore the intricate relationship between modern living patterns and the prevalence of gout in contemporary society.

Additional factors linked to gout and hyperuricemia include older age, male sex, obesity, a purine-rich diet, alcohol, certain medications, comorbid diseases, and genetic predisposition (see Table. Causes of Hyperuricemia). Medications such as diuretics, low-dose aspirin, ethambutol, pyrazinamide, and cyclosporine have been identified as potential contributors to elevated uric acid levels and gout development.  

Table 3. Risk Factors of Hyperuricemia and Gout [1][8][16]

Table 4. Causes of Hyperuricemia

Triggers

Any condition leading to changes in extracellular urate concentration has the potential to trigger a gout flare-up. These conditions include various factors such as stress (mainly due to medical illnesses like cardiovascular illnesses, recent surgical procedure, trauma, dehydration, or starvation), dietary choices (such as the consumption of high-purine foods like organ meats or seafood, as well as alcoholic beverages like beer, wine, and spirits), and drugs (including aspirin, diuretics, or even allopurinol).

Dietary Factors That May Lower Serum Uric Acid

Certain dietary practices have been shown to lower serum uric and reduce the risk of incident gout. Higher consumption of meat and seafood is associated with an increased incidence of gout in men. Conversely, increased intake of dairy products is associated with decreased incident gout in men.[17] Additionally, following the Dietary Approaches to Stop Hypertension (DASH) diet has been proven to decrease serum uric acid levels and mitigate the risk of gout.[18][19] Adequate vitamin C intake is associated with decreased serum uric acid and a reduced risk of gout.[20][21][22][23][24] Furthermore, incorporating cherries into the diet has demonstrated a decrease in serum uric acid[25] and a reduced risk of recurrent gout attacks.[18][26]

Epidemiology

Epidemiological estimates depend on the disease definition. A definitive diagnosis of gout is accepted in the presence of monosodium urate monohydrate crystals in the joint fluid or the identification of tophus. However, given the impracticality of identifying gout through these criteria alone, various case definitions have been devised like self-reports, Rome criteria, the New York criteria, the American College of Rheumatology (ACR) criteria, and the 2015 ACR/European League Against Rheumatism (EULAR) criteria. The 2015 ACR/EULAR criteria have a sensitivity of 92% and specificity of 89%, surpassing the accuracy of all previous definitions and ensuring a more precise and reliable diagnosis of gout in epidemiological studies. 

In men, serum urate levels typically range from 5 to 6 mg/dL and are usually attained during puberty, with a slight increase in levels due to age alone.[27] Conversely, women exhibit lower serum urate concentrations averaging 1.0 to 1.5 mg/dL, less than men of corresponding ages,[28][29] a difference likely influenced by renal uric acid clearance under the influence of estrogen. Following menopause, urate concentrations in women rise to levels comparable to those in adult men.[30] The gender-based variation in urate concentration affects the clinical differences between women and men at the onset of gout.[31][32]

The prevalence of gout can vary by age, sex, and country of origin. Generally, the prevalence of gout is 1% to 4%. Older age and male sex are 2 common risk factors recognized globally. In Western nations, the prevalence of gout is significantly higher in men (3%-6%) compared to women (1%-2%), with a notable 2- to 6-fold difference. The prevalence of gout rises with age but plateaus after 70 years (see Table. Prevalence by Age Range).

Data from 2007 to 2008 revealed that around 3.9% of US adults received a gout diagnosis.[33] Estimates regarding gout prevalence in the United States range from less than 3 million to over 8 million individuals. The latest estimates suggest a gout prevalence of over 3% among the adult American population.[34][35][36] 

Additionally, data based on the National Health and Nutrition Examination Survey (NHANES)  from 2007 to 2016 indicate a higher prevalence of gout in African-American individuals than in White individuals in the USA. Among females, gout prevalence is 3.5% in African Americans and 2.0% in White Americans, with an odds ratio (OR) of 1.81. Among males, the prevalence in African Americans is 7.0% and 5.4% in White Americans, with an OR of 1.26. Hyperuricemia was also more prevalent in African American females and males than their White counterparts, with OR of 2.00 and 1.39, respectively.[37]  

Table 5. Prevalence by Age Range 

The incidence rates of gout have displayed an upward trend over the past several decades, with a higher incidence observed in men than women and the incidence rising with age. A study conducted in Olmsted County, MN, from 1989 to 2009 revealed increased gout incidence and comorbidities over the 20 years.[38] Similarly, in the United Kingdom, the prevalence of gout experienced an escalation from 1.52% to 2.49% between 1997 and 2012.[39]

Comorbidities

Gout is associated with health risks, including obesity, hypertension (HTN), chronic kidney disease (CKD), diabetes mellitus (DM), hyperlipidemia (HLD), and metabolic syndrome. A study conducted in Olmsted County, MN, highlighted the increased prevalence of various comorbidities in gout patients compared to the general population. The prevalence of obesity (defined as BMI >35 kg/m2) was 29% in gout patients versus 10% in the general population, HTN was 69% versus 54%, CKD was 28% versus 11%, DM was 25% versus 6%, HLD was 61% versus 21%.[38] 

Gaining weight during adulthood has been consistently associated with a heightened risk of developing gout.[40][41][42] Studies from the United Kingdom and Germany have revealed associations between gout and various comorbidities, including DM, congestive heart failure (CHF), HTN, myocardial infarction (MI), and obesity. Additionally, the prevalence of comorbidities increased with higher serum uric acid levels.[43] 

Other gout-related comorbidities include HLD, hypothyroidism, anemia, psoriasis, chronic pulmonary disease, osteoarthritis, and depression.[44] Due to increased cell turnover in the epidermis, psoriasis leads to elevated uric acid production. At the same time, patients with CKD experience reduced urate excretion, resulting in hyperuricemia and an increased risk of incident gout.[45] 

Gout is associated with a heightened risk of ischemic heart disease (hazard ratio [HR] 1.86), MI (HR 3.246), and cerebrovascular disease (HR 1.552).[46] Moreover, individuals with recent gout flares experience a transient increase in cardiovascular events.[47]

Gout is linked to increased overall mortality, encompassing all-cause mortality and specific causes such as cardiovascular disease, infectious disease, and cancer-related deaths.[48] Particularly, gout is strongly associated with elevated cardiovascular mortality [49] and contributes to mortality related to renal disease, digestive diseases, and dementia.[50]

The connection between gout and dementia, including Parkinson disease, is complex and not fully understood. Studies have shown varied associations, with some indicating a lower risk of dementia,[51][52][53] specifically Alzheimer disease,[54][55] in individuals with hyperuricemia and gout. However, conflicting data suggests that hyperuricemia and gout are associated with an increased risk of dementia.[56][57] Similarly, the relationship between gout and Parkinson disease is inconclusive, with studies showing differing results, including lower,[58][59][60] no specific,[61][62] or a higher risk of Parkinson disease in patients with gout.[63]

Pathophysiology

Gout is an inflammatory arthritis triggered by the deposition of MSU crystals, the end product of human purine metabolism, in joints, soft tissues, and bones. This condition may manifest in many forms, including acute gout flare (acute arthritis), chronic gouty arthritis (chronic arthritis), tophaceous gout (formation of tophi), renal functional impairment, and urolithiasis.[64][65][66] 

The pathophysiology of gout involves a series of complex and interacting processes as follows:[67]

• Various genetic and metabolic factors contribute to hyperuricemia in the bloodstream.

• Metabolic, physiologic, and other characteristics are responsible for MSU crystal formation.

• Soluble inflammatory factors, cellular elements, innate immune processes, along with the characteristics of MSU crystals, promote an acute inflammatory response.

• Immune mechanisms come into play to mediate the resolution of acute inflammation induced by MSU crystals.

• Chronic inflammatory processes coupled with the effects of immune cells and crystals on osteoblasts, chondrocytes, and osteoclasts contribute to cartilage attrition, bone erosion, joint injury, and the formation of tophi. 

Uric Acid Physiology

Uric acid is the final product of purine metabolism in humans and higher primate species due to a mutation that silences the gene decoding the enzyme uricase.[8][9] Traditionally, it was believed that uric acid played a crucial role as a natural antioxidant in the human body, primarily responsible for eliminating reactive oxygen species. However, recent studies revealed that uric acid is not a significant factor in controlling oxidative stress. Instead, it is thought to be involved in immune surveillance and regulating blood pressure and intravascular volume.

Uric acid is a weak organic acid that predominantly exists in its ionized form, MSU, at pH 7.4. This form is less soluble due to the high sodium concentration. In acidic environments like urine, uric acid exists in its nonionized form, which is even less soluble within the physiological range. Consequently, uric acid crystals and stones can form in the urinary tract, distinguishing them from MSU associated with gout.[8]

Most urate in the body is produced endogenously in the liver with a minor contribution from the small intestines. Renal excretion is pivotal in managing the body's urate pool under steady-state conditions since the glomerulus filters nearly all urate. In a hyperuricemic state, the urate pool expands.

In men, the normal urate range is 800 to 1000 mg; in women, it ranges from 500 to 1000 mg. Urate turnover ranges from 500 to 1000 mg daily. During male puberty, serum urate concentrations increase to reach the adult range, whereas urate levels remain low in females of reproductive age. This disparity is due to estrogen's impact on renal urate transporters, resulting in less renal urate reabsorption and increased clearance in women. However, in menopausal and postmenopausal women, urate levels approach those of adult males and may be influenced by hormone replacement therapies.[8]

The following distinguishes between causes of lower and higher urate levels:

Lowered urate pool                        Raised urate pool

Hyperuricemia

Hyperuricemia plays a pivotal role in developing gout as it facilitates the nucleation and growth of MSU crystals by reducing urate solubility. Several factors promote hyperuricemia in humans, like the genetic absence of uricase, the reabsorption of 90% of filtered uric acid, and the limited solubility of MSU and urate in body fluids. An imbalance in the production and excretion of uric acid leads to rising serum uric acid levels.[10] When renal urate excretion is decreased, intestinal uricolysis increases to half of the total urate disposal, with the transporter ABCG2 playing a pivotal role. Serum urate concentrations exceeding 6.8 mg/dL become saturated and increase the risk of crystal deposition. Hyperuricemia affects 20% of adult white men in the US and is associated with several chronic disorders. 

Hyperuricemia can occur as either primary (idiopathic) or secondary. Overproduction of uric acid is observed in several diseases, toxic states, and due to certain medications. Examples include acute leukemia, tumor lysis syndrome, and psoriasis.

Purine Metabolism

Purines consist of 9-carbon purine nuclei that form fused pyrimidine and imidazole rings. Purines perform essential functions in all living cells through purine-based nucleic acids, including adenine, guanine, and hypoxanthine. The contribution of dietary purines to the urate pool is significant. Removing purines from the diet of normal individuals for 10 days reduces urate levels by 25% and urinary uric acid excretion by 50%. However, implementing severely purine-restricted diets is impractical. Conversely, diets high in fructose, meat, alcohol, and fish promote hyperuricemia.[17]

The endogenous pathway of purine production, known as de novo purine synthesis, involves the conversion of ribose-5-phosphate from 5-phosphoribosyl 1-pyrophosphate (PRPP) into nucleotide inosine monophosphate through 10 key steps. This energy-intensive process prompts energy conservation through the interconversion and salvage of purine nucleotides. Urate precursors of purine degradation are hypoxanthine and guanine, most of which are salvaged. Unused guanine is deaminated to become xanthine, while hypoxanthine is oxidized to xanthine by xanthine oxidase.[8]

Xanthine oxidase is a flavoprotein containing molybdenum-pterin and iron sulfide clusters. It operates in 2 forms: as an oxidase, utilizing oxygen to convert hypoxanthine to xanthine and then to urate, and as a dehydrogenase, using nicotinamide adenine dinucleotide (NAD+). Inhibiting xanthine oxidase is the primary target for lowering urate levels in patients with gout.

The primary regulatory steps in purine synthesis include:

1. The synthesis of PRPP in the PRPP synthetase pathway.
2. The utilization of PRPP in the first step of de novo purine synthesis.

The pathway is regulated through inhibition by purine nucleotide products of purine synthesis and activation by increased PRPP. This antagonistic control mechanism is disrupted in 2 rare X-linked disorders: deficiency of the salvage enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and overactivity of PRPP synthetase (PRS1). Conditions such as excessive adenosine triphosphate (ATP) depletion during tissue hypoxia or acute alcohol intoxication can lead to decreased concentrations of inhibitory nucleotides and excess urate production.

Renal Uric Acid Secretion

In adults, only 5% to 10% of uric acid is cleared compared to creatinine clearance, despite 100% uric acid filtration at the glomerulus. This is because 90% of the filtered uric acid is reabsorbed in the renal tubules. Consequently, individuals with hyperuricemia resulting from impaired renal excretion may exhibit normal urinary urate levels due to impaired uric acid clearance. Through genomic and molecular studies, researchers have identified several renal uric acid clearance transporters. Among these, glucose transporter 9 (GLUT9) and urate anion transoporter 1 (URAT1) strongly affect serum urate levels.[6][66]

Glucose Transporter 9 (GLUT9)

GLUT9, a product of the SLC2A9 genel, functions as a voltage-driven urate transporter responsible for mediating uric acid reabsorption from tubular cells. GLUT9 exists in 2 isoforms: GLUT9L, located on the basolateral side of the proximal renal tubular epithelium, and GLUT9S, located on the apical side. This transporter is also expressed in the hepatocytes and regulates serum urate concentrations through its dual effects in the kidney and the liver. Additionally, GLUT9 facilitates the transfer of glucose and fructose, which could explain the dietary influence of these substances on hyperuricemia. Studies involving mice with a GLUT9 knockout had moderate hyperuricemia, massive hyperuricosuria, and early-onset nephropathy.[6]

URAT1

URAT1, encoded by the SLC22A12 gene, is highly specific for uric acid and influences renal uric acid transport by mediating the exchange of various anions. Mutations in SLC22A12 can lead to hypouricemia, hyperuricosuria, and exercise-induced renal functional impairment. Uricosuric drugs like probenecid, benzbromarone, and lesinurad inhibit URAT1 and increase uric acid excretion. Other urate transporters include ABCG2, NPT1, NPT4, and multidrug resistance protein 4 (MRP4).[6]

Autosomal Dominant Tubulointerstitial Kidney Disease

Tubulointerstitial kidney disease, caused by pathogenic variants in the UMOD gene, is characterized by early-onset hyperuricemia (with or without gout), hypertension, and progressive tubulointerstitial inflammation and fibrosis. This condition leads to end-stage renal disease by the age of 40. Previously known as familial juvenile hyperuricemia nephropathy and medullary cystic kidney disease, most affected patients exhibit a mutation in uromodulin, which encodes the Tamm-Horsfall protein. Uromodulin maintains the integrity of the ascending loop of Henle by forming a gel-like lattice that coats the luminal side of the tubule. Defects in the lattice alter solute fluxes, reducing Na and Cl reabsorption, decreasing extracellular volume, and compensatory enhancement of sodium-dependent urate transport in the proximal tubule. 

Extrarenal Urate Excretion

In the intestines, urate excretion is facilitated by the ABCG2 transporter. Studies involving reduced ABCG2 knockout mice revealed that reduced intestinal urate excretion increased serum urate levels. Consequently, hyperuricemia resulting from urate overproduction can be classified as a renal overload type consisting of extrarenal underexcretion and genuine urate overproduction subtypes. 

Urate Crystal Formation

The formation of MSU crystals requires sustained supersaturated concentrations of urate. Factors like the presence of particulate seed, local cation concentrations, pH, temperature, and dehydration influence crystal formation (see Table. Factors Influencing Urate Crystal Formation).[66][68][69][70] Immunoglobulin (Ig) G may also facilitate crystal formation and growth in patients with gout. MSU crystals tend to form in the first metatarsophalangeal joint, midfoot, and Achilles tendon. Emerging evidence indicates a connection between osteoarthritis (OA) and sites of MSU crystal deposition. In osteoarthritic joints, cartilage degradation products like chondroitin sulfate lowers urate solubility, promoting nucleation and crystal growth.[68] The solubility of MSU drops rapidly with decreasing temperature, further impacting crystal formation and deposition.[5]

Table 6. Factors Influencing Urate Crystal Formation

Inflammatory Response

Histopathologic and imaging studies have shown the presence of urate crystals within joints for prolonged periods without causing overt inflammatory reactions. Heavily crystal-laden fluids (urate milk) are sometimes found in uninflamed joints and bursae. The dense urate crystal mass in tophi sometimes reaches massive dimensions with minor inflammation and symptoms until they exert critical compression of surrounding tissues.

The initiation of inflammation in gout involves microcrystals usually shed from preexisting synovial tophi. This is supported by observing acute gout flares with rapid changes in urate concentrations. The initiation of inflammation depends on multiple factors like the crystal size, the proteins and molecules coating them, and the recruitment of inflammatory cells. MSU crystal surfaces can bind to various proteins, including IgG, lipoproteins, and lipids (see Table. Inflammatory Events in Acute Gout Flare).[8]

The IgG conformational changes encourage phagocytosis by cells possessing Fc-y receptors, such as neutrophils and macrophages.[71] IgG also activates the classical complement pathway. MSU crystals can also directly activate the classical and alternative complement pathways,[72][73] leading to opsonization by depositing the complement split product C3b on the crystals. The apolipoprotein coating on the MSU crystals counteracts the opsonic effects of the IgG Fc and complement proteins. Additionally, it inhibits neutrophil stimulation. Thus, the inflammatory potential of the MSU crystals is a balance between the proinflammatory and anti-inflammatory elements coating the crystal surface. In acute gout, neutrophils are the predominant inflammatory cells in the synovial tissue and fluid, contributing significantly to the proinflammatory stimulus.[8]

In patients with asymptomatic tophi, synovial fluid macrophages frequently contain MSU microcrystals, suggesting active engagement with phagocytes without apparent inflammation. Synovial macrophages and blood monocytes mount a vigorous response to MSU crystals compared to well-differentiated macrophages due to the release of TGF-b1. Researchers have studied 2 main mechanisms of MSU crystal interaction with phagocytes.

1. Activation of phagocytes leads to lysosomal fusion, respiratory burst, and the release of lysosomal enzymes and inflammatory mediators, including TNF-alpha and IL-8.[67]
2. The predominant pathway of cytosolic protein complex activation involves the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. MSU crystals activate macrophages and monocytes via toll-like receptors (TLR) 2 and 4, resulting in signal transduction by My88, interleukin-1 receptor-associated kinase 1 (IRAK1), and IRAK4. This activation triggers nuclear factor-kB, which activates the NLRP3 inflammasome. The activated NLRP3 inflammasome subsequently recruits caspase-1, which processes pro-interleukin-1Β (IL-1Β) into its active form, IL-1Β. IL-1Β plays an important role in the inflammatory response to gout by promoting vasodilatation, recruiting monocytes, and initiating and amplifying the inflammatory cascade. Additionally, IL-1Β secretion can result in bone and cartilage breakdown. Other cytokines, such as TNF-alpha, IL-6, CXCL8, and cyclooxygenase 2 (COX-2), are also involved in the inflammatory response.[66][67][70][74][75][76]

Unlike most external stimuli that activate inflammatory cells by a carefully coordinated cell surface signal transduction involving a cascade of tyrosine kinase phosphorylation, MSU crystals bypass this process and directly activate second messenger systems. 

Table 7. Inflammatory Events in Acute Gout Flare

Termination of The Acute Flare

Acute gout is inherently self-limiting, even without intervention, typically resolving spontaneously within a few days to a few weeks. This phenomenon is intriguing, given the similarity in the molecular mediators of inflammation in gout and other arthropathies and the persistence of MSU crystals.

Following MSU crystal ingestion, neutrophils undergo NETosis (neutrophil extracellular traps). These NETs aggregate and densely pack MSU crystals while degrading the proinflammatory cytokines, including IL-Β, TNF-α, and IL-6. The increased vascular permeability after acute synovitis allows increased entry of anti-inflammatory cytokines and crystal-coating molecules like apolipoprotein B (apoB). Coating with apoB and locally produced apoE and transforming growth factor Β (TGF-Β) inhibits neutrophil activation. Systemic anti-inflammatory mediators like melanocortins decrease joint inflammation by the macrophage melanocortin receptors (MCRs), and adenosine monophosphate-activated protein kinase inhibits NLRP3 expression, which inhibits the cleavage of caspase-1 and secretion of IL-1Β.[66][67][74][76] 

Advanced Gout

Tophi are deposits of MSU crystals associated with granulomatous inflammation. They are nests of crystals surrounded by a corona zone composed of differentiated macrophages and multinucleated giant cells encased within a fibrous layer. Proinflammatory cytokines like IL-1 and TNF-α are expressed within the corona. Aggregated NETs are also part of the tophus. The tophus is a dynamic chronic inflammatory response to MSU crystal deposition that is complex and organized.

Tophi are primarily found in periarticular, articular, and subcutaneous areas, including cartilage, bone, joints, tendons, and skin, all rich in proteoglycan. The tissue reaction to tophus is generally chronic inflammation and is both adaptive and innate immunity. Few patients with tophaceous gout also present with chronic gouty arthritis (chronic synovitis). There is a close relationship between MSU crystal deposits and the development of cartilage and bone erosions.[77] 

Tophi contribute to joint damage and bone erosion in gout.[78] At the bona and a tophus interface, MSU crystal deposits are surrounded by osteoclast-like cells.[79] T-cells within the tophus express the receptor activator of nuclear factor κB ligand (RANKL), continuing to bony erosions. Additionally, urate crystals decrease osteoblasts' function, viability, and differentiation and reduce osteoprotegerin expression. Hence, more osteoclasts and reduced osteoblasts are present at the bone-tophus interphase.

The double-contoured ultrasound sign is observed in the superficial articular cartilage of patients with chronic gout and represents the presence of urate deposits. Urate crystals degrade cartilage matrix by inducing nitric oxide generation and the expression of matrix metalloprotease 3. Consequently, joints with persistent crystals experience ongoing progressive damage in the absence of acute flares. 

Histopathology

When examined under polarized light microscopy, MSU crystal deposition is typically described as a rod or long needle-shaped crystal with negative birefringence.[80] When viewed under light microscopy, tophi exhibit distinct zones: the crystalline center, the surrounding corona zone, and the fibrovascular zone. The corona zone contains multinucleated giant cells, histiocytes, and plasma cells.[81]

History and Physical

Gout has been described as a chronic disease characterized by 4 distinct stages.[3]

1. Asymptomatic hyperuricemia
2. Acute gout attacks
3. Intercritical period
4. Chronic tophaceous gout. 

Asymptomatic Hyperuricemia

The majority of patients with asymptomatic hyperuricemia never develop gout. The risk of an acute gout attack increases with the serum urate level. This stage ends with the occurrence of the first gout attack.

Acute Gout Attack

The initial manifestation of gout is an acute attack of arthritis, usually monoarticular, marked by the abrupt onset of severe pain and swelling. Maximum inflammation occurs within 12 to 24 hours. Gout flares are typically monoarticular, with 85% to 90% of cases occurring in the lower extremities.[3][82] The first metatarsophalangeal joint is the most commonly involved, with about 50% of initial attacks occurring there and 90% of patients experiencing at least 1 attack in this joint.[3] The talar, subtalar, ankle, and knee can also be involved. In 3% to 14% of cases, the initial attack is polyarticular, causing some confusion.[3] 

Although affliction of the joints mentioned above is common in gout, healthcare professionals should also consider other joints, specifically those with underlying osteoarthritis. Periarticular structures such as tendons and bursa may also be involved.[1] While gout can occur in axial joints such as sacroiliac joints and the spine, this is much less common than peripheral involvement, leading to diagnostic confusion.[83][84] Acute gouty arthritis may be associated with fever and leukocytosis, making it difficult to differentiate from septic arthritis. The initial attack resolves within 3 to 14 days, even without pharmacotherapy. Over time, gout flares occur more frequently, become less intense, and involve more joints.[3] 

Polyarticular gout flares are more likely to occur in patients with longstanding disease. Initial presentation of polyarticular gout is more frequent in patients in whom gout and hyperuricemia arise secondary to lymphoproliferative or myeloproliferative disorders or in organ transplant recipients receiving tacrolimus or cyclosporine.[85][86]  Additionally, in South Africa, a polyarticular presentation in women, with only a small number starting with acute podagra. Rarely, patients may develop tophi without a history of acute gouty flares.

Gout flares are more common at night and early morning when cortisol levels are low.[87] The pain is often sudden, waking the patient from sleep, or it may have developed gradually over a few hours before the presentation, reaching its maximum intensity of pain at 24 hours.[87] Signs of inflammation may extend beyond the joint involved, giving the impression of cellulitis with erythema and desquamation or dactylitis (sausage digit). The pain is usually severe and not responsive to usual home remedies; even touching the joint can be excruciatingly painful. Gout flare-ups often incite local inflammation, which presents as erythematous, swollen, and warm joints. The erythema over the affected joint during an attack is characteristic of gouty synovitis. Systemic inflammatory features may include fever, malaise, and fatigue.[1] 

Around 60% of the patients experience a second attack within 1 year, and 80% within 3 years. Acute attacks can be precipitated by local trauma, alcohol binges, overeating or fasting, weight changes, use of diuretics, and initiation of urate-lowering drugs. In a hospital setting, postoperative status or acute severe medical illnesses such as myocardial infarction, exacerbation of congestive heart failure, or cerebrovascular accident may precipitate attacks.[3] It is not unusual for patients to receive urate-lowering therapy (ULT) during hospitalization, possibly leading to a gout flare. Additionally, the spring season has reportedly been associated with increased gout attacks.  

Physical examination findings in gout align with the patient's history. The affected joint is typically red, swollen, warm, and tender.[88] The flare-up in patients with chronic gout may involve multiple joints, causing a systemic inflammatory response syndrome that may mimic sepsis.[89] Tophi, subcutaneous deposits of urate which form nodules, can be found in patients with persistent hyperuricemia. Tophi typically occur in the joints, ears, finger pads, tendons, and bursae.[1]

Intercritical Gout

After resolving the acute attack, the patient enters the intercritical stage. Patients typically feel well during this stage without experiencing joint pain or swelling. Despite the apparent inactivity of the disease, hyperuricemia persists, and crystal deposition continues. Subclinical inflammation may be present in the joints during this period.

Chronic Tophaceous Gout

Patients with gout who are untreated or undertreated may develop chronic tophaceous gout over several years, leading to gradual progressive joint destruction. Gouty tophi, which are foreign bodies surrounded by granulomas containing deposits of MSU crystal, manifest as chalk-like subcutaneous nodules beneath transparent skin with increased vascularity. These nodules may or may not drain. While some patients may present with tophi as their initial symptom, chronic tophaceous gout usually develops 10 or more years after an acute attack. However, microtophi can be observed early in the disease, especially in patients with hyperuricemia. MSU crystal deposition is evident in joints affected by osteoarthritis, primarily in the connective tissue and articular cartilage.

Tophi may occur intraarticularly, periarticularly, or extra-articularly, with common sites including the digits of hands and feet, knees, and the olecranon bursa. This condition leads to destructive deforming arthritis, extensive bone destruction, and severe deformities. Women develop tophaceous deposits on the Heberden nodes and Bouchard nodes. Finger pad tophi were observed in 30% of patients with chronic tophaceous gout. Postmenopausal women with CKD may exhibit finger pad tophi before the onset of an acute attack.[3][2][66]

Tophaceous deposits have been documented in various uncommon sites, including the eye cornea and heart valves. These deposits highlight the systemic nature of gout and its potential to affect diverse tissues and organs beyond the joints.

Evaluation

Synovial Fluid Analysis

Monosodium urate crystal identification remains the gold standard for diagnosing gout.[80] Gout flares are marked by MSU crystals in synovial fluid obtained from affected joints of bursas, visualized through direct examination of a fluid sample using compensated polarized light microscopy. The crystals are often intracellular, indicating active phagocytosis. This technique can also identify uric acid crystals from tophaceous deposits and joints during the intercritical period.[90] During a gout flare-up, synovial fluid is usually yellow and cloudy, containing crystals and white blood cells (WBCs) with neutrophil predominance.

In patients with septic arthritis, the synovial fluid will be more opaque, with a yellow-green appearance. Microscopic examination reveals a higher WBC count (>50000/microL) with a predominance of neutrophils. However, there is considerable overlap in WBC counts and neutrophil percentages between patients with acute gouty arthritis and septic arthritis, making these parameters unreliable for diagnosis. Positive synovial fluid gram stains and cultures, along with low synovial fluid glucose levels, are common findings in septic arthritis. It is essential to note that the presence of crystals in synovial fluid analysis does not rule out septic arthritis, as both conditions can coexist.[91][92]

Under polarizing microscopy, synovial fluid or tophus aspiration analysis reveals needle-shaped, negatively birefringent crystals.[1][3][93] Arthrocentesis is essential to confirm the diagnosis and differentiate it from other conditions such as septic arthritis, Lyme disease, or pseudogout (caused by calcium pyrophosphate crystals).[93]

Laboratory Study

The examination usually reveals elevations in the WBC, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during acute gouty arthritis. These features are nonspecific and do not confirm or differentiate the diagnosis from septic arthritis.[91]

During acute gouty arthritis, the serum urate level may be high, normal, or low. About 50% of patients with acute gouty arthritis will not have an elevated serum uric acid. Serum uric acid measurement during an acute attack is of no diagnostic value; it is most useful when checked after the resolution of the flare. Hyperuricemia is helpful in the clinical diagnosis of gout in symptomatic patients, but hyperuricemia alone does not confirm the diagnosis. Asymptomatic hyperuricemia is not uncommon in the general population. Persistently low serum uric acid concentrations make the diagnosis of gout unlikely.[3] In patients suspected of gout based on clinical features, an elevated serum uric acid level (>6.8 mg/dL) can support the diagnosis but is neither diagnostic nor required to establish the diagnosis. The most accurate time to assess serum urate level to establish a baseline value is 2 weeks or more after a gout flare has subsided.

Urinary fractional excretion of uric acid can be measured, especially in young populations with nonspecific causes of hyperuricemia. The measurement can help differentiate between overproduction or underexcretion of uric acid and can guide therapy.

Imaging

Although not routinely used, ultrasonography and dual-energy CT (DECT) can assist in diagnosing gout.[94][95][96][97] On ultrasound, MSU deposition appears as a hyperechoic enhancement over the cartilage, known as the double contour sign. DECT can identify urate deposits based on the beam attenuation after exposure to 2 different X-ray spectra.[1][3] In a pooled analysis, the ultrasound double contour sign had a sensitivity of 83% and a specificity of 76%, while DECT had a sensitivity of 87% and a specificity of 84% for diagnosing gout.[95] A meta-analysis of ultrasound's diagnostic accuracy, which included features like the double contour sign, tophus, or bony erosion, showed a sensitivity of 65.1% and specificity of 89% for a diagnosis of gout.[98] 

Treatment / Management

Specific goals guide the treatment of gout. During acute flares, the primary objective is to alleviate inflammation and symptoms. In the long term, the goal shifts toward reducing serum urate levels to suppress flare-ups and regression of tophi.[3][99][100]

General Principles of Therapy

• Early on, introducing treatment for a gout flare leads to a more rapid resolution of symptoms.

• The duration of gout flare therapy ranges from a few days to several weeks, depending on the timing of treatment initiation.

• Anti-inflammatory gout flare prophylaxis should generally be continued during the early months (up to 6 months) of ULT.

• For patients receiving ULT at the time of gout flare, the urate-lowering medication should be continued without interruption as there is no benefit to temporary discontinuation.

• The presence of tophi indicates initiating long-term ULT either during or following the resolution of a gout flare to reverse or prevent joint damage and chronic gouty arthritis.

Acute Gout Flare

The management of acute flares of gouty arthritis aims to decrease inflammation and resulting pain. Treatment should commence within the first 24 hours of onset to reduce the severity and duration of the flare-up if possible.[10] Nonpharmacological management, such as rest with topical application of ice packs [101] can be combined with medications that reduce inflammation.[102] First-line treatments for gout flares are nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or systemic glucocorticoids.[103] The length of treatment should be at least 7 to 10 days to prevent rebound flare-ups.[104] Early initiation of NSAIDs may lead to the resolution of the attack with a single dose.

NSAIDs

NSAIDs are most effective when therapy is initiated within 48 hours of the onset of gout symptoms. Indomethacin and naproxen are the more potent NSAIDs for gout, although many other commonly used NSAIDs exist. NSAID names and dosing are as follows:

• Indomethacin 50 mg 3 times daily
• Naproxen 500 mg twice daily
• Naproxen 500 mg twice daily
• Ibuprofen 800 mg 3 times daily
• Diclofenac 50 mg 2 to 3 times daily
• Celecoxib 200 mg twice daily

Typically, NSAID treatment for gout flare lasts for 5 to 7 days. There is no significant preference for one NSAID over another, but high-dose, fast-acting NSAIDs such as naproxen or diclofenac are options. Indomethacin is not preferable due to its toxicity profile.[10] NSAIDs are usually given in full doses for the first 3 days and then tapered according to the clinical improvement. COX2 selective inhibitors like celecoxib can be used to reduce adverse GI effects.

Contraindications for the use of NSAIDs include active duodenal or gastric ulcer, cardiovascular disease (uncontrolled HTN or CHF), NSAID allergy, and CKD with creatinine clearance (CrCl) of less than 60 ml/minute per 1.73 square meters. Aspirin is not recommended for treating gout flares due to the paradoxical effects of salicylic acid on serum urate levels.[105][106] This paradoxical effect results from uricosuria at higher doses and renal uric acid retention at lower doses (less than 2 to 3 g/day).[107][108]

Oral Glucocorticoids

Glucocorticoids are recommended for gout patients with contraindications to NSAIDs and colchicine, and they are also preferred for patients with renal insufficiency. The initial dose for a gout flare is:

• Prednisolone or prednisone 30 to 40 mg once daily or divided into twice-daily doses until resolution begins. Taper the dose over the next 5 to 10 days.

This has been proven to be at least comparable to NSAID efficacy. High starting doses of systemic steroids (>0.5 mg/kg body weight) are required for acute gout, especially in patients with a polyarticular presentation. A depot preparation for triamcinolone (60mg once) or methylprednisolone has been reported to be effective.[109][110] However, the dose may need to be repeated at intervals of 48 hours to achieve resolution of the flare. Glucocorticoids can be administered intra-articularly for a monoarticular gout flare-up or orally for polyarticular flare-ups. The efficacy of glucocorticoids is similar to or superior to other agents and has no greater risk of adverse effects in most patients.[111][112][113]

In patients with an unclear diagnosis of an acute gout flare, arthrocentesis and synovial fluid analysis should be performed, and oral and intra-articular glucocorticoids should be avoided until the results are available. Initiation of other agents, such as NSAIDs or colchicine, should be considered. Frequent adverse effects of moderate- to high-dose, short-term glucocorticoid use include hyperglycemia, fluid retention, increased blood pressure, and mood changes. Repeated and regular courses of glucocorticoids should be avoided to limit adverse effects.

In patients with concomitant or suspected infections, uncontrolled diabetes mellitus, prior glucocorticoid intolerance, and post-operative status, glucocorticoids may heighten the risk of impaired wound healing. Careful consideration of these factors is crucial when determining the appropriate course of treatment for patients with gout flares.

Parenteral Glucocorticoids

Intravenous or intramuscular glucocorticoids are suggested for patients who are not candidates for intraarticular glucocorticoid injection or cannot take oral medications. A typical methylprednisolone dose is 20 mg intravenously twice daily, with a stepwise reduction and rapid transition to oral prednisone when improvement begins. Adrenocorticotropic hormone (ACTH) is also efficacious for treating gout flare, but limited availability and high cost restrict its use.

Colchicine

Colchicine, derived from the Colchicum autumnale plant and with a history spanning over 3500 years,[114] has proven comparable in efficacy to other agents when taken within 24 hours of gout flare onset. In a randomized control trial, colchicine reduced pain by over 50% at 24 hours compared to a placebo. The lipophilic nature of colchicine makes it readily bioavailable for cellular uptake after oral administration. The primary target of colchicine is tubulin, and it is metabolized through hepatic elimination.

Colchicine acts by binding tightly to unpolymerised tubulin and forms a colchicine-tubulin complex that regulates microtubule and cytoskeletal function. This regulation extends to diverse cellular processes, including cell proliferation, gene expression, signal transduction, chemotaxis, and neutrophil secretion of granule contents. Furthermore, colchicine decreases neutrophil adhesion by suppressing E-selectin redistribution in the endothelial membrane.

EULAR consensus guidelines recommend a maximum of 3 doses of 0.5mg of colchicine daily for treating acute gout. The total colchicine dose should not exceed 1.8 mg on day 1, 1.2 mg for the first dose followed by 0.6 mg an hour later [US Food and Drug Administration (FDA) approved dose] or 0.6 mg 3 times on the first day.[115] On subsequent days, colchicine should be taken once or twice daily until the gout flare resolves.[116]

A reduced dose of colchicine may be required for patients with diminished hepatic or renal function or those at risk of potential drug interactions. Colchicine toxicity can occur with ABCB1 inhibitors like cyclosporin and clarithromycin; neuromyopathy may develop weeks after initiating cyclosporin. High-dose colchicine regimens should be avoided due to their high toxicity. Adverse effects of colchicine include gastrointestinal (GI) symptoms like nausea and diarrhea, myotoxicity, and myelosuppression (leukopenia, thrombocytopenia, and aplastic anemia).[117] The most common adverse effects are abdominal cramping and diarrhea.[115][118] Intravenous colchicine is strongly discouraged due to serious adverse effects, including death, and it is no longer approved by the FDA in the US.

Colchicine dosing adjustments for certain high-risk groups of patients should follow the guidelines outlined in the manufacturer's FDA-approved information. Typically, a maximum of 0.3 mg dose is administered on the day of a gout flare, and the dose is not repeated for at least 3 to 7 days or longer in such patients. The high-risk groups include: 

• Individuals who have used colchicine prophylaxis in the last 14 days possess normal hepatic and renal function and have taken a medication that inhibits P-glycoprotein or is a potent inhibitor of CYP3A4 within the previous 14 days. 

• Individuals who have used colchicine prophylaxis in the last 14 days, regardless of hepatic and renal status, and have taken a medication that is a moderate CYP3A4 inhibitor within the same timeframe.

• Individuals with advanced hepatic or renal impairment (Child-Pugh C cirrhosis or equivalent CrCl of <30 mL/min), regardless of recent colchicine use. 

Colchicine exhibits interesting effects beyond treating and preventing gouty arthritis flares. Research suggests it has a beneficial effect on cardiovascular events.[114][119][120] A population study linked colchicine use in patients with gout to reduced cardiovascular events and all-cause mortality.[121] In a randomized, double-blind trial involving post-MI patients within 30 days (n = 4,745), low-dose colchicine use lowered the risk of cardiovascular events (resuscitated cardiac arrest, MI, stroke, and angina leading to revascularization) compared to placebo: 5.5% with colchicine versus 7.1% with placebo; HR 0.77 (95% CI 0.61-0.96; P=0.02).[122] While colchicine did not affect outcomes like death from cardiovascular causes, resuscitated cardiac arrest, or MI, it notably reduced stroke and angina, leading to coronary revascularization.

Prophylaxis For Acute Gout

The subclinical joint inflammation in gout justifies colchicine prophylaxis, as acute gout flares are ULT's most common adverse effect. For prophylaxis, low-dose colchicine therapy is the first choice.[123][124] It is commenced 1 or 2 weeks before using urate-lowering drugs and continues for up to 6 months after normalizing uric acid levels or until the clinically visible tophi are resolved.[124][123]  Low-dose NSAIDs and low-dose corticosteroids can be used but carry more toxicity.[125] The recommended colchicine dosage is 0.6 mg once or twice daily without renal or hepatobiliary compromise. In patients with renal impairment, the colchicine dose may be reduced to 0.3 mg daily or 0.6 mg every other day.

Interleukin-1 Inhibition

IL-1 antagonists have shown efficacy in refractory cases of gouty arthritis. Anakinra, a soluble IL1 receptor antagonist, is administered at 100 mg/day subcutaneously for 3 days [126][127] or a single dose of IL-1 beta monoclonal antibody, canakinumab.[128][129] The subcutaneous dose of 150 mg canakinumab was more effective than a single-dose intramuscular (IM) dose of triamcinolone acetonide, although the risk-benefit ratio is uncertain.

Urate lowering therapy (ULT)

Non-pharmacologic treatment

Gout is associated with several comorbidities, including obesity.[38] In a study examining the association between obesity and gout, adults aged 40 to 75 years (n = 11,079) in NHANES 2007 to 2014 were categorized into 4 groups: stable obese, weight gain, weight loss, and those maintaining a normal BMI over time (reference group).[40] Among those with stable obesity, the risk of gout was the highest, with an HR of 1.84 (95% CI 1.08-3.14). Patients who gained weight as adults also exhibited an increased risk of gout with HR of 1.65 (95% CI 1.19-2.29).

Diet can affect serum uric acid levels. Weight loss and dietary adjustments can reduce serum uric acid by 1 to 2 mg/dL. Foods high in purines, such as organ meats, shellfish, and beer, can elevate uric acid levels. Soft drinks containing high-fructose corn syrup are associated with an increased risk of gout;[14][15] therefore, reducing their intake can help reduce serum uric acid. The DASH diet has been proven to lower serum uric acid compared to a standard Western diet, making it beneficial for gout management.[18] Consuming at least 500 mg daily of vitamin C has also been shown to decrease serum uric acid levels and lower the risk of incident gout.[20][21][22][23][24] Studies have shown that higher doses of vitamin C correspond to reduced risk of gout in men.[23] Cherry consumption has also been linked to lowered serum uric acid levels[25] and a decreased risk of recurrent gout attacks[26].

Pharmacologic

The 2020 American College of Rheumatology Guideline for managing gout [100] advises against initiating ULT after the first episode of acute gouty arthritis. ULT should not be initiated in patients with asymptomatic hyperuricemia. The guidelines provide specific criteria for initiating ULT, including the following:

• Frequent or disabling gout flares (≥2 yearly) that are difficult to treat
• Gout with chronic kidney disease (stage 3 or higher)
• Tophus diagnosis on physical examination or imaging
• Past urolithiasis
• Chronic tophaceous gout

The decision to initiate ULT should be individualized. For instance, in a younger patient with their first gout attack with elevated serum uric acid levels, the likelihood of future gout attacks and progressive joint damage with tophi is higher, making it prudent to start ULT. Conversely, in an elderly patient with gout, multiple comorbidities, and taking multiple medications, the decision to treat may be more nuanced, and careful consideration should be given in this scenario. It is essential to note that the guidelines are to provide guidance but not dictate therapy.

ULT is started at a low dose to monitor the side effects and treatment response. Dose adjustments are made every 2 to 6 weeks to achieve serum urate levels of less than 6 mg/dL or 5 mg/dL in patients with tophi.[100][130] The 2020 American College of Rheumatology Guideline conditionally recommends starting ULT during acute gout flares, with some evidence supporting its safety with medications like allopurinol [131][132] and febuxostat.[133] However, initiating therapy during an acute attack might pose challenges regarding patient compliance, especially considering that patients experiencing acute flares are often hospitalized for the first time.

During the initiation of ULT, there is an increased risk of gout flare-ups. As a prophylactic measure, colchicine is recommended for 3 months after achieving the serum urate goal in patients without tophi or 6 months in those with tophi. This strategy helps to minimize the risk of flare-ups during this critical period.[100]

ULT can be categorized into 3 classes based on their mechanisms:

Xanthine oxidase inhibitors (XOI) 

XOIs work by inhibiting uric acid synthesis. This class includes allopurinol and febuxostat. Allopurinol is the recommended first-line pharmacologic ULT in gout.[100] Physicians should regularly monitor liver enzymes, renal function, and blood count. Adverse effects from allopurinol can range from skin rashes to life-threatening severe allopurinol hypersensitivity, especially in HLA-B*5801-positive patients.[1][100]

Allopurinol

Allopurinol is converted to its active metabolite oxypurinol in the liver and has a half-life of 24 hours. The initial allopurinol dose is 100 mg daily in patients with CrCl more significant than 60 mL/min and is titrated upward by 100 mg every 2 to 4 weeks. A daily dose of 300 mg of allopurinol reduces serum urate levels in 33% of the population. Allopurinol can be increased above 300 mg daily to achieve the target serum uric acid.

Allopurinol is taken once daily. Medications like allopurinol and oxypurinol lower the serum urate by a dual action of inhibiting xanthine oxidase inhibitor and by competing with phosphoribosylpyrophosphate in the salvage pathway and through suppressive effects of drug nucleotides on aminotransferase activity. Allopurinol also nonselectively inhibits pyrimidine metabolism. In patients with stage 3 or greater CKD, the starting dose of allopurinol should be 50 mg daily.[100] 

Adverse effects associated with allopurinol include the potential to trigger gout flares, pruritic and maculopapular rashes, leukopenia, thrombocytopenia, diarrhea, and severe cutaneous adverse reactions. Bone marrow suppression is uncommon but may occur at very high doses or in patients with CKD. Allopurinol can lead to a drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, a life-threatening reaction to allopurinol.

Major hypersensitivity reactions like Steven-Johnson syndrome or toxic epidermal necrolysis may occur in major allopurinol hypersensitivity syndrome (AHS). The highest risk for AHS occurs in the first 60 days after initiating allopurinol therapy. Patients who carry the HLA-B*5801 allele are at increased risk for developing severe hypersensitivity reactions, which are more common in people of Han Chinese, Korean, or Thai descent.[100][134] Testing for this allele is advisable in high-risk patients. Starting at a low dose and gradually increasing it can decrease the risk of adverse reactions. The recommended starting dose is 1.5 mg per unit of estimated GFR.[135] Interestingly, allopurinol can be safely increased above 300 mg daily, even in patients with CKD, to achieve the target serum uric acid.[136]

Allopurinol can enhance the cytolytic and immunosuppressive effects of azathioprine and 6-mercaptopurine (6-MP), as these drugs are partially metabolized by xanthine oxidase.[137] Therefore, allopurinol should be avoided in patients undergoing treatment with these agents.[138] Additionally, in patients on warfarin, their anticoagulation status must be carefully monitored when allopurinol is prescribed.

Febuxostat

Febuxostat is a selective XOI that occupies the access channel to the molybdenum-pterin active site of the enzyme. Renal elimination plays a minor role in febuxostat pharmacokinetics. FDA approval for febuxostat in treating patients with gout and hyperuricemia includes initial daily doses of 40 mg. If the urate levels do not normalize within 2 weeks, the dosage is increased to 80 mg daily. Studies have demonstrated the superior effectiveness of febuxostat over allopurinol (maximum dose of 300 mg daily).[139][140] However, febuxostat may be more common with allopurinol than cardiovascular and hepatic abnormalities. In patients with CKD, febuxostat exhibits a more potent urate-lowering than allopurinol. Febuxostat has a distinct chemical structure, making it an option for patients who have experienced hypersensitivity reactions to allopurinol. Patients taking azathioprine, 6-MP, and theophylline are considered contraindications for the use of febuxostat.

In the CARES trial, which focused on cardiovascular safety in patients with gout and a history of cardiovascular disease, febuxostat and allopurinol were compared.[141] The primary endpoint, a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or unstable angina requiring revascularization, showed no significant difference between the 2 drugs. However, febuxostat was associated with an increased risk of cardiovascular death (HR of 1.34, 95% CI 1.03-1.73, P=0.03) and higher all-cause mortality (HR of 1.22, 95% CI 1.01-1.47, P=0.04). Some population studies have also shown an increased risk of cardiovascular events and death.[142][143] However, some studies do not show an increased risk of cardiovascular events, including a randomized, open-label noninferiority study,[144] 2 population studies,[145][146] and a systematic review[147]. In a follow-up investigation of the CARES trial, patients who discontinued ULT experienced increased cardiovascular events and deaths at 30 days and 6 months.[148]

Allopurinol and febuxostat are similarly effective, although some data suggest that febuxostat may be more effective in patients with CKD. In a comparative noninferiority trial of allopurinol and febuxostat, where at least 33% of patients had stage 3 CKD, both drugs showed similar efficacy in managing flares and reducing serum uric acid levels to the target range.[149]

XOIs have demonstrated various effects, particularly in population studies focusing on cardiovascular disease.[150] The theory is that chronic hyperuricemia and MSU deposition result in chronic inflammation, thereby enhancing the progression of atherosclerosis. Notably, allopurinol has been associated with a modest reduction in all-cause mortality among patients with gout.[151][152] A case-matched cohort study conducted in Taiwan revealed that patients with gout faced an increased risk of cardiovascular and all-cause mortality. However, ULT treatment was linked to a reduced risk of cardiovascular (HR 0.29, 95% CI 0.11-0.80) and all-cause mortality (HR 0.47, 95% CI 0.29-0.79).[153] Allopurinol use was correlated with a lower risk of developing incident atrial fibrillation.[154] 

ULT may also slow the progression of CKD,[155][156][157][158] and allopurinol is associated with a lower risk of incident renal disease in elderly patients compared to febuxostat.[159] Literature suggests that ULT in gout patients might affect outcomes, including dementia, erectile dysfunction, and other comorbidities. While some controlled trials have explored the effect of allopurinol on the incident rate of cardiovascular events, renal disease, and DM, these studies were performed in at-risk patients, not specifically in those with gout. Therefore, the relevance of these findings to patients with gout remains unclear. 

Uricosuric Drugs 

The uricosuric agents work by increasing renal urate clearance.[1][66] Patients with low or normal urinary uric acid excretion in the presence of hyperuricemia are potential candidates for uricosuric therapy. Drugs in this class include probenecid and lesinurad (withdrawn from the US market). These agents inhibit URAT1 at the apical membrane of the renal proximal tubule epithelial cell. However, they are ineffective as monotherapy in patients with low creatinine clearance (<30 ml/min) and contraindicated in patients with a history of nephrolithiasis.[160] 

Probenecid, the only agent approved as a monotherapy, is initiated at 250 mg twice daily. Dose adjustments are made according to the serum urate concentration level, with increments every few weeks. The usual maintenance dose ranges from 500 to 1000 mg (taken 2 to 3 times daily), aiming to achieve target urate levels of less than 6 mg/dL (<357 µmol/L).

The significant side effects of uricosuric drugs are the precipitation of a gout flare, uric acid urolithiasis, gastrointestinal intolerance, and rash. Uricosuric agents are not appropriate for patients with CKD and a creatinine clearance of less than 60 mL/min. Patients with tophi are best treated with XOIs or pegloticase.

Uricase Pegloticase (urate oxidase)

Uricase is present in nonprimates and lower primates. Pegloticase, a pegylated recombinant form of uricase, is a potent agent that rapidly reduces serum urate levels by directly degrading uric acid into highly soluble allantoin. Polyethylene glycol (PEG) molecules are attached to the recombinant porcine-baboon uricase in a process known as PEGylation.This process extends the PEG molecule's half-life to days or weeks and decreases but does not eliminate immunogenicity.[161] 

Pegloticase is reserved for patients with refractory gout, usually those with a high tophaceous burden. Patients must discontinue ULT while starting this medication because antibodies against pegloticase may develop. Pegloticase is administered as intravenous infusions every 2 weeks, and before each infusion, serum urate levels should be monitored to confirm urate-lowering efficacy. If the serum uric acid rises above 4 mg/dL, the infusions should be stopped, indicating that the patient is developing antibodies to pegloticase, which could lead to infusion reactions.

Pegloticase has effectively lowered serum uric acid in patients with refractory gout, as evidenced by short and long-term clinical trials.[162][163] Phase 3 studies revealed complete resolution of 1 or more tophi in 20% of patients by 13 weeks and lowered uric acid levels to less than 6 mg/dl in 42% of subjects within 6 months.[164] During the initial 6 months of pegloticase therapy, all patients should receive gout flare prophylaxis.

Due to the risk of severe hemolytic anemia, pegloticase is contraindicated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Acute gout flares are observed in 80% of patients during the first few months of pegloticase therapy, even with prophylactic measures in place. Moderate infusion reactions like flushing, urticaria, and hypotension are expected, with 2% of patients experiencing severe reactions like anaphylaxis. Some reactions, such as severe muscle pain and cramping, occur due to unknown mechanisms. Efforts to reduce the immunogenicity of pegloticase with concomitant use of methotrexate or mycophenolate mofetil have been effective, although infusion reactions remain a major issue.

Rasburicase, a nonpegylated recombinant uricase, has not received FDA approval for gout treatment. It prevents acute uric acid nephropathy due to tumor lysis syndrome in patients with high-risk leukemia and lymphoma.

Other Drugs With an Effect on Serum Uric Acid

Several drugs used to treat conditions like hypertension, type 2 DM, and HLD can affect the serum uric acid (see Table. Urate-Lowering Drugs and Mechanisms and Table. Urate-Increasing Drugs and Mechanisms).[165] The sodium-glucose cotransporter-2 inhibitors (SGLT2i) are particularly noteworthy. Studies have demonstrated their effectiveness in lowering serum uric acid levels.[166] In an investigation on the effect of empagliflozin therapy on heart failure, significant interactions were observed between empagliflozin treatment and baseline serum uric acid levels, affecting cardiovascular and all-cause mortality.[167] Additionally, SGLT2 inhibitors have been shown to reduce the risk of developing incident gout and acute flares of gouty arthritis.[167][168] 

Table 8. Urate-Lowering Drugs and Mechanisms [165]

Table 9. Urate-Increasing Drugs and Mechanisms [165]

Differential Diagnosis

The differential diagnosis for an acute gout flare includes the following:

• Calcium pyrophosphate crystal deposition disease
• Basic calcium phosphate crystal disease
• Septic arthritis (crystal arthritis and septic arthritis may coexist) [92]
• OA
• Psoriatic arthritis
• Cellulitis
• Trauma

The differential diagnosis for tophaceous gout includes:

• Dactylitis
• Rheumatoid arthritis
• Osteomyelitis

Prognosis

The prognosis of gout varies based on the individual comorbidities. Patients with cardiovascular comorbidities tend to have higher mortality rates. Most patients can lead an everyday life with mild sequelae with proper treatment. Those experiencing symptoms early in life often present with more severe disease. Without lifestyle modifications, recurrent flare-ups are common. 

Complications

Complications of gout are diverse and may encompass various systemic issues, including the following:[169]

Skeletal Complications

• Tophi
• Joint deformity
• OA
• Bone loss

Urological Complications

• Urate nephropathy
• Nephrolithiasis

Ocular Complications

• Conjunctivitis
• Uveitis
• Scleritis

Deterrence and Patient Education

Patients should be educated about lifestyle modifications and strategies to reduce the risk of gout flares and the condition's progression. Important points to discuss with patients include:

• Lifestyle changes are encouraged for patients with gout, including weight loss, limiting alcohol consumption, and avoiding certain foods. While these changes can significantly complement medical therapy, they might not always suffice to manage or reverse gout effectively.

• Weight gain and increased adiposity are risk factors for gout. In individuals with established gout who are overweight, weight loss is likely beneficial, leading to reductions in serum urate and alleviation of gout symptoms.[170][171]

• The optimal diet composition for managing gout includes adequate protein intake, especially from plant sources and low-fat dairy sources, while reducing consumption of animal sources high in purine, such as shellfish or red meat. Decreasing saturated fat intake and replacing simple sugars with complex carbohydrates is essential.

• It is advisable to avoid or significantly reduce the consumption of sugar-sweetened juices, alcoholic beverages, and drinks containing high-fructose corn syrup.

Pearls and Other Issues

IL-1 is an important mediator of inflammation in gout and represents a potential therapeutic target for managing gout flares.[172] For patients with multiple medical comorbidities or are on anticoagulation, a short-acting IL-1 inhibitor, like anakinra, can be considered an an alternative treatment for gout flare as an alternative to the first-line therapies.

Enhancing Healthcare Team Outcomes

Most patients with gout commonly have accompanying comorbidities. The prevalence of gout is higher among individuals with chronic diseases such as HTN, CKD, DM, obesity, CHF, and MI.[173]

Gout treatment necessitates a collaborative approach from an entire interprofessional healthcare team. The healthcare professional must swiftly identify the pathology and rule out other causes. In some cases, a rheumatology consult might be necessary. When developing pharmacological approaches, considering comorbidities is essential, and monitoring their response to treatment is crucial.

The pharmacist and nurse are pivotal in educating the patient on medication compliance. Pharmacists should also assist the team by conducting medication reconciliation, verifying appropriate dosing, and providing input on agent selection if the initial treatment proves ineffective.

Dietitians should encourage patients to abstain from alcohol, avoid purine-rich foods, and maintain a healthy body weight. The collaborative efforts of specialists, primary care providers, nurses, nurse practitioners, and dieticians are instrumental in reducing gout morbidity associated with gout. Effective communication among all team members is vital in coordinating patient education on lifestyle modifications, significantly reducing the risk and frequency of gout flare-ups.

Healthcare providers, including primary care physicians, physician assistants, and nurse practitioners, should be adept at identifying classic gout symptoms and have a low threshold for referring patients for an arthrocentesis if there is any uncertainty about the diagnosis. Collaborating with the interprofessional team, as detailed earlier, is essential.

Referral to a specialist, such as a rheumatologist, should be considered for patients with joint pain in the following situations: 

• Unclear etiology with hyperuricemia
• Unclear etiology with normal serum urate level
• Patients with renal impairment
• Failed trial of XOI treatment
• Multiple side effects from the medications
• Refractory gout [102]

Only through an interprofessional team approach with close communication can the morbidity of gout be lowered. Directing the treatment appropriately and maintaining active communication within the team is vital to achieving favorable outcomes.