initial presentation of gout

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Johns Hopkins Arthritis Center

Symptoms and Diagnosis of Gout

Arthritis / acute gout attack  .

Gout is a form of arthritis , hence it causes pain and discomfort in the joints. A typical gout attack is characterized by the sudden onset of severe pain, swelling, warmth, and redness of a joint. The clinical presentation of acute gouty arthritis is not subtle with very few mimics other than a bacterial infection.

The joint most commonly involved in gout is the first metatarsophalangeal joint (the big toe), and is called podagra. Any joint may be involved in a gout attack (and it may be more than one) with the most frequent sites being in the feet, ankles, knees, and elbows.

An acute gout attack will generally reach its peak 12-24 hours after onset, and then will slowly begin to resolve even without treatment . Full recovery from a gout attack (without treatment) takes approximately 7-14 days.

An accurate and colorful discription of a gout attack was elegantly written in 1683 by Dr. Thomas Sydenham who was himself a sufferer of gout:

The victim goes to bed and sleeps in good health. About 2 o’clock in the morning, he is awakened by a severe pain in the great toe; more rarely in the heel, ankle or instep. This pain is like that of a dislocation, and yet the parts feel as if cold water were poured over them. Then follows chills and shiver and a little fever. The pain which at first moderate becomes more intense. With its intensity the chills and shivers increase. After a time this comes to a full height, accommodating itself to the bones and ligaments of the tarsus and metatarsus. Now it is a violent stretching and tearing of the ligaments– now it is a gnawing pain and now a pressure and tightening. So exquisite and lively meanwhile is the feeling of the part affected, that it cannot bear the weight of bedclothes nor the jar of a person walking in the room.

Chronic Tophaceous Gout

Some patients only experience acute gout attacks which may be limited to 1-2 times per year (or even 1-2 times in lifetime). However, for some patients, gout can be a chronic, relapsing problem with multiple severe attacks that occur at short intervals and without complete resolution of inflammation between attacks. This form of gout, called chronic gout, can cause significant joint destruction and deformity and may be confused with other forms of chronic inflammatory arthritis such as rheumatoid arthritis. Frequently, uric acid tophi (hard, uric acid deposits under the skin) are present and contribute to bone and cartilage destruction. Tophi are diagnostic for chronic tophaceous gout. Tophi can be found around joints, in the olecranon bursa, or at the pinna of the ear. With treatment, tophi can be dissolved and will completely disappear over time.

Asymptomatic Hyperuricemia

It is important to recognize that although almost uniformly all patients with gout have hyperuricemia (high levels of uric acid in the blood)…all patients with hyperuricemia do not have gout. Although most patients will have elevated levels of uric acid in the blood for many years before having their first gout attack, there is no current recommendation for treatment during this period in the absence of clinical signs or symptoms of gout. This is termed ‘asymptomatic hyperuricemia’. The risk of a gout attack increases with increasing uric acid levels, but many patients will have attacks with “normal” levels of uric acid and some will never have an attack despite very high levels of uric acid.

Diagnosis of Gout

A diagnosis of gout can be made with the documentation of the presence of uric acid crystals in synovial fluid or from a tophaceous deposit. In the setting of an acute gout attack, aspiration of joint fluid (by using a needle to draw fluid out of the swollen joint) and examination of the fluid under polarized light can yield the definitive diagnostic finding of needle shaped negatively-birefringent uric acid crystals (yellow when parallel to the axis of polarization). Intracellular crystals within a neutrophil are characteristic during an acute attack.

As the clincal features of acute gout and a septic joint (bacterial infection) can be very similar, arthrocentesis is important to rule out infection by sending the joint fluid for culture in these circumstances. Importantly, gout and infection can co-exist in the same joint (they are not mutually exclusive) and consideration should be made for sending joint fluid for culture even in a patient with an established history of gout if they are at risk for infection.

Tophi can be aspirated or the tophaceous material expressed and examined under polarize microscopy as well to confirm a diagnosis of chronic tophaceous gout.

Serum uric acid concentrations may be supportive of a diagnosis of gout, but alone the presence of hyperuricemia or normal uric acid concentrations do not confirm or rule out the diagnosis of gout as frequently uric acid levels may be normal during an acute gout attack.

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• 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.

• 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

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.

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:

• The synthesis of PRPP in the PRPP synthetase pathway.
• 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, 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.

• 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]
• 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]

• Asymptomatic hyperuricemia
• Acute gout attacks
• Intercritical period
• 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.

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.

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 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
• 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, 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 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]
• Psoriatic arthritis

The differential diagnosis for tophaceous gout includes:

• Rheumatoid arthritis
• Osteomyelitis

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

• Joint deformity

Urological Complications

• Urate nephropathy
• Nephrolithiasis

Ocular Complications

• Conjunctivitis
• 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.

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Hand Radiograph, Gout Contributed by Scott Dulebohn, MD

Gout, [SATA] Contributed by Steve Bhmji, MS, MD, PhD

Gout in the Ear Image courtesy S Bhimji MD

Acute gout attack Image courtesy O.Chaigasame

Gout Tophi Contributed by Dr. Shyam Verma, MBBS, DVD, FRCP, FAAD, Vadodara, India

Disclosure: Ardy Fenando declares no relevant financial relationships with ineligible companies.

Disclosure: Manjeera Rednam declares no relevant financial relationships with ineligible companies.

Disclosure: Rahul Gujarathi declares no relevant financial relationships with ineligible companies.

Disclosure: Jason Widrich declares no relevant financial relationships with ineligible companies.

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Gout: An old disease in new perspective – A review

Gaafar ragab, mohsen elshahaly, thomas bardin.

• Author information
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Corresponding author. [email protected]

Received 2017 Feb 28; Revised 2017 Apr 11; Accepted 2017 Apr 13; Issue date 2017 Sep.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Graphical abstract

Keywords: Hyperuricemia, Gout, Pathogenesis, Clinical picture of gout, Imaging modalities, Management of gout

Gout is a picturesque presentation of uric acid disturbance. It is the most well understood and described type of arthritis. Its epidemiology is studied. New insights into the pathophysiology of hyperuricemia and gouty arthritis; acute and chronic allow for an even better understanding of the disease. The role of genetic predisposition is becoming more evident. The clinical picture of gout is divided into asymptomatic hyperuricemia, acute gouty arthritis, intercritical period, and chronic tophaceous gout. Diagnosis is based on laboratory and radiological features. The gold standard of diagnosis is identification of characteristic MSU crystals in the synovial fluid using polarized light microscopy. Imaging modalities include conventional radiography, ultrasonography, conventional CT, Dual-Energy CT, Magnetic Resonance Imaging, nuclear scintigraphy, and positron emission tomography. There is remarkable progress in the application of ultrasonography and Dual-Energy CT which is bound to influence the diagnosis, staging, follow-up, and clinical research in the field. Management of gout includes management of flares, chronic gout and prevention of flares, as well as management of comorbidities. Newer drugs in the pharmacological armamentarium are proving successful and supplement older ones. Other important points in its management include patient education, diet and life style changes, as well as cessation of hyperuricemic drugs.

Introduction

Gout distinguished itself in the history of Homo sapiens since time immemorial. It appeared in medical records very early in the history of medical writing, and was also mentioned in the biographies of many famous names. It was depicted as the fate of a life of affluence as much as the challenge to a physician’s skill, and truly it was. Modern ages witnessed remarkable progress in managing gout. More recently, thanks to quantum leaps in molecular biology, diagnostic modalities, and pharmacotherapy, we enjoy deeper understanding of the disease and a more sophisticated armamentarium.

Gout is a systemic disease that results from the deposition of monosodium urate crystals (MSU) in tissues. Increased serum uric acid (SUA) above a specific threshold is a requirement for the formation of uric acid crystals. Despite the fact that hyperuricemia is the main pathogenic defect in gout, many people with hyperuricemia do not develop gout or even form UA crystals. In fact, only 5% of people with hyperuriceamia above 9 mg/dL develop gout. Accordingly, it is thought that other factors such as genetic predisposition share in the incidence of gout [1] , [2] .

MSU crystals can be deposited in all tissues mainly in and around the joints forming tophi. Gout is mainly diagnosed by identification of the pathognomonic MSU crystals by joint fluid aspiration or in tophi aspirate. Early presentation of gout is an acute joint inflammation that is quickly relieved by NSAIDs or colchicine. Renal stones and tophi are late presentations. Lowering SUA levels below deposition threshold either by dietary modification and using serum uric acid lowering drugs is the main goal in management of gout. This results in dissolution of MSU crystals preventing further attacks [3] , [4] .

Epidemiology

The general prevalence of gout is 1–4% of the general population. In western countries, it occurs in 3–6% in men and 1–2% in women. In some countries, prevalence may increase up to 10%. Prevalence rises up to 10% in men and 6% in women more than 80 years old. Annual incidence of gout is 2.68 per 1000 persons. It occurs in men 2–6 folds more than women. Worldwide incidence of gout increases gradually due to poor dietary habits such as fast foods, lack of exercises, increased incidence of obesity and metabolic syndrome [5] .

Pathogenesis of hyperuricemia

Urate is the ionized form of uric acid present in the body. Uric acid is a weak acid with pH of 5.8. Urate crystals deposition in tissues starts to occur when serum uric acid level rises above the normal threshold. Pathological threshold of hyperuricemia is defined as 6.8 mg/dL [1] , [6] .

Some factors may affect the solubility of uric acid in the joint. These include synovial fluid pH, water concentration, electrolytes level, and other synovial components such as proteoglycans and collagen. SUA level in the body is determined by the balance between its production either from purine intake in diet or endogenous production by cellular turnover and its excretion by the kidneys and GIT. Increased production of UA is responsible for only 10% of cases of gout while the remaining 90% are caused by its renal under-excretion [7] .

Factors affecting SUA levels include age and gender. SUA is low in children. After puberty, SUA levels start to increase to reach their normal levels. In men, levels are higher than in women. However, SUA levels in postmenopausal women increase to reach men’s levels. This explains why gout is usually a disease of middle aged and older men, and postmenopausal women. Rarely, it may happen in children and young adults in some rare inborn errors of purine metabolism. These enzymatic defects result in increased SUA with consequent production of UA crystals in kidneys and joints ( Fig. 1 ) [8] .

Pathogenesis of hyperuriceamia (perceived and designed by Dr. EL-Shahaly).

Overproduction of uric acid

Deficiency of enzymes involved in purine metabolism leads to overproduction of UA. For example, Lesch-Nyhan syndrome is an inborn error of metabolism resulting from deficiency of an enzyme involved in UA metabolism named hypoxanthine–guanine phosphoribosyltransferase. It is a genetic X-linked recessive disorder with varying degrees of severity according to the type of mutation. The clinical picture of this disease involves neurological abnormalities such as dystonia, chorea, cognitive dysfunction, compulsive injurious behavior, self-mutilation and articular manifestations (early onset gout) in addition to renal stones. If left untreated, it may lead to tophi formation and renal failure [9] .

Another enzymatic abnormality that causes gout in the young is the superactivity of phosphoribosyl pyrophosphate synthetase. It is an X-linked dominant inherited disorder. The syndrome has two clinical forms, a severe early onset form in children and a mild late juvenile or early adult onset form. Clinical picture includes neurological abnormalities such as sensorineural hearing loss, hypotonia and ataxia in the severe form. The mild form manifests as uric acid renal stones and arthritis. However, these enzymatic disorders constitute only less than 10% of cases of overproduction of urates [10] .

Ingestion of foods rich in purines such as cooked or processed food especially from animal and seafood origin is a key element of increasing uric acid precursors. While foods rich in purine of vegetable origin such as beans, lentils, mushrooms, peas, legumes, and dairy products do not carry any risk on hyperuriceamia and gout, thus, can be allowed in gout patients. Furthermore, foods rich in vitamin C, low fat dairy products, plant oils such as olive, sunflower and soy were associated with reduced risk for hyperuriceamia and gout. Vitamin C was found to increase renal excretion of uric acid so it can be used as a supplement during management of gout [11] , [12] .

Alcohol is a well-known risk factor for gout. Studies showed that alcohol consumption is related to the amount consumed. Additionally, the risk for gout and hyperuriceamia depends on the type of different alcoholic drinks. For instance, beer is the worst in increasing the risk for gout compared to liquor. While the lowest risk among alcoholic drinks was for wine [11] .

Endogenous urate production

Increased endogenous production of uric acid occurs in accelerated cellular turnover such as in malignancies, heamatological and inflammatory diseases. Also, increased purine production may result from chemotherapy and tissue damage. Furthermore, increased body weight and obesity leads to enhanced production of uric acid aggravating the risk of hyperuriceamia. Leptin was found to increase serum levels of urate. So, weight loss and exercises are very useful in reducing SUA levels and gout risk [13] , [14] , [15] , [16] .

Decreased excretion of uric acid

Two thirds of urate excretion occurs in the kidneys while the rest is excreted through the gastrointestinal tract (GIT). Reduced secretory function of the transporter ABCG2 leads to decreased excretion of uric acid through the GIT resulting in rise of serum levels of uric acid and enhanced renal excretion [7] , [17] .

Uric acid crystals are not soluble so require specific membrane transporters in order to cross cell membranes. Of these transporters are the urate transporter/channel (URAT) mainly URAT1 and the organic anion transporters (OAT1 and OAT3) [7] , [18] .

Renal excretion of uric acid is the end result of 4 phases. The first phase is the passage of UA across the Bowman’s capsule (glomerular filtration); followed by reabsorption of almost all urates passing in the proximal tubules. The third phase involves secretion of part of the reabsorbed UA ending with another reabsorption phase in the proximal tubules. The excreted UA is almost 10% of the filtered urate through Bowman’s capsule and the rest is reabsorbed in the body ( Fig. 2 ) [19] .

Renal excretion of uric acid (perceived and designed by Dr. EL-Shahaly).

Reduced renal excretion of urate is associated with some autosomal dominant disorders. Uromodulin is a gene that is expressed in the thick ascending limb of the loop of henle. It is responsible for regulating water permeability. Mutations of uromodulin gene result in decreased fractional excretion of UA, which in turn increases SUA [20] .

URAT1 transports UA in the filtered fluid passing through the proximal tubules into the tubulules by an active transport process. Uricosuric drugs such as probenecid, benzbromarone and sulfinpyrazone decrease URAT1 activity, and consequently UA reabsorption in proximal tubules. On the other hand, drugs such as pyrazinamide, nicotinate and lactate increase urate reabsorption by acting on URAT1, moving UA from the lumen into the tubular cells. They both increase glomerular filtration and tubular reabsorption of UA preventing its loss in urine and increasing UA levels in serum [21] .

Substances that affect URAT1 activity can both potentiate or inhibit its activity according to their dose. For example, low doses of aspirin have an anti-uricosuric effect while high doses have a uricosuric effect. High dose aspirin inhibits URAT1, hence its uricosuric effect. This process is called cis-inhibition of URAT1. The anti-uricosuric effect is caused by trans-stimulation of URAT1 by aspirin [22] .

Genes responsible for uric acid regulation

SLC22A12 gene encodes for the transporter URAT1 present on the apical membrane of renal tubules. SLC2A9 is another gene involved in regulation of UA excretion. It encodes for a transporter protein in the membrane of renal tubules. Polymorphism of both genes results in decreased fractional excretion of UA leading to increased SUA levels. ABCG2 is a gene transporter for UA in the proximal tubular cells of the kidney as well as in the GIT. SLC17A1, SLC17A3 genes are important determinants of SUA levels acting as membrane transporters in the kidenys. Other genes involved in determination of SUA levels include SLC22A11, the glucokinase regulatory protein (GCKR), Carmil (LRRC16A), and near PDZ domain containing 1 (PDZK1) genes [23] , [24] .

Pathogenesis of acute gouty arthritis

Deposition of UA crystals in the joint cavity is the triggering cause of gout. These crystals initiate the inflammatory process by being engulfed by synovial phagocytic cells leading to release of lysosomal enzymes and production of inflammatory chemokines. Another mechanism is that UA crystals change the stability of cell membrane of phagocytic cells by direct crosslinkage with membrane lipids and glycoproteins. This involves the triggering of G protein, phospholipase A2, C and D, tyrosine kinase and other kinases such as mitogen-activated kinases (ERK1/ERK2, p38) and c-Jun N-terminal kinase. This interaction leads to increased IL-8 in phagocytes resulting in activation of neutrophils [25] , [26] .

The pathogenesis of gouty arthritis involves initial activation of monocytes and mast cells followed by neutrophils. Before the first attack of gout and in the inter-critical period, macrophages engulf UA crystals. Well-differentiated macrophages have the capability to contain these crystals without inducing an inflammatory response. While less-differentiated monocytes produce abundant amounts of TNF, IL-1, IL-6 and IL-8 along with endothelial activation following phagocytosis of urate crystals. Also, mast cells are key players in inducing the acute gouty attack by producing histamine and IL-1. This results in increasing vascular permeability and vasodilatation. Interestingly, it is thought that may even end the inflammatory phase by engulfing the crystals and the inflammatory debris [26] , [27] .

The chemotactic factors produced by monocytes and mast cells and the local vasodilatation stimulates neutrophilic chemotaxis. Also, endothelial cells activation further aggravates the inflammatory response and migration of neutrophils. This leads to an influx of neutrophils locally. Colchicine is thought to act by stopping the acute attack through changing the affinity of selectins on endothelial cells and neutrophils to inflammatory mediators and also by blocking the neutrophilic stimulation induced by endothelial cells [28] , [29] .

Inside the synovium, the abundance of chemotactic factors such as leukotrienes, platelet activating factor and interleukins mainly IL-8 is responsible for 90% of neutrophils activation and exacerbation of acute inflammation. Accordingly, targeting IL-8 can be promising for stopping the acute attack of gout [26] .

The acute attack of gout is usually self-limited. It resolves within hours to few days of its beginning. This occurs by removal and phagocytosis of crystals by macrophages, hence suppressing cellular and chemokine activation. Also, macrophages clear the cellular apoptotic remnants to help stop the inflammatory cascade. Additionally, macrophages secrete TGF-β that eliminates IL-1, another key player in enhancing the inflammatory process [30] .

Anti-inflammatory cytokines play an important role in inhibiting the inflammatory process. Other mechanisms involved in terminating the acute attack include proteolysis of pro-inflammatory cytokines, decreasing expression of receptors for TNFα and interleukins on the surface of leukocytes. Vasodilatation and increased vascular permeability is also important to allow extravasation of macrophages into the synovial fluid to clear the inflammatory area ( Fig. 3 ) [30] .

Pathogenesis of acute gouty inflammation (perceived and designed by Dr. EL-Shahaly).

Pathogenesis of chronic gout

Chronicity is a feature of gout. It results from chronic inflammation that follows recurrent attacks of gout. Chronic gout manifests by chronic synovitis, bony erosions, cartilage damage and tophi formation. This can be explained by different mechanisms. Presence of urate crystals in the synovium leads to stimulation of chondrocytes to produce inflammatory cytokines, nitric oxide and matrix metalloproteases resulting in cartilage damage [31] , [32] .

On the bone level, IL-1β and activation of receptor for nuclear factor κ B (RANK) and RANK ligand (RANK-RANKL) pathway are key players in osteoclastogensis and the formation of bone erosions. Gouty erosions are characterized by having overhanging edges and partial preservation of joint space. Furthermore, osteoblasts release pro-inflammatory cytokines leading to erosions and bone destruction in addition to compromising their own bone formation function. In the intercritical phase, there is persistent low-grade inflammation in affected joints. The same cytokines responsible for the acute flare up can be found at lower concentrations inbetween attacks. Although chronicity may result even with the use of uric acid lowering drugs and appropriate management of acute flare ups, yet its incidence is lower compared to patients with recurrent inappropriately treated attacks. Chronicity can be decreased by long-term use of low dose anti-inflammatory agents such as colchicine and lowering SUA to safe levels (<6 mg/dL) [32] , [33] .

Increased uric acid excretion in urine is usually calculated by the fractional excretion of urate compared to creatinine clearance. Both urine and blood samples are taken at the same time. The formula to calculate this parameter is [urine UA × serum Cr/serum UA x urine Cr]. The normal fractional excretion of uric acid is 7–10%. When it decreases, this reflects a reduction of uric acid excretion resulting in increased serum urate level [34] .

Interestingly, it appears that levels of SUA actually decrease during the acute attack of gout. Furthermore, precipitation of an attack is common following the introduction of allopurinol or febuxostat without the prophylactic use of NSAID or colchicine. Also, states with increased excretion of SUA such as during surgery can trigger an acute gouty attack. Accordingly, it is assumed that sudden reduction of SUA precipitates acute gout [35] .

Although hyperuriceamia is the main cause of gout, uric acid itself is an anti -oxidant that has a protective role on vascular endothelium. So, the presence of uric acid is essential for vascular integrity and homeostasis of human body’s functions. On the other hand, some studies found that allopurinol, a xanthine oxidase inhibitor used for treatment of hyperuriceamia and gout, has protective effects on vascular endothelial cells reducing cardiovascular risk. What determines whether presence of uric acid is beneficial or not is the type of tissue affected, whether it is intracellular or extracellular and its concentration. [36] , [37] .

Impact of systemic diseases on uric acid

Gout seems to affect osteoarthritic joints more often. This observation shows that cartilage damage resulting from OA induces formation of MSU crystals. Interestingly, UA crystals seem to affect the cartilage from its outer surface. Oppositely, pseudogout crystals appear inside the cartilage. Accumulation of UA crystals in the joint results from decreased vascularity and susceptibility of the synovial membrane to pass the crystals. Thus, gout tends to affect peripheral joints such as the big toe [38] .

Hypertension is known as a risk factor for hyperuricemia and gout. Increased systemic blood pressure results in reduced glomerular filtration rate leading to decreased glomerular blood flow and decreased excretion of UA [34] . However, recent data suggest that hyperuricemia leads to increased blood pressure and that uric acid is a true modifiable risk factor for development of essential hypertension [39] .

Diabetes mellitus (DM) is also a significant risk factor for hyperuriceamia and gout. Failure of oxidative phosphorylation increases adenosine levels resulting in increased production of uric acid and reduction of its renal excretion. Insulin treatment increases SUA by increasing its renal reabsorption from renal tubules. Metabolic syndrome is also associated with hyperuriceamia and gout [40] .

Clinical diagnosis

Asymptomatic hyperuriceamia.

Gout undergoes 4 stages during its course starting with asymptomatic hyperuriceamia. In this stage, patients have no symptoms or signs and are usually accidentally discovered when measuring SUA (serum level greater than 7 mg/dL). However, some patients with hyperuriceamia may develop an acute gouty attack.

Acute gouty attack

Acute gouty attack is usually monoarthritic that peaks within hours to severely inflamed joint with cardinal signs of inflammation including redness, hotness, tenderness, swelling and loss of function. In large joints such as knees and ankles, skin signs are infrequent, but swelling and pain can be intense.

Gout has a predilection for lower extremities such as the first MTP, which is the commonest site for acute gout known as podagra [41] . Other joints that can be affected are the tarsal and metatarsal joints, ankles, knees, wrists, MCPs as well as interphalangeal joints of the hands. Rarely, hip and shoulder joints can be involved. Vertebral column involvement is extremely rare. Soft tissue inflammation may also occur including olecranon bursitis and Achilles tendonitis [42] .

Arthritis of more than one joint at the same time is not very rare. It is more common in long-term untreated gout or in postmenopausal women. Constitutional symptoms such as fever, headache, and malaise can be present. In such case, the joint has to be managed as septic arthritis until proven otherwise. Extreme caution should be taken when dealing with such cases, as septic arthritis may happen in a gouty joint with the presence of MSU crystals. On the other hand, gouty attack can be mild with low-grade inflammation [43] .

Intercritical period

When the acute attack settles down within hours to days following the introduction of colchicine or NSAIDs, patients enter into a remission phase. This period is characterized by the absence of symptoms. It may be interrupted suddenly by newer attacks if proper treatment for hyperuriceamia has not been introduced. This quiescent stage can be prolonged after the first attack. Without proper treatment, however, attacks become more frequent and more severe [44] .

Chronic tophaceous gout

Untreated disease progresses into destruction of joints with formation of palpable tophi. A tophus is a mass formed of large amounts of accumulated crystals. It happens in chronic untreated gout. It can be present around the joints in the ears, the subcutaneous tissue or the skin. It is a manifestation of chronicity and uncontrolled disease. Macroscopically, tophi contain a white chalky material. Tophi may lead to joint destruction and deformity. Bony erosions may also occur as growing tophi extend to the bone. Differentiation of tophi from other nodules such as rheumatoid nodules, osteoarthritic Heberden’s and Bouchard’s nodules, lipomas or is essential for further management. This can be easily done by taking a simple needle biopsy that will show MSU crystals characteristic of gout [45] .

Clinical diagnosis of gout is widely used allover the world especially in developing countries where resources are limited. However, when clinical diagnosis has been compared to microscopic diagnosis of crystals, it appeared to have low sensitivity and specificity [46] .

In certain circumstances with atypical presentation of gout such as in multiple joint affection or atypical joint distribution, identification of MSU is mandatory to differentiate gout from other diagnoses. Elevated levels of SUA associated with typical joint involvement such, as podagra is usually a straightforward diagnosis. However, according to the EULAR recommendations, synovial fluid analysis is still advised to exclude other causes mainly septic arthritis [47] .

Formation of tophi is a late clinical manifestation of gout ( Fig. 4 ), though it may develop early in the disease course. When present, it can be a good indicator of gout. But still differentiation from other arthritides associated with nodules needs to be excluded before jumping to a definite diagnosis of gout [48] .

Chronic tophaceous gout: (a) hands, (b) ankle, (c) left greater toe (from the private collection of the authors).

Laboratory diagnosis

Diagnosis of gout based on hyperuricemia is a common misconcept among non-rheumatologists. Hyperuriceamia is usually asymptomatic and does not necessitate the diagnosis of gout. Among patients with SUA levels between 7 and 7.9 mg/dL only 0.09% will develop gout every year. As for patients with SUA between 8 and 8.9 mg/dl, 0.4% out of them may develop gout. With hyperuriceamia above 9 mg/dl, only 0.5% of patients may get gout [49] .

Although hyperuriceamia is a characteristic feature of gout; it should be noted that during gouty attacks, SUA might drop to normal levels. Hyperuricemia is a weak marker for gout diagnosis and the disease might still be diagnosed even with normal serum levels [50] .

The gold standard of diagnosis is the identification of MSU crystals in synovial fluid aspirate using polarized light microscopy. Better diagnostic yields can be obtained when using compensator. However, a regular light microscope can also be used for identification of crystals and differentiating MSU from other crystals such as calcium pyrophosphate dehydrate (CPPD) crystals. MSU crystals are found in the synovial fluid in all stages of the disease; during attacks, in the intercritical period or in chronic tophaceous gout [51] .

Samples should be examined as soon as possible; better within 6 h. Though, they can be examined within 24 h if kept refrigerated at 4 °C. This is to avoid cellular dissolution and disappearance of crystals. In order to examine a specimen, a small drop is placed on a glass slide and covered with another, then placed under the microscope [52] .

Using simple light microscopy, UA crystals are needle-like in shape, with different sizes. They can be seen clearly with 600× magnification. More magnification allows identification of further details. These can be easily distinguished from pseudogout (CPPD) crystal, which are usually rhomboidal in shape. Size can be similar to MSU crystals. Similar magnification to UA crystals ranging from 600× to 1000× can easily differentiate both crystals from each other [52] .

Using a polarized filter helps better detection of crystals and birefringence. MSU crystals appear as shiny strong negatively birefringent crystals against dark background. They appear yellow when aligned parallel to the axis of red plate compensator. CPPD crystals, on the other hand, show positive birefringence and appear blue in color under the same circumstances [53] .

Further analysis of synovial fluid should include leukocytic count, chemistry, culture and sensitivity. In acute gout, synovial fluid leukocytic count may exceed 50.000 cells/µL in some cases mostly polymorphs. Chemistry reveals normal glucose levels contrary to septic arthritis, in which bacteria consume glucose leading to low levels. Care should be taken to exclude septic arthritis in gouty cases, as both may be present in the same joint. So, culture and sensitivity along with gram stain is crucial to confirm the diagnosis [54] .

Analysis of amount of uric acid in urine over 24 h is useful in assessing the etiology of hyperuriceamia in gout patients. Urinary uric acid of more than 800 mg/24 h indicates that such patients have increased production of uric acid, thus they excrete a large amount of uric acid. They require a drug that prevents uric acid production such as xanthine oxidase inhibitors rather than a uricosuric agent. Renal function tests should be done regularly for such patients due to the high risk for stone formation [55] .

Radiological diagnosis

The significance of imaging in gouty arthritis cannot be overemphasized. It is extremely important for diagnosis and follow-up in clinical practice. Also, its potential as an outcome measure in clinical trials is growing. Recently, developments in the field of technology are influencing the staging, and even the type of gout nomenclature.

Conventional Radiography (CR)

It is the most widely used method in clinical practice, however in early stages of the disease it is not very helpful [56] . Radiographic changes may be missed for a minimum of 10 years after the first gouty attack [57] . During the early stages of gout, radiographic images are usually normal or may show asymmetric soft tissue swelling near the affected joints, but subtle early lesions such as small erosions and tophi are difficult to detect [58] .

In chronic tophaceous gout, the main radiographic features are:

Tophi which are articular or periarticular soft tissue dense nodules [59] , [60]

MSU deposits in the cartilaginous part

Joint space narrowing in advanced disease [61]

Bone erosions are characteristic. They are well circumscribed intraarticular or juxtarticular lesions with overhanging margins [62] . They result from the growth of tophi into the bone, hence are usually seen near tophi [63] .

Periarticular osteopenia is usually absent and proliferating bone can be seen mostly as irregular spicules [64]

Calcified MSU deposits can penetrate in the bone; in severe cases, they should not be confused with bone infarcts or enchondromas. Radiography has low sensitivity (31%), however, its specificity is high (93%) [65] .

CR is widely available, inexpensive, quick, and acceptable to patients. Radiation hazard is small [66] . The CR Sharp-van de Hejde scoring system for gout (SvdH-G), has been adapted from its RA counterpart and modified. The gout version, includes scoring for bone erosions as well as joint space narrowing with the distal interphalangeal joints (DIPjs) added [67] .

Ultrasound (US)

Recently, progress in US technology (machines, transducers, techniques), encouraged its use by rheumatologists for the diagnosis and management of gout. In their excellent review, Nestrova and Foder [68] , listed the main indications for using US in crystal-induced arthritis. These include detection of joint effusion and synovitis, differentiating between active and inactive synovitis, studying cartilage, describing bone contour for erosions and osteophytes, evaluation of tendons, evaluation of crystal deposition, execution of US-guided procedures (diagnostic and/or therapeutic), monitoring disease evolution as well as being helpful for the differential diagnosis with other arthritides ( Fig. 5 ).

Three examples of Ultrasonography in gout. (a) Intraarticular tophus, metatarsophalangeal joint; (b) Double contour sign; (c) Longitudinal image of extensor digitorum longus (EDL) tendon showing markedly distended sheath with synovial effusion, synovial hypertrophy and crystal aggregates (arrows) (Courtesy of Dr. Adham Aboul-Fotouh, Kasr Alainy Teaching Hospital, Cairo University).

In gout US features can be either nonspecific or specific. Nonspecific features include:

Synovial fluid

Synovial fluid varies from being totally anechoic to containing aggregates of variable echogenicity. Aggregates of MSU microcrystals can be detected as hyperechoic spots or bright stippled foci. They tend to float in the joint space sometimes giving a snow-storm appearance when applying gentle pressure on the skin surface [69] , [70] .

Synovial proliferation and hypervascularization

The doppler mode can differentiate active from inactive synovial tissue by assessing its vascularity. This is essential for diagnosis and in monitoring the disease and its response to therapy [68] .

Bone erosions

These are defined in gout as “intra- and/or extra-articular discontinuity of the bone surface (visible in two perpendicular planes) [71] . They are more likely found in patients who experience frequent attacks, or who have long disease duration, and tophi [71] . US has a threefold sensitivity than CR in detecting erosions < 2 mm ( P  < 0.001) [68] . There is, however, standardized US scoring system for erosions in gout [68] .

Specific US features in gout

Articular cartilage “double contour sign” (dcs).

DCS is very specific for gout. It is defined as abnormal hyperechoic band over the superficial margin of the articular hyaline cartilage, independent of the angle of insonation and which may be either irregular or regular, continuous or intermittent and can be distinguished from the cartilage interface sign [71] .

DCS is reported in acute flare-up in clinically uninvolved joints, and in patients with asymptomatic hyperuricemia [68] . False-positive results have also been reported [72] , [73] . Threle and Schlesinger demonstrated that DCS can disappear when SUA levels were lowered to 6 mg/dl for 7 months or more [74] .

MSU deposits (Tophi and Aggregates)

A tophus is a circumscribed, inhomogeneous, hyperechoic, and/or hypoechoic aggregation (that may or may not generate posterior acoustic shadow), which may be surrounded by a small anechoic rim. Aggregates are heterogeneous hyperechoic foci that maintain their high degree of reflectivity even when the gain setting is minimized or the insonation angle is changed and which occasionally may generate posterior acoustic shadow.

Tophi have been also described by US as “wet sugar clumps” with an oval or irregular shape [75] .

Intra-articular and intrabursal tophi have been defined as heterogeneous hyperechoic (relative to subdermal fat) aggregates with poorly defined margins with or without areas with acoustic shadowing within the synovial recesses or bursae, respectively [76] .

Doppler US can distinguish between active/hot tophi and inactive/cold ones based on their doppler signal [68] . Tophi can directly be measured by US using special calipers. There is good sensitivity to change associated with ULT [77] . US is feasible as it can be performed in the clinic and there are no radiation hazards involved. The time required for scanning, however may be significant and training costs may be considerable [66] .

Conventional CT (CCT)

CT is characterized by excellent resolution and high contrast, hence it is the best technique for the assessment and characterization of crystal arthropathies [61] .

CCT is not helpful in the diagnosis of acute gout as it can’t detect inflammation, synovitis, tenosynovitis and osteitis. This handicap is however, more than counterbalanced by its role in chronic gout. It is able to detect erosions better than Magnetic Resonance Imaging (MRI) or CR [78] . These are described as well defined, punched out lytic bone lesions, with sclerotic overhanging edges [79] .

The specificity of CCT for the assessment of tophi exceeds that of US or MRI [80] . CT of tophi has been confirmed microscopically by identifying MSU crystals [66] . Its measurement of tophi has also been compared to physical exam using Vernier calipers [81] , [82] . Tophi, soft tissue, intra-articular as well as intra-osseous ones appear as soft tissue masses with well described attenuation, making it easier to distinguish them from other soft tissue lesions [79] , [80] , [81] , [82] , [83] .

CCT can help to monitor disease burden and response to therapy [81] , but has the disadvantage of radiation exposure [84] , [85] .

Dual-Energy CT (DECT)

The introduction of this new imaging technique opened a new horizon. It allows the differentiation of deposits based on their different X-ray spectra. It applies the concept that the attenuation of tissues depends on their density, atomic number as well as the photon beam energy [86] . Like CCT, it can detect damage but does not help in inflammation. It is superior to all other available imaging technologies in its ability to identify all urate deposition in the area imaged [66] ( Fig. 6 ).

DECT of a gouty patient showing two views of MSU deposits (in red) in the tibialis posterior tendon (from the private collection of prof. Bardin.

DECT can offer a quick, non-invasive method to visualize MSU crystals, soft tissue changes, and early erosions at high-resolution, even before CR. This, particularly, helps in the differential diagnosis from pigmented villo-nodular synovitis, psoriasis, and septic arthritis which can share clinical features with gout [87] . DECT is highly accurate in detecting MSU crystals in joints, tendons, ligaments and soft tissues and can be used to identify subclinical gout with high specificity [79] . It, however, misses crystal deposition on the surface of cartilage, a feature US can detect as the DCS [88] .

There are many causes of false negatives; lower density of tophi due to lower crystal concentrations, small size of tophi or crystals (less than 2 mm.) or technical parameters [89] , [90] , [91] . On the other hand, false-positive results were described around nail beds, in the skin, in regions of metal artifacts and in severe OA [89] , [90] , [91] , [92] .

DECT is not widely available, which limits its application for clinical and research purposes. Its costs are equivalent or higher than CCT and it entails radiation exposure [66] .

MRI features of arthritis are those of nonspecific inflammation, synovial thickening, effusion, erosion, and bone marrow edema. Tophi show homogenous T1 signal intensity (low to intermediate) and heterogeneous T2 signal intensity (variable low to intermediate), depending on the degree of its hydration and classification [93] .

MRI role is limited because of expense and limited availability. It is, however, useful for evaluation of gout at unusual sites. The literature abounds with case reports in the axial skeleton [94] , [95] , [96] , [97] , [98] , [99] , or presentation as spondyloarthritis [100] , [101] , carpal tunnel syndrome [102] , [103] , crown dens syndrome [104] , paraspinal abscess [105] , or intra-abdominal mass [106] . The diagnosis in these reports was made by MRI, which was occasionally combined with other modalities.

Nuclear scintigraphy

Nuclear Scintigraphy is rarely used for evaluation. Positive results are often found incidentally when a study is performed for other indications.

Positron emission tomography (PET)

Case reports of (PET/CT) in gout showed articular and periarticular FDG (18 F-fluoro-2-deoxy-D-glucose) uptake. Soft tissue FDG uptake identifying tophi has also been reported. This can be helpful when gout presents at unusual locations [93] .

Major advances in the imaging of gout took place in the last decade. Despite this, it is currently unknown which, if any, imaging techniques can provide valid outcome measures for clinical studies in gout [66] . It has been advocated that multiple imaging modalities need to be further developed for use as outcome measures in chronic gout as different modalities have relevance and potential for different domains [107] .

Dalbeth and Choi [108] proposed a roadmap to improve upon the current generation of global outcomes and their associated outcomes in gout. To refine the disease stages they suggested prospective studies of individuals with hyperuricemia and gout, using advanced techniques such as US and DECT. They also proposed the development of novel prognostic markers and gout-specific disease activity indices beyond SUA levels including new applications of advanced imaging (US, DECT and potentially MRI) [108] .

Gout appears as the best-understood and most manageable rheumatic disease. Lifelong lowering of uricemia under specific targets allows dissolving the pathogenic crystals and suppressing disease manifestations. However, therapeutic failure is frequent [109] and has led to the production of recommendations [110] , [111] , [112] . Failure is often due to poor adherence to urate-lowering drugs ULD [113] , underlining the need for patient and physician education.

Management of flares

Gout flare medications include colchicine, Non-Steroidal anti-inflammatory Drugs (NSAIDs) and steroids, which can be taken together in severe cases and are most efficient when taken early after the flare onset ( Fig. 7 ). This has led the European League against Rheumatism (EULAR) panel to recommend that patients be educated to auto medicate [112] .

EULAR recommendation for the management of flares in patients with gout [112] .

When taken within 12 h after flare onset, 1.8 mg (1.2 mg then 0.6 mg one hour later) of colchicine has been shown to be as effective as the traditional higher doses [114] . In clinical practice this drug appears as much less efficient when given long after the flare onset. The EULAR and American College of Rheumatology (ACR) have restricted the use of colchicine to patients presenting within 12 and 24 h of flare onset respectively.

Practitioners should keep in mind that colchicine has a narrow therapeutic toxicity window and can be very toxic when used inappropriately. Gastrointestinal intolerance (diarrhea, nausea, or vomiting) is common. It is usually the first feature of colchicine toxicity and should lead to dose reduction or interruption. Further toxicity includes neutropenia and multi-organ failure, which can be lethal. The maximum daily dose has been recently reduced to 2 mg (in divided doses) in France.

Renal failure decreases colchicine excretion. Doses should be limited to 0.5–0.6 mg/d in patients with moderate renal insufficiency (eGFR from 30 to 60 mL/min) and to 0.5–0.6 mg every 2 or 3 days in those with eGFR from 15 to 30 mL/min. Colchicine is contra-indicated in CKD stage 5 patients (eGFR < 15 mL/min or dialysis).

Doses should also be reduced in patients with hepatic failure, as the drug is predominantly eliminated through the hepato-biliary system. Inhibitors of cytochrome P450 3A4 or P glycoprotein increase plasma concentration and toxicity of colchicine. The doses of colchicine should be reduced to 0.3 mg every 3 days when cyclosporine, ketokonazole, erythromycin, retronavir are co-prescribed and to 1.2 mg every 3 days when diltiazem or verapramil are used [115] . The French regulatory agency contraindicates co-prescription of macrolide antibiotics and colchicine, even though azythromycin has been found to have no pharmacokinetic interaction with colchicine. Muscle toxicity, including rhabdomyolysis has been reported with the concomitant use of colchicine and statins, especially in renal failure patients [116] . Nerve and muscle toxicity can be observed in long term low dose colchicine users who have kidney transplant or chronic kidney disease CKD, usually with 30 mL/min of eGFR or less [117] . This toxicity is usually slowly reversible after drug cessation and requires CK monitoring.

NSAIDs or COXIBs are used at the maximum authorized dose, with proton inhibitors when indicated. Their efficacy is largely accepted, even though no placebo controlled trial has been performed. Early prescription allows reducing administered doses.

Oral prednisone, at a daily dose of 30 mg/d for 7 days has been shown to be effective [118] , [119] , [120] and is recommended by the ACR and EULAR panels as potential first line therapy in the management of gout flares [111] , [112] . However steroids can worsen hypertension and diabetes [121] and are, in our view, best indicated in patients contra indicated for NSAIDs or colchicine (i.e. CKD patients). Co-prescription of a small dose (0.5–1 mg/d) of colchicine, when not contraindicated, may avoid rare inflammation relapses after steroid cessation. Open studies also suggest that ACTH can relieve gouty inflammation [122] .

Intra-articular steroid injections appear as very efficient and are recommended by both the ACR and the EULAR in the management of mono or pauci-articular flares, despite the lack of randomized clinical trials (RCT).

IL-1 blockers

Open studies of the IL-1 receptor antagonist anakinra [123] , [124] support its off-label use in patients resistant or contraindicated to NSAIDs, colchicine and steroids. Canakinumab, a long lasting antibody to IL-1 beta, has been approved by the European Medical Agency, following 2 RCT trials against intramuscular triamcinolone acetonide [125] . The EULAR recommends considering IL-1 blockers for the management of gout flares in patients with frequent flares contraindicated to NSAIDs, colchicine and steroids (oral or injectable). Current infection is a contra indication [112] .

Management of chronic gout and prevention of flares

Uricemia targets.

To obtain MSU crystal dissolution, SUA should be lowered to values which are under the MSU saturation point. Both the ACR and the EULAR indicate that the SUA target is below 6 mg/dL in all gouty patients and below 5 mg/dL in severe gout patients, to allow more rapid dissolution of the crystal load. Hyperuricemia must be routinely checked by measuring SUA levels [110] , [111] , [112] . This approach has been recently challenged by the American College of Physicians (ACP) who recommended to treat gout to control symptoms rather than to target an uricemia level [126] . The main reason for this GP guideline is the present lack of rigorous treat to target trial. Such a trial is underway in New-Zealand and should definitively settle the issue. However, numerous clinical and pathophysiological data already tell us that lowering uricemia under the saturation point is the best and most reliable way to control gout symptoms in the long run, and that prescribing ULTs without checking that uricemia is lowered enough is a frequent cause of gout treatment failure. This ACP guideline therefore appears, in our view, as detrimental and should not be followed.

Patient education

As already emphasized above, patient education is key to gout management success, as shown by a preliminary study that explored the effect of a predominantly nurse-delivered education program. Following this program, 98 of 103 included patients had their uricemia at target after one year of allopurinol treatment, in sharp contrast with what is usually observed [127] . Information should be given on the pathophysiology of the disease, its relationship with uricemia, its curable nature, uricemic targets to be reached, the life-long nature of urate-lowering treatment, the importance to treat flares early, the mechanisms of ULD-induced flares and ways to prevent them. Patient education takes time and must frequently be repeated, but it is a mandatory tool to achieve success in long-term gout management.

Diet and life style changes

Following epidemiologic demonstration of the influence of these lifestyle factors on the risk of gout, EULAR and ACR recommended weight loss in obese patients; avoidance of beer (including non-alcoholic), spirit, and sugar sodas; restriction of meat and seafood intake; and increased intake of skimmed-milk products, together with enhanced physical activity [110] , [111] , [112] . Very scarce evidence however supports the efficacy of these changes. Small and short term controlled studies showed that milk decreased uricemia and that weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fats were found to have a beneficial effect on serum urate and lipoprotein levels [16] , [128] .

Diet modification appears to be less effective than ULD to control hyperuricemia. However, combining both is very successful in management of chronic gout. Furthermore, to allow moderate SUA reduction, lifestyle changes, exercises and most importantly loss of weight are important tools to control the metabolic syndrome and cardiovascular diseases associated with gout [129] , [130] . Diet modification aiming to correct hypertension or metabolic syndrome have been shown to lower uricemia [131] , [132] .

Targeting SUA is a key component of gout treatment, which allows, when properly done in the long run, disappearance of disease features [133] .

Cessation of hyperuricemic drugs

Attempts should be made to stop drugs that increase uricemia. This is mainly the case with antihypertensive drugs. Thiazide and loop diuretics increase uricemia by an average of 0.65 and 0.96 mg/dL respectively (134). Beta-blockers, non-losartan ARBs and ACE inhibitors have also been associated with an increased risk of gout (135) and increased uricemia. Calcium channel inhibitors and losartan should be privileged. In cardiac failure, spironolactone, which has no effect on uric acid (136) can be advised when possible. Cardio-protective aspirin modestly increases uricemia and replacement by clopidogrel can be considered.

Urate lowering drugs (ULDs)

Indications.

Indications for ULD have increased over the years following better awareness of potential adverse effects of hyperuricemia on the cardio-vascular system and that long standing gout associates with comorbidities and large MSU deposits which will make crystal dissolution more difficult. According to the recent EULAR recommendations, ULDs are indicated in severe gout or when associated with uric acid lithiasis as traditionally, but also in patients with cardio-vascular or renal comorbidities, or with high (>8 mg/dL) uricemia or young age (<40 years), as these are likely to have frequent attacks. In patients with a definite diagnosis of gout, the EULAR advises to discuss with the patient the indication of ULD as soon as after the first flare [112] .

General principles

The initiation of ULDs is associated with an increased risk of gout flares due to crystal mobilization: schematically, when they start to dissolve, deposits become more fragile and crystals can shed into the joint space and trigger inflammation. This should be explained to the patient and the risk should be reduced by progressive titration of ULDs and prescription of low dose (0.5–1 mg/d) of colchicine or NSAID (e.g. naproxen 250 mg/d) as a prophylaxis against ULD-induced gout flares in patients with no contraindications to these drugs [110] , [112] , [134] . Prophylaxis is usually indicated during the first 6 months of ULD prescription. It may be prolonged in tophaceous gout in which complete dissolution of crystal deposits takes a longer time. Interestingly long term low dose colchicine has been shown to be cardio-protective [135] , an additional benefit for gouty patients who are known to be at increased cardiovascular risk [136] .

Even after obtaining whole crystal dissolution, uricemia should be kept lifelong under 6 mg/dL, to avoid recurrence of crystal formation and flares. Uricemia should be checked every 6 months in the long run [110] , [137] , to encourage patient’s adherence to ULD and avoid increases of uricemia above the target, due to new medication or weight gain. Gout must therefore be considered as a chronic disease and the frequent misconception of considering gout as the archetype of an acute disease should be combated through education of patients and doctors.

Lack of adherence to ULD is the main cause of gout management failure. Gout is the worst chronic disease in term of treatment adherence [138] . This is probably due to the lack of explanation and prevention of the ULD-induced flares, the perception of gout as an acute disease, which would only require flare management, and the lack of proper patients’ information. Patient education is a key toll to increase management success.

Allopurinol

Allopurinol is an oral xanthine oxidase inhibitor, first introduced to the clinic in the sixties. Allopurinol is a purine, which is rapidly converted into its active metabolite, oxypurinol, by the xanthine oxidase enzyme. Xanthine accumulation has been seldom reported to cause urinary xanthine stone [139] which can be fully prevented by sufficient fluid intake. In addition to inhibiting xanthine oxidase, oxypurinol inhibits the synthesis of purines, a mechanism that requires the intervention of the enzymes hypoxanthine guanine phosphoribosyl transferase and phosphoribosyl pyrophosphate synthetase and is not observed when these enzymes are deficient. Excretion of oxypurinol is mainly through the kidney and is decreased by renal failure and increased by uricosurics. Dose requirements to reach uricemia targets are increased by body weight increase and diuretic use [140] . ABCG2 loss of function polymorphism decreases its urate-lowering effect [141] .

Because oxypurinol has a long half-life, allopurinol can be prescribed once a day. The urate-lowering effect is dose dependent. Over the world, allopurinol is prescribed at the dose of 300 mg/d or less in more than 90–95% of gouty patients [142] . At the daily dose of 300 mg, allopurinol used to bring uricemia to less than 6 mg/dL in nearly every gouty patient when the drug was initially launched [143] . But this has now largely changed, possibly because gouty patients’ uricemia and weight have substantially increased since the sixties: recent studies have shown that only a minority of patients receiving 300 mg/d of allopurinol reached the desirable uricemia target (<6 mg/dL) [144] , [145] , [146] .

The maximal approved daily dose of allopurinol is 800 or 900 mg/d according to countries and in, patients with normal renal function, increasing the dose above 300 mg/d is often necessary to attain the uricemia target [147] . Allopurinol and other xanthine oxidase inhibitors should not be prescribed with azathioprine and 6-mercaptopurine, as xanthine oxidase is involved in the metabolism of these drugs.

Allopurinol is usually well tolerated. Abdominal discomfort, nausea and diarrhea, liver [148] or bone marrow toxicity [149] , acute interstitial nephritis [150] are very rare early side effects which can be part of the allopurinol hypersentivity syndrome; gynecomastia and peripheral neuropathy [151] have been observed, very rarely, during long-term allopurinol treatment. Patients should be told that cutaneous side effects may develop during the 2 or 3 first months of treatment and should lead to immediate, life-long, allopurinol cessation. They include benign maculo-papular rash, reported in 2–4% of allopurinol initiators, and life- threatening severe skin reactions which can take the form of an acute generalized exanthematous pustulosis [152] , toxic epidermolysis/Steven Johnson syndrome [153] or Drug Related Eosinophilia with Systemic Symptoms (DRESS) syndrome [154] . The incidence of these severe skin reactions has been estimated at 0.7 [95%CI0;5–9.9] per 1000 allopurinol initiators-years in the USA [155] , but they are more frequent in Asia, due to more common genetic predisposition [156] .

Risk factors include recent (<3 months) allopurinol initiation, use of allopurinol for asymptomatic hyperuricemia, female gender [156] , a history of skin reaction to allopurinol, HLA∗B-5801 carriage [157] , [158] , high initial dose [159] and renal failure [160] , [161] .

In Taiwan, where both the frequency of the allele and related relative risk are high, HLA∗B-5801 typing allows preventing major skin reactions by avoiding allopurinol prescription in carriers of the allele [162] and the ACR recommends to genotype patients from Han, Korean and Thai ancestries before prescribing allopurinol [110] .

In Caucasians and Japanese, the association exists but the risk allele is very rare and most of the patients who developed serious skin reactions did not carry the allele so that genotyping is seldom used. It is important to start allopurinol at a low dose (50-100 mg/d) to be progressively increased every 2–4 weeks until the targeted uricemia is obtained, as recommended by the EULAR [112] . Lack of titration has been associated with severe skin reaction [159] .

The impact of renal function on allopurinol dosage is debated. The ACR does not follow the traditional guideline, still implemented by most regulatory agencies, that is to reduce the maximum allopurinol dose according to the creatinine clearance, but recommends increasing allopurinol until the target is reached, with no limitation in CKD patients [110] . Reasons for this are that adjustment of allopurinol according to creatinine clearance seldom allows proper control of uricemia in patients with renal failure [163] and small series have not shown an increased incidence of severe reactions in patients with allopurinol progressively titrated above the authorized dose [164] .

The EULAR recommends to keep limiting allopurinol dose according to the creatinine clearance and to use alternative drugs when this fails to reach uricemia targets [112] .

Febuxostat is an oral, once a day, non-purine xanthine oxidase inhibitor, which is available as 40 and 80 mg tablets in the USA and 80 and 120 mg tablets in Europe. At the doses of 80 and 120 mg/d, the maximum doses approved in the USA and Europe respectively, febuxostat is a more potent ULD than allopurinol 300 mg/d [144] , [145] . Because of its mixed renal and hepatic metabolism, the drug can be prescribed with no dose reduction in patients with moderate renal failure. Recent small studies have suggested that efficacy and safety is maintained in patients with creatinine clearance below 30 mL/min [165] . Because the drug inhibits xanthine oxidase, febuxostat should not be co-prescribed with azathioprine or 6-mercaptopurine.

Side effects to febuxostat include rare and early liver or kidney hypersensitivity reactions, and benign skin rashes which have been reported in about 5% of patients during phase 3 trials. Serious cutaneous reactions have been very rarely reported [166] . Skin reactions to febuxostat appear as slightly more frequent in patients with previous cutaneous intolerance to allopurinol; the increased risk does not result from cross-reactivity but from the increased likelihood for any known allergic patient to develop skin reaction to another drug [167] . In phase 3 studies, cardiovascular side effects and mortality were numerically increased in the febuxostat-treated as compared to the allopurinol-treated patients. This has led the European agency to recommend caution in prescribing febuxostat in patients with a history of heart disease and to ask for a postlicensing cardiovascular safety trial comparing febuxostat to allopurinol, the results of which are still pending [168] .

ACR considers febuxostat as a first line ULD [110] , whereas for EULAR, the drug is indicated in patients intolerant or refractory to allopurinol. Dose titration is recommended to reduce ULD-induced flares, even though there is no evidence that this improves febuxostat tolerance [112] .

Uricosurics

Uricosurics lower uricemia by increasing uric acid output in the urine. Therefore they expose the patients to the risk of uric acid stone, which is worse at the onset of treatment. When uricemia has decreased, uricuria and the risk become lower, as uricuria also decreases. They should not be administered as a monotherapy in patients with a history of uric acid stone or hyperuricuria and should be taken with abundant water intake; the urinary pH should also be checked and kept above 6 to decrease the concentration of uric acid in urine, which governs the risk of lithiasis. Except for lesinurad, uricosurics can be used alone; they are now most often used in combination with xanthine oxidase inhibitors, when these fail to obtain the uricemia targets.

Probenecid has been the first commercialized ULD [169] and was at first a very popular drug. When allopurinol became available, probenecid was much less used because it had to be given in divided doses and required high fluid intakes and adjustment of the urine pH. In addition, probenecid, which was first developed to decrease the renal excretion of penicillin, could interfere with the excretion of other organic acid drugs and gastro-intestinal or cutaneous intolerance were fairly common. It has been recently confirmed to be a decent ULD, including those patients with moderate kidney involvement and remains one of the therapeutic options in patients intolerant or refractory to allopurinol [170] . The initial dose is 250 mg twice daily, which can be weekly increased up to 1 g twice daily. Larger doses expose to major central nervous system toxicity.

Sulfinpyrazone is not universally available. This uricosuric drug is usually given twice daily at the total daily doses of 200–400 mg, progressively attained. Side effects include gastrointestinal intolerance, skin rashes, platelet aggregation impairment and rare bone marrow toxicity.

Benzbromarone is a powerful uricosuric drug, which is used once a day at a dose of 100–200 mg/d. [147] , [171] , [172] . Following reports of severe liver toxicity, the drug has been retrieved from Europe, where it can still be prescribed on a named patient basis, but is still largely used in Asia. The uricosuric property is largely retained in renal failure patients [172] .

Lesinurad is selective URAT1 inhibitor which has been recently approved at the dose of 200 mg/d in the USA and Europe, as an add-on therapy to xanthine oxidase inhibitors when these failed to lower uricemia down to the suitable target [173] , [174] . Serum creatinine elevations have been observed, which although most often transient, require renal function monitoring.

Fenofibrate, atorvastatin and losartan are non-licensed uricosurics which can be used to treat gout comorbidities or in association with xanthine oxidase inhibitors [175] , [176] .

Urate oxidases

Rasburicase is a short-life IV uricase, which is approved for the management of tumor lysis syndrome. Its non-licensed use has been reported in tophaceous gout [177] . Pegloticase is a PEGylated uricase which has been approved, in the USA and Europe, for the management of severe gout, refractory to oral ULDs, and is commercially available in the USA. The drug is administered by IV infusions of 8 mg every 2 weeks and has been shown to be very effective [178] . Antibodies develop at high titers in about half of the patients, leading to loss of uricemia response and to an increased risk of serious infusion reactions. It is therefore recommended to measure uricemia in the 24 h preceding every planned reinfusion and to stop the drug if uricemia is not decreased. No other ULD should be prescribed concomitantly to keep this warning signal ( Fig. 8 ).

EULAR recommendation for the management of hyperuricemia in patients with gout [112] .

Management of comorbidities

Cardiovascular and renal diseases, the metabolic syndrome should be screened and properly treated in gouty patients, and smoking cessation should be advised to decrease mortality [112] . In order to help lowering SUA levels, hypertension treatment should favor losartan and calcium channel inhibitors, statins or fenofibrate should be used in dyslipidemic patients, insulin lowering drugs should be privileged in type 2 diabetic patients. The recently introduced SGLT2 inhibitors also have interesting urate lowering effects [179] .

Conclusions and future perspectives

To understand gout, and consequently to manage it, has been a challenge to the skill of physicians along the history of medicine. Advances in this field that took the shape of continuous progress, have recently witnessed quantum leaps. We enjoy a deeper insight into the disease pathogenesis. We can rely on more sophisticated diagnostic modalities, and most importantly, we have at our disposal, a wider array of therapeutic options to deal with it.

Gout has been considered the nemesis of longevity. That gloomy outlook is exemplified in Lord Byron’s [180] (1788–1824) reflections on old age: “They kindly leave us, though not quite alone; but in good company- the gout or the stone”

We are now entitled to a more optimistic view that we owe to modern science.

The future agenda in the field is likely to address the following issues:

Intensive studies in genomics and proteomics. These further our understanding of disease predisposition and susceptibility to drug adverse effects. They also offer potential therapeutic breakthroughs.

Investigating the possible role of the microbiome in gout parallel to its metabolic counterparts.

Attempts to standardize international medical approaches regarding gout; outcome measures, staging and management.

Emphasis on patient and physician education. This is a highly cost-effective approach.

Conflict of Interest

The authors have declared no conflict of interest .

Compliance with Ethics Requirements

This article does not contain any studies with human or animal subjects .

Biographies

Prof. Gaafar Ragab graduated from the Faculty of Medicine, Cairo University, 1976, where he got his degrees in Internal Medicine: MSc, 1980, and PhD, 1985. He served his faculty as a Resident, Assistant Lecturer (1980), Lecturer (1985), Assistant Professor (1990), and Professor (1995) till now. He spent a sabbatical year 1989 at the UAB, USA in the department of Clinical Immunology and Rheumatology. He headed the Clinical Immunology & Rheumatology Unit affiliated to the Internal Medicine Department 2010–2015. He was Chief of the Internal Medicine Department’s Research Committee 1995–2013. He is Fellow of the American College of Rheumatology (ACR) since 1989. He is a Co-founder of the Egyptian Society of Immunology and Rheumatology (EGYSIR) which he headed as its President 2010–2013. He was chosen as President of the Egyptian League Against Rheumatism (ELAR) annual meeting in Alexandria 2013. He is member of the Advisory Board of the Egyptian Society of Internal Medicine (ESIM) and its Journal and served as President of ESIM annual meeting, Cairo, 2014. He is the associate editor of the Journal of Advanced Research (JARE), the interdisciplinary publication of Cairo University, in charge of its medical branch. He won the prize of honour, Cairo University, for the great efforts in international publications, for the Year 2008. Member of the Egyptian National Committee for the management of Hepatitis C Virus (the extrahepatic manifestation) as well as the International Study Group of Extrahepatic Manifestations Related to Hepatitis C Virus infection (ISGEHCV). He is member of Geographical Variation in Rheumatoid Arthritis Group (GEO RA).

Dr. Mohsen Elshahaly is a Lecturer of Rheumatology, Physical medicine and Rehabilitation, Faculty of medicine-Suez Canal University since 2014 till now. He was born on the 3rd of March 1981 in Giza – Egypt. He graduated in 2004 from school of medicine – Suez Canal University. He got a master’s degree in Rheumatology, physical medicine and rehabilitation awarded by Suez Canal University. Also, he got a joint master’s degree in health professions eduction awarded by Maastricht University and Suez Canal University in 2011. He passed the specialty exam in rheumatology of the royal college of physicians and the British Society of Rheumatology in 2013. Dr. Elshahaly awarded M.D. degree in Rheumatology, Physical medicine and Rehabilitation from Suez Canal University and Newcastle University in 2014. He has also been awarded a musculoskeletal doctor of medicine degree by Newcastle University – UK in 2017 and passed the first two parts of the membership of royal college of physicians – UK. Dr. Elshahaly worked as a house officer in Suez Canal university hospitals from 1/3/2005 till 28/2/2006. He was assigned the job of demonstrator of Rheumatology, Physical medicine and rehabilitation, Suez Canal University from 23/6/2009 till 2/12/2009. He was promoted to assistant lecturer in 2/12/2009. He worked as a clinical research fellow in the musculoskeletal research group, Institute of cellular medicine, Newcastle University and The James cook university hospital, United Kingdom.

Thomas Bardin is a professor of Rheumatology at Paris Diderot University, a full time physician in the Department of Rheumatology at the Hôpital Lariboisière, Paris, France, and a member of the INSERM OSCAR unit. Dr. Bardin received his medical degree from the University Paris V in 1980, and he was accredited in rheumatology in 1981. He has been head of his department, president of the Société Française de Rhumatologie, chief editor of Revue du rhumatisme and Joint Bone Spine, associate editor of the Annals of the Rheumatic Diseases and a member of the editorial boards of Arthritis & Rheumatism, Clinical Experimental Rheumatology and Amyloid International. He is an international member of the American College of Rheumatology. Dr. Bardin has published over 290 articles in international peer-reviewed journals, and has been the editor or co-editor of more than 30 books in the field of rheumatology, including Therapeutics in Rheumatology and the rheumatology section of a French-language textbook on internal medicine. He has a strong interest in gout and was the convenor of the 2016 EULAR recommendations on the management of gout.

Peer review under responsibility of Cairo University.

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