In which time frame should the nurse tell the patient that the symptoms of gouty arthritis will dissipate?

Continuing Education Activity

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

Objectives:

• Identify the etiology of gout.

• Explain the common physical exam findings associated with gout.

• Describe the pathophysiology of gout arthritis.

• Summarize interprofessional team strategies for improving care coordination and communication to advance gout and improve outcomes.

Access free multiple choice questions on this topic.

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 in the tissues.[1][2] Gout was first recognized even before the common era, and 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 micromol/L); this level is the approximate limit of urate solubility.[5] The clinical manifestations of gout may include:

• Acute gout flare (recurrent flares of inflammatory arthritis)

• Chronic gouty arthropathy

• Accumulation of urate crystals in the form of tophaceous deposits

• Uric acid nephrolithiasis

• Chronic nephropathy

Etiology

Risk Factors

Humans are the only known mammals to develop spontaneous gout, as hyperuricemia commonly develops in humans. Hyperuricemia is the leading cause of gout.[1][6] People with higher serum urate levels are at an elevated risk for gout flare-ups and will also have more frequent flare-ups over time. In a study of more than 2000 older adults with gout, those with levels more than 9 mg/dl were three times more likely to have a flare over the next 12 months than those with levels less than 6 mg/dl.[7]

Hyperuricemia is not the only risk factor for gout, and in fact, only a minority of these patients develop gout. The lower physiological uric acid range can assess the impact of diet on the uric aid levels in other non-uricase-producing species. Dietary sources that can contribute to hyperuricemia and gout include the consumption of animal food such as seafood (e,g., shrimp, lobster), organs (e.g., liver and kidney), and red meat (pork, beef). Some drinks like alcohol, sweetened beverages, sodas, and high-fructose corn syrup may also contribute to this disease.[1]

epidemiological studies reported an increased disease burden of gout, which is largely explained by lifestyle changes like increased protein consumption and a sedentary lifestyle. 

Other factors implicated in gout and/or hyperuricemia include older age, male sex, obesity, a purine diet, alcohol, medications, comorbid diseases, and genetics. Offending medications include diuretics, low-dose aspirin, ethambutol, pyrazinamide, and cyclosporine. Genome-wide association studies (GWAS) have found several genes associated with gout. These include SLC2A9, ABCG2, SLC22A12, GCKR, and PDZK1.[8]

Risk factors of Hyperuricemia and Gout

Causes of Hyperuricemia

Table

Causes of hyperuricemia due to decreased uric acid clearance

Triggers

Every condition that causes alterations in extracellular urate concentration can trigger a flare-up. These conditions include stress (surgical procedure, recent trauma, or starvation), dietary factors (e.g., fatty food, beer, wine, and spirits), and drugs (e.g., aspirin, diuretics, or even allopurinol).

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 presence of tophus. Since identification by this definition is impractical, a number of case definitions have been developed like self-reports, Rome criteria, the New York criteria, the American College of Rheumatology criteria(ACR), and the 2015 ACR/European League Against Rheumatism (EULAR) criteria. The 2015 ACR/EULAR criteria have a sensitivity of 92% and specificity of 89% and are superior to all previous criteria. 

The prevalence of gout can vary by age, sex, and country of origin. In general, the prevalence of gout is 1 to 4%. Older age and male sex are two common risk factors noted globally. In western nations, the prevalence of gout in men (3 to 6%) is 2 to 6 fold higher than in women (1 to 2%). Prevalence increases with age but plateaus after 70 years of age. From 2007 to 2008, around 3.9% of U.S. adults received a diagnosis of gout.[9] Estimates of the gout prevalence in the United States range from less than three million to eight million or more individuals. The last of these estimates suggest gout prevalence of over 3% of the adult American population.[10][11][12]

The incidence rates of gout have seen an increasing trend over the past several decades, with a higher incidence noted in men than women, and the incidence increased with age. In men, adult serum urate levels of 5 to 6 mg/dL are usually reached at puberty, with a slight increase thereafter due to age alone.[13] The serum urate levels differ in women, whose serum urate concentrations average 1.0 to 1.5 mg/dL lower than men of corresponding ages.[14][15] This is likely due to renal uric acid clearance under the influence of estrogen in women. The urate concentrations in women after menopause rise to levels comparable to those in adult men.[16] The gender differences in patterns of urate concentration tend to affect the clinical differences between women and men in the age of onset of gout.[17][18]

Comorbidities

Hypertension, diabetes mellitus, hyperlipidemia, and metabolic syndrome are often associated with gout. Individuals with psoriasis have increased urate production and are prone to gout. On the other hand, patients with renal insufficiency have decreased urate excretion, resulting in gouty attacks. The prevalence of gout is also higher among individuals with chronic diseases such as hypertension, chronic kidney disease, diabetes mellitus, obesity, congestive heart failure, and myocardial infarction.[19]

Pathophysiology

Gout is an inflammatory arthritis that occurs in response to the deposition of MSU crystals, the end product of human purine metabolism, in joints, soft tissues, and bones. It may manifest as a gout flare (acute arthritis), chronic gouty arthritis (chronic arthritis), tophaceous gout (tophi), renal functional impairment, and urolithiasis.[20][21] 

Following are a number of complex and interacting processes responsible for the pathophysiology of gout:

• Genetic, metabolic, and other factors that result in hyperuricemia

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

• The soluble inflammatory, cellular, and innate immune processes and characteristics of MSU crystals themselves promote the acute inflammatory response.

• Immune mechanisms that mediate the resolution of acute MSU crystal-induced acute inflammation

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

Uric Acid Physiology

Uric acid is the final product of purine metabolism in humans and higher primate species as the gene decoding the enzyme uricase is silenced by mutation. Uric acid is the most abundant natural antioxidant in the human body, the traditional role of which was believed to be to remove reactive oxygen species. However, recent studies revealed that it is not a significant factor in controlling oxidative stress in the body. It is believed to have a role in immune surveillance and maintaining blood pressure and intravascular volume. Uric acid is a weak organic acid. It exists in the ionized form at pH 7.4 and functions as monosodium urate(which is less soluble) due to the high sodium concentration. In acid fluids like urine, uric acid exists in the non-ionized form, which is less soluble even in the physiological range. This explains the presence of uric acid crystals and stones in the urinary tract in distinction to MSU.

The bulk of urate in the body is from endogenous production in the liver with a small contribution from the small intestines. The glomerulus filters nearly all urate; hence under steady-state conditions, the body pool of urate is managed through renal excretion. The urate pool is expanded in a hyperuremic state. In men, the normal urate range is from 800 to 1000 mg, and in women 500 to 1000 mg. The daily turnover of urate is between 500 to 1000 mg. Serum urate concentrations in children are lower, and during male puberty, the value increases to the adult range. Serum urate levels remain low in women of reproductive age. The difference results from the effect of estrogen on renal urate transporters, resulting in less renal urate reabsorption and increased clearance in women. In menopausal and postmenopausal women, the urate levels approach those of adult males and may be altered by hormone replacement therapies.

Hyperuricemia

Hyperuricemia is a crucial factor in developing gout as it can promote monosodium urate crystal nucleation and growth by reducing urate solubility. Several factors promote hyperuricemia in humans, like the genetic absence of uricase, reabsorption of 90% of filtered uric acid, and limited solubility of MSU and urate in body fluids. Overproduction and/or underexcretion of uric acid is the foundation for rising serum uric acid levels.[6] When renal urate excretion is decreased, the intestinal uricolysis increases to half of the total urate disposal, and the transporter ABCG2 plays a key role. Serum urate concentrations exceeding 6.8mg/dl are saturating and increase the risk of deposition. It is seen in 20% of adult white men in the united states and is associated with several chronic disorders. 

Hyperuricemia may be primary/idiopathic or secondary. Overproduction is seen in several diseases, toxic states, and due to medications, like acute leukemia, tumor lysis syndrome, psoriasis, etc.

Purine Metabolism

Purines contain nine carbon purine nuclei of fused pyrimidine and imidazole rings. Purines perform essential functions in all living cells through purine-based nucleic acids adenine, guanine, and hypoxanthine. The dietary purine contribution to the urate pool is significant. Purine removal from the diet of normal individuals for a period of 10 days reduces the urate levels by 25% and urinary uric acid excretion by 50%. But severe purine restricted diets are impractical, and diets high in fructose, meat, alcohol, and fish promote hyperuricemia.

The endogenous pathway of purine production is called the de-novo purine synthesis and involves the conversion of ribose-5-phosphate from PRPP (5-phosphoribosyl 1-pyrophosphate) into nucleotide inosine monophosphate through 10 ey steps. This is an energy-costly process; hence energy is saved by interconversion and salvage of purine nucleotides. The urate precursors of purine degradation are hypoxanthine and guanine. These are mostly salvaged, and the unused guanine is deaminated to xanthine. The hypoxanthine is oxidized to xanthine by xanthine oxidoreductase.

Xanthine oxidoreductase is a molybdenum-pterin and iron sulfide cluster containing flavoprotein. It exists in oxidase form that uses oxygen to convert hypoxanthine to xanthine and xanthine to urate and in a dehydrogenase form that uses NAD+. Inhibition of xanthine oxidoreductase is the most common target of urate-lowering in patients with gout.

The major steps in purine synthesis targetted by regulation are

1. The synthesis of PRPP in the PRPP synthetase pathway

2. The utilization of PRPP in the first step of de-novo purine synthesis

The pathway is inhibited by purine nucleotide products of purine synthesis and activated by increased PRPP. This antagonistic control mechanism malfunctions in two rare X-linked disorders—deficiency of salvage enzyme HPRT and overactivity of PRS1. Excessive ATP(adenosine triphosphate) depletion in tissue hypoxia or acute alcohol intoxication leads to decreased concentration of inhibitory nucleotides and excess urate productions.

Renal Uric Acid Secretion

Uric acid clearance in adults averages only 5 to 10% that of 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. People with hyperuricemia due to impaired renal excretion have normal urinary urate levels due to impaired clearance of uric acid. Genomic and molecular studies have identified several transporters involved in renal uric acid clearance; two of them, GLUT9 and URAT1 (members of the organic acid transporter family), strongly affect serum urate levels. 

Glucose Transporter 9 (GLUT9)

GLUT9 is a product of the SLC2A9 gene. It is a voltage-driven urate transporter that mediates uric acid reabsorption from tubular cells. GLUT9 exists in 2 isoforms GLUT9L on the basolateral side of the proximal renal tubular epithelium and GLUT9S on the apical side. It is also expressed in the hepatocytes and regulates serum urate concentrations by dual effects in the kidney and the liver. It also transfers glucose and fructose, which might explain the dietary influence of these substances on hyperuricemia. Mice with a knockout of GLUT9 had moderate hyperuricemia, massive hyperuricosuria, and early onset nephropathy.

URAT1

URAT1 is encoded by the SLC22A12 gene and is highly specific for uric acid. It affects renal uric acid transport by mediating the exchange of various anions. Mutations in SLC22A12 lead to hypouricemia, hyperuricosuria, and exercise-induced renal functional impairment. The uricosuric drugs probenecid and benzbromarone and lesinurad inhibit URAT1 and increased uric acid excretion. Other urate transporters include ABCG2, NPT1, NPT4, MRP4 (multidrug resistance protien4), etc.

Autosomal Dominant Tubulointerstitial Kidney Disease caused by UMOD pathogenic variants is characterized by early-onset hyperuricemia (with or without gout), hypertension, and progressive tubulointerstitial inflammation and fibrosis leading to end-stage renal failure by the age of 40 years. This was previously described as familial juvenile hyperuricemia nephropathy and medullary cystic kidney disease. Most show a mutation in uromodulin(Tamm-Horsfall protein) which 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, leading to decreased extracellular volume and compensatory enhancement of sodium-dependent urate transport in the proximal tubule. 

Extra-renal Urate Excretion

This is by the ABCG2 transporter in the intestines. A reduced intestinal urate excretion in ABCG2 knockout mice caused an increased serum urate, but this was partially compensated by increased renal uric acid excretion. Hence, urate overproduction hyperuricemia is a renal overload type consisting of  "extrarenal underexcretion" type and "genuine urate overproduction" subtypes. 

Urate Crystal Formation

The formation of MSU crystals requires sustained supersaturated concentrations of urate. Crystal formation is influenced by factors like the presence of particulate seed, local cation concentrations, pH, temperature, and dehydration. Immunoglobulin G and Ig M may also aid in crystal formation and growth in patients with gout. MSU crystals formation is seen preferentially in the first metatarsophalangeal joint, midfoot, and Achilles tendon. Growing evidence shows the relation between OA and sites of MSU crystal deposition. The osteoarthritic joint, with products of cartilage degradation like chondroitin sulfate, lowers the urate solubility and promotes nucleation and growth of crystals.[22] The solubility of MSU drops rapidly with decreasing temperature.[5]

Inflammatory Response

microscopic and imaging studies have shown the presence of urate crystals within the joints for prolonged periods without overt inflammatory reactions. Heavily crystal-laden fluids(urate milk) are sometimes found in uninflamed bursae and joints. The dense urate crystal mass in tophi sometimes reaches massive dimensions with little inflammation and symptoms till there is critical compression of the surrounding tissues. The crystals initiating inflammation are microcrystals usually shed from preexisting synovial tophi. This is supported by observing acute gout flares with rapid changes in urate concentrations. Initiation of inflammation depends on multiple factors like crystal size, the proteins and molecules coating them, and inflammatory cells encountered. MSU crystal surface binds to various proteins, lipoproteins, and lipids, including IgG.

The IgG conformational changes encourage phagocytosis by cells with Fc-y receptors. The IgG also activates the classical complement pathway. The MSU crystals directly activate both complement pathways. This promotes further opsonization by depositing the complement split product C3b on the crystals. Apolipoprotein coating on the MSU crystals counters the opsonic effects of the IgG Fc and complements. It also inhibits neutrophil stimulation. Thus the inflammatory potential of the MSU crystals is a balance between the pro and anti-inflammatory elements coating the surface. In acute gout, the predominant inflammatory cell in the synovial tissue and fluid is the neutrop[hil, which contributes to the bulk of the proinflammatory stimulus.

Synovial fluid macrophages in patients with asymptomatic tophi often contain MSU microcrystals. This indicates the absence of overt inflammation despite active engagement with phagocytes. Immortal macrophages and blood monocytes mount a vigorous response to MSU crystals compared to well-differentiated macrophages due to the release of TGF-b1. Two broad mechanisms of MSU crystal interaction with phagocytes have been studied.

1. activation of phagocytes leading to lysosomal fusion, respiratory burst, and release of inflammatory mediators,

2. the more predominant pathway of cytosolic protein complex activation(NLRP2 inflammasome).[23] These complexes subsequently recruit caspase-1, which activates pro-IL-1beta to IL-1beta.  IL-1beta plays an important role in the inflammatory response to gout.[3][23][24] It promotes vasodilatation and recruitment of monocytes and initiates and amplifies the inflammatory cascade. Further IL-1beta secretion can result in bone and cartilage breakdown. Other cytokines, such as TNF-1, IL-6, CXCL8, and COX-2, are also involved in the inflammatory response.[24]

Most external stimuli activate inflammatory cells by a carefully coordinated cell surface signal transduction by a cascade of tyrosine kinase phosphorylation. But MSU crystals bypass and directly activate second messenger systems. 

Table

8. ACTIVATION OF NEUTROPHILS 11. REMOVAL OF CRYSTAL COATING AND PHAGOLYSOSOMAL RUPTURE, ENZYME AND MEDIATOR RELEASE          

Termination Of The Acute Flare

Acute gout is always self-limiting, even without medication. It resolves spontaneously in a week or two. Given the similarity in the molecular mediators of inflammation in gout and other arthropathies and the persistence of MSU crystals, this is an intriguing phenomenon. After MSU crystal ingestion, neutrophils undergo NETosis (neutrophil extracellular traps). The NETs aggregate and densely pack MSU crystals and degrade the pro-inflammatory cytokines, including IL-beta, TNF-alpha, IL-6, etc. The increased vascular permeability after acute synovitis allows increased entry of antiinflammatory cytokines crystal coating molecules like ApoB. This coating with ApoB and locally produced ApoE and TGF-beta inhibit neutrophil activation. Systemic anti-inflammatory mediators like melanocortins decrease joint inflammation by the MCRs(macrophage melanocortin receptors), adenosine monophosphate-activated protein kinase inhibits NLRP3 expression and inhibits caspase1 and IL-1beta. 

Advanced Gout

Tophi are deposits of MSU crystals encompassing granulomatous inflammation. They are nests of crystals with a corona zone of differentiated macrophages and multinucleated giant cells surrounded by a fibrous layer. Proinflammatory cytokines like IL-1 and TNF-alpha 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 most often found in periarticular, articular, and subcutaneous areas, including cartilage, bone, joints, tendons, and skin, rich in proteoglycan. The tissue reaction to tophus is generally chronic inflammation and involves 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.[25] 

Tophi contribute to joint damage and bone erosion in gout.[26] MSU crystal deposits are surrounded by osteoclast-like cells at the interface of the bone and a tophus.[27] T-cells in the tophus express RANKL and contributor to bony erosions. Urate crystals also decrease the function, viability, and differentiation of osteoblasts and reduce osteoprotegerin expression. Hence, a high number of osteoclasts and reduced osteoblasts are present at the bone tophus interphase.

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

Histopathology

Monosodium urate crystal deposition, under polarizing light microscopy, is typically described as a rod or long needle-shaped crystals with negative birefringence.[28] Under light microscopy, tophi consist of several zones; the crystalline center, the surrounding corona zone, and then the fibrovascular zone. Multinucleated giant cells, histiocytes, and plasma cells are present in the corona zone.[29]

History and Physical

Gout has been described as a chronic disease characterized by four distinct stages.

1. Asymptomatic hyperuricemia

2. Acute gout attacks

3. Inter-critical period

4. Chronic tophaceous gout. 

Asymptomatic Hyperuricemia

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

Acute Gout Attack

This is the initial manifestation of gout. It is characterized by abrupt onset of severe pain and swelling. The maximum inflammation occurs within 12 to 24 hours. Gout flare is typically monoarticular, often occurring in the lower extremities.[30] The most commonly involved joint is the first metatarsophalangeal joint. The talar, subtalar, ankle, and knee can also be involved in some cases. Although affliction of the joints mentioned above is common in gout, the physician should pay attention to other joints, specifically those with underlying osteoarthritis. Besides joints, other periarticular structures such as tendons and bursa may also be affected.[1] Gout can occur in axial joints such as sacroiliac joints and the spine, though much less common than peripheral involvement, leading to diagnostic confusion.[31][32]  The initial attack resolves within 3 to 14 days, even in the absence of pharmacotherapy, but the subsequent attacks are prolonged.

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 disorder or in organ transplant recipients receiving tacrolimus or cyclosporine.[33][34]  In women, a polyarticular presentation has been reported in South Africa, with only a small number starting with acute podagra.

Gout flares are more common at night and in the early morning when cortisol levels are low.[35] The pain is often sudden, waking the patient from sleep or may have developed gradually over a few hours before the presentation, with the maximum intensity of pain at 24 hours.[35] Signs of inflammation extend beyond the joint involved; this may give the impression of cellulitis or dactylitis (sausage digit) or may actually be due to tenosynovitis or arthritis in contiguous joints. The pain is usually severe and not responsive to the usual home remedies; even touching the joint can be excruciatingly painful. Gout flare-ups often incite local inflammation, which presents as erythematous, swollen, and a warm joint. The erythema over the affected joint during an attack is characteristic of gouty synovitis. Systemic features of joint inflammation may include fever, general malaise, and fatigue.[1] 

Around 60% of the patients experience a second attack within one year and 80 % within three years. Local trauma, alcohol binges, overeating or fasting, weight changes, use of diuretics, and initiation of urate-lowering drugs may precipitate an acute attack. in a hospital setting, post-operative status or acute severe medical illnesses may precipitate attacks. The spring season has been reportedly associated with an increase in gout attacks.  

The physical exam findings align with the patient's history. The affected joint is typically red, swollen, warm, and tender.[36] In patients with chronic gout, the flare-up may involve multiple joints. With the involvement of many joints, it can cause a systemic inflammatory response syndrome that may masquerade as sepsis.[37] Tophi, which are subcutaneous depositions of urate that form nodules, can also be found in patients with persistent hyperuricemia. Tophi typically occur in the joints, ears, finger pads, tendons, and bursae.[1]

Intercritical Gout

After resolution of the acute attack, the patient is in the inter-critical stage. in some patients, a stage of incomplete remissions is present with the persistence of pain. Although the disease seems to be inactive, hyperuricemia persists, and subclinical inflammation may be present in the joints.

Chronic Tophaceous Gout

Gouty tophi are foreign body granulomas around deposits of MSU crystal. They appear as chalk-like subcutaneous nodules under transparent skin with increased vascularity, which may or may not drain. Although patients may present with tophi as their initial symptom, chronic tophaceous gout usually develops ten or more years after an acute attack. However, microtophi are documented early in the disease in patients with hyperuricemia. MSU crystal deposition is seen in joints affected by osteoarthritis. It usually occurs in the connective tissue and articular cartilage. Tophi may be intraarticular, periarticular, or extra-articular, the most common sites being the digits of hands and feet, knees, and the olecranon bursa. They lead to destructive deforming arthritis with extensive bone destruction and grotesque deformities. Women develop tophaceous deposits on the Heberden nodes and Bouchard nodes. 30% of the patients with chronic tophaceous gout had finger pad deposits. In postmenopausal women with CKD finger pad, tophi were seen before the onset of an acute attack.

Tophaceous deposits have been reported in the cornea in the eye and the heart valves. 

Evaluation

Synovial Fluid Analysis

Monosodium urate crystal identification remains the gold standard for gout diagnosis. Gout flare is marked by the presence of MSU crystals in synovial fluid obtained from affected joints of bursas visualized by direct examination of a fluid sample using compensated polarized light microscopy. This technique may also identify uric acid crystals from previously affected tophaceous deposits and joints during the inter-critical period.[38] Synovial fluid during a gout flare-up usually is yellow in color and cloudier in appearance, and it contains crystals and white blood cells with neutrophil predominance. The synovial fluid will be more opaque in patients with septic arthritis with a yellow-green appearance. Under a microscopic examination, synovial fluid for septic arthritis will have a higher white blood cell count (over 50000/ml) than in gout and a positive gram stain. Additionally, cultures will be positive for bacteria and negative for crystals.

Under polarizing microscopy, synthetic fluid or tophus aspiration analysis reveals needle-shaped, negatively birefringent crystals.[1][3][39] Arthrocentesis is also necessary to confirm the diagnosis and rule out other septic arthritis, Lyme disease, or pseudogout (calcium pyrophosphate).[39]

Laboratory Study

The examination usually reveals elevations in the white blood cell count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) during a gout flare-up. Still, these features are non-specific and do not confirm the diagnosis.

During an acute gout flare-up, serum urate level may be high, normal, or low. The physician should repeat the serum urate level in patients with an uncertain gout diagnosis after the resolution of the flare-up. Hyperuricemia is helpful in the clinical diagnosis of gout in symptomatic patients, but hyperuricemia alone does not definitively confirm the diagnosis. Asymptomatic hyperuricemia is not uncommon in the general population. Persistently low serum urate concentrations make the diagnosis of gout less likely.[3] In patients suspected of gout based on clinical features, elevated serum urate level (>6.8 mg/dL) can support the diagnosis but is neither diagnostic nor required to establish the diagnosis. The most accurate time for assessing serum urate level to establish a baseline value is two weeks or more after a gout flare completely subsides.

Urinary fractional excretion of uric acid can be measured, especially in young populations with a non-specific cause of hyperuricemia. It will help differentiate between overproduction or under excretion of uric acid and can act as a guide for therapy.

Imaging

Although not routinely used, ultrasonography and dual-energy CT (DECT) can assist in diagnosing gout. Monosodium urate deposition will be apparent on ultrasound as a hyperechoic enhancement over the cartilage, also known as a double contour sign. DECT can identify urate due to the beam attenuation after exposure to two different X-ray spectra.[1][3]

Treatment / Management

The treatment of gout is based on the goals of treatment. During acute flares, the goal is solely to reduce the inflammation and symptoms. Long term goal is to reduce serum urate levels to achieve suppression of flare-ups and regression of tophi.[3]

General Principles of Therapy

• The earlier the treatment is introduced for a gout flare, the rapid and complete resolution of symptoms occurs.[40]

• The duration of gout flare therapy ranges from a few days to several weeks, depending on the timing of treatment initiation.[41]

• Anti-inflammatory gout flare prophylaxis should generally be continued during the early months of urate-lowering therapy.[42]

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

• Tophus is an indication to initiate long-term urate-lowering therapy either during or following the resolution of a gout flare to reverse or prevent joint damage and chronic gouty arthritis.

Acute Gout Flare

Management of acute flares aims at decreasing the inflammation and the resulting pain. The physician should start the treatment within the first 24 hours of onset to reduce the severity and duration of the flare-up.[6] Non-pharmacological management such as rest with topical application of ice packs can combine with medications that reduce inflammation.[43] First-line treatments for gout flares are (nonsteroidal anti-inflammatory drugs) NSAIDs, colchicine, or systemic glucocorticoids.[44] The length of the treatments should be at least 7 to 10 days to prevent rebound flare-ups.[45]

NSAIDs

NSAIDs are most effective when therapy is initiated within 48 hours of the onset of gout symptoms. A potent oral NSAID, such as indomethacin (50 mg three times daily) or naproxen (500 mg twice daily), is initiated. Other NSAIDs include meloxicam (15 mg daily), ibuprofen (800 mg three times daily), diclofenac (50 mg two to three times daily, and celecoxib (200 mg twice daily). Typically NSAID treatment for gout flare lasts for five to seven days. No data favors one NSAID over the other. High-dose, fast-acting NSAIDs such as naproxen or diclofenac are options, and indomethacin is not preferable due to its toxicity profile.[6] NSAIDs are usually given in full doses for the first three days and then tapered according to the progress. COX2 selective inhibitors like celecoxib can be given to prevent adverse GI effects.

Contraindications for the use of NSAIDs include active duodenal or gastric ulcer, cardiovascular disease (uncontrolled hypertension or heart failure), NSAID allergy, and chronic kidney disease with creatinine clearance (CrCl) of less than 60 ml/minute per 1.73 square meters. Aspirin is not used to treat gout flare due to the paradoxical effects of salicylic acid on serum urate levels.[46][47] This results from uricosuria at higher doses and renal uric acid retention at low doses (less than 2 to 3 g/day).[48][49]

Oral Glucocorticoids

Glucocorticoids are recommended in gout patients with contraindications to NSAIDs and/or colchicine. These agents are also drugs of choice for patients with renal insufficiency. The initial dose for gout flare is 30 to 40 mg of prednisolone or prednisone once daily or given in a divided twice-daily dose until flare resolution begins, and then taper the dose of glucocorticoids over the next 7 to 10 days. This has been proven to be at least comparable to NSAID efficacy. High starting doses of systemic steroids(>0.5mg/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.[50][51] 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.[52]

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 must be avoided until the results are available initiation of other agents like NSAID or colchicine 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 frequent courses of glucocorticoids should be avoided to limit adverse effects. In patients with concomitant or suspected infections, uncontrolled diabetes mellitus, prior glucocorticoid intolerance, and in post-operative status, glucocorticoids may heighten the risk of impaired wound healing.

Initiation of daily low dose adjunctive colchicine may be done to prevent rebound flare-ups during tapering. Extended tapering doses of glucocorticoids up to 14 or even 21 days are advised in patients with rebound flares, shortened inter-critical periods, and not receiving anti-inflammatory prophylaxis.

Parenteral Glucocorticoids

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

Colchicine

Colchicine is comparably effective to other agents if taken within 24 hours of gout flare onset. Colchicine has been shown to reduce pain by over 50% in a randomized control trial at 24 hours compared to a placebo. The lipophilic nature of colchicine makes it readily bioavailable for cellular uptake after oral administration. Its primary target is tubulin, and it is eliminated by hepatic elimination. It acts by binding tightly to unpolymerised tubulin and forms a colchicine - tubulin complex which regulates microtubule and cytoskeletal function. It regulates cell proliferation, gene expression, signal transduction, chemotaxis, and neutrophil secretion of granule contents. It decreases neutrophil adhesion by suppressing E-selectin redistribution in the endothelial membrane.

EULAR consensus guidelines for treating acute gout with colchicine advise a maximum of 3 doses of 0.5mg per day. The total dose of colchicine should not exceed 1.8 mg on day 1 (either 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 three times on the first day.[53] On subsequent days, colchicine should be taken once or twice daily until the resolution of a gout flare.[54]

A reduced dose of colchicine may be required for patients with diminished hepatic or renal function or potential drug interactions. ABCB1 inhibitors like cyclosporin and clarithromycin may cause colchicine toxicity. Colchicine neuromyopathy may develop weeks after initiation of cyclosporin. High-dose colchicine regimens should not be encouraged due to unacceptably high toxicity. The adverse effects of colchicine comprise gastrointestinal symptoms (nausea and diarrhea), myotoxicity, and myelosuppression (leukopenia, thrombocytopenia, and aplastic anemia).[55] The frequent adverse effects of colchicine are abdominal cramping and diarrhea.[53][56] Intravenous colchicine is strongly advised against due to serious adverse effects, including death.

• Colchicine dosing adjustments for certain high-risk groups of patients should follow the guidelines provided in the manufacturer's FDA-approved information. Usually, no more than 0.3 mg dose is administered on the day of a gout flare, and the dose is not repeated for at least three to seven days or more in such patients. Following are the high-risk groups:

  • Patients taking colchicine prophylaxis within the past 14 days, with normal hepatic and renal function, who have taken a medication that inhibits P-gp and a potent CYP3A4 inhibitor within the last 14 days

  • Patients taking colchicine prophylaxis within the past 14 days, with any hepatic and renal impairment, who have taken a medication that is a moderate CYP3A4 inhibitor within the last 14 days

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

Prophylaxis For Acute Gout

The subclinical joint inflammation in gout forms the basis for colchicine prophylaxis. An acute gout flare is the most common adverse effect of urate-lowering therapy. For prophylaxis, low-dose colchicine therapy is the first choice. It is commenced 1 or 2 weeks before using urate-lowering drugs and continued for up to 6 months after normalization of the uric acid levels or until the clinically visible tophi resolve. Low-dose NSAIDs and low-dose corticosteroids are rarely used. The recommended dosage of colchicine is 0.5mg once or twice daily in the absence of any renal or hepatobiliary compromises.

Interleukin 1 Inhibition

Interleukin 1 antagonists have shown efficacy in refractory cases of gouty arthritis. Soluble IL1 receptor antagonist - ANAKINRA 100mg/day subcutaneously for three days or IL1 beta specific monoclonal antibody canakinumab. A single dose of 150 mg subcutaneously was more effective than a single-dose IM dose of triamcinolone acetonide though the risk-benefit ratio is uncertain.

Non-acute Flares

Pharmacologic

The clinician should not start urate-lowering therapy (ULT) in patients with asymptomatic hyperuricemia or gout with rare attacks (1 flare/year). The American College of Rheumatology (ACR) 2012, Guidelines for starting ULT include the following:

1. Frequent or disabling gout flares (greater than or equal to two per year) that are difficult to treat

2. Gout with chronic kidney disease (stage 3 or higher)

3. Tophus diagnosis on physical examination or imaging

4. Past urolithiasis

5. chronic tophaceous gout

Urate-lowering therapy is started at a low dose to monitor the side effects and response to treatment. Titration of the dose is every 2 to 6 weeks to achieve serum urate levels of less than 6 mg/dl or 5 mg/dl in those patients with tophi.[43]

During the initiation of ULT, there is an increased risk of gout flare-ups, so colchicine prophylaxis is recommended for three months after achieving the serum urate goal in the patients without tophi or six months with tophi to reduce the flare-up risk.[57]

ULT can categorize into three classes (based on the mechanisms).

Xanthine oxidase inhibitors (XOI) - XOI works by inhibiting uric acid synthesis. This class includes allopurinol and febuxostat. Allopurinol is the recommended first-line pharmacologic ULT in gout.[43] The physician should monitor liver enzymes, renal, and blood count regularly. Adverse effects from allopurinol can range from skin rashes to life-threatening severe allopurinol hypersensitivity (especially in HLA-B*5801 positive patients).[1]

Allopurinol

Allopurinol is covert to its active metabolite oxypurinol in the liver; the drug has a half-life of 24 hours. The initial allopurinol dose is 100 mg daily in patients with CrCl greater than 60 mL/minute and is titrated upward by 100 mg every 2 to 4 weeks. A dose of 300 mg of allopurinol once daily reduces serum urate levels in 33% of the population. Doses less than 300 mg are given in a once-daily regimen, and more than 400 mg are given in two divided doses. Allopurinol and oxypurinol lower the serum urate by a dual action of inhibiting xanthine oxidase inhibitor as well as by competing with phosphoribosylpyrophosphate in the salvage pathway and by suppressive effects of drug nucleotides on the aminotransferase activity. Allopurinol non-selectively also inhibits pyrimidine metabolism. A starting dose of allopurinol of <1.5 mg per mL/minute of estimated glomerular filtration rate (eGFR) is advised in patients with stage 3 or greater chronic kidney disease.

Adverse effects of allopurinol - may precipitate gout flares, pruritic and maculopapular rashes, leukopenia, thrombocytopenia, diarrhea, and severe cutaneous adverse reactions. bone marrow impression is uncommon but may occur at very high doses or in patients with CKD. (DRESS) syndrome - drug reaction with eosinophilia and systemic symptoms is a potentially life-threatening reaction to allopurinol. Steven johnson syndrome or toxic epidermal necrolysis may occur in major allopurinol hypersensitivity(AHS). The highest risk for AHS occurs in the first 60 days after initiation of allopurinol therapy. Allopurinol can potentiate the cytolytic and immunosuppressive effects of azathioprine and 6-mercaptopurine (6-MP), which are in part metabolized by xanthine oxidase.[58] Hence, allopurinol should be avoided in patients treated with these agents.[59] in patients taking warfarin, anticoagulation status must be carefully monitored.

Febuxostat

it is a selective xanthine oxidase inhibitor that occupies the access channel to the molybdenum-pterin active site of the enzyme. Renal elimination plays a minor role in febuxostat kinetics. Febuxostat received FDA approval to treat gout patients with hyperuricemia at daily doses of 40, and if the urate levels do not normalize in 2 weeks dose is increased to 80 mg daily. Cardiovascular and hepatic abnormalities may be more common with febuxostat compared with allopurinol. In patients with CKD, the urate-lowering effect of febuxostat is superior to allopurinol. Patients taking azathioprine, 6-MP, and theophylline are considered contraindications to the use of febuxostat.

Uricosuric Drugs 

The uricosuric agents work by increasing renal urate clearance.[1] 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 market in the United States). They inhibit URAT1 at the apical membrane of the renal proximal tubule epithelial cell. These agents are ineffective as monotherapy in patients with low creatinine clearance (less than 30 ml/minute) and contraindicated with patients with a history of nephrolithiasis.[60] Probenecid is the only agent approved for use as a monotherapy. Probenecid is initiated at a dose of 250 mg twice daily, and dose increments are titrated according to the serum urate concentration level. The dose is typically increased every several weeks to a usual maintenance dose of 500 to 1000 mg (taken 2 to 3 three times daily), aiming for the target urate levels of <6 mg/dL (<357 micromol/L). The major side effects of uricosuric drugs are the precipitation of a gout flare, uric acid urolithiasis, gastrointestinal intolerance, and rash.

Uricase Pegloticase (urate oxidase) - Uricase is present in non-primates and lower primates. Pegloticase (a pegylated recombinant form of uricase) is a potent agent that rapidly reduces serum urate levels. It directly degrades the uric acid to highly soluble allantoin. PEGylation of the recombinant porcine-baboon uricase pegloticase has a circulating half-life of days to weeks and decreases but does not eliminate immunogenicity. Uricase is reserved only for patients with refractory gout.  Patients have to discontinue urate-lowering therapy while starting this medication because they may develop antibodies against uricase. Pegloticase is administered as intravenous infusions every two weeks, and before each infusion, serum urate levels should be monitored to confirm urate-lowering efficacy.

For at least the first six months of treatment, all patients treated with pegloticase should receive gout flare prophylaxis. In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, pegloticase is contraindicated. Another agent Rasburicase (non-pegylated recombinant uricase), has not been approved by FDA for use in gout. It is used to prevent acute uric acid nephropathy due to tumor lysis syndrome in patients with high-risk leukemia and lymphoma. phase 3 studies of pegloticase have shown complete resolution of one or more tophi on 20% of patients by 13 weeks and lowered uric acid levels to less than 6mg/dl in 42% of subjects by six months.[61]

Acute gout flares are seen in 80% of patients on pegloticase in the first few months of therapy, even with prophylaxis. Moderate infusion reactions like flushing, urticaria, and hypotension are seen, and in 2%, severe reactions like anaphylaxis are seen. Reactions also include severe muscle pain and cramping due to unknown mechanisms. 

Non-Pharmacologic

Patients with gout are encouraged to modify their lifestyles to prevent future attacks.[62]

Diet recommendations include reducing alcohol consumption, limiting purine-rich foods (meat, seafood, high fructose corn syrup, and sweetened soft drinks), and substituting low-fat or non-fat dairy products for their higher fat content counterparts. Weight loss and adequate hydration will also help reduce gout flare-up frequency.

Differential Diagnosis

Gout Flare

• Calcium pyrophosphate crystal deposition disease

• Basic calcium phosphate crystal disease

• Septic arthritis

• Osteoarthritis

• Psoriatic arthritis

• Cellulitis

• Trauma

Tophaceous Gout

• Dactilytis

• Rheumatoid arthritis

• Osteomyelitis

Prognosis

The prognosis of gout depends on the comorbidity of each individual. Mortality is higher in individuals with cardiovascular comorbidity. When gout receives proper treatment, most patients will live a normal life with mild sequelae. Patients whose symptoms appear earlier in life will usually have a more severe disease at presentation. For those who do not modify their lifestyle, recurrent flare-ups are common.

Complications

Tophi, joint deformity, osteoarthritis, bone loss.

Urate nephropathy and nephrolithiasis.

Gout might also cause ocular complications, such as conjunctivitis, uveitis, or scleritis from the urate crystal precipitation.[63]

Deterrence and Patient Education

Lifestyle Modification and Strategies to Reduce the Risk of Out Flares and Progression of Gout

• Lifestyle changes are encouraged in gout patients, including weight loss, limiting alcohol intake, and avoiding certain foods. These changes will complement medical therapy but often are not enough by themselves to combat or reverse gout.

• Weight gain and increased adiposity are risk factors for gout, while in overweight patients with established gout, weight loss likely benefits in reducing serum urate and gout symptoms.[64][65]

• The diet composition optimum for gout is likely to be one with adequate protein intake, especially from plant sources and low-fat dairy sources, with reduced intake from animal sources of purine such as shellfish or red meat; decreased saturated fat; and replacement of simple sugars with complex carbohydrates.

• Avoid or minimize the frequency of sugar-sweetened juices and alcohol-containing beverages or beverages containing high-fructose corn syrup.

Pearls and Other Issues

Interleukin (IL) 1 is an important mediator of inflammation in gout and a potential target for therapy in gout flares.[66] For patients with multiple medical comorbidities and those on anticoagulation, a short-acting (IL) 1 inhibitor, such as anakinra, can be used to treat gout flare as an alternative to the first-line therapies.

Enhancing Healthcare Team Outcomes

Most patients with gout have other comorbidities. The prevalence of gout is higher among individuals with chronic diseases such as hypertension, chronic kidney disease, diabetes, obesity, congestive heart failure, and myocardial infarction.[19]

Gout treatment requires the collaboration of an entire interprofessional healthcare team approach. The physician (MD, DO, NP, PA) must promptly identify the pathology and rule out differentials. Some cases may require a rheumatology consult. The pharmacological approaches to gout require considering these comorbidities and monitoring their response to treatment. The pharmacist and nurse both must educate the patient on medication compliance. Also, the pharmacist should assist the team by performing medication reconciliation, verifying appropriate dosing, and consulting on agent selection in the event of initial treatment failure. The dietitian should urge the patient to abstain from alcohol, avoid meat-containing foods, and maintain a healthy body weight. The role of specialists, primary care physicians, nurses, nurse practitioners, and dieticians are all critical in reducing gout morbidities. The medical team should coordinate the patient's education on lifestyle modification, which can contribute to reducing the risk and frequency of gout flare-ups; this is only possible via open communication between all disciplines on the interprofessional team.  

All healthcare providers, including primary care and nurse practitioners, should identify classic gout symptoms and have a low threshold for referring the patients for an arthrocentesis if they are uncertain of the diagnosis. Then, working with the interprofessional team as outlined above, direct the treatment as needed and interact with the interprofessional team to drive outcomes. [Level 5]

Referral to a specialist/rheumatologist should be a consideration in the following patients with joint pain: 

• Unclear etiology with hyperuricemia

• Unclear etiology with normal serum urate level

• Patients with renal impairment

• Failed trial of xanthine oxidase inhibitor treatment

• Multiple side effects from the medications

• Refractory gout[43]

Only through an interprofessional team approach with close communication can the morbidity of gout be lowered.

Review Questions

Figure

Hand Radiograph Gout. Contributed by Scott Dulebohn, MD

Figure

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

Figure

Gout in the Ear. Image courtesy S Bhimji MD

Figure

Acute gout attack. Image courtesy O.Chaigasame

Figure

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

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How long does it take for gout to go away?

How soon should a patient be treated for an acute gout attack?

How long does it take for uric acid levels to drop?

How long does it take for gout crystals to dissolve?