Differential Diagnosis of Gout: A Comprehensive Guide for Clinicians

Gout, a prevalent form of inflammatory arthritis, arises from the deposition of monosodium urate (MSU) monohydrate crystals within bodily tissues. This condition, known since antiquity, stands out as one of the most thoroughly understood and effectively managed rheumatic diseases. This article delves into the diagnostic challenges presented by gout, focusing on its differential diagnosis, and underscores the crucial role of an interprofessional healthcare team in delivering comprehensive patient care and optimizing health outcomes.

Objectives:

Distinguish gout from other conditions presenting with similar symptoms by employing a systematic differential diagnosis approach.
Analyze the clinical features and laboratory findings that aid in differentiating gout from its mimics.
Identify and evaluate conditions that commonly present as differential diagnoses for gout, such as septic arthritis, pseudogout, and inflammatory cellulitis.
Understand the importance of synovial fluid analysis and crystal identification in confirming gout and excluding other diagnoses.

Introduction

Gout, historically dubbed the “disease of kings,” remains a widespread cause of chronic inflammatory arthritis in the United States. It is pathologically defined by the accumulation of monosodium urate (MSU) monohydrate crystals in various tissues.[1][2] Recognized since the era of Hippocrates, gout is arguably the most well-understood and manageable condition within the spectrum of rheumatic diseases.[3][4]

The biochemical hallmark of gout is extracellular fluid urate supersaturation, clinically reflected as hyperuricemia. This state is characterized by serum urate concentrations exceeding 6.8 mg/dL (approximately 400 µmol/L), the approximate solubility limit of urate.[5] Gout’s clinical manifestations are diverse and include:

Recurrent acute gout flares (inflammatory arthritis episodes)
Chronic gouty arthropathy
Tophaceous deposits (urate crystal accumulation)
Uric acid nephrolithiasis (kidney stones)
Chronic nephropathy

While gout often presents with distinctive features, its diagnosis is not always straightforward. Several conditions can mimic gout, particularly in its acute phase. Therefore, a robust differential diagnosis is essential to ensure accurate management and prevent misdiagnosis. This article will focus on the differential diagnosis of gout, exploring conditions that share overlapping clinical features and outlining strategies for accurate differentiation.

Etiology of Gout and Hyperuricemia

The development of gout is typically multifactorial, influenced by a combination of genetic predisposition, existing medical conditions, and dietary habits. In rare instances, a single genetic defect may be the primary cause, often associated with other health complications. Regardless of the specific trigger, the fundamental pathway involves elevated serum uric acid levels, which can manifest as clinical gout in susceptible individuals.

Genetic Factors in Gout

Genetics play a significant role in gout, with heritability estimated at approximately 73% for hyperuricemia and 40% to 50% for gout itself. A substantial proportion of gout patients report a family history of the condition.[6] Genes implicated in gout are categorized into four main groups (refer to Table 1. Genes Associated With Gout). [6][7]

Table 1. Genes Associated With Gout.

(Note: As the original article only provides a link to a table icon and not the actual table data, I cannot reproduce the table here. In a real-world scenario, I would access the linked table and include the relevant information in markdown format.)

Risk Factors for Hyperuricemia and Gout

Uric acid is the end product of purine metabolism. The final steps involve xanthine oxidase converting hypoxanthine to xanthine, and then xanthine to uric acid. Uricase then further metabolizes uric acid into allantoin, which is far more soluble. Humans, along with certain primates, giraffes, and Dalmatians, carry gene mutations that prevent uricase production.[8][9] This genetic inactivation of uricase occurred approximately 25 million years ago, coinciding with an increase in URAT1 activity, which regulates uric acid excretion. Around 20 million years ago, humans and primates lost the ability to produce vitamin C,[9] leading to the antioxidant theory that uric acid replaced ascorbic acid as a primary antioxidant.

This evolutionary path resulted in humans developing hyperuricemia, making them unique among mammals in their susceptibility to spontaneous gout. Hyperuricemia is the primary risk factor for gout,[1][10] as elevated uric acid levels facilitate crystal formation in joints, triggering inflammation and pain. Studies demonstrate a direct correlation between serum urate levels and gout risk and flare frequency.[11][[12]](#article-22376.r12] A study of over 2000 older adults with gout found that those with serum urate levels exceeding 9 mg/dL were three times more likely to experience a flare within 12 months compared to those with levels below 6 mg/dL (see Table 2. Relationship Between Serum Uric Acid Concentration and Incident Gout). [13]

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

However, hyperuricemia alone is not sufficient to cause gout in all individuals (see Table 3. Risk Factors of Hyperuricemia and Gout). Only a fraction of hyperuricemic individuals develop gout. Dietary factors significantly influence uric acid levels. Diets rich in animal products like seafood (shrimp, lobster), organ meats (liver, kidney), and red meat (pork, beef) elevate uric acid. Similarly, beverages such as alcohol, sweetened drinks, sodas, and those with high-fructose corn syrup contribute to hyperuricemia and gout.[1][14][15]

Epidemiological trends show an increasing incidence of gout, largely attributed to lifestyle changes including higher protein diets and sedentary behaviors. These shifts highlight the impact of modern lifestyles on gout prevalence.

Additional risk factors for gout and hyperuricemia include older age, male sex, obesity, purine-rich diets, alcohol consumption, certain medications, comorbidities, and genetic predisposition (see Table 4. Causes of Hyperuricemia). Medications like diuretics, low-dose aspirin, ethambutol, pyrazinamide, and cyclosporine are known to increase uric acid levels and gout risk.

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

Table 4. Causes of Hyperuricemia.

Triggers for Gout Flares

Acute gout flares can be triggered by any condition that alters extracellular urate concentrations. These triggers include physical stress (due to medical illnesses, surgery, trauma, dehydration, or starvation), dietary indiscretions (high-purine foods, alcohol), and certain drugs (aspirin, diuretics, and even initiation of allopurinol).

Dietary Factors That May Lower Serum Uric Acid

Conversely, certain dietary modifications can reduce serum uric acid levels and gout risk. Higher meat and seafood consumption is linked to increased gout incidence in men, whereas higher dairy intake is associated with decreased gout risk.[17] The DASH (Dietary Approaches to Stop Hypertension) diet has been shown to lower serum uric acid and reduce gout risk.[18][19] Adequate vitamin C intake is also associated with lower serum uric acid and reduced gout risk.[20][21][22][23][[24]](#article-22376.r24] Cherries have also been shown to decrease serum uric acid[25] and reduce recurrent gout attacks.[18][26]

Epidemiology of Gout

Epidemiological data on gout vary based on the diagnostic criteria used. The definitive diagnosis requires identifying MSU monohydrate crystals in joint fluid or tophi. However, due to the impracticality of this approach for large-scale studies, various case definitions have been developed, including self-reports, Rome criteria, New York criteria, ACR criteria, and the 2015 ACR/EULAR criteria. The 2015 ACR/EULAR criteria demonstrate high accuracy with 92% sensitivity and 89% specificity, improving diagnostic reliability in epidemiological research.

In men, serum urate levels typically range from 5 to 6 mg/dL, reaching adult levels during puberty and increasing slightly with age.[27] Women generally have lower serum urate levels, averaging 1.0 to 1.5 mg/dL less than men of comparable age,[28][29] likely due to estrogen’s influence on renal uric acid clearance. Post-menopause, women’s urate levels rise to match those of adult men.[30] These gender differences in urate levels contribute to variations in gout onset and presentation between men and women.[31][[32]](#article-22376.r32]

Gout prevalence varies by age, sex, and geographic location, generally ranging from 1% to 4%. Older age and male sex are consistent risk factors globally. In Western countries, gout is significantly more prevalent in men (3%-6%) than women (1%-2%), with a 2- to 6-fold difference. Prevalence increases with age, plateauing after age 70 (see Table 5. Prevalence by Age Range).

Data from 2007-2008 indicate a gout diagnosis in approximately 3.9% of US adults.[33] US prevalence estimates range from under 3 million to over 8 million individuals, with recent estimates suggesting over 3% prevalence in the adult American population.[34][35][[36]](#article-22376.r36]

NHANES data from 2007-2016 reveal a higher gout prevalence among African Americans compared to White Americans. Among women, prevalence is 3.5% in African Americans and 2.0% in White Americans (OR 1.81). Among men, prevalence is 7.0% in African Americans and 5.4% in White Americans (OR 1.26). Hyperuricemia is also more prevalent in African American women and men compared to their White counterparts (ORs of 2.00 and 1.39, respectively).[37]

Table 5. Prevalence by Age Range .

Gout incidence rates have increased over recent decades, with higher incidence in men than women and increasing incidence with age. A study in Olmsted County, MN, from 1989-2009 showed increased gout incidence and comorbidities over 20 years.[38] Similarly, in the UK, gout prevalence rose from 1.52% to 2.49% between 1997 and 2012.[39]

Comorbidities Associated with Gout

Gout is frequently associated with other health conditions, including obesity, hypertension (HTN), chronic kidney disease (CKD), diabetes mellitus (DM), hyperlipidemia (HLD), and metabolic syndrome. An Olmsted County, MN, study highlighted higher comorbidity prevalence in gout patients compared to the general population: obesity (BMI >35 kg/m2) 29% vs. 10%, HTN 69% vs. 54%, CKD 28% vs. 11%, DM 25% vs. 6%, and HLD 61% vs. 21%.[38]

Weight gain during adulthood is consistently linked to increased gout risk.[40][41][[42]](#article-22376.r42] Studies in the UK and Germany have shown associations between gout and DM, congestive heart failure (CHF), HTN, myocardial infarction (MI), and obesity, with comorbidity prevalence increasing with higher serum uric acid levels.[43]

Other gout-related comorbidities include HLD, hypothyroidism, anemia, psoriasis, chronic pulmonary disease, osteoarthritis, and depression.[[44]](#article-22376.r44] Psoriasis, due to increased epidermal cell turnover, leads to elevated uric acid production. CKD reduces urate excretion, resulting in hyperuricemia and increased gout risk.[45]

Gout is associated with increased risks of ischemic heart disease (HR 1.86), MI (HR 3.246), and cerebrovascular disease (HR 1.552).[[46]](#article-22376.r46] Recent gout flares are linked to a transient increase in cardiovascular events.[47]

Gout is also linked to increased overall mortality, including cardiovascular, infectious disease, and cancer-related deaths.[48] It is particularly associated with elevated cardiovascular mortality [[49]](#article-22376.r49] and contributes to mortality from renal disease, digestive diseases, and dementia.[[50]](#article-22376.r50]

The relationship between gout and dementia, including Parkinson’s disease, is complex and not fully understood. Studies show varied associations, with some suggesting a lower dementia risk,[51][52][[53]](#article-22376.r53] particularly Alzheimer’s disease,[54][[55]](#article-22376.r55] in individuals with hyperuricemia and gout. However, conflicting data suggest an increased dementia risk.[56][[57]](#article-22376.r57] The association between gout and Parkinson’s disease is also inconclusive, with studies showing lower,[58][59][60] no specific,[61][62] or higher risk of Parkinson’s in gout patients.[63]

Pathophysiology of Gout

Gout is an inflammatory arthritis initiated by the deposition of MSU crystals, the end product of human purine metabolism, in joints, soft tissues, and bones. It manifests in various forms: acute gout flare, chronic gouty arthritis, tophaceous gout, renal impairment, and urolithiasis.[64][65][[66]](#article-22376.r66]

The pathophysiology of gout involves a sequence of interacting processes:[67]

Genetic and metabolic factors contribute to hyperuricemia.
Metabolic, physiologic, and other factors lead to MSU crystal formation.
Inflammatory factors, cellular components, innate immunity, and MSU crystal characteristics trigger acute inflammation.
Immune mechanisms resolve acute inflammation.
Chronic inflammation, immune cell effects, and crystal impact on osteoblasts, chondrocytes, and osteoclasts contribute to cartilage damage, bone erosion, joint injury, and tophi formation.

Uric Acid Physiology

Uric acid, the final product of purine metabolism in humans and higher primates due to a uricase gene mutation,[8][9] was traditionally thought to be a key antioxidant. However, recent studies suggest its role in oxidative stress is minor. It is now believed to be involved in immune surveillance and blood pressure/volume regulation.

Uric acid is a weak acid, predominantly ionized as MSU at pH 7.4, which is less soluble due to high sodium concentration. In acidic urine, it is nonionized and even less soluble, leading to uric acid crystal and stone formation in the urinary tract, unlike MSU in gout.[8]

Most urate is endogenously produced in the liver, with a minor contribution from the small intestine. Renal excretion is critical for maintaining urate balance. In hyperuricemia, the urate pool expands.

Normal urate pool in men is 800-1000 mg, and 500-1000 mg in women, with daily turnover of 500-1000 mg. Serum urate levels increase in men during puberty to adult levels, while women maintain lower levels until menopause due to estrogen’s effect on renal urate transporters, leading to less reabsorption and increased clearance. Postmenopausal women’s urate levels approach those of men, potentially influenced by hormone replacement therapy.[8]

Differences between lowered and raised urate pools are outlined below:

Lowered Urate Pool vs. Raised Urate Pool

Table 6. Lowered Urate Pool vs. Raised Urate Pool.

Hyperuricemia and MSU Crystal Formation

Hyperuricemia is central to gout development, promoting MSU crystal nucleation and growth due to reduced urate solubility. Factors contributing to hyperuricemia include the genetic absence of uricase, 90% renal reabsorption of filtered uric acid, and low MSU/urate solubility in body fluids. Imbalance between uric acid production and excretion elevates serum uric acid.[[10]](#article-22376.r10] Reduced renal urate excretion leads to increased intestinal uricolysis via ABCG2 transporter. Serum urate levels above 6.8 mg/dL saturate body fluids, increasing crystal deposition risk. Hyperuricemia affects 20% of adult white men in the US and is linked to several chronic diseases.

Hyperuricemia can be primary (idiopathic) or secondary. Uric acid overproduction occurs in conditions like acute leukemia, tumor lysis syndrome, and psoriasis.

Purine Metabolism and Uric Acid Production

Purines are 9-carbon molecules with fused pyrimidine and imidazole rings, essential in nucleic acids (adenine, guanine, hypoxanthine). Dietary purines significantly contribute to the urate pool. Purine-restricted diets for 10 days can reduce urate levels by 25% and urinary uric acid excretion by 50%. However, strict purine restriction is impractical. High-fructose, meat, alcohol, and fish diets promote hyperuricemia.[17]

Endogenous purine production (de novo synthesis) converts ribose-5-phosphate from 5-phosphoribosyl 1-pyrophosphate (PRPP) to inosine monophosphate in 10 steps. This energy-intensive process is regulated by purine nucleotide interconversion and salvage. Urate precursors from purine degradation are hypoxanthine and guanine, mostly salvaged. Unused guanine is deaminated to xanthine, and hypoxanthine is oxidized to xanthine by xanthine oxidase.[8]

Xanthine oxidase, a flavoprotein with molybdenum-pterin and iron sulfide clusters, exists as oxidase (using oxygen) and dehydrogenase (using NAD+). Inhibiting xanthine oxidase is the primary strategy to lower urate levels in gout.

Purine synthesis regulation involves:

PRPP synthesis in the PRPP synthetase pathway.
PRPP utilization in de novo purine synthesis initiation.

The pathway is inhibited by purine nucleotide products and activated by increased PRPP. This control is disrupted in rare X-linked disorders: hypoxanthine-guanine phosphoribosyl transferase (HGPRT) deficiency and PRPP synthetase overactivity (PRS1). ATP depletion during hypoxia or alcohol intoxication can reduce inhibitory nucleotides and increase urate production.

Renal Uric Acid Secretion and Transporters

In adults, only 5-10% of filtered uric acid is excreted due to 90% reabsorption in renal tubules. Hyperuricemia from impaired renal excretion may present with normal urinary urate levels. Renal uric acid clearance transporters include glucose transporter 9 (GLUT9) and urate anion transporter 1 (URAT1), which significantly impact serum urate levels.[6][[66]](#article-22376.r66]

Glucose Transporter 9 (GLUT9)

GLUT9 (SLC2A9 gene product) is a voltage-driven urate transporter mediating uric acid reabsorption from tubular cells. Two isoforms exist: GLUT9L (basolateral proximal tubule) and GLUT9S (apical). It’s also in hepatocytes, regulating serum urate via kidney and liver effects. GLUT9 also transports glucose and fructose, explaining dietary influence on hyperuricemia. GLUT9 knockout mice show moderate hyperuricemia, massive hyperuricosuria, and early nephropathy.[6]

URAT1

URAT1 (SLC22A12 gene) is highly specific for uric acid, mediating renal uric acid transport via anion exchange. SLC22A12 mutations cause hypouricemia, hyperuricosuria, and exercise-induced renal impairment. Uricosuric drugs (probenecid, benzbromarone, lesinurad) inhibit URAT1, increasing uric acid excretion. Other urate transporters include ABCG2, NPT1, NPT4, and multidrug resistance protein 4 (MRP4).[6]

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD)

ADTKD, due to UMOD gene variants, is characterized by early hyperuricemia (± gout), hypertension, and progressive tubulointerstitial inflammation/fibrosis, leading to end-stage renal disease by age 40. Formerly known as familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease, it’s usually caused by uromodulin mutations (Tamm-Horsfall protein). Uromodulin maintains the ascending loop of Henle integrity, forming a gel-like lattice. Defects alter solute fluxes, reduce Na/Cl reabsorption, decrease extracellular volume, and enhance sodium-dependent urate transport in the proximal tubule.

Extrarenal Urate Excretion

Intestinal urate excretion is mediated by ABCG2 transporter. Reduced ABCG2 in knockout mice increases serum urate. Hyperuricemia from overproduction can be renal overload type, with extrarenal underexcretion and genuine urate overproduction subtypes.

Urate Crystal Formation

MSU crystal formation needs sustained urate supersaturation. Factors include particulate seeds, local cation concentrations, pH, temperature, and dehydration (see Table 7. Factors Influencing Urate Crystal Formation). [66][68][69][[70]](#article-22376.r70] IgG may also promote crystal formation and growth in gout. MSU crystals commonly form in the first metatarsophalangeal joint, midfoot, and Achilles tendon. There’s emerging evidence linking osteoarthritis (OA) to MSU crystal deposition sites. In OA joints, cartilage degradation products like chondroitin sulfate reduce urate solubility, promoting nucleation and crystal growth.[[68]](#article-22376.r68] MSU solubility decreases rapidly with temperature, affecting crystal formation and deposition.[5]

Table 7. Factors Influencing Urate Crystal Formation.

Inflammatory Response in Gout

Urate crystals can be present in joints for long periods without causing inflammation. Crystal-laden fluids (“urate milk”) are found in uninflamed joints and bursae. Tophi can be massive with minimal inflammation until they compress surrounding tissues.

Inflammation in gout is initiated by microcrystals shed from existing synovial tophi, supported by acute flares with rapid urate changes. Inflammation initiation depends on crystal size, protein/molecule coating, and inflammatory cell recruitment. MSU crystals bind proteins like IgG, lipoproteins, and lipids (see Table 8. Inflammatory Events in Acute Gout Flare). [8]

IgG conformational changes promote phagocytosis by Fc-y receptor cells (neutrophils, macrophages).[[71]](#article-22376.r71] IgG also activates the classical complement pathway. MSU crystals can directly activate both classical and alternative complement pathways,[72][[73]](#article-22376.r73] leading to opsonization by C3b deposition. Apolipoprotein coating on MSU crystals counteracts IgG Fc and complement opsonization and inhibits neutrophil stimulation. Inflammatory potential of MSU crystals is balanced between pro- and anti-inflammatory coating elements. In acute gout, neutrophils are dominant inflammatory cells, significantly contributing to proinflammatory stimuli.[8]

Synovial fluid macrophages in asymptomatic tophi often contain MSU microcrystals, indicating phagocyte engagement without overt inflammation. Synovial macrophages and blood monocytes respond more vigorously to MSU crystals than differentiated macrophages due to TGF-b1 release. MSU crystal interaction with phagocytes involves two main mechanisms.

MSU crystals bypass typical cell surface signal transduction and directly activate second messenger systems, unlike most external inflammatory stimuli.

Table 8. Inflammatory Events in Acute Gout Flare.

Termination of Acute Gout Flare

Acute gout is self-limiting, resolving spontaneously in days to weeks, even without treatment. This is notable given the similar inflammatory mediators in gout and other arthropathies and the persistence of MSU crystals.

Following MSU crystal ingestion, neutrophils undergo NETosis (neutrophil extracellular traps). NETs aggregate and pack MSU crystals, degrading proinflammatory cytokines (IL-β, TNF-α, IL-6). Increased vascular permeability in acute synovitis allows entry of anti-inflammatory cytokines and crystal-coating molecules like apolipoprotein B (apoB). ApoB, apoE, and TGF-β coating inhibit neutrophil activation. Systemic anti-inflammatory mediators like melanocortins reduce joint inflammation via macrophage melanocortin receptors (MCRs), and adenosine monophosphate-activated protein kinase inhibits NLRP3 expression, which inhibits caspase-1 cleavage and IL-1β secretion.[66][67][74][[76]](#article-22376.r76]

Advanced Gout and Tophaceous Deposits

Tophi are MSU crystal deposits with granulomatous inflammation, consisting of crystal nests surrounded by a corona zone of differentiated macrophages and giant cells, enclosed in a fibrous layer. Proinflammatory cytokines (IL-1, TNF-α) are expressed in the corona. Aggregated NETs are also part of tophi. Tophi represent a dynamic chronic inflammatory response to MSU crystal deposition.

Tophi primarily occur in periarticular, articular, and subcutaneous areas rich in proteoglycans, such as cartilage, bone, joints, tendons, and skin. Tissue reaction to tophi is generally chronic inflammation, involving both adaptive and innate immunity. Some patients with tophaceous gout also have chronic gouty arthritis (chronic synovitis). There’s a strong link between MSU crystal deposits and cartilage/bone erosions.[[77]](#article-22376.r77]

Tophi contribute to joint damage and bone erosion in gout.[[78]](#article-22376.r78] At the bone-tophus interface, MSU crystals are surrounded by osteoclast-like cells.[[79]](#article-22376.r79] T-cells in tophi express RANKL, contributing to bone erosions. Urate crystals also decrease osteoblast function, viability, and differentiation, and reduce osteoprotegerin expression, resulting in more osteoclasts and fewer osteoblasts at the bone-tophus interface.

The double-contoured ultrasound sign in superficial articular cartilage of chronic gout patients indicates urate deposits. Urate crystals degrade cartilage matrix by inducing nitric oxide and matrix metalloprotease 3 expression. Persistent crystals lead to ongoing progressive joint damage even without acute flares.

Histopathology of Gout

Under polarized light microscopy, MSU crystals are rod or needle-shaped with negative birefringence.[[80]](#article-22376.r80] Tophaceous deposits viewed under light microscopy show distinct zones: a crystalline center, a corona zone, and a fibrovascular zone. The corona zone contains multinucleated giant cells, histiocytes, and plasma cells.[81]

History and Physical Examination in Gout

Gout is clinically characterized by four stages:[3]

Asymptomatic hyperuricemia
Acute gout attacks
Intercritical period
Chronic tophaceous gout

Asymptomatic Hyperuricemia

Most individuals with asymptomatic hyperuricemia never develop gout. The risk of acute gout increases with serum urate levels. This stage ends with the first gout attack.

Acute Gout Attack

The initial gout manifestation is an acute arthritis attack, typically monoarticular, with abrupt onset of severe pain and swelling. Peak inflammation occurs within 12-24 hours. Flares are usually monoarticular, affecting lower extremities in 85-90% of cases.[3][[82]](#article-22376.r82] The first metatarsophalangeal joint is most commonly involved (50% of initial attacks, 90% of patients experience it at some point).[3] Ankle, subtalar, talar, and knee joints can also be affected. Initial attacks are polyarticular in 3-14% of cases, causing diagnostic challenges.[3]

While joints mentioned above are common, consider other joints, especially those with osteoarthritis. Periarticular structures (tendons, bursae) can also be involved.[1] Axial joint gout (sacroiliac, spine) is less common than peripheral involvement, leading to diagnostic confusion.[83][[84]](#article-22376.r84] Acute gouty arthritis may present with fever and leukocytosis, mimicking septic arthritis. Initial attacks resolve in 3-14 days, even without treatment. Over time, flares become more frequent, less intense, and involve more joints.[3]

Polyarticular flares are more common in longstanding gout. Polyarticular onset is more frequent in gout secondary to lymphoproliferative/myeloproliferative disorders or in organ transplant recipients on tacrolimus/cyclosporine.[85][[86]](#article-22376.r86] In South Africa, polyarticular presentation is more common in women, with fewer initial podagra cases. Rarely, tophi develop without prior acute flares.

Gout flares are more common at night and early morning when cortisol levels are low.[[87]](#article-22376.r87] Pain is often sudden, waking patients, or develops over hours, peaking at 24 hours.[[87]](#article-22376.r87] Inflammation may extend beyond the joint, resembling cellulitis with erythema and desquamation or dactylitis. Pain is severe, unresponsive to home remedies; even touch is excruciating. Flare-ups cause local inflammation with erythematous, swollen, warm joints. Erythema over the affected joint is characteristic of gouty synovitis. Systemic inflammatory features include fever, malaise, and fatigue.[1]

About 60% of patients experience a second attack within 1 year, and 80% within 3 years. Acute attacks can be triggered by local trauma, alcohol binges, overeating/fasting, weight changes, diuretics, and urate-lowering drug initiation. In hospitals, postoperative status or severe medical illnesses (MI, CHF exacerbation, stroke) can trigger attacks.[3] Urate-lowering therapy (ULT) initiation during hospitalization can also provoke flares. Spring season has been associated with increased gout attacks.

Physical exam findings in gout align with history. Affected joints are typically red, swollen, warm, and tender.[[88]](#article-22376.r88] Flares in chronic gout may involve multiple joints, causing systemic inflammatory response syndrome mimicking sepsis.[[89]](#article-22376.r89] Tophi, subcutaneous urate deposits forming nodules, are found in persistent hyperuricemia, typically in joints, ears, finger pads, tendons, and bursae.[1]

Intercritical Gout

After acute attack resolution, patients enter the intercritical stage, feeling well without joint pain or swelling. Hyperuricemia and crystal deposition persist, and subclinical inflammation may be present.

Chronic Tophaceous Gout

Untreated or undertreated gout can progress to chronic tophaceous gout over years, causing progressive joint destruction. Gouty tophi are foreign body granulomas with MSU crystal deposits, manifesting as chalk-like subcutaneous nodules under thin, vascular skin, which may or may not drain. While tophi can be the initial symptom, chronic tophaceous gout typically develops 10+ years after the first acute attack. Microtophi can appear early, especially with hyperuricemia. MSU crystal deposition is common in osteoarthritic joints, particularly in connective tissue and articular cartilage.

Tophi can be intraarticular, periarticular, or extra-articular, commonly in finger/toe digits, knees, and olecranon bursae. This leads to destructive, deforming arthritis, bone destruction, and severe deformities. Women develop tophi on Heberden’s and Bouchard’s nodes. Finger pad tophi are seen in 30% of chronic tophaceous gout patients. Postmenopausal women with CKD may develop finger pad tophi before acute attacks.[3][2][[66]](#article-22376.r66]

Tophi have been documented in unusual locations, including the eye cornea and heart valves, highlighting gout’s systemic nature and potential to affect diverse tissues beyond joints.

Evaluation and Differential Diagnosis of Gout

The evaluation of suspected gout is crucial for confirming the diagnosis and differentiating it from other conditions that may mimic its presentation. The differential diagnosis of gout is broad, particularly in the acute inflammatory phase, and includes conditions such as septic arthritis, pseudogout, cellulitis, rheumatoid arthritis, and osteoarthritis.

Synovial Fluid Analysis: The Gold Standard for Gout Diagnosis

Synovial fluid analysis with MSU crystal identification is the gold standard for gout diagnosis.[80] Gout flares are characterized by the presence of MSU crystals in synovial fluid from affected joints or bursae, visualized using compensated polarized light microscopy. Crystals are often intracellular, indicating active phagocytosis. This technique can also detect uric acid crystals from tophi and joints during intercritical periods.[90] During a gout flare, synovial fluid is typically yellow and cloudy, containing crystals and white blood cells (WBCs) with neutrophil predominance.

Differentiating Gout from Septic Arthritis

Septic arthritis is a critical differential diagnosis for acute gout, as both conditions can present with acute, monoarticular joint pain, swelling, and erythema. In septic arthritis, synovial fluid is usually more opaque, with a yellow-green appearance. Microscopic examination reveals a higher WBC count (>50,000/µL) with neutrophil predominance. However, there is overlap in WBC counts and neutrophil percentages between acute gout and septic arthritis, making these parameters unreliable for differentiation. Positive synovial fluid Gram stain and cultures, along with low synovial fluid glucose levels, are common in septic arthritis and are key differentiating factors. Importantly, the presence of crystals in synovial fluid does not exclude septic arthritis, as both conditions can coexist (co-infection).[91][[92]](#article-22376.r92] Therefore, in any acute monoarthritis, especially in patients with risk factors for infection (e.g., diabetes, immunocompromised state, intravenous drug use), septic arthritis must be ruled out.

Differentiating Gout from Pseudogout (Calcium Pyrophosphate Deposition Disease – CPPD)

Pseudogout, or calcium pyrophosphate deposition disease (CPPD), is another common mimic of gout. Both conditions can cause acute inflammatory arthritis. The key differentiator is the type of crystal found in the synovial fluid. Under polarizing microscopy, MSU crystals in gout are needle-shaped and negatively birefringent, while calcium pyrophosphate crystals in pseudogout are rhomboid-shaped or rod-shaped and weakly positively birefringent. Clinical features can sometimes help differentiate: pseudogout more commonly affects larger joints like the knee and wrist, while gout often affects the first metatarsophalangeal joint. However, joint distribution is not always definitive.

Differentiating Gout from Cellulitis

In some cases, acute gout, particularly podagra (gout in the first MTP joint), can mimic cellulitis due to the significant erythema, warmth, and swelling. However, cellulitis typically involves the skin and subcutaneous tissues more broadly, often with spreading borders and without joint involvement. Gout, while causing periarticular inflammation, is primarily a joint-based inflammation. Fever and systemic signs may be present in both conditions, but skin breaks, wounds, or other signs of infection are more suggestive of cellulitis. Synovial fluid analysis is critical if there is diagnostic uncertainty.

Differentiating Gout from Rheumatoid Arthritis (RA) and Osteoarthritis (OA)

While acute gout flares are usually monoarticular, chronic gouty arthritis can become polyarticular and mimic rheumatoid arthritis (RA) or exacerbate osteoarthritis (OA). RA is a chronic, systemic autoimmune disease characterized by symmetrical polyarthritis, morning stiffness, and systemic symptoms. Blood tests for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are positive in many RA patients and negative in gout. OA is a degenerative joint disease characterized by joint pain, stiffness, and functional limitation. OA is typically non-inflammatory, although inflammatory flares can occur. OA often affects weight-bearing joints and distal interphalangeal joints. While gout can occur in joints with pre-existing OA, the acute inflammatory nature and crystal identification help differentiate gout flares from OA exacerbations.

Laboratory Studies in Gout

Laboratory tests can support the diagnosis of gout but are not definitive on their own. During acute gouty arthritis, WBC count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) may be elevated, reflecting inflammation. However, these are non-specific and do not distinguish gout from septic arthritis or other inflammatory conditions.[[91]](#article-22376.r91]

Serum urate levels can be high, normal, or even low during an acute gout attack. Approximately 50% of patients with acute gout do not have elevated serum uric acid at the time of the flare. Therefore, serum uric acid measurement during an acute attack is not diagnostically reliable for acute gout. It is most useful when measured after flare resolution to establish a baseline. Hyperuricemia supports a gout diagnosis in symptomatic patients, but it is neither diagnostic nor required for diagnosis. Asymptomatic hyperuricemia is common in the general population. Persistently low serum uric acid makes gout less likely.[3] If gout is suspected clinically, an elevated serum uric acid level (>6.8 mg/dL) strengthens the diagnosis but is not mandatory. The optimal time to assess serum urate level for baseline is 2 or more weeks after a gout flare has subsided.

Urinary fractional excretion of uric acid can be measured, particularly in younger patients with hyperuricemia of unclear cause. This can help differentiate between uric acid overproduction and underexcretion, guiding treatment strategies.

Imaging in Gout Diagnosis

Imaging modalities like ultrasonography and dual-energy CT (DECT) can aid in gout diagnosis, although they are not routinely used.[94][95][96][97] Ultrasound can detect MSU deposition as a hyperechoic enhancement over cartilage, known as the double contour sign. DECT can identify urate deposits based on differential X-ray beam attenuation.[1][3] Meta-analyses indicate that the ultrasound double contour sign has a sensitivity of 83% and specificity of 76%, while DECT has 87% sensitivity and 84% specificity for gout diagnosis.[[95]](#article-22376.r95] A meta-analysis of ultrasound diagnostic accuracy, including double contour sign, tophus, and bony erosion features, showed 65.1% sensitivity and 89% specificity for gout diagnosis.[98] Imaging can be useful in cases where synovial fluid aspiration is not feasible or when evaluating chronic tophaceous gout.

Summary of Differential Diagnosis Strategies

Synovial Fluid Analysis: Essential to definitively diagnose gout and exclude septic arthritis and pseudogout. Polarized light microscopy is critical for crystal identification.
Clinical History and Physical Exam: Detailed history focusing on onset, location, and triggers of joint pain. Physical exam assessing for joint inflammation, erythema, warmth, and tophi.
Serum Uric Acid Levels: Helpful in supporting the diagnosis, but not diagnostic during acute flares. Baseline levels should be assessed after flare resolution.
Laboratory Tests (WBC, ESR, CRP): Non-specific markers of inflammation, useful for assessing inflammatory burden but not for differential diagnosis.
Imaging (Ultrasound, DECT): Can support diagnosis, especially when synovial fluid analysis is not possible or in chronic tophaceous gout.

By systematically considering these factors and employing a robust differential diagnostic approach, clinicians can accurately diagnose gout and differentiate it from its mimics, ensuring appropriate and timely management.

Treatment and Management of Gout

Gout treatment has specific goals. During acute flares, the primary goal is to reduce inflammation and alleviate symptoms. Long-term management focuses on lowering serum urate levels to prevent future flares and promote tophus regression.[3][99][[100]](#article-22376.r100]

General Principles of Gout Therapy

Early treatment of gout flares leads to faster symptom resolution.
Flare treatment duration varies from days to weeks, depending on treatment initiation timing.
Anti-inflammatory gout flare prophylaxis is generally continued for the first months (up to 6 months) of ULT.
For patients on ULT at the time of a flare, urate-lowering medication should be continued without interruption.
Tophi presence indicates the need for long-term ULT, initiated during or after flare resolution, to prevent joint damage and chronic gouty arthritis.

Management of Acute Gout Flare

Acute gout flare management aims to reduce inflammation and pain. Treatment should begin within 24 hours of onset to minimize flare severity and duration if possible.[[10]](#article-22376.r10] Nonpharmacological measures like rest and ice packs [[101]](#article-22376.r101] can be combined with anti-inflammatory medications.[[102]](#article-22376.r102] First-line treatments are nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, or systemic glucocorticoids.[103] Treatment duration should be at least 7-10 days to prevent rebound flares.[[104]](#article-22376.r104] Early NSAID initiation may resolve the attack with a single dose.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs) for Gout

NSAIDs are most effective when started within 48 hours of gout symptom onset. Indomethacin and naproxen are potent NSAIDs for gout, but many others are used. NSAID examples and dosing:

Indomethacin 50 mg three times daily
Naproxen 500 mg twice daily
Sulindac 200 mg twice daily
Ibuprofen 800 mg three times daily
Diclofenac 50 mg 2-3 times daily
Celecoxib 200 mg twice daily

NSAID treatment for gout flares typically lasts 5-7 days. No single NSAID is definitively preferred, but high-dose, fast-acting NSAIDs like naproxen or diclofenac are options. Indomethacin is less favored due to its toxicity profile.[10] NSAIDs are usually given at full doses for the first 3 days, then tapered based on clinical improvement. COX-2 selective inhibitors like celecoxib can reduce GI side effects.

NSAID contraindications include active peptic ulcer disease, cardiovascular disease (uncontrolled HTN or CHF), NSAID allergy, and CKD with creatinine clearance (CrCl) <60 mL/min/1.73 m2. Aspirin is not recommended for gout flares due to its paradoxical effect on serum urate levels (uricosuria at high doses, renal uric acid retention at low doses [<2-3 g/day]).[105][106][107][[108]](#article-22376.r108]

Oral Glucocorticoids for Gout

Glucocorticoids are recommended for gout patients with NSAID and colchicine contraindications, and are preferred in renal insufficiency. Initial gout flare dose:

Prednisolone or prednisone 30-40 mg once daily or divided twice daily until resolution begins, then taper over 5-10 days.

Efficacy is comparable to NSAIDs. High starting doses of systemic steroids (>0.5 mg/kg body weight) are needed for acute gout, especially polyarticular presentations. Depot triamcinolone (60 mg once) or methylprednisolone have been reported effective.[109][[110]](#article-22376.r110] Doses may need repeating at 48-hour intervals. Glucocorticoids can be intra-articular for monoarticular flares or oral for polyarticular flares. Efficacy is similar or superior to other agents with no greater adverse effect risk in most patients.[111][112][[113]](#article-22376.r113]

In unclear acute gout flare diagnoses, arthrocentesis and synovial fluid analysis should be done, and oral/intra-articular glucocorticoids avoided until results are available. NSAIDs or colchicine can be considered initially. Common short-term glucocorticoid adverse effects include hyperglycemia, fluid retention, increased blood pressure, and mood changes. Repeated glucocorticoid courses should be avoided to limit adverse effects.

Glucocorticoids may increase infection risk, impair wound healing in patients with concomitant infections, uncontrolled diabetes, prior glucocorticoid intolerance, or postoperative status. Careful consideration is crucial when determining treatment.

Parenteral Glucocorticoids for Gout

Intravenous or intramuscular glucocorticoids are suggested for patients unsuitable for intra-articular injections or unable to take oral medications. Typical methylprednisolone dose is 20 mg IV twice daily, with stepwise reduction and rapid oral prednisone transition upon improvement. Adrenocorticotropic hormone (ACTH) is also effective but limited by availability and cost.

Colchicine for Gout

Colchicine, from Colchicum autumnale, has been used for over 3500 years.[114] It is comparable in efficacy to other agents when taken within 24 hours of gout flare onset. In a randomized controlled trial, colchicine reduced pain by over 50% at 24 hours compared to placebo. Colchicine is lipophilic, readily bioavailable after oral administration, targets tubulin, and is hepatically metabolized.

Colchicine binds tightly to unpolymerized tubulin, forming a colchicine-tubulin complex that regulates microtubule and cytoskeletal function, affecting cell proliferation, gene expression, signal transduction, chemotaxis, and neutrophil granule secretion. It also reduces neutrophil adhesion by suppressing E-selectin redistribution in the endothelial membrane.

EULAR guidelines recommend a maximum of 3 doses of 0.5 mg colchicine daily for acute gout. Total colchicine dose should not exceed 1.8 mg on day 1 (1.2 mg initially, followed by 0.6 mg an hour later (FDA approved dose) or 0.6 mg three times on day 1). [115] Subsequent days involve once or twice daily dosing until flare resolution.[116]

Reduced colchicine doses may be needed for patients with hepatic or renal impairment or drug interaction risks. Colchicine toxicity can occur with ABCB1 inhibitors like cyclosporine and clarithromycin; neuromyopathy can develop weeks after cyclosporine initiation. High-dose colchicine regimens should be avoided due to toxicity. Colchicine side effects include gastrointestinal symptoms (nausea, diarrhea), myotoxicity, and myelosuppression (leukopenia, thrombocytopenia, aplastic anemia).[117] Abdominal cramping and diarrhea are most common.[115][[118]](#article-22376.r118] Intravenous colchicine is strongly discouraged due to severe adverse effects, including death, and is no longer FDA-approved in the US.

Colchicine dosing adjustments for high-risk patients should follow FDA guidelines. Typically, a maximum of 0.3 mg dose is given on the flare day, and not repeated for 3-7 days or longer. High-risk groups include:

Individuals using colchicine prophylaxis in the last 14 days, with normal hepatic and renal function, taking P-glycoprotein inhibitors or potent CYP3A4 inhibitors within 14 days.
Individuals using colchicine prophylaxis in the last 14 days, regardless of hepatic/renal status, taking moderate CYP3A4 inhibitors in the same period.

[Include relevant images from the original article here, with appropriate alt text. For example, images of MSU crystals under polarized light, tophi, or joint inflammation.]

Conclusion

The differential diagnosis of gout is critical for accurate patient management. While gout has characteristic features, it shares clinical overlap with several other conditions, particularly in its acute presentation. A systematic approach, incorporating synovial fluid analysis, clinical evaluation, laboratory investigations, and imaging when necessary, is essential to differentiate gout from its mimics, such as septic arthritis, pseudogout, and cellulitis. Understanding the nuances of gout’s presentation and its differential diagnoses ensures that patients receive appropriate and timely treatment, leading to improved outcomes and quality of life. Effective management strategies, including NSAIDs, colchicine, and corticosteroids for acute flares, and urate-lowering therapies for chronic management, are available to control gout and minimize its long-term complications. The collaborative efforts of an interprofessional healthcare team are paramount in providing comprehensive care and optimizing outcomes for patients with gout.

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