Gout: Hyperuricemic Metabolic Condition

• Gout is a hyperuricemic metabolic condition
• It manifests as episodic inflammatory arthritis with disabling pain
• Gout is common among middle-aged to elderly men and postmenopausal women
• Gout stems from an increased body pool of urate
• Chronic hyperuricemia leads to urate supersaturation
• Monosodium urate (MSU) crystal formation and deposition occurs within joints and connective tissue
• Untreated gout progresses to chronic gouty arthritis
• Persistent synovitis and erosive deformities occur due to MSU crystal deposition
• Humans spontaneously develop gout because they lost uricase in evolution
• Uricase converts urate into water-soluble allantoin
• Chronic hyperuricemia is a prerequisite for gout development
• Hyperuricemic individuals develop gout during their lifetime at a minority rate
• At physiologic pH, uric acid exists as urate, the ionized form, due to its weak acidic property (pKa, 5.8)
• Hyperuricemia and gout are associated with cardiovascular-metabolic comorbidities

Risk factors

• Insulin resistance syndrome
• Obesity, hypertension, type 2 diabetes
• Myocardial infarction, stroke, and urate nephrolithiasis
• Modifiable risk factors include obesity, Western diet, alcohol, sedentary lifestyle, and diuretics

Clinical Manifestations

• Early sign is acute recurrent gout flares
• Typically, one joint is initially affected, though oligo- and polyarticular flares can develop
• The metatarsophalangeal joint of the first toe (podagra) is involved in 70–90% of cases
• Followed by tarsal joints, ankles, and knees
• Finger, wrist, and elbow joints can also be involved, particularly in elderly patients or advanced disease
• Gout flares often begin at night to early morning
• Affected joints become warm, red, tender, and substantially swollen
• The clinical appearance mimics cellulitis (pseudocellulitis)
• Typical flares subside spontaneously within 1-2 weeks
• Intercritical gout is the interval with no residual symptoms until the next episode for most patients
• Triggers include purine-rich food, alcohol, diuretic use, initial introduction of urate-lowering therapy, local trauma, and medical illnesses
• Congestive heart failure and respiratory hypoxic conditions can trigger gout

Untreated Gout

• Chronic gouty arthritis can develop after years of gout flares
• Often associated with ongoing synovitis, subcutaneous tophi, deformity, and bony destruction
• Less commonly, chronic gouty arthritis is the only manifestation
• Rarely, gout can manifest only as tophi
• Women represent only 5-20% of all patients with gout
• Most women with gout are postmenopausal and elderly and tend to have osteoarthritis, hypertension, or mild renal insufficiency
• Premenopausal gout is rare

Diagnosis

• Presumptive diagnosis should be confirmed by needle aspiration of involved joints or tophaceous deposits
• Septic arthritis, other crystal-associated arthropathies, palindromic rheumatism, and psoriatic arthritis can mimic presentations
• Needle-shaped MSU crystals are present both intracellularly and extracellularly during acute flares
• Under compensated polarized light, MSU crystals show bright, negative birefringence
• Synovial fluid appears cloudy due to increased leukocytes (e.g., from 5000–75,000/μL)
• Large amounts of crystals occasionally produce thick, pasty, chalky joint fluid or drainage from distended tophus
• Joint fluid is often stained and cultured for potential septic arthritis because bacterial infection can coexist with MSU crystals
• MSU crystals can be demonstrated in the first metatarsophalangeal joint and knees not acutely involved with gout
• Arthrocentesis of these joints is useful for gout diagnosis between flares
• Serum urate levels can be normal or low at the time of an acute flare
• Inflammatory cytokines' uricosuric property (e.g., IL-6) can lower the level by ~2 mg/dL
• Serum urate values are almost always elevated at some time in a gout patient's lifetime
• Historical or postflare serum urate values are a diagnostic clue or therapeutic target to urate-lowering therapy
• Serum creatinine, liver function tests, hemoglobin, white blood cell (WBC) count, hemoglobin A1c, and serum lipids are obtained at baseline
• Lab tests are performed to assess risk factors and comorbidities and monitored for potential adverse effects

Radiographic Features

• In plain radiography, cystic changes, well-defined erosions with sclerotic margins (often with overhanging bony edges), and soft tissue masses are features
• Findings may be absent in earlier stages of gout
• Musculoskeletal ultrasound can timely aid diagnosis by revealing a double-contour sign overlying the articular cartilage
• This signifies MSU deposition
• Dual-energy computed tomography (CT) utilizes two different energy beams
• Identifies MSU based on its chemical composition to indicate MSU crystal presence

Treatment for Acute Gout

• Nonpharmacologic measures, such as ice pack application and rest, can be helpful
• The mainstay of acute gout care is anti-inflammatory drugs, colchicine, and glucocorticoids
• Choice depends on the patients' comorbidities, concurrent medications, and previous response if recurrent flares
• Early initiation of antiinflammatories helps abort or reduce the severity of flares
• Provide recurrent flare patients with a supply of medications ready to start at the first sign
• NSAIDs are used most often in individuals without complicating comorbidities
• Full anti-inflammatory doses of NSAIDs are effective for most patients
• Oral colchicine is also effective, particularly if used early in a gout flare
• Low-dose regimen (1.2 mg, then 0.6 mg in 1 h, then subsequent-day dosing) is as effective as higher-dose regimens
• Colchicine is eliminated through P-glycoprotein (MDR1) in the liver, small intestine, and kidneys via enteric and hepatic cytochrome P450 3E4 (CYP3A4)
• The dose of Colchicine is reduced among patients with renal disease or when used with P-glycoprotein or CYP3A4 inhibitors
• Use caution with clarithromycin or tacrolimus due to potential liver impairment
• Glucocorticoids given as an intramuscular injection or orally (e.g., prednisone, 30-50 mg/d tapered) can be effective
• Intraarticular glucocorticoid injection is effective and well tolerated for a single joint or a few joints involved
• Anakinra is useful with the central role of the inflammasome and IL-1β in flares when other treatments are contraindicated

Urate-Lowering Therapy

• Ultimate control requires correction of chronic hyperuricemia
• Normalize serum urate to a subsaturation point (<300-360 µmol/L [5.0-6.0 mg/dL]) to prevent recurrent gout flares and eliminate tophi are critical
• This entails a lifelong commitment to urate-lowering regimens
• Consider urate-lowering drug therapy when hyperuricemia cannot be corrected by risk factor interventions
• Risk factor interventions include control of body weight, healthy diet, limitation of alcohol, decreased fructose-rich foods, and avoidance of thiazide and loop diuretics
• The decision to initiate urate-lowering drug therapy considers the number of gout flares, severity and duration of flares, quality of life, or willingness to commit
• Initiate urate-lowering therapy in any patient who already has subcutaneous tophi or chronic gouty arthritis or known uric acid stones
• Allopurinol, a xanthine oxidase inhibitor, is the first-line urate-lowering drug
• It can be given in a single morning dose, starting at 100 mg daily or less and titrating up (to 800 mg daily)
• Target serum urate level is <5-6 mg/dL (i.e., a subsaturation point of MSU crystals)
• The starting allopurinol dose should be lowered in patients with chronic kidney disease (CKD)
• For example, start at 50 mg daily and titrate up slowly with a estimated glomerular filtration rate of 30-45 mL/min
• Starting at a low dose and titrating up reduces the risk of severe cutaneous adverse reactions (SCARs), Stevens-Johnson syndrome and toxic epidermal necrolysis
• It also reduces the risk of gout flares associated with rapid serum urate reduction due to introduction of urate-lowering therapy
• Mild cutaneous reactions can develop in ~2% of users and allopurinol is generally well tolerated
• SCARs to allopurinol are rare but can be life-threatening, and thus, appropriate precaution is advised
• Risk factors include CKD, higher allopurinol initial dosing (>100 mg daily in CKD patients), and HLA-B*5801 carriage

HLA-B*5801 risks

• Older age and female sex are also associated with a higher risk of SCARs
• HLA-B*5801 carriage rate is substantially higher among Southeast Asians (except Japanese), Pacific Islanders, and blacks than whites or Hispanics
• Leading to racial disparity in the risk of SCARs
• Screening for HLA-B*5801 should be performed before starting allopurinol in those Asians and blacks
• An alternative urate-lowering agent should be administered if patients carry HLA-B*5801 allele
• Febuxostat is a newer xanthine oxidase inhibitor metabolized by glucuronide formation and oxidation in the liver
• Febuxostat is considered to not require dose adjustment in moderate to severe CKD and has also been used in patients who carry the HLA-B*5801 allele
• Uricosuric agents such as probenecid are considered second-line urate-lowering therapies
• Uricosuric agents can be used in patients with good renal function either alone or in combination with xanthine oxidase inhibitors such as allopurinol
• Probenecid can be started at 250 mg twice daily and increased gradually as needed up to 3 g/d to achieve and maintain a target serum urate level
• Probenecid is generally not effective in patients with serum creatinine levels >177 µmol/L (2 mg/dL)
• Benzbromarone (not available in the United States) is another uricosuric drug effective in patients with CKD
• Thiazide and loop diuretics increase serum urate levels and trigger gout attacks
• Losartan, amlodipine, fenofibrate, and sodium-glucose cotransporter-2 inhibitors are common comorbidity drugs that also help lower serum urate levels
• Pegloticase is a pegylated uricase available for patients who do not tolerate or fail full doses of other treatments
• Urate-lowering drugs are not initiated during active ongoing gout flares
• Urate-lowering drugs can worsen the flare by acutely lowering serum urate levels
• Urate-lowering therapy can be started during the resolution phase of or after a gout flare
• Urate-lowering medications can be given with anti-inflammatory prophylaxis (e.g., colchicine 0.6 mg one to two times daily or naproxen 250 mg twice daily)
• This reduces the risk of flares that often occur with the initiation of urate-lowering therapy
• Paradoxical flares are inflammatory reactions to MSU crystals shed from dissolution of organized MSU deposits (synovial tophi) induced by rapid serum urate reduction
• Faster urate reduction has been associated with a higher risk of flares in clinical trials of urate-lowering drugs
• Continuing concomitant anti-inflammatory prophylaxis is usually recommended until the patient is normouricemic and without gouty attacks for 3-6 months or tophi disappear

Description

• Gout is a form of inflammatory arthritis characterized by recurrent attacks of acute joint pain and swelling
• The attacks happen due to the deposition of monosodium urate crystals in joints and surrounding tissues
• Definition of hyperuricemia: serum uric acid levels above 6.8 mg/dL, the saturation point of urate in body fluids
• Gout typically affects peripheral joints
• The first metatarsophalangeal joint is the most commonly involved site in initial attacks
• Untreated gout can lead to chronic arthropathy, tophi formation, and increased risk of cardiovascular and renal complications

Etiology

• Gout results from the accumulation and crystallization of uric acid in joints and tissues
• This crystallization is due to either overproduction or underexcretion of uric acid, or a combination of both
• Elevated uric acid levels can occur due to increased purine intake, enhanced purine synthesis, or decreased renal excretion
• The acute gout attack is triggered by the release of urate crystals from deposits or newly formed crystals
• This leads to an intense inflammatory response mediated by neutrophils and pro-inflammatory cytokines
• Genetic factors influence the risk of developing gout

Incidence

• Estimated global prevalence of gout: 1-4% of the adult population
• Higher rates occur in developed countries
• In the United States, gout affects approximately 4% of adults
• Men are 3-4 times more likely to develop the condition than women

Risk factors for gout

• Men are at higher risk, with peak onset between 30-50 years; women's risk increases post-menopause
• High intake of purine-rich foods (e.g., red meat, seafood), alcohol (especially beer), and fructose-sweetened beverages increases risk
• Obesity and Metabolic Syndrome is associated with increased uric acid production and decreased excretion
• Alcohol use or abuse may trigger an episode of gout

Prevention

• Maintain a healthy weight through balanced diet and regular physical activity
• Limit intake of purine-rich foods, alcohol (especially beer), and sugar-sweetened beverages
• Stay well-hydrated to promote uric acid excretion
• Manage comorbidities such as hypertension, diabetes, and hyperlipidemia

Assessment Findings

• Sudden onset of severe pain, often in the first metatarsophalangeal joint (podagra)
• The affected joint appears red, swollen, and warm to touch
• Limited Range of Motion is present
• Tophi formation
• Low-grade fever, fatigue, and malaise may accompany acute attacks

Assessment tools and Grading

• Used for diagnosis and classification of gout
  • Gout Classification Criteria (ACR/EULAR)
• Assesses disease activity and response to treatment
  • Gout Activity Score (GAS)
• Measures the extent of tophaceous deposits in chronic gout
  • Tophus Burden Assessment

Differential Diagnosis

• Acute monoarthritis, hyperuricemia
  • Gout - Synovial fluid crystal analysis
• Fever, single hot swollen joint
  • Septic Arthritis - Joint aspiration, culture
• Similar presentation, older patients
  • Pseudogout - Synovial fluid CPPD crystals
• Symmetric polyarthritis, morning stiffness
• Rheumatoid Arthritis - RF, anti-CCP antibodies

Diagnostic Studies and Possible Findings

• Presence of negatively birefringent, needle-shaped urate crystals under polarized light microscopy is diagnostic
  • Synovial Fluid Analysis
• Elevated levels (>6.8 mg/dL), though may be normal during acute attacks
  • Serum Uric Acid
• Elevated ESR and CRP during acute attacks
  • Inflammatory Markers
• May show soft tissue swelling acutely; punched-out erosions with overhanging edges in chronic gout
  • X-rays
• Can detect urate crystal deposits in tissues, useful for diagnosing chronic gout
  • Dual-Energy CT
• Normal uric acid levels are common during an acute attack
• Always look at the clinical presentation in conjunction with diagnostic studies

Treatment Prioritization

• Manage acute gout attacks to relieve pain and inflammation
• Implement urate-lowering therapy to prevent recurrent attacks and complications
• Address modifiable risk factors and comorbidities
• Provide patient education on lifestyle modifications and medication adherence

Nonpharmacological Management

• Rest and elevate the affected joint during acute attacks
• Apply ice to reduce pain and inflammation
• Implement dietary modifications to reduce purine intake
• Encourage weight loss in overweight/obese patients

Pharmacological Management

• 1st Line for Acute Attacks:
• Naproxen 500 mg twice daily or Indomethacin 50 mg three times daily for 3-5 days NSAIDs
• 1.2 mg initially, followed by 0.6 mg one hour later, then 0.6 mg daily for 7-10 days
  • Colchicine
• Prednisone 30-40 mg daily, tapered over 7-10 days (for those unable to take NSAIDs or colchicine)
  • Corticosteroids
• Urate-Lowering Therapy (for frequent attacks or chronic gout):
• Start at 100 mg daily, titrate up to achieve serum uric acid <6 mg/dL
  • Allopurinol
• Alternative for those intolerant to allopurinol, start at 40 mg daily
  • Febuxostat
• Prophylaxis during initiation of urate-lowering therapy:
• Low-dose colchicine (0.6 mg daily) or low-dose NSAIDs for 3-6 months
• Serum uric acid levels, renal function, and liver function tests regularly Monitor

Acute attacks

• Medication management should ideally be initiated within 24 hours of flare onset
• Monotherapy is appropriate using colchicine, oral steroids, NSAIDS, OR COX-2 inhibitors
• If mild to moderate pain
• Combination therapy is appropriate
• If severe polyarticular gout flare
• Reduce dose as soon as symptoms High-dose NSAIDs for 2-5 days with precautions
• Best if initiated within 36 hours of flare onset
  • Colchicine
• May be effective if patient cannot tolerate NSAIDs
  • Oral or injectable corticosteroids
• May be contributing to hyperuricemia; consider modifying or eliminating as possible
  • Review medications patient is taking
• Can provide rapid relief; should be considered if flare involves one or two large joints
  • Intra-articular injection of corticosteroids

NSAIDs

• MOA: inhibit cyclooxygenase (COX-1 and COX-2) activity and prostaglandin synthesis
• FDA indication: management of pain and inflammation in acute gouty arthritis
• May cause serious Gl events including bleeding, ulceration, perforation, with or without warning
• Avoid in patients with sulfonamide hypersensitivity
• Use with caution in patients with known or suspected cardiovascular risk factors
• May lead to or worsen hypertension
• May lead to fluid retention or worsen heart failure
• Avoid concomitant use with salicylates
• Use with caution in patients with asthma
• Avoid use in patients with renal disease
• Titrate for effect, 50 mg PO TID until pain resolved
  • Indomethacin/Indocin Usual: 50 mg PO BID for shortest duration possible Max: 150 mg/day PO Availability: Caps: 25 mg, 50 mg
• May diminish effect of ACE inhibitors
• Avoid late in pregnancy due to premature closure of ductus arteriosus
• Available by prescription or OTC
• Initial: 500 mg PO BID; titrate for effect
  • Naproxen/Naprosyn Availability: Tabs: 250 mg, 375 mg, 500 mg
• Avoid late in pregnancy due to premature closure of ductus arteriosus
• Dose strengths and formulations not necessarily bioequivalent
• Consider when changing formulation

Urate Lowering Agents

• Allopurinol and febuxostat inhibit xanthine oxidase; probenecid inhibits uric acid reabsorption; uricase decreases serum uric acid; colchicine reduces pain and inflammation associated with gout attack
• MOA FDA indication: management of symptoms associated with gout
• All should be accompanied by adequate daily fluid intake
• Allopurinol preferred first-line urate-lowering therapy (ULT) agent for all patients
• A xanthine oxidase inhibitor (XOI) is recommended over probenecid for patients with CKD stage >3
• Concomitant anti-inflammatory prophylaxis therapy for 3-6 months is recommended when initiating ULT
• If a patient is taking a maximum dose of a single XOI and does not achieve SUA target, continues to have gout flares, or tophi are not resolving, consider switching to a different XOI agent prior to adding a uricosuric agent
• If a patient has not achieved SUA target, continues to have gout flares, and/or tophi are not resolving with XOI, uricosurics, and other interventions, consider switching to pegloticase
• Initial: 100-200 mg/day PO
  • Allopurinol/Zyloprim Usual: 200-300 mg/day PO Max: 800 mg/day PO Availability: Tabs: 100 mg, 300 mg
• Mild Disease
• Initial: 400-600 mg/day PO
• Usual: 200-300 mg/day PO
• Max: 800 mg/day PO Moderate/Severe Disease
• Maintain adequate fluid hydration
• Baseline BUN/creatinine before initiation
• Monitor CBC, renal and hepatic function at 1 wk, 6 wk, and every 3 months while on allopurinol
• Bone marrow suppression, as well as renal and hepatic impairment, can occur
• Consider starting at a low dose, then titrate to target
• Administered doses >300 mg
• Consider alkaline urine state
• Educate patients about the potential for allopurinol hypersensitivity reaction
• Consider HLA-B*5801 testing before starting allopurinol therapy for populations that have high risk for hypersensitivity reaction

Acute Attack Prevention

• Colchicine/Colcrys
• Initial Flare
• If on dialysis, max dose is 0.6 mg
  • May take without regard to meals
• 1.2 mg PO initially, then 0.6 mg 1 hr later; wait 12 hr, then 0.6 mg BID
• Availability: Tabs: 0.6 mg
• Probenecid/Benemid Prevention - 0.6 mg PO BID Initial (post attack) If moderate or severe renal or hepatic dysfunction, treatment course can be repeated no more than once every 2 wk GI side effects common Caution in older adults or debilitated patients Caution with anticoagulants Do not initiate therapy during acute gout attack
• 250-500 mg PO BID (with food) for 7 days; advance to 500 mg PO BID; may increase every 4 wk thereafter Availability: Tabs: 500 mg Max: 2 g PO

Urate-Lowering Agents - FebuxoStat/Uloric

• Initial: 40 mg PO daily
• Max: may increase to 80 mg daily if serum uric acid remains >6 mg/dL after 2 wk therapy
• Initial: 100 mg/day PO; consider 50 mg/day for patients with stage 4 chronic kidney disease
• Increase Dose & Max 6mg: Availability: Tabs: 40 mg, 80 mg Anaphylaxis and infusion reactions can occur
• If attack-free for >6 months, may decrease daily dose (monitor serum urate levels)
• Patients should be adequately hydrated
• Contraindicated in patients receiving azathioprine (Imuran) and mercaptopurine
• High risk for adverse CV events; use with extreme caution
• Consider switching to an alternative ULT agent for patients with a history of CVD or a new CV event
• Indicated for refractory gout
• Prevent Acute Attack If attack-free for >6 - months, may decrease daily dose (monitor -serum urate levels)
• Patients should be, adequately hydrated
• Max dose for initial 6mg; Indications for Consultation
• Preventive therapy includes urate-lowering agents
• Allopurinol Febuxostat Probenecid for patients that have difficulty achieving the goals.

Preventive Agents

• Consider urate lowering therapy in patients
• Prior Stones: Urate renal stones
• CKD Factors: diagnosed with a first gout flare and with stage 3 or greater chronic kidney disease; SUA >9 mg/dL, or urolithiasis; 2 or greater CKD; With tophi
• Agents dosed for long term

Considerations for Preventive Agents:

• Alternate first-line agent: uricosurics increase excretion of uric acid Treat patient to target serum urate level of <6 mg/dL Initiate anti-inflammatory prophylaxis therapy, up to 3-6 months, to avoid mobilization flare when initiating urate-lowering therapy
• Urate-lowering therapy is generally not recommended for patients with asymptomatic hyperuricemia and no prior gout flares or subcutaneous tophi

Consulation or Referral

• Difficult achieveing treatment goals,
• Neurology if issues
• Cardiology Management

Initial Diagnostic Patient Guidance

• Explain nature of the illness and relation to uric acid levels
• Discuss management/ and the prevention
• diet and lifestyle changes

Follow Up

• Make frequent visits to monitor, and assess current attacks
• Expected is a 3-10 day resolution of acute gout
• Treatment can prevent attacks and dissolute over time
• Make sure to reinforce lifestyle, and meds

Complications:

• Joint destruction with topography, renal failure
• CVD issues from increased attacks Overall: There can a reduced life quaitly