Tophi" (singular: tophus) are deposits of monosodium urate crystals that accumulate in soft tissues due

to chronic hyperuricemia, typically seen in advanced cases of gout. They often appear as hard,
painless nodules beneath the skin, especially around joints, cartilage, and in areas such as fingers,
toes, elbows, and the outer ear. Tophi can cause joint damage and deformities over time and are
considered a sign of untreated or poorly managed gout.

Heberden's and Bouchard's nodes are bony enlargements at the joints of the fingers associated with
osteoarthritis. Heberden's nodes occur at the distal interphalangeal joints (DIP), the joints closest to
the fingertips, while Bouchard's nodes are at the proximal interphalangeal joints (PIP), the middle joints
of the fingers.Although these nodes are more commonly linked with osteoarthritis, when they become
inflamed, red, or painful, it could signal other types of arthritis, such as gouty arthritis. Gouty arthritis
is usually marked by the deposition of monosodium urate crystals in joints, leading to intense
inflammation and pain. In this case, inflamed Heberden’s or Bouchard’s nodes as a first manifestation
of gouty arthritis could mean that instead of osteoarthritis, the patient is experiencing early signs of
gout in these finger joints.

Signs and Symptoms of Gout

1. Acute Gout Attack:

o Sudden onset of severe joint pain, often at night.
o The affected joint is red, swollen, warm, and exquisitely tender to the touch.
o The first metatarsophalangeal (MTP) joint of the big toe is frequently affected—a
presentation known as podagra.
o Other commonly affected joints include the ankles, knees, elbows, wrists, and fingers.
o Systemic symptoms such as fever, chills, and malaise can accompany an acute flare,
mimicking an infection.
2. Intercritical Periods:
o These are symptom-free intervals between acute gout attacks.
o During this period, patients usually feel asymptomatic, though subclinical inflammation
and urate deposition may persist.
3. Chronic Tophaceous Gout:
o Over time, chronic gout can lead to persistent joint discomfort and the development of
tophi—visible deposits of urate crystals in soft tissues.
o Tophi can form in areas like the ears, fingers, elbows, Achilles tendons, and other
pressure sites.
o Chronic gouty arthritis can lead to joint damage and deformity, reduced range of
motion, and persistent pain.

Differential Diagnosis

1. Pseudogout (Calcium Pyrophosphate Deposition Disease - CPPD):

o This condition presents similarly to gout with acute arthritis but involves the deposition
of calcium pyrophosphate crystals rather than urate.
o Joints often affected include the knees and wrists.
o Synovial fluid analysis under polarized light microscopy will reveal positively
birefringent, rhomboid-shaped crystals, distinguishing it from gout.
2. Septic Arthritis:
o Characterized by an acute, painful, swollen joint, often accompanied by fever.
o Typically affects a single joint (monoarticular), such as the knee, and is more common
in individuals with compromised immunity or pre-existing joint disease.
o Diagnosis requires synovial fluid analysis with Gram stain and culture.
3. Rheumatoid Arthritis (RA):
o Unlike gout, RA usually presents with symmetrical polyarthritis, particularly affecting
the small joints of the hands and wrists.
o RA generally causes persistent inflammation rather than sudden, severe flares.
o Presence of autoantibodies, such as rheumatoid factor (RF) and anti-CCP, and
radiographic findings help differentiate RA from gout.
4. Osteoarthritis (OA):
 o OA generally leads to chronic joint pain and stiffness without the severe inflammatory
flares seen in gout.
o Typically affects weight-bearing joints (e.g., knees, hips) and the distal interphalangeal
(DIP) joints in the hands.
o Nodules such as Heberden’s and Bouchard’s nodes in OA are non-inflammatory, but
gout may mimic OA if it involves these joints.
5. Reactive Arthritis:
o An inflammatory arthritis that occurs as a reaction to infection, typically following a
gastrointestinal or genitourinary infection.
o Affects large joints asymmetrically and may be accompanied by symptoms like
conjunctivitis and urethritis.
6. Psoriatic Arthritis:
o An inflammatory arthritis associated with psoriasis.
o Joint involvement is often asymmetrical and can include "sausage digits" (dactylitis).
o Presence of psoriasis and nail changes help distinguish it from gout.

Gouty arthritis, according to Harrison's Principles of Internal Medicine (20th edition), is an

inflammatory condition caused by the deposition of monosodium urate (MSU) crystals in joints and
tissues due to hyperuricemia (elevated serum urate levels). Here's an overview of its pathophysiology,
pathology, etiology, epidemiology, and risk factors:

Pathophysiology

Gouty arthritis begins with hyperuricemia, which can result from either increased production or
reduced excretion of uric acid. When serum urate levels exceed the solubility threshold (around 6.8
mg/dL), MSU crystals can form and deposit in joints and surrounding tissues. These crystals trigger an
immune response, leading to acute inflammation as neutrophils and other immune cells infiltrate the
joint. The result is the release of inflammatory cytokines, such as interleukin-1β (IL-1β), causing
intense pain, redness, and swelling characteristic of gouty arthritis.

Pathology

In gout, the classic pathological findings include:

 Tophi formation: Aggregates of MSU crystals surrounded by granulomatous inflammation in

joints and soft tissues, known as tophi.
 Synovitis: Chronic inflammation of the synovial membrane with the infiltration of
lymphocytes, plasma cells, and macrophages.
 Joint damage: With chronic gout, erosions and joint deformities can occur due to ongoing
inflammation and crystal deposition.

Etiology

The primary cause of gouty arthritis is hyperuricemia. Hyperuricemia can result from:

1. Increased uric acid production: This can occur in conditions with high cell turnover (e.g.,
leukemia, lymphoma) or metabolic overproduction due to enzymatic defects.
2. Reduced uric acid excretion: Factors reducing renal clearance of urate include kidney
disease, metabolic syndrome, and certain medications (e.g., diuretics).

Epidemiology

Gout prevalence varies but is higher in affluent societies with Western diets. It affects approximately 3-
5% of adults in the United States and is more common in males, particularly those over age 30.
Incidence rates increase with age, peaking around 75 years. There has also been a recent rise in
prevalence due to lifestyle changes, dietary habits, and the increased incidence of metabolic
syndrome.

Risk Factors

Gouty arthritis is thus a multifactorial disease influenced by genetic, dietary, and metabolic

Risk Factors

1. Age and Sex

 Sex: Gout is more common in men than in women due to naturally higher levels of uric acid in
men. Estrogen in premenopausal women promotes uric acid excretion, lowering their risk until
menopause.
 Age: Gout incidence rises with age, particularly after 50. Aging can affect kidney function and
may lead to increased uric acid levels and reduced renal clearance, contributing to gout risk.

2. Genetics

 Genetic variations significantly impact urate metabolism and excretion. Specific gene
mutations, like those in the SLC2A9 and ABCG2 genes, are associated with an increased risk of
hyperuricemia and gout.
 Family history of gout increases the risk, indicating a heritable component to uric acid
regulation.

3. Dietary Habits

 Purine-rich foods: Red meats, seafood, organ meats, and foods high in purines increase uric
acid production when metabolized. The breakdown of purines, nitrogenous compounds in these
foods, leads to uric acid production.
 Alcohol: Alcohol, particularly beer, raises uric acid levels. Beer contains guanosine, which
metabolizes to uric acid, and alcohol itself inhibits renal uric acid excretion.
 Sugary drinks: Sugary sodas and fruit juices (especially those with high fructose corn syrup)
increase uric acid by accelerating ATP turnover in the liver and leading to uric acid as a
byproduct.

4. Obesity and Metabolic Syndrome

 Obesity: Excess body fat promotes uric acid production. Obesity also contributes to insulin
resistance, which can impair uric acid excretion.
 Metabolic Syndrome: Metabolic syndrome includes a combination of conditions like
hypertension, dyslipidemia, and insulin resistance. These conditions interfere with the kidneys'
ability to excrete uric acid, thereby raising levels in the bloodstream.
 Hypertension: High blood pressure is closely linked with hyperuricemia. Many
antihypertensive drugs, like diuretics, also increase uric acid levels.

5. Renal Impairment and Kidney Disease

 The kidneys play a critical role in clearing uric acid from the bloodstream. Reduced kidney
function, whether due to chronic kidney disease, aging, or other factors, results in impaired
urate excretion.
  In individuals with chronic kidney disease (CKD), this effect is more pronounced, making them
highly susceptible to developing hyperuricemia and gout.

6. Medications

 Diuretics: Often prescribed for high blood pressure or heart failure, diuretics reduce blood
volume and concentrate uric acid, making it harder for the kidneys to excrete.
 Low-dose aspirin: Regular use of low-dose aspirin can impair urate excretion. High-dose
aspirin, however, has a uricosuric effect, meaning it can help lower uric acid levels.
 Immunosuppressive drugs: Cyclosporine, often used post-transplant, raises uric acid levels
and predisposes individuals to gout.
 Niacin (vitamin B3): Commonly used for dyslipidemia, niacin can reduce uric acid clearance
and is thus another risk factor.

7. Medical Conditions

 Diabetes Mellitus: Insulin resistance seen in type 2 diabetes affects renal uric acid clearance.
Also, high blood sugar levels can worsen the kidneys’ ability to process uric acid.
 Psoriasis: Increased cell turnover in psoriasis results in more purine production, contributing
to higher uric acid levels.
 Heart disease: Cardiovascular conditions often coincide with metabolic syndrome
components, contributing indirectly to gout risk.

8. Physical Trauma and Surgery

 Trauma: Joint injury can promote local inflammation and facilitate MSU crystal deposition,
potentially triggering gout flares.
 Surgery: Surgical stress and subsequent inflammation can precipitate acute gout, often due to
changes in urate levels triggered by physical stress, dehydration, or fasting associated with
surgery.

9. Dehydration and Fasting

 Dehydration: Dehydration concentrates uric acid in the blood due to reduced kidney
perfusion, increasing gout risk.
 Fasting or Rapid Weight Loss: Increases in ketone bodies from fasting or extreme dieting
inhibit urate excretion by the kidneys.

Laboratory Tests for Gouty Arthritis

Test Details
1. Serum Uric Acid
- Measures the concentration of uric acid in the blood.
Level
 Test Details
- Normal Range: Typically 3.5-7.2 mg/dL (varies by lab).
- Interpretation: Elevated levels (>6.8 mg/dL) indicate hyperuricemia, but
may not confirm gout.
- Note: Some patients may have normal uric acid levels during acute
attacks.
- Procedure: Aspiration (arthrocentesis) of synovial fluid from the affected
2. Joint Fluid Analysis
joint.
- Microscopic Examination: Look for monosodium urate crystals under
polarized light.
- Crystals: Needle-shaped and exhibit strong negative birefringence.
- Infection: Ruling out infection (septic arthritis) through culture and cell
count.
3. Imaging Studies
- Initial Imaging: Can help assess joint damage and rule out other
A. X-rays
conditions.
- Findings in Chronic Gout: Erosions, joint space narrowing, and
subcortical cysts.
B. Ultrasound - Uses: Detects synovitis and tophi, and can visualize urate deposits.
- Benefits: Non-invasive, useful for monitoring progression.
C. Dual-Energy CT - Application: Highly sensitive for detecting urate crystals in joints and soft
Scan tissues.
- Details: Useful in atypical presentations or difficult cases.
- Purpose: Measures uric acid excretion in urine to evaluate kidney function
4. 24-Hour Urine Test
and uric acid production.
- Interpretation: Elevated excretion (>800 mg/day) suggests
overproduction; low excretion (<800 mg/day) suggests underexcretion.
5. Other Blood Tests
A. Complete Blood - Application: Checks for signs of inflammation (elevated white blood cell
Count (CBC) count) and to rule out infection.
B. Kidney Function - Includes: Serum creatinine and blood urea nitrogen (BUN) to assess renal
Tests function, as gout is often associated with renal impairment.
C. Erythrocyte
Sedimentation Rate - Purpose: Indicates inflammation; often elevated during gout attacks.
(ESR)
D. C-Reactive Protein - Purpose: A sensitive marker for inflammation, may be elevated in acute
(CRP) attacks

Conditi Clinical Diagnostic

on Manifestations Findings
Elevated serum urate levels; needle-
Gouty Sudden onset of severe pain, erythema,
shaped, negatively birefringent
Arthriti warmth, and swelling in joints (commonly 1st
monosodium urate crystals in synovial
s MTP); may present with tophi in chronic cases
fluid
Acute, painful joint inflammation, Rhomboid-shaped, positively birefringent calcium
Pseudogou
often in knees and wrists; similar pyrophosphate crystals in synovial fluid;
t (CPPD)
presentation to gout chondrocalcinosis visible on X-ray
Joint pain, swelling, erythema, warmth, and Positive synovial fluid culture; high white
Septic
fever; commonly affects large joints like the blood cell count in joint fluid; elevated ESR
Arthritis
knee and CRP
 Symmetrical joint inflammation, often Positive rheumatoid factor and anti-CCP
Rheumatoi
in small joints (hands, wrists); antibodies; elevated ESR and CRP; radiographic
d Arthritis
morning stiffness (>1 hour) changes like joint space narrowing and erosions
Joint space narrowing, osteophytes on X-ray; normal
Osteoarthri Gradual onset of joint pain and
synovial fluid analysis; absent inflammatory
tis (OA) stiffness, typically in weight-bearing
markers (normal ESR, CRP)
joints (hips, knees)
Negative synovial fluid culture; history of
Reactive Acute joint pain, often in large joints (knees,
recent infection; elevated ESR and CRP; HLA-
Arthritis ankles), following infection; may include
B27 positivity in some cases
conjunctivitis and urethritis
Radiographic changes like “pencil-in-cup”
Psoriatic Joint pain, swelling, often in hands and
deformity; dactylitis ("sausage fingers"); negative
Arthritis feet; associated with skin and nail
rheumatoid factor
changes
Celluli No crystals in joint fluid; positive skin cultures may
Redness, warmth, swelling, tenderness
tis indicate infection; elevated WBC, ESR, CRP
over the skin; not confined to a joint
Joint pain, typically in hands Elevated serum ferritin and transferrin saturation;
Hemochroma
and wrists; may mimic chronic chondrocalcinosis on imaging; iron overload on liver
tosis
gout biopsy or MRI

Drug/
Mechanism of Action (MOA)
Treatment
Allopurinol is a xanthine oxidase inhibitor. Xanthine oxidase is an enzyme involved in
purine metabolism, which converts hypoxanthine to xanthine and then to uric acid.
Allopurinol
By inhibiting this enzyme, allopurinol reduces the production of uric acid, leading to
lower serum urate levels and preventing crystal deposition in joints.

Similar to allopurinol, febuxostat is a non-purine selective inhibitor of xanthine

Febuxostat oxidase. It inhibits both oxidized and reduced forms of the enzyme, providing a
potent reduction in uric acid synthesis without direct purine structure, making it
especially useful for patients intolerant of allopurinol.

Probenecid is a uricosuric agent that increases uric acid excretion by inhibiting renal
Probenecid tubular reabsorption in the proximal tubules. This inhibition prevents uric acid from
being reabsorbed into the bloodstream, thus promoting its excretion through urine,
effectively lowering serum urate levels.

Pegloticase is a recombinant uricase enzyme that catalyzes the oxidation of uric acid
into allantoin, a more soluble and easily excreted compound. This conversion
Pegloticase
drastically reduces serum urate levels, especially in patients with chronic refractory
gout. Since humans lack functional uricase, pegloticase compensates for this
deficiency in those with severe hyperuricemia.
Colchicine acts by disrupting microtubule formation in neutrophils, which is critical
for their mobility and activity in inflammation. This inhibition reduces neutrophil
Colchicine migration and adhesion at sites of inflammation and interferes with inflammasome
activation, particularly affecting the interleukin-1β (IL-1β) pathway, which is a central
mediator in gouty inflammation.
NSAIDs (e.g., Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX)
 Drug/
Mechanism of Action (MOA)
Treatment
enzymes (both COX-1 and COX-2), which are responsible for
prostaglandin synthesis. Prostaglandins are pro-inflammatory mediators that
ibuprofen)
contribute to pain, fever, and swelling in gouty joints. By inhibiting COX, NSAIDs
reduce inflammation, swelling, and pain in affected joints.
Glucocorticoids work by binding to glucocorticoid receptors, which regulate the
Glucocorticoid
transcription of genes that suppress pro-inflammatory pathways. They decrease the
s (e.g.,
release of pro-inflammatory cytokines, inhibit immune cell activation, and block
prednisone)
inflammatory pathways, leading to rapid symptom relief in gout flares.
Interleukin-1 (IL-1) inhibitors like anakinra block IL-1 receptors or IL-1 signaling
IL-1 Inhibitors pathways. IL-1 is a cytokine that plays a major role in the inflammatory response in
(e.g., gout flares by promoting neutrophil recruitment to the joint. Blocking IL-1 reduces
anakinra) the acute inflammatory response, especially helpful for patients with recurrent or
refractory gout flares

Disease/ Drug/ Dosa Indicati

Condition Treatment ge ons

Acute Initial dose of 1.2 mg, followed by 0.6 mg Recommended as first-line therapy for
Colchici
Gout one hour later; maintenance 0.6 mg once or acute flares within 36 hours of
ne
Flares twice daily as needed symptom onset.

NSAIDs (e.g., Naproxen: 750 mg initially, then 250 mg every 8 NSAIDs are preferred for
naproxen, hours until symptoms subside; Indomethacin: 50 patients without
indomethacin, mg three times daily until pain is manageable; contraindications like GI disease,
ibuprofen) Ibuprofen: 400-800 mg three to four times daily renal disease, or hypertension.

Oral prednisone: 0.5 mg/kg daily for 5–10

Glucocorticoids (oral, For patients intolerant to NSAIDs
days or 30–60 mg daily tapered over 7–10
intraarticular, or colchicine, and for patients
days; intraarticular dose depends on joint
intramuscular) with polyarticular flares.
size

IL-1 Inhibitors (e.g., Anakinra: 100 mg subcutaneously daily Reserved for refractory flares or
anakinra, for 3 days; Canakinumab: 150 mg when conventional therapies are
canakinumab) subcutaneously once contraindicated.

Chronic Gout Initial dose of 100 mg daily (or 50 mg in CKD), Preferred first-line ULT
(Urate- Allopurin titrated up every 2–5 weeks by 100 mg until target for chronic gout,
Lowering ol uric acid <6 mg/dL; typical maintenance dose 300– especially for patients
Therapy) 800 mg/day depending on serum urate with CKD.

Febuxost Start at 40 mg daily, increase to 80 mg if For patients who cannot tolerate allopurinol or
at uric acid target not achieved have an inadequate response.

Initial dose of 250 mg twice daily, increasing Suitable for patients who have
Probenec
to 500 mg twice daily after one week, up to contraindications to xanthine oxidase
id
a maximum of 2 g/day inhibitors; promotes uric acid excretion.

Peglotica 8 mg IV infusion every For chronic, refractory gout when target serum urate levels are not
se two weeks achieved with other therapies.

Gout Colchicine: 0.6 mg once or twice Used during ULT initiation to

NSAIDs or low-
Prophylaxis with daily; NSAIDs (e.g., naproxen): 250 prevent flares for the first 3–6
dose colchicine
ULT Initiation mg twice daily months.
MOA of Xanthine

The development of gout begins with purine intake from dietary sources like red meat, seafood,
and alcohol, or from the body’s recycling of purines from DNA and RNA. These purines are
broken down into intermediates, including hypoxanthine and xanthine, and finally converted to
uric acid by the enzyme xanthine oxidase. When uric acid production increases or kidney
excretion decreases, uric acid accumulates in the blood, causing hyperuricemia. When blood uric
acid levels become too high, monosodium urate crystals can form, especially in cooler areas like
the joints. These crystals often deposit in joint spaces, such as the big toe, and can trigger an
immune response when the body’s neutrophils attempt to engulf them. This immune reaction
releases inflammatory molecules like cytokines and reactive oxygen species, resulting in intense
pain, swelling, and redness known as a gout attack. To manage gout, treatments focus on
lowering uric acid levels: xanthine oxidase inhibitors (like allopurinol and febuxostat) reduce uric
acid production, while uricosuric agents (like probenecid) increase uric acid excretion. By
lowering uric acid levels, these treatments reduce crystal formation and help prevent and
control gout symptoms.