Gout

A 48-year-old man presents to his primary care physician with sudden onset of severe pain in the great toe of his left foot for 24 hours. The pain is intense and prevents him from bearing weight or performing his usual daily activities. He has a history of hypertension and takes losartan and hydrochlorothiazide. He drinks alcohol regularly. On examination, the first metatarsophalangeal joint is swollen, erythematous, warm, and exquisitely tender. Serum urate is within the normal range. Synovial fluid analysis demonstrates needle-shaped, negatively birefringent crystals. X-ray of the foot is normal. Diagnosis?

Diagnosis is Acute gout flare presenting as podagra.

1. Definition

Gout is an inflammatory crystal arthropathy caused by deposition of monosodium urate crystals within joints and periarticular tissues.

Acute gout involving the first metatarsophalangeal joint is termed podagra.

2. Epidemiology and Risk Factors

1.      Male sex

2.      Increasing age

3.      Hyperuricemia

4.      Hypertension

5.      Chronic kidney disease

6.      Obesity and metabolic syndrome

7.      Excessive alcohol consumption

8.      Thiazide and loop diuretics

9.      Purine-rich dietary intake

10.  Conditions associated with increased cell turnover

In this patient, hydrochlorothiazide and regular alcohol consumption are important risk factors.

Hydrochlorothiazide can increase serum urate by reducing renal urate excretion.

Losartan has a modest uricosuric effect and may lower serum urate. It may be preferentially selected when otherwise clinically appropriate in patients with gout.

3. Pathophysiology

1.      Persistent elevation of the body urate pool can lead to supersaturation of urate.

2.      Monosodium urate crystals form and deposit within joints and periarticular tissues.

3.      The crystals activate innate inflammatory pathways, particularly the NLRP3 inflammasome.

4.      This promotes release of inflammatory mediators, especially interleukin-1 beta, with recruitment of neutrophils.

5.      The resulting inflammatory response produces the characteristic abrupt, intensely painful arthritis of an acute gout flare.

Most hyperuricemia results predominantly from reduced renal urate excretion rather than excessive urate production.

Importantly:

A normal serum urate concentration during an acute gout flare does not exclude gout.

Serum urate may transiently decrease during an acute inflammatory episode.

4. Causes

Hyperuricemia may result from reduced urate excretion, increased urate production, or a combination of both.

4.1 Underexcretion

Reduced renal urate excretion is the predominant mechanism in most patients.

Important causes include:

1.      Chronic kidney disease

2.      Thiazide diuretics

3.      Loop diuretics

4.      Volume depletion

5.      Certain medications

6.      Metabolic abnormalities affecting renal urate handling

4.2 Overproduction

Important causes include:

1.      High cell turnover

o    Hematologic malignancy

o    Tumor lysis

o    Psoriasis

2.      Purine-rich dietary intake

3.      Increased purine or ATP metabolism associated with alcohol consumption

4.      Rare disorders of purine metabolism

Alcohol can contribute to gout through effects on both urate production and renal urate excretion.

5. Clinical Features

1.      Sudden onset of severe monoarticular pain

2.      Rapid progression to maximal intensity

3.      Marked tenderness

4.      Swelling

5.      Erythema

6.      Warmth

7.      Restricted joint movement

The first MTP joint is the classic site.

Other commonly affected sites include:

·         Ankle

·         Midfoot

·         Knee

·         Wrist

·         Elbow

Potential precipitants include:

·         Alcohol intake

·         Acute illness

·         Surgery or trauma

·         Dehydration

·         Certain medications

·         Rapid changes in serum urate concentration

6. Diagnosis

1.      Synovial fluid analysis

Identification of monosodium urate crystals in synovial fluid or a tophus establishes a definite diagnosis of gout.

The characteristic finding is:

Needle-shaped, strongly negatively birefringent monosodium urate crystals on polarized light microscopy.

In comparison, calcium pyrophosphate deposition disease typically demonstrates rhomboid-shaped or rod-shaped crystals with weak positive birefringence.

2.      Serum urate

A normal serum urate concentration during an acute gout flare does not exclude gout.

Serum urate may transiently fall during an acute inflammatory episode.

If gout is suspected but not confirmed and serum urate is low or normal during the flare, it should be repeated after the acute episode has resolved.

In this patient, crystal identification already establishes the diagnosis.

3.      Septic arthritis

A red, hot, swollen joint should always prompt consideration of septic arthritis.

The presence of monosodium urate crystals does not completely exclude concomitant septic arthritis.

If infection is clinically suspected, synovial fluid should also undergo appropriate microbiological testing, including culture.

4.      Laboratory findings

Acute gout may be associated with:

o    Leukocytosis

o    Elevated CRP

o    Elevated ESR

These findings are nonspecific and cannot reliably distinguish gout from septic arthritis.

5.      Imaging

A normal radiograph is common in acute gout and does not exclude the diagnosis.

With longstanding or chronic gout, radiographs may demonstrate:

o    Well-defined juxta-articular erosions

o    Punched-out erosions

o    Sclerotic margins

o    Overhanging edges

o    Tophi

When crystal analysis is unavailable or the diagnosis remains uncertain, ultrasound or dual-energy CT may help demonstrate urate deposition.

7. Acute Management

1.      NSAIDs

Common options include:

o    Naproxen

o    Ibuprofen

o    Indomethacin

NSAIDs should be avoided or used cautiously in patients with significant renal impairment, active peptic ulcer disease, or other relevant contraindications.

2.      Colchicine

Low-dose colchicine is preferred over high-dose therapy because it provides similar efficacy with fewer gastrointestinal adverse effects.

Common adverse effects include:

o    Diarrhea

o    Nausea

o    Abdominal discomfort

Renal function, hepatic function, and clinically important drug interactions should be considered.

3.      Glucocorticoids

Glucocorticoids may be administered:

o    Orally

o    Intra-articularly

o    Intramuscularly

Intra-articular glucocorticoids can be particularly useful when one or a small number of joints are involved, provided joint infection has been reasonably excluded.

4.      Adjunctive therapy

Ice application may be used as an adjunct for pain relief.

The choice among NSAIDs, colchicine, and glucocorticoids depends on renal function, gastrointestinal disease, cardiovascular risk, comorbidities, drug interactions, and contraindications.

8. Chronic Management

Long-term management aims to prevent recurrent flares, eliminate urate crystal deposition, prevent tophi, and prevent chronic joint damage.

1.      Lifestyle and risk-factor modification

o    Limit excessive alcohol consumption

o    Achieve and maintain a healthy body weight when appropriate

o    Follow a healthy balanced diet

o    Manage hypertension, chronic kidney disease, and metabolic comorbidities

o    Review medications that increase serum urate

For patients with gout who are taking hydrochlorothiazide, switching to an alternative antihypertensive may be considered when clinically feasible.

Losartan may be preferentially selected or continued when otherwise appropriate because of its modest uricosuric effect.

2.      Urate-lowering therapy

When long-term urate-lowering therapy is indicated, allopurinol is the preferred first-line agent in the American College of Rheumatology guideline, including in patients with chronic kidney disease when started at an appropriately low dose and titrated carefully.

Other options in selected patients include:

o    Febuxostat

o    Probenecid

o    Pegloticase for severe refractory disease

Pegloticase is not a first-line urate-lowering therapy.

3.      Indications for urate-lowering therapy

According to the American College of Rheumatology, ULT is generally recommended for patients with:

o    Tophi

o    Radiographic damage attributable to gout

o    Frequent gout flares

After a first uncomplicated flare, ACR generally recommends against routine ULT unless important additional factors are present, such as:

o    CKD stage 3 or greater

o    Serum urate >9 mg/dL

o    Urolithiasis

NICE recommends offering ULT more broadly, including to patients with gout who are receiving diuretic therapy.

Therefore, in this patient taking hydrochlorothiazide, long-term ULT should be considered in the context of the applicable guideline, recurrence risk, comorbidities, medication review, and patient preference.

4.      Treat-to-target approach

The usual target is:

Serum urate <6 mg/dL (<360 micromol/L)

A lower target, such as:

Serum urate <5 mg/dL (<300 micromol/L)

may be considered in patients with more severe disease, particularly those with tophi or persistent frequent flares.

5.      Flare prophylaxis during initiation of ULT

Initiation or escalation of ULT can transiently precipitate gout flares.

Anti-inflammatory prophylaxis is commonly used with:

o    Low-dose colchicine

o    An NSAID when appropriate

The ACR recommends prophylaxis for 3 to 6 months, with continuation beyond this period when clinically indicated because flares persist.

If a patient is already taking established ULT when an acute flare develops, the ULT should generally be continued rather than stopped.

9. Key Clinical Insight

Acute severe monoarthritis of the first MTP joint with needle-shaped, strongly negatively birefringent monosodium urate crystals confirms acute gout presenting as podagra.

A normal serum urate concentration during an acute flare does not exclude gout.

A normal X-ray is common in acute gout and does not exclude the diagnosis.

The presence of urate crystals does not completely exclude concomitant septic arthritis when infection is clinically suspected.

In this patient, hydrochlorothiazide and alcohol consumption are relevant risk factors, while losartan has a modest uricosuric effect.

References

1.      FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180. PMID: 32391934.

2.      National Institute for Health and Care Excellence. Gout: diagnosis and management. NICE Guideline NG219. Published June 9, 2022.

3.      Richette P, Doherty M, Pascual E, et al. 2018 updated European League Against Rheumatism evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis. 2020;79(1):31-38. doi:10.1136/annrheumdis-2019-215315. PMID: 31167758.