Gout

Gout is characterized by painful intermittent flares of inflammatory arthritis in response to intraarticular crystal deposition. Excessive levels of urate in the serum. Increasingly common - U.S prevalence of 4%.

Factors: dietary changes, obesity, age. Most patients with gout have comorbidities including HTN, CAD, DLD, DM, CKD, etc. Comorbidities complicated therapeutic options such as NSAIDs.

Men reach a steady-state serum urate level after puberty, whereas premenopausal women are generally protected from hyperuricemia by estrogenic effects. Men can have their first gout flare in the third to fifth decade; women are more likely to experience the first flare after menopause.

Pathophysiology

Uric acid is the end result of purine metabolism. Urate production is 2/3 from cellular turnover, and the remainder is from dietary intake of purines (red meat, liver, offals, shellfish, alcohol, fructose...)

Humans do not expressive uricase, which converts urate into soluble allantoin. Therefore urate accumulates and can precipitate as crystals if serum concentrations exceed the saturation point (0.40 mmol/L in normal conditions).

Most serum urate is filtered in the glomerulus, but 90% is reabsorbed in the proximal tubule. In most patients with gout, hereditary under-excretion is the primary cause of hyperuricemia. A serum urate level greater than 10 mg/dL (0.59 mmol/L) is associated with a 30% likelihood of an initial gout flare within 5 years.

An acute arthritic gouty flare is triggered by a macrophage-led IL-based inflammatory response to ingestion of monosodium urate (MSU) → neutrophilic recruitment.

Clinical Manifestations

The clinical diagnosis of gout requires (1) hyperuricemia (2) monosodium urate deposition in joints or soft tissues (3) acute inflammatory response to the MSU crystals.

Gout Flares

Typically monoarticular, and 50% of first flares in men involve the first MTP of the great toe (i.e. podagra). Can be provoked by inflammatory states. Hallmarks are pain, tenderness, swelling, erythema, warmth. Flares begin at night and peak within 12-24 hours.

Most gout flares self-resolve within days to weeks, although chronic gout can flare for months. Eventually with established gout, flares can involve the ankles, proximal feet, knees, and even the spine and any other joint.

Postmenopausal women can present with initial flares of the knees, or fingers joints coaffected by OA.

Severe or chronic gout can lead to polyarticular flares. Soft tissues (bursitis, periathritis, panniculitis, cellulitis) can be involved as well.

Chronic Aspects of Gout

If gout is not treated early, flares become increasingly frequent and severe with a reduced intercritical latent period. The extent of joint involvement spreads. This can transition to a persistent inflammatory arthritis.

Tophi can develop (solid chalky white masses of uric acid with inflammatory rind) around joints and soft tissues, with a predilection for extensor surfaces, Achilles tendon, fingers, ear helices (kinda of like xanthoma). They are deforming, debilitating, and cause bony erosion and damage. Can lead to superficial ulceration and superimposed infection.

Diagnosis of Gout

Consider the diagnosis in any patient with 1+ episodes of acute monoarticular or oligoarticular inflammatory arthritis.

Clinical clues: rapid onset, CV risk factors, male middle-aged or female post-menopausal aged. History of similar monoarticular or oligoarticular involvement. First MTP location. Low-grade fever can be present. Elevated CRP and ESR.

DDx: infectious arthritis, pseudogout, trauma, other forms of inflammatory arthritis

Synovial Fluid: Gold standard of diagnosis: identification of negatively birefringent needle-like MSU crystals and neutrophils in synovial fluid. Synovial fluid aspirate >2000/uL leukocytes, often above 100,000/uL with a neutrophilic predominance.

Urate levels: can drop during a gout flare, and a normal serum urate level acutely does not rule out the diagnosis. A serum urate level 2 weeks after flare resolution more accurately measures the baseline level.

Established gout can have detectable changes on dual energy CT or MSK US.

Management of Gout

Acute Gout Flares

Anti-inflammatory therapy is the mainstay of treatment. Options are (1) colchicine (2) NSAIDs (3) glucocorticoids. Treatment is determined by drug interactions and comorbidities (age, GIB, AKI/CKD, CV, etc)

1. Colchicine 1.2 mg x 1, then 0.6 mg 1 hour later. Most effective when used less than 24h after symptom onset.
2. High-dose NSAIDs for 5-7 days
3. Glucocorticoids in any form (prednosine 0.5 mg/kg/d x 5d, intra-articular, intramuscular)

Consider topical ice or NSAIDs as adjunctive therapies.

Most acute flares respond to a week or less of therapy, although severe flares may require longer treatment.

Anakinra can be used off-label for very severe and refractory flares, or with contraindications to any other treatment.

Treat gouty cellulitis the same as any other acute gout flare.

Chronic Management

Lifestyle Changes

Guidelines conflict as to whether patients with gout should receive dietary counseling to reduce serum urate levels. If recommended, patients may limit intake of shellfish, oily fish, red meat, high-fructose foods, and alcohol. However, overly strict diets that are unlikely to be adhered to are not helpful. Weight loss (when appropriate) and increasing dairy intake may also lower serum urate levels.

Urate-Lowering Therapy

Indications for ULT per 2020 ACR Guidelines:

• Strongly recommended for all patients with gout and any of:
  • Any number of subcutaneous tophi;
  • Any radiographic damage attributable to gout;
  • Two or more gout flares per year
• Conditionally recommended for patients with gout and:
  • First flare with CKD stage III or greater;
  • First flare with urate >0.53 mmol/L;
  • First flare with urolithiasis

ULT during acute flares: If the patient is on ULT already, then continue it. Evidence supports starting ULT during an acute flare if indications are met, but adequate anti-inflammatory therapy needs to be started because this can precipitate/lengthen a flare.

Target Urate Level: If ULT is indicated, then 2020 ACR and 2016 EULAR recommendations are to "treat-to-target" to less than 0.35 mmol/L (ACR), or less than 0.30 mmol/L (EULAR) in patients with tophi.

Xanthine oxidase inhibitors (reduce urate production)

Allopurinol is the first line therapy for most patients and FDA approved up to 800 mg/d. Start at 100 mg/d and titrate in 100mg increments every few weeks until urate level at target. With CKD IV-V, start at 50 mg/d and titrate half as fast.

• Drug-induced hypersensitivity syndrome can lead to DRESS in patients on allopurinol. Characterized by a RASH --> stop drug with rash on allopurinol. Patients with HLA-B*58:01 allele have a much higher incidence of this syndrome (more common in SEA, African descent). 2020 ACR guidelines conditionally recommend genetic testing in these patients. Positive HLA allele --> receive alternative therapy

Febuxostat is as effective or more effective than allopurinol. Less likely to cause hypersensitivity reactions, does not need dose adjustments in mild to moderate CKD. Slightly increased CV risk compared to allopurinol --> relative contraindication.

Uricosuric agents (decrease renal urate resorption)

Probenecid is rarely used as a single agent because less effective than XOI. Avoid in CKD eGFR < 50 or with kidney stones. Combination therapy with XOI can be more effective than XOI monotherapy.

Losartan is unique in the antihypertensive class due to its uricosuric effects. Diuretics for CV disease tend to block urate excretion and should be avoided if possible.

Pegloticase (uricase)

This is an option with severe recurrent and/or tophaceous gout who cannot tolerate or improve on other therapies. Infusion every 2 weeks, and reduces serum urate to almost zero. 30-50% of patients develop antibodies within weeks which renders the drug ineffective and increases the chance of reactions such as anaphylaxis. If the drug stops working (pre-infusion serum urate >0.35 mmol/L x 2) it should be discontinued.

Contraindicated with G6PD deficiency. Should also not be given with other ULT.

Prophylaxis

Because initiating ULT can precipitate a flare, patients starting ULT during intercritical latent periods should be started on anti-inflammatory prophylaxis for 3-6 months (e.g. colchicine 0.6 mg daily or BID, or low-dose NSAIDs or steroids).

References

1. MKSAP 19
2. 2020 American College of Rheumatology Guideline for the Management of Gout - PubMed
3. 2016 updated EULAR evidence-based recommendations for the management of gout | Annals of the Rheumatic Diseases