Gout

Background

• Gout is a chronic disease characterized by recurrent attacks of severe joint pain and swelling (gout flare) due to an inflammatory reaction directed against monosodium urate (MSU) crystals. When gout is improperly managed, chronic joint inflammation may develop, as well as tophi, which are mass-like deposits of crystals surrounded by inflammatory aggregates and fibrous capsules. Tophi have the capacity to permanently damage bone and cartilage.
• Patients with gout have high rates of comorbidities, including hypertension, renal disease, cardiac disease, osteoarthritis, metabolic syndrome, diabetes, and obesity, which may increase the complexity of management.
• Reported prevalence of gout worldwide ranges from 0.1% to about 10%.
  • Gout is the most common inflammatory arthritis
  • Rates are usually higher in male patients compared to female patients, with gout in female patients who are premenopausal being particularly rare.
  • Highest rates are reported in some ethnic groups such as indigenous Taiwanese and Pacific Islanders, including Maori (New Zealand).
• 4 stages of gout are recognized; asymptomatic hyperuricemia, flare, intercritical, and chronic.
• Asymptomatic hyperuricemia occurs when the serum urate level is > 6.8 mg/dL (408 mcmol/L), the saturation point for urate (at pH 7.4). In the presence of asymptomatic hyperuricemia, there is an increased likelihood of MSU crystal deposition which may result in a clinical diagnosis of gout. However, the majority of patients with asymptomatic hyperuricemia do not develop symptomatic gout (although they may deposit MSU crystals on the surface of cartilage).
• The major causes of hyperuricemia are hereditary. Most patients fail to excrete uric acid adequately from the kidneys and/or the gastrointestinal system.
• Multiple factors can increase the risk of hyperuricemia and therefore gout, including:
  • fructose or high purine foods
  • alcohol consumption
  • acute or chronic kidney disease
  • medications, such as
    • low-dose aspirin
    • beta-blockers
    • diuretics (except potassium-sparing diuretics)
    • tuberculous medications (pyrazinamide, ethambutol)
• A gout flare is defined as acute joint inflammation (either first or subsequent episodes) in response to MSU crystals. After a flare, the transition from asymptomatic hyperuricemia to gout has occurred, which is generally considered a lifelong diagnosis.
• Intercritical gout are those periods of time between gout flares. Early in the course of gout, patients typically appear completely asymptomatic during intercritical periods, which may last months or years.
• Patients with gout cycle between flares and intercritical periods. If not adequately treated, the flares tend to come more often, and be more severe and long-lasting. Eventually the flares may merge into a persistent chronic joint inflammation with intermittent exacerbations.
• Secondary prevention of acute gouty attacks includes modifying risk factors (high-purine foods, fructose, alcohol, obesity, and diuretics) and the long-term use of urate-lowering medications. Urate lowering may have benefical impacts on some gout comorbidities, although this is still being studied.

Evaluation

• The most common initial presentation is a self-limiting inflammatory flare.
  • Typical gout flares occur during the night and are characterized by severe pain, erythema, warmth, and swelling of 1 or more joints, which peak within 24 hours. Spontaneous resolution usually occurs within 7-14 days.
  • The first metatarsophalangeal joint is the most commonly affected joint in early flares (podagra). Other frequently involved joints include the midfoot, ankles, and knees. Most early flares are monoarticular; subsequently polyarticular flares may occur.
  • MSU deposition and gout flares in axial joints are a recognized phenomenon but diagnosis is difficult.
  • Gout may ultimately progress to include persistent arthritis with or without tophi, along with recurrent acute flares of localized joint regions.
• The gold standard for diagnosis of a gout flare is the demonstration of MSU crystals (needle-shaped with strong negative birefringence by polarized light microscopy), along with a high number of white blood cells (can be > 50,000 cells/mm³) in the synovial fluid of a patient with an acute monoarticular inflammatory arthritis. Typically there is a neutrophil predominance and neutrophils can be seen phagocytosing MSU crystals.
• In a patient who has had at least one episode of inflammatory arthritis typical of gout, and has documented MSU crystals in a joint or tophus, the diagnosis of chronic gout is considered to be established.
• Gout as a chronic disease may also be diagnosed using the American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Gout Classification Criteria (originally designed for research). A printable scoring sheet is available online from the University of Auckland.
• Synovial fluid analysis should be performed whenever possible including cell count, polarized light microscopy for crystals, Gram stain, and culture with sensitivity.
• Other testing typically includes
  • serum urate level (however, serum urate may transiently decline and even normalize during gout flares)
  • inflammatory markers, including erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP)
  • imaging, including
    • x-rays which may identify characteristic bony damage from tophi
    • ultrasound
    • dual energy computed tomography (DECT) which can identify tophi and MSU deposition on cartilage
• The differential diagnosis of gout flare includes:
  • infection (septic arthritis or cellulitis, particularly with monoarticular presentation)
  • other crystalline-induced inflammatory arthritis (such as calcium pyrophosphate dihydrate [CPPD] deposition disease, also known as “pseudogout”)
  • autoimmune inflammatory arthritis (such as rheumatoid arthritis or psoriatic arthritis, particularly with polyarticular presentation)
  • variant presentation of osteoarthritis with inflammatory features (most typically in distal interphalangeal [DIP] joints of fingers).

Management

• For acute gout flares:
  • Although flares can be self-limited with spontaneous resolution in 1-2 weeks, they are very painful; treatment hastens symptom resolution and is recommended as soon as possible after onset of a flare (Strong recommendation).
  • Treatment options include:
    • Low-dose colchicine (1 or 1.2 mg orally followed by 0.5 or 0.6 mg 1 hour later); start treatment preferably within 24 hours of flare onset (ideally within 12 hours) (Strong recommendation).
      • Patients with mild-to-moderate pain receiving low-dose colchicine may require supplemental therapy such as nonsteroidal anti-inflammatory drugs (NSAIDs) if symptoms persist.
    • Oral nonsteroidal anti-inflammatory drugs (NSAIDs) (Strong recommendation)
      • Recommended as a first-line therapeutic option (Strong recommendation).
      • Options include naproxen or ibuprofen available OTC or others by prescription. Give maximal dosing for the best anti-inflammatory effect.
    • Corticosteroids
      • Glucocorticoids (oral, intra-articular, or intramuscular) are an option for first-line therapy for gout flares (Strong recommendation) due to significant effect and rapidity of response. Adrenocorticotropic hormone (ACTH) can promote innate cortisol release and be effective, but is not used as first-line therapy due to prohibitive cost considerations.
      • Oral corticosteroid treatment regimens (prednisone, prednisolone, methylprednisolone, etc.), typically start at a medium-high dose for several days and then taper down as clinically appropriate over several days or weeks:
        • prednisolone 30-35 mg/day orally for 3-5 days
        • prednisone starting at 40-60 mg/day followed by a rapid taper; slower taper may be needed depending on clinical response to prevent a rapid recurrent flare
      • In patients who cannot take anything by mouth, use IV, intramuscular, or intra-articular glucocorticoids depending on which and how many joints are involved (Strong recommendation).
    • Interleukin-1 blockers should be considered as an option in patients who have a current gout flare that is refractory to other therapy, or who have intolerance or contraindications to anti-inflammatory therapies (Strong recommendation).
  • In patients with severe acute gout
    • consider combination therapy, such as colchicine plus an NSAID, or colchicine plus corticosteroids
    • avoid combination of NSAIDs plus corticosteroids
  • Consider nonpharmacologic treatments in addition to medication, including rest, ice packs, and elevation of affected joints (Weak recommendation).
  • Maintain any established urate-lowering therapy (ULT) during acute attack. Stopping and then re-starting ULTs may precipitate further flares.
• For prevention of recurrent attacks:
  • The definitive therapy for gouty arthritis is the dissolution of the monosodium urate tissue deposits, not just treating acute attacks. The dissolution of monosodium urate crystal deposits is believed to result in the elimination of the foreign body stimulus for acute inflammatory flares as well as the lower grade chronic inflammation that might cause erosive changes in and around joints.
    • When serum urate concentrations are lowered below the saturation point (about 6.8 mg/dL), uric acid crystal precipitation is prevented and existing crystals dissolve back into solution.
    • Use of ULT to achieve and maintain a serum urate target of < 6 mg/dL is the threshold that has been used to decrease risk of further gout flares. (Strong recommendation).
  • ULT should be considered and discussed with every patient with gout (Strong recommendation).
    • Initiate ULT in patients with any of the following (Strong recommendation):
      • presence of any subcutaneous tophi, which suggests a chronic state of hyperuricemia
      • evidence of radiographic damage (via any modality) attributable to gout or monosodium urate deposition
      • frequent flares (≥ 2 flares/year)
    • Consider initiating ULT in patients with any of the following (Weak recommendation):
      • history of > 1 flare, but with infrequent flares (< 2 flares/year)
      • experiencing first flare in the presence of ≥ stage 3 chronic kidney disease (CKD), serum urate > 9 mg/dL, or urolithiasis
    • In patients with gout experiencing first flare, initiating ULT is conditionally recommended against (Weak recommendation).
    • In patients with asymptomatic hyperuricemia (serum urate > 6.8 mg/dL without previous flares or subcutaneous tophi), initiating pharmacologic ULT is conditionally recommended against (Weak recommendation), as evidence of a significant medical benefit of lowering uric acid levels in these patients is lacking. (However, note that the Japan Society for Gout recommends treating asymptomatic hyperuricemia under some specific circumstances.)
  • Medication selection when lowering serum urate:
    • Xanthine oxidase inhibitors (XOI), which includes allopurinol and febuxostat, are the first-line option (Strong recommendation).
    • Allopurinol is the preferred first-line agent for patients starting ULT, including in those with ≥ stage 3 CKD (Strong recommendation).
    • Usual dosing:
      • Start allopurinol at ≤ 100 mg/day (lower doses preferred in patients with chronic kidney disease [CKD] ≥ stage 3) with subsequent dose titration to achieve target serum urate level (Strong recommendation), up to the maximum FDA-approved dose of 800 mg/day (maximum dose is 900 mg/day according to European recommendations).
      • If allopurinol not adequately effective or contraindicated, switch to febuxostat at an initial dose of ≤ 40 mg/day with subsequent dose titration to achieve target serum urate level. In the U.S, the maximum approved febuxostat dose is 80 mgs/day. In Europe the maximum approved dose is 120 mgs/day. (Strong recommendation).
      • In Han Chinese, Korean, Thai, and African American patients, consider testing HLA-B*5801 prior to starting allopurinol, as they have a higher prevalence of the HLA-B*5801 allele (Weak recommendation), which is associated with a significantly increased risk for allopurinol hypersensitivity syndrome
    • In patients taking a first XOI as monotherapy who have persistently high serum urate concentrations despite maximized treatment, and have continued frequent gout flares (> 2 flares/year) or nonresolving subcutaneous tophi, consider switching to an alternate XOI agent rather than adding a uricosuric agent (Weak recommendation).
    • In patients not responding adequately to an XOI, other options in patients with normal renal function include uricosuric agents, such as probenecid (Weak recommendation).
      • When using probenecid, consider starting at a low dose (500 mg once or twice daily) with dose titration (Weak recommendation). Advise patient to maintain adequate hydration.
      • In patients with ≥ stage 3 CKD, use XOI rather than probenecid (Strong recommendation), as adequate renal function is needed for probenecid to predictably have therapeutic effect.
    • For patients who failed to achieve serum urate target with XOI, uricosurics, and other interventions, if patient has frequent gout flares (≥ 2 flares/year) or nonresolving subcutaneous tophi, consider use of pegloticase (pegylated uricase) rather than continuing current ULT (Weak recommendation).
  • Anti-inflammatory prophylaxis is recommended for gout patients when ULT is started (Strong recommendation).
    • ULT initiation is often accompanied by a transient increase in gout flares which may lead patients to not comply with their ULT unless prophylaxis is applied.
    • Options include colchicine 0.5-0.6 mg once or twice daily, a nonsteroidal anti-inflammatory drug, or if necessary low-dose corticosteroid.
    • Continue for at least 3-6 months, with ongoing evaluation.
  • Management of patients on ULT:
    • Use ULT to achieve and maintain a serum urate target of < 6 mg/dL (Strong recommendation).
    • Use a treat-to-target strategy that includes dose titration and subsequent dosing guided by serial serum urate levels to achieve the serum urate target (Strong recommendation).
    • For patients in clinical remission, consider indefinite use of ULT as maintenance therapy if well-tolerated by patient, due to possibility of return or worsening gout symptoms (Weak recommendation).
  • In patients experiencing gout flare where ULT is indicated, consider starting ULT during flare rather than starting upon resolution of flare, as long as adequate anti-inflammatory therapy has been initiated (Weak recommendation).