Gout and Hyperuricemia

Gout is caused by chronic hyperuricemia leading to the deposition of monosodium urate (MSU) crystals in joints, periarticular soft tissue (cartilage, tendon, bursa), and renal tissue (glomeruli, interstitium, tubules), producing gouty arthritis, tophi, or uric acid nephrolithiasis/nephropathy. It is the most common cause of inflammatory arthritis in adults. Disease progresses through 4 clinically distinct stages — asymptomatic hyperuricemia, acute gouty flare, intercritical gout (the asymptomatic interval between flares, when flare prophylaxis and urate-lowering therapy are managed), and chronic tophaceous gout — and management differs meaningfully by stage: an acute flare needs fast anti-inflammatory treatment, while sustained hyperuricemia needs a treat-to-target urate-lowering strategy that, once started, continues indefinitely.^[1][2]

Acute gouty flare

Abrupt onset of excruciating pain and inflammation in a joint, classically overnight or in the early morning, often severe enough that the patient cannot tolerate even light pressure (such as a bedsheet) on the affected joint. Attacks typically resolve spontaneously over days to about a week if untreated, though resolution can take longer in longstanding disease. The 1st metatarsophalangeal (MTP) joint (podagra) is the single most common site, especially for a first attack; other frequently involved sites in decreasing order include the midfoot/instep, ankle, heel, knee, wrist, finger joints, and elbow. Acute gouty bursitis can occur in the prepatellar or olecranon bursa. There is a predilection for joints already damaged by osteoarthritis. A first attack is usually monoarticular; polyarticular presentations become more common with recurrent attacks, in older-onset disease, and in women, who also have a higher relative frequency of upper-limb joint involvement than men.

Intercritical gout

The asymptomatic interval between flares. Without urate-lowering therapy, subsequent attacks tend to become more frequent, more severe, longer-lasting, and increasingly polyarticular with upper-extremity involvement and constitutional symptoms, and erosive joint damage and tophi can develop even during this "quiet" phase.

Chronic tophaceous gout

Tophi are painless, chalky nodular deposits of MSU crystals that develop after years of sustained, inadequately controlled hyperuricemia. They can cause joint destruction and visible deformity even though they are not themselves painful. Common locations include the synovium, subchondral bone, the digits of the hands and feet, the olecranon bursa, the Achilles tendon, and the helix of the ear, though tophi can occur anywhere, including rarely the cardiac conduction system. The strongest risk factor for tophus development is the degree and duration of uncontrolled serum urate elevation; aggressive correction of hyperuricemia is the key preventive and therapeutic strategy, and tophi gradually resorb and can fully resolve after sustained serum urate control.

Drugs associated with hyperuricemia and gout

• Alcohol.
• Cyclosporine and tacrolimus.
• Cytotoxic chemotherapy.
• Diuretics — thiazide and loop diuretics specifically (not other antihypertensive classes).
• Ethambutol and pyrazinamide.
• Interferon plus ribavirin.
• Levodopa.
• Nicotinic acid (niacin).
• Low-dose salicylates (e.g., low-dose ASA).
• Teriparatide.

Conditions associated with hyperuricemia and gout

• Excessive alcohol intake.
• Atherosclerosis and ischemic heart disease.
• Chronic kidney, glomerular, or interstitial renal disease.
• Diabetes and metabolic syndrome.
• Dietary factors — high purine intake, high-fructose corn syrup.
• Hyperlipidemia and hypertension.
• Lead intoxication.
• Myeloproliferative disorders and some malignancies.
• Obesity.
• A personal history of urolithiasis.
• Rarely, genetic or acquired causes of uric acid overproduction.

Additional patient-level risk factors

• Male sex over age 40, or postmenopausal status in women — estrogen has a uricosuric effect, so gout is uncommon in premenopausal women.
• A first flare before age 30 in men or age 50 in women without a clear precipitant — suggests an inherited purine-metabolism enzyme abnormality and warrants further workup.
• A prior gout flare — the single strongest predictor of a future flare.
• Chronic kidney disease stage 3 or higher.
• Solid organ transplantation (calcineurin inhibitor use plus reduced renal clearance).

Differentiating an acute hot, swollen joint

Gout and septic arthritis can coexist, and a dramatic response to colchicine does not exclude infection — when there is any diagnostic uncertainty, arthrocentesis with synovial fluid cell count, Gram stain, culture, and crystal analysis is mandatory before treating empirically as gout.

History

• Precipitants of the acute attack — acute illness, surgery, trauma, alcohol intake, a high-purine meal, or a drug from the hyperuricemia-associated list in Risk Factors.
• Pattern and location of joint or bursa involvement, and whether the joint was previously damaged (e.g., by osteoarthritis).
• Character of the episode — abrupt onset, severity, nocturnal or early-morning onset, inability to tolerate light pressure on the joint.
• Time course — most flares resolve spontaneously over days if untreated; longer courses are more common in longstanding disease.
• Presence of a known tophus, and prior gout flares (number, frequency, and whether they involved 1 or multiple joints).

Physical examination

• Confirm the joint/bursa involvement pattern described above.
• Examine specifically for tophi at their common locations (digits, olecranon bursa, Achilles tendon, helix of the ear).

Investigations

• Serum urate — supportive but not definitive; a normal level during a flare does not rule out gout, since urate can transiently fall during an acute attack.
• Synovial fluid analysis — the diagnostic gold standard: identification of intracellular, needle-shaped, negatively birefringent monosodium urate crystals under polarized microscopy confirms the diagnosis. Send synovial fluid for cell count, Gram stain, and culture in the same tap whenever septic arthritis has not been confidently excluded — this is not optional when there is diagnostic uncertainty.
• Imaging (ultrasound double-contour sign, dual-energy CT showing urate deposition, or conventional radiography showing punched-out erosions with overhanging sclerotic margins in established disease) — useful when the diagnosis remains uncertain after history, exam, and available fluid analysis, or to document structural damage in chronic disease. Not required for a classic presentation in a patient with prior crystal-proven gout — do not routinely re-image or re-tap every recurrent, typical flare.

Presumptive versus definitive diagnosis

A presumptive diagnosis of gout is supported by the triad of acute monoarthritis, hyperuricemia, and a dramatic response to colchicine, but a definitive diagnosis requires identification of intracellular monosodium urate crystals in synovial fluid.

2015 ACR/EULAR gout classification criteria

Developed as a research classification tool (entry criterion: at least 1 episode of swelling, pain, or tenderness in a peripheral joint or bursa), not a mandatory clinical diagnostic requirement — synovial fluid crystal identification remains the clinical gold standard. Identification of MSU crystals in a symptomatic joint, bursa, or tophus is sufficient on its own to classify gout without needing to sum the remaining domains below.^[5]

A total score of 8 or more classifies the patient as having gout.

• Terminate the acute flare as quickly as possible — start anti-inflammatory therapy within 24 hours of flare onset.
• Reach and maintain a treat-to-target serum urate below 360 µmol/L for most patients.
• For patients with more severe disease (e.g., tophaceous gout), reach a lower target of under 300 µmol/L until visible/palpable urate crystal burden has resolved, then relax the maintenance target to under 360 µmol/L to prevent new tophi.
• Prevent flare recurrence, especially during the higher-risk period immediately after starting urate-lowering therapy, with anti-inflammatory prophylaxis.
• Prevent or reverse gout complications — erosive joint damage, tophi, uric acid nephrolithiasis, and urate nephropathy.
• Identify and manage associated comorbidities — metabolic syndrome, hypertension, dyslipidemia, and cardiovascular and renal disease.
• Sustain adherence to urate-lowering therapy indefinitely once started — this is lifelong treatment, not a fixed course.

• Apply ice to the affected joint during an acute flare as an appropriate adjunct to pharmacologic therapy.
• Recommend a structured weight-loss program for patients with overweight or obesity, regardless of current disease activity.
• Encourage regular exercise and adequate hydration.
• Limit purine intake regardless of disease activity — advise avoiding organ meats high in purine content (sweetbreads, liver, kidney) and limiting beef, lamb, pork, and high-purine seafood (sardines, shellfish).
• Limit high-fructose corn syrup intake regardless of disease activity.
• Limit alcohol intake regardless of disease activity — particularly beer, though wine and spirits also count — to under 2 servings/day for men or under 1 serving/day for women; advise avoiding alcohol entirely during periods of frequent flares or poorly controlled gout.
• Review the patient's medication list for nonessential hyperuricemic drugs (see Risk Factors) and discontinue or substitute where feasible; preferentially select losartan when an ARB is otherwise indicated for another reason, and switch hydrochlorothiazide to an alternative antihypertensive class when feasible.
• Continue low-dose ASA for cardiovascular protection when it is already indicated — do not stop it solely because of a gout diagnosis, but recognize it may increase the importance of adequate ULT.
• Dietary supplements, including vitamin C, are not recommended specifically for lowering serum urate — current evidence is insufficient to support this use.

Pregnancy

Gout is uncommon in premenopausal women because estrogen has a uricosuric effect; when a flare does occur in pregnancy, oral or intra-articular corticosteroids are generally the preferred treatment. Avoid NSAIDs, particularly from around 20 weeks' gestation onward, given fetal renal effects and the risk of premature closure of the ductus arteriosus. Colchicine has more accumulated pregnancy safety experience than urate-lowering therapy (from long-standing use in familial Mediterranean fever) and may be considered under specialist guidance if corticosteroids are inadequate, though it is not the first choice. Xanthine oxidase inhibitors (allopurinol, febuxostat) and probenecid are generally not initiated in pregnancy given insufficient safety data — defer ULT initiation to the postpartum period unless a specialist determines ongoing therapy is essential.

Breastfeeding

Corticosteroids are compatible with breastfeeding. NSAIDs are generally compatible for short-term use. Colchicine transfer into breast milk appears low; use the lowest effective dose. Data on allopurinol and probenecid in lactation are limited — weigh benefit and risk with specialist input, and prefer an alternative when one is adequate.

Pediatrics

Gout is rare in children. Pediatric gout warrants specialist evaluation for an underlying inherited enzyme disorder of purine metabolism (e.g., hypoxanthine-guanine phosphoribosyltransferase deficiency in Lesch-Nyhan syndrome, or PRPP synthetase overactivity) or a secondary cause such as malignancy or tumor lysis, rather than routine adult-pattern management. Probenecid is contraindicated under age 2.

Renal impairment

Allopurinol: reduce the starting dose to 50 mg/day if eGFR is 29 mL/min/1.73m² or under; titrate cautiously and more slowly, monitoring renal function.^[10] Febuxostat: no dose adjustment is required across mild-to-severe CKD, though the cardiovascular risk-benefit assessment still applies. Colchicine: reduce the dose/frequency or avoid when combined with a strong CYP3A4 or P-glycoprotein inhibitor in the setting of renal impairment — this combination has caused fatal toxicity.^[4] NSAIDs: avoid in significant renal impairment (ClCr under 30 mL/min). Probenecid/uricosurics: not appropriate as first-line monotherapy if ClCr is under 50 mL/min, and effectiveness declines further as renal function worsens.

Hepatic impairment

Reduce or avoid colchicine with interacting drugs as above, and use general caution with colchicine in significant hepatic impairment. Monitor liver enzymes with both allopurinol (rare hepatotoxicity) and febuxostat (more frequent mild transaminase elevation), and use febuxostat with caution in significant hepatic impairment.

• During an acute flare: confirm symptom resolution and tolerance of the chosen agent within the expected timeframe.
• Serum urate: recheck every 2-5 weeks during ULT titration; once the target is reached, recheck every 6 months.
• Renal function, CBC, and liver enzymes periodically while on allopurinol or febuxostat, and for patients on colchicine, particularly if an interacting drug is added.
• Watch closely for a new rash in the first weeks after starting allopurinol — instruct the patient to report this immediately, and do not continue allopurinol if hypersensitivity is suspected.
• Track flare frequency and tophus size/number over time as measures of treatment adequacy — both should decline once serum urate has been sustained below target.
• Reassess the ongoing need for anti-inflammatory flare prophylaxis at 3-6 months after ULT initiation; continue longer if the patient is still experiencing flares.
• Periodically reassess associated comorbidities — blood pressure, lipids, glucose/HbA1c, and weight — given the established link between gout and metabolic syndrome.
• Colchicine therapy in gout has also been associated with a reduced risk of cardiovascular events in cohort data — an incidental benefit worth being aware of in patients with overlapping cardiovascular risk factors, though this association is not itself a reason to add colchicine for a patient who does not otherwise have gout.^[11]
• Community pharmacists are well positioned to catch ULT nonadherence, since patients often stop therapy once symptom-free without understanding that lifelong continuation is required to prevent recurrence and complications.

1. Reconsider the diagnosis if the response to appropriately dosed flare therapy is atypical or absent — reassess for septic arthritis, CPPD (pseudogout), or another cause.
2. For an inadequately controlled acute flare: confirm adherence and correct dosing of the chosen agent, then escalate to combination therapy (colchicine plus NSAID, colchicine plus oral corticosteroid, or intra-articular corticosteroid plus an oral agent) if not already combined.
3. For a flare unresponsive to combination therapy, or in a patient who cannot use colchicine, NSAIDs, or corticosteroids at all: refer for specialist-directed IL-1 inhibitor therapy — not an approved indication in Canada, so this route requires rheumatology involvement.
4. For serum urate not at target despite the maximum tolerated allopurinol dose: switch to febuxostat, or add a uricosuric (probenecid, if ClCr is 50 mL/min or higher and there is no urolithiasis history) for combination ULT.
5. For serum urate still not at target despite combination xanthine-oxidase-inhibitor plus uricosuric therapy, or for continued frequent flares despite urate at target: refer to rheumatology for further workup and specialist-directed options.
6. At every step, screen for unaddressed reversible contributors — ongoing use of a hyperuricemic drug (especially a thiazide or loop diuretic), high alcohol intake, poor ULT adherence, or an inadequate duration of flare prophylaxis during ULT initiation.

• Stopping or altering the dose of urate-lowering therapy during an acute flare — continue it unchanged.
• Starting ULT without concurrent flare prophylaxis (colchicine or a low-dose NSAID).
• Treating asymptomatic hyperuricemia — this is not an indication for ULT.
• Starting ULT after a first, isolated gout flare without any of the specific indications present.
• Using the outdated repeated-hourly high-dose colchicine regimen instead of the current low-dose regimen.
• Missing a dangerous colchicine interaction (a strong CYP3A4 or P-glycoprotein inhibitor such as clarithromycin) in a patient with renal or hepatic impairment — this combination is potentially fatal.
• Not considering HLA-B*58:01 screening before starting allopurinol in a patient of Han Chinese, Korean, Thai, or African descent.
• Choosing febuxostat ahead of allopurinol as first-line ULT without a specific reason to avoid allopurinol.
• Starting a uricosuric in a patient with ClCr under 50 mL/min or a history of urolithiasis.
• Continuing a thiazide or loop diuretic without considering an alternative when clinically feasible in a patient with gout.
• Treating an acutely inflamed joint as gout without considering septic arthritis, especially with fever, systemic toxicity, or genuine diagnostic uncertainty.
• Assuming a normal serum urate level during a flare excludes gout.

How to use this table: doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Antimitotics

Corticosteroids, intra-articular

Corticosteroids, systemic

Nonsteroidal anti-inflammatory drugs (NSAIDs)

No good evidence that one NSAID is more effective than another for gout. Avoid in patients with a history of peptic ulcer disease, cardiovascular risk factors, renal failure, or asthma; consider adding a PPI in patients at risk for peptic ulcer disease. Avoid NSAIDs in severe renal impairment (ClCr under 30 mL/min).

Uricosurics

Contraindicated in gross uric acid overproducers (elevated urine uric acid). Urine alkalinization is not recommended with uricosuric therapy. Confirm creatinine clearance before selecting therapy — avoid as first-line monotherapy if ClCr is under 50 mL/min or with urolithiasis.

Xanthine oxidase inhibitors

The mainstay of treat-to-target therapy; can be started during a flare as long as effective anti-inflammatory treatment has also been started. Urate levels should be checked every 6 months once the target has been reached.

Agents not routinely available or not approved for this indication in Canada