16:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/1jvnwmb7jnkpz.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 17:T58ac,## Summary Gout is an inflammatory crystal disease caused by deposition of **monosodium urate (MSU)** in joints and periarticular tissues. Hyperuricemia is necessary for crystal formation but is not itself diagnostic of gout. Serum urate may fall during an acute flare, so a value below the treatment target during active inflammation does not exclude the diagnosis.[1,2] For an undifferentiated hot swollen joint, the most definitive test is synovial-fluid identification of **needle-shaped, strongly negatively birefringent MSU crystals**. A crystal-positive aspirate does **not** exclude septic arthritis; send Gram stain and culture whenever infection is clinically plausible and treat suspected infection without waiting for crystal results.[1,2] Treat a flare promptly with **low-dose colchicine, an NSAID, or a glucocorticoid**, selected according to kidney function, GI and cardiovascular risk, anticoagulation, diabetes, drug interactions, infection risk, and number of joints involved.[1] Current U.S. colchicine labeling for an adult flare uses **1.2 mg orally at onset followed by 0.6 mg one hour later**; higher acute dosing adds toxicity without greater benefit.[3] Long-term control depends on sustained reduction of serum urate. The American College of Rheumatology (ACR) recommends a **treat-to-target** approach with serial serum urate and a target **<6 mg/dL (<360 micromol/L)** in patients receiving urate-lowering therapy (ULT).[1] NICE also targets <6 mg/dL and recommends considering **<5 mg/dL (<300 micromol/L)** in tophaceous or chronic gouty arthritis, or when frequent flares continue despite urate below 6 mg/dL.[2] **Allopurinol is preferred first-line ULT in ACR guidance, including in chronic kidney disease (CKD)**. Start low and titrate upward to target rather than fixing the maintenance dose according to kidney function alone.[1] ULT is strongly indicated for tophi, radiographic damage attributable to gout, or frequent flares. When ULT is started or escalated, ACR recommends anti-inflammatory prophylaxis for at least **3–6 months**, and longer if flares persist.[1] > **Caution:** A new rash, fever, mucosal lesions, eosinophilia, hepatitis, or kidney injury after allopurinol may represent a severe hypersensitivity reaction. Stop allopurinol immediately and arrange urgent assessment; do not rechallenge after a serious hypersensitivity syndrome.[4] ## Disease states Gout can be considered across four clinically useful states: 1. **Asymptomatic hyperuricemia** — elevated serum urate without prior gout flare or tophus. 2. **Gout flare** — acute crystal-triggered inflammation, commonly monoarticular but sometimes oligoarticular or polyarticular. 3. **Intercritical gout** — symptom-free interval between flares while tissue crystals may remain. 4. **Chronic/tophaceous gout** — persistent crystal burden with tophi, erosions, chronic synovitis, tendon disease, or recurrent flares. Routine pharmacologic treatment of asymptomatic hyperuricemia solely to prevent first-onset gout is not recommended by ACR or NICE for most patients.[1,2] ## Pathophysiology Uric acid is the final major purine metabolite in humans. Steady-state serum urate reflects production and renal plus intestinal excretion. Most gout is driven by impaired urate excretion rather than extreme overproduction. When extracellular urate remains supersaturated, MSU crystals nucleate preferentially in cooler peripheral tissues and previously damaged joints. Crystal exposure activates innate immune pathways, particularly the NLRP3 inflammasome and interleukin-1 signaling, followed by intense neutrophil recruitment. Tophi are organized crystal deposits with surrounding chronic inflammation. Untreated crystal burden can erode bone, damage cartilage, weaken tendons, compress nerves, ulcerate skin, and progressively impair joint function. Rapid changes in serum urate can destabilize deposits. Flares may therefore temporarily increase after effective ULT is started; this does not mean ULT is failing. ## Risk factors and secondary contributors Important contributors include: - CKD and reduced urate excretion; - obesity and metabolic syndrome; - hypertension and heart failure; - loop and thiazide diuretics; - high alcohol intake; - high intake of fructose-sweetened drinks; - high intake of purine-rich meat and some seafood; - dehydration or rapid volume change; - calcineurin inhibitors; - high cell-turnover states; - genetic variants affecting urate transport; - family history.[1,2] When clinically feasible, ACR conditionally recommends replacing hydrochlorothiazide with another antihypertensive and preferentially using losartan when an appropriate antihypertensive is needed because losartan has a modest uricosuric effect.[1] Do not stop low-dose aspirin that is indicated for cardiovascular prevention solely to reduce serum urate.[1] ## Clinical features ### Typical flare - abrupt severe pain, often reaching maximal intensity within 24 hours; - marked tenderness; - swelling, warmth, and erythema; - restricted movement; - first metatarsophalangeal joint, ankle, and knee are common sites.[1,2] A flare may resemble cellulitis, septic arthritis, or another inflammatory arthropathy. Fever can occur in gout and therefore does not reliably distinguish infection. ### Atypical patterns Polyarticular disease, upper-limb involvement, chronic synovitis, or less dramatic inflammation is more frequent in: - older adults; - people with CKD; - transplant recipients; - patients with longstanding untreated gout; - postmenopausal women. ### Tophi Common sites include: - ear helix; - fingers and toes; - olecranon and prepatellar bursae; - Achilles tendon; - periarticular soft tissue. Tophi are often firm and irregular. Ulceration or chalk-like drainage can occur in advanced disease and may be complicated by infection. ## Dangerous alternative: septic arthritis A red, hot joint can represent gout, infection, or both. Lower the threshold for aspiration and culture when there is: - systemic toxicity; - prosthetic joint; - immunosuppression; - recent bacteremia; - overlying skin infection; - recent joint procedure; - first unexplained acute monoarthritis; - persistent inflammation despite appropriate gout treatment. Synovial WBC count overlaps substantially between crystal arthritis and infection. Culture remains decisive when sepsis is a concern. ## Diagnosis ### Synovial fluid When diagnostic certainty matters, aspirate the affected joint or bursa and send: - cell count with differential; - Gram stain; - aerobic/anaerobic culture; - crystal analysis. **MSU crystals:** needle-shaped and strongly negatively birefringent under compensated polarized light microscopy. **Calcium pyrophosphate crystals:** usually rhomboid or rod-shaped and weakly positively birefringent. ### Serum urate Serum urate is central to long-term management but is an imperfect acute diagnostic test. NICE advises repeating urate at least **2 weeks after a flare settles** if the level is below 6 mg/dL during the flare but clinical suspicion remains high.[2] ### Imaging Imaging is most useful when aspiration is not feasible, the presentation is atypical, or chronic structural burden needs characterization. **Ultrasound** may show: - double-contour sign; - tophi; - aggregates; - effusion and synovitis. **Dual-energy CT (DECT)** can identify urate deposits at difficult-to-aspirate sites. Nail, skin, metal, and motion artifacts can produce false-positive findings. **Plain radiographs** in longstanding disease may show punched-out or juxta-articular erosions with sclerotic margins and relative preservation of joint space until later stages. ## Differential diagnosis | Alternative | Clues | Action | |---|---|---| | Septic arthritis | Toxicity, bacteremia risk, positive culture; may coexist with crystals | Aspirate and culture; treat infection when suspected | | Calcium pyrophosphate deposition | Older age, knee/wrist disease, chondrocalcinosis, positive birefringent crystals | Crystal confirmation when possible | | Cellulitis | Skin-centered inflammation without true effusion | Assess for portal of entry and soft-tissue infection | | Rheumatoid arthritis | Chronic symmetric inflammatory polyarthritis | Inflammatory-arthritis workup | | Psoriatic arthritis | Psoriasis, nail disease, dactylitis, enthesitis | Rheumatology assessment | | Hemarthrosis | Trauma or anticoagulation; bloody aspirate | Identify bleeding trigger and structural injury | See [Rheumatoid Arthritis](rheumatoid-arthritis.md) and [Osteoarthritis](osteoarthritis.md). ## Acute flare management Treat early and continue established ULT through the flare unless a drug-specific adverse reaction requires discontinuation.[1] ### Treatment selection | Therapy | Typical role | Adult dose / approach | Major cautions | Monitoring | |---|---|---|---|---| | Colchicine | Early flare; oral therapy | 1.2 mg once, then 0.6 mg 1 hour later per U.S. label[3] | Renal/hepatic impairment, P-gp/CYP3A4 interactions, myopathy | GI toxicity, weakness, cytopenia, drug interactions | | NSAID | Effective when renal/GI/CV risk is acceptable | Full anti-inflammatory dose according to selected agent/local label | CKD, ulcer/GI bleed, HF, anticoagulation, uncontrolled hypertension | Renal function, BP, GI toxicity, fluid status | | Oral glucocorticoid | When NSAID/colchicine unsuitable; polyarticular flare | Short course individualized to severity/comorbidity | Hyperglycemia, infection, psychiatric effects | Glucose, infection risk, symptom response | | Intra-articular glucocorticoid | One or few accessible joints | Local procedure after infection is reasonably excluded | Do not inject a potentially infected joint | Local response, infection | | IL-1 inhibitor | Selected refractory/contraindicated cases | Product/jurisdiction-specific | Infection risk, access, cost | Infection and product-specific safety | ### Colchicine safety Current U.S. labeling uses **1.2 mg at the first sign of flare followed by 0.6 mg one hour later**, maximum **1.8 mg over one hour** for the acute regimen.[3] Colchicine toxicity can cause: - severe diarrhea and vomiting; - cytopenias; - neuromyopathy; - rhabdomyolysis; - multiorgan failure. Strong CYP3A4 or P-glycoprotein inhibitors can markedly increase colchicine exposure, particularly in renal or hepatic impairment. Use current product labeling for interaction-specific contraindications and dose adjustment.[3] ### NSAIDs Choose an anti-inflammatory NSAID regimen according to local labeling and stop after the flare resolves. Avoid or use cautiously with: - significant CKD; - active peptic ulcer or GI bleeding; - decompensated heart failure; - substantial cardiovascular risk; - anticoagulation; - marked volume depletion. ### Glucocorticoids Oral glucocorticoids are often the simplest option when NSAIDs and colchicine are unsuitable. Intra-articular injection is useful for one or a few joints once infection is adequately excluded. Do not delay septic-joint treatment in order to give a steroid injection. ## When to start urate-lowering therapy ACR strongly recommends ULT for:[1] - one or more subcutaneous tophi; - radiographic damage attributable to gout; - frequent flares, generally **2 or more per year**. After a first flare, ACR generally recommends against routine ULT but conditionally supports initiation when any of the following is present:[1] - CKD stage 3 or worse; - serum urate >9 mg/dL; - urolithiasis. ULT may be started during an active flare if anti-inflammatory treatment is also provided and the patient is ready to begin long-term therapy.[1] ## Treat-to-target urate lowering Use serial serum urate measurements and titrate ULT to target rather than leaving patients indefinitely on a fixed low dose.[1,2] ### Targets - **ACR:** <6 mg/dL (<360 micromol/L).[1] - **NICE:** <6 mg/dL; consider <5 mg/dL (<300 micromol/L) for tophi, chronic gouty arthritis, or ongoing frequent flares despite urate below 6 mg/dL.[2] NICE recommends monthly urate checks while titrating ULT until target is achieved.[2] Local monitoring intervals can be individualized once stable. > **Clinical pearl:** Continued flares early after ULT initiation do not prove treatment failure. The key long-term measure is sustained urate below target with progressive reduction in flare and tophus burden. ## Allopurinol Allopurinol inhibits xanthine oxidase and is ACR’s preferred first-line ULT, including in CKD.[1] ### Initiation and titration - Start **≤100 mg/day** in most adults.[1] - Use a lower initial dose in CKD when appropriate.[1,4] - Titrate progressively to serum urate target while monitoring tolerance and renal function. - Do not impose an arbitrary low maintenance ceiling solely because CKD is present; many patients require higher doses to reach target.[1] ### HLA-B*58:01 and hypersensitivity HLA-B*58:01 markedly increases risk of severe allopurinol hypersensitivity. ACR conditionally recommends testing before starting allopurinol in people of Southeast Asian ancestry with higher allele prevalence and in African American patients, while recommending against universal testing in lower-prevalence groups.[1] Current U.S. labeling advises considering screening in populations with high prevalence of HLA-B*58:01 and emphasizes permanent discontinuation if a serious hypersensitivity reaction occurs.[4] Potential severe reaction features include: - rash or mucosal lesions; - fever; - eosinophilia; - hepatitis; - acute kidney injury; - systemic illness. ## Febuxostat Febuxostat is another xanthine oxidase inhibitor and is used when allopurinol is not tolerated, contraindicated, or insufficient under the relevant national pathway. Cardiovascular evidence is nuanced: - **CARES** studied patients with established cardiovascular disease and found similar major cardiovascular composite outcomes but higher cardiovascular and all-cause mortality with febuxostat.[5] - **FAST** found febuxostat noninferior to optimized allopurinol for its cardiovascular composite and did not show increased death with febuxostat in its studied population.[6] Because trial populations and design differ, regulatory and guideline positions vary. ACR conditionally recommends switching to an alternative ULT when a patient on febuxostat has established cardiovascular disease or develops a new cardiovascular event and another suitable option is available.[1] U.S. labeling retains a cardiovascular boxed warning. Document the jurisdictional framework and shared decision when febuxostat is used in high-risk cardiovascular disease. ## Uricosuric therapy Uricosuric drugs increase renal urate excretion. Their usefulness is limited by: - reduced kidney function; - nephrolithiasis risk; - drug interactions; - jurisdictional availability. Probenecid can be used in selected patients but is generally not preferred over a xanthine oxidase inhibitor in moderate-to-severe CKD.[1] ## Pegloticase and refractory severe gout Pegloticase is an IV uricase for **severe uncontrolled gout** after failure, intolerance, or contraindication of standard oral ULT. It is not first-line therapy.[1,7] Current U.S. labeling uses **8 mg IV every 2 weeks** and recommends coadministration with weekly methotrexate when appropriate because immunomodulation improves sustained response and reduces infusion-reaction risk.[7] Key safety actions include: - screen for G6PD deficiency in patients at increased risk before treatment; - premedicate for infusion reactions; - check serum urate before infusions; - stop according to label-defined loss of urate response because rising urate is associated with anti-drug antibodies and infusion reactions.[7] Specialist management is required. ## Flare prophylaxis when ULT starts ACR strongly recommends anti-inflammatory prophylaxis during ULT initiation for **at least 3–6 months**, with continuation if flares remain active.[1] Options include: - colchicine; - low-dose NSAID when safe; - selected low-dose glucocorticoid when alternatives are unsuitable.[1] Current U.S. colchicine labeling uses **0.6 mg once or twice daily**, maximum 1.2 mg/day, for prophylaxis, with renal/hepatic and interaction-specific adjustment.[3] ## Monitoring ### During ULT titration Track: - serum urate after dose changes; - renal function; - adherence; - flare frequency; - tophus burden and function; - drug-specific adverse effects; - liver tests when clinically indicated. ### When target is not reached 1. Verify adherence and actual dose taken. 2. Review urate-raising drugs and alcohol/fructose burden where relevant. 3. Titrate the xanthine oxidase inhibitor as tolerated. 4. Reassess kidney function and drug interactions. 5. Confirm that persistent joint symptoms are truly gout rather than infection, osteoarthritis, or another inflammatory disease. 6. Consider rheumatology referral for combination therapy, refractory tophi, or pegloticase. ## CKD CKD both increases gout risk and restricts flare-treatment options. - Allopurinol remains preferred first-line ULT in ACR guidance.[1] - Start low and titrate carefully to target.[1] - NSAIDs are often unsuitable. - Colchicine exposure increases as renal clearance falls and can become hazardous with interacting drugs.[3] - Systemic or intra-articular glucocorticoids are commonly used when infection has been excluded. Use [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) and [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) for renal comorbidity management. ## Cardiovascular disease and heart failure Do not use NSAIDs reflexively in heart failure or high GI/cardiovascular risk. Preserve cardiovascular therapies that have a strong primary indication rather than stopping them solely for modest effects on urate. When febuxostat is considered in established cardiovascular disease, discuss the differing CARES and FAST findings and follow the applicable regulator and guideline.[5,6] ## Pregnancy and lactation Gout is uncommon in pregnancy. Acute monoarthritis during pregnancy still requires careful assessment for infection and other crystal disease. Medication choice should use pregnancy-specific prescribing guidance. NSAIDs, colchicine, glucocorticoids, and ULT each require individualized assessment according to gestation, comorbidity, and local labeling. Rheumatology plus obstetric input is appropriate when gout is active or chronic ULT is required. ## Lifestyle and comorbidity care Dietary change can modestly lower urate but rarely replaces ULT when ULT is clearly indicated. Useful measures include: - gradual weight reduction when appropriate; - limiting heavy alcohol intake; - reducing sugar/fructose-sweetened beverages; - moderating excessive purine-rich meat and seafood intake; - maintaining hydration; - treating hypertension, diabetes, CKD, dyslipidemia, heart failure, and sleep apnea according to their own indications.[1,2] Avoid stigmatizing counseling. Genetics and renal urate handling are major determinants of gout biology. ## Complications | Complication | Recognition | Action | |---|---|---| | Tophaceous joint destruction | Deformity, erosions, impaired motion | Intensify sustained urate lowering; rheumatology review | | Tendon involvement | Nodular deposits, pain, functional compromise | Imaging and surgical review when threatened | | Urolithiasis | Renal colic, hematuria | Stone evaluation plus urate management | | Severe allopurinol hypersensitivity | Rash/systemic illness/organ injury | Stop permanently; urgent care | | Colchicine toxicity | Severe GI symptoms, weakness, cytopenia, neuromyopathy | Stop; assess interactions and organ function | | Pegloticase infusion reaction | Reaction during infusion or rising serum urate | Stop/manage per label and infusion protocol | ## Practical decision pathways ### Acute hot joint **Acute red swollen joint** → assess infection risk → aspirate if septic arthritis is plausible → send culture and crystal analysis → treat gout with colchicine, NSAID, or glucocorticoid according to comorbidity → continue established ULT unless a drug reaction requires stopping → plan long-term urate strategy after acute stabilization. ### Long-term gout control **Tophus / radiographic gout damage / frequent flares** → start low-dose allopurinol unless unsuitable → add flare prophylaxis → serial serum urate → titrate to <6 mg/dL → consider <5 mg/dL in severe disease under NICE framework → address adherence and drug interactions if target is not reached → specialist escalation for persistent severe disease.[1,2] ## Related library topics - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Rheumatoid Arthritis](rheumatoid-arthritis.md) - [Osteoarthritis](osteoarthritis.md) - [Septic Arthritis of a Native Joint](../orthopedics/septic-arthritis-native-joint.md) ## 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. https://pubmed.ncbi.nlm.nih.gov/32391934/ 2. National Institute for Health and Care Excellence. Gout: diagnosis and management (NG219). Published 2022; current recommendations accessed September 23, 2026. https://www.nice.org.uk/guidance/ng219 3. U.S. National Library of Medicine. Colchicine tablets — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/ 4. U.S. National Library of Medicine. Allopurinol tablets — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/ 5. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. *N Engl J Med.* 2018;378:1200-1210. DOI: 10.1056/NEJMoa1710895. PMID: 29527974. https://doi.org/10.1056/NEJMoa1710895 6. Mackenzie IS, Ford I, Nuki G, et al; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. *Lancet.* 2020;396(10264):1745-1757. DOI: 10.1016/S0140-6736(20)32234-0. PMID: 33181081. https://pubmed.ncbi.nlm.nih.gov/33181081/ 7. U.S. National Library of Medicine. Pegloticase injection — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/18:T58cc,## Summary Gout is an inflammatory crystal disease caused by deposition of **monosodium urate (MSU)** in joints and periarticular tissues. Hyperuricemia is necessary for crystal formation but is not itself diagnostic of gout. Serum urate may fall during an acute flare, so a value below the treatment target during active inflammation does not exclude the diagnosis.[1,2] For an undifferentiated hot swollen joint, the most definitive test is synovial-fluid identification of **needle-shaped, strongly negatively birefringent MSU crystals**. A crystal-positive aspirate does **not** exclude septic arthritis; send Gram stain and culture whenever infection is clinically plausible and treat suspected infection without waiting for crystal results.[1,2] Treat a flare promptly with **low-dose colchicine, an NSAID, or a glucocorticoid**, selected according to kidney function, GI and cardiovascular risk, anticoagulation, diabetes, drug interactions, infection risk, and number of joints involved.[1] Current U.S. colchicine labeling for an adult flare uses **1.2 mg orally at onset followed by 0.6 mg one hour later**; higher acute dosing adds toxicity without greater benefit.[3] Long-term control depends on sustained reduction of serum urate. The American College of Rheumatology (ACR) recommends a **treat-to-target** approach with serial serum urate and a target **<6 mg/dL (<360 micromol/L)** in patients receiving urate-lowering therapy (ULT).[1] NICE also targets <6 mg/dL and recommends considering **<5 mg/dL (<300 micromol/L)** in tophaceous or chronic gouty arthritis, or when frequent flares continue despite urate below 6 mg/dL.[2] **Allopurinol is preferred first-line ULT in ACR guidance, including in chronic kidney disease (CKD)**. Start low and titrate upward to target rather than fixing the maintenance dose according to kidney function alone.[1] ULT is strongly indicated for tophi, radiographic damage attributable to gout, or frequent flares. When ULT is started or escalated, ACR recommends anti-inflammatory prophylaxis for at least **3–6 months**, and longer if flares persist.[1] > **Caution:** A new rash, fever, mucosal lesions, eosinophilia, hepatitis, or kidney injury after allopurinol may represent a severe hypersensitivity reaction. Stop allopurinol immediately and arrange urgent assessment; do not rechallenge after a serious hypersensitivity syndrome.[4] ## Disease states Gout can be considered across four clinically useful states: 1. **Asymptomatic hyperuricemia** — elevated serum urate without prior gout flare or tophus. 2. **Gout flare** — acute crystal-triggered inflammation, commonly monoarticular but sometimes oligoarticular or polyarticular. 3. **Intercritical gout** — symptom-free interval between flares while tissue crystals may remain. 4. **Chronic/tophaceous gout** — persistent crystal burden with tophi, erosions, chronic synovitis, tendon disease, or recurrent flares. Routine pharmacologic treatment of asymptomatic hyperuricemia solely to prevent first-onset gout is not recommended by ACR or NICE for most patients.[1,2] ## Pathophysiology Uric acid is the final major purine metabolite in humans. Steady-state serum urate reflects production and renal plus intestinal excretion. Most gout is driven by impaired urate excretion rather than extreme overproduction. When extracellular urate remains supersaturated, MSU crystals nucleate preferentially in cooler peripheral tissues and previously damaged joints. Crystal exposure activates innate immune pathways, particularly the NLRP3 inflammasome and interleukin-1 signaling, followed by intense neutrophil recruitment. Tophi are organized crystal deposits with surrounding chronic inflammation. Untreated crystal burden can erode bone, damage cartilage, weaken tendons, compress nerves, ulcerate skin, and progressively impair joint function. Rapid changes in serum urate can destabilize deposits. Flares may therefore temporarily increase after effective ULT is started; this does not mean ULT is failing. ## Risk factors and secondary contributors Important contributors include: - CKD and reduced urate excretion; - obesity and metabolic syndrome; - hypertension and heart failure; - loop and thiazide diuretics; - high alcohol intake; - high intake of fructose-sweetened drinks; - high intake of purine-rich meat and some seafood; - dehydration or rapid volume change; - calcineurin inhibitors; - high cell-turnover states; - genetic variants affecting urate transport; - family history.[1,2] When clinically feasible, ACR conditionally recommends replacing hydrochlorothiazide with another antihypertensive and preferentially using losartan when an appropriate antihypertensive is needed because losartan has a modest uricosuric effect.[1] Do not stop low-dose aspirin that is indicated for cardiovascular prevention solely to reduce serum urate.[1] ## Clinical features ### Typical flare - abrupt severe pain, often reaching maximal intensity within 24 hours; - marked tenderness; - swelling, warmth, and erythema; - restricted movement; - first metatarsophalangeal joint, ankle, and knee are common sites.[1,2] A flare may resemble cellulitis, septic arthritis, or another inflammatory arthropathy. Fever can occur in gout and therefore does not reliably distinguish infection. ### Atypical patterns Polyarticular disease, upper-limb involvement, chronic synovitis, or less dramatic inflammation is more frequent in: - older adults; - people with CKD; - transplant recipients; - patients with longstanding untreated gout; - postmenopausal women. ### Tophi Common sites include: - ear helix; - fingers and toes; - olecranon and prepatellar bursae; - Achilles tendon; - periarticular soft tissue. Tophi are often firm and irregular. Ulceration or chalk-like drainage can occur in advanced disease and may be complicated by infection. ## Dangerous alternative: septic arthritis A red, hot joint can represent gout, infection, or both. Lower the threshold for aspiration and culture when there is: - systemic toxicity; - prosthetic joint; - immunosuppression; - recent bacteremia; - overlying skin infection; - recent joint procedure; - first unexplained acute monoarthritis; - persistent inflammation despite appropriate gout treatment. Synovial WBC count overlaps substantially between crystal arthritis and infection. Culture remains decisive when sepsis is a concern. ## Diagnosis ### Synovial fluid When diagnostic certainty matters, aspirate the affected joint or bursa and send: - cell count with differential; - Gram stain; - aerobic/anaerobic culture; - crystal analysis. **MSU crystals:** needle-shaped and strongly negatively birefringent under compensated polarized light microscopy. **Calcium pyrophosphate crystals:** usually rhomboid or rod-shaped and weakly positively birefringent. ### Serum urate Serum urate is central to long-term management but is an imperfect acute diagnostic test. NICE advises repeating urate at least **2 weeks after a flare settles** if the level is below 6 mg/dL during the flare but clinical suspicion remains high.[2] ### Imaging Imaging is most useful when aspiration is not feasible, the presentation is atypical, or chronic structural burden needs characterization. **Ultrasound** may show: - double-contour sign; - tophi; - aggregates; - effusion and synovitis. **Dual-energy CT (DECT)** can identify urate deposits at difficult-to-aspirate sites. Nail, skin, metal, and motion artifacts can produce false-positive findings. **Plain radiographs** in longstanding disease may show punched-out or juxta-articular erosions with sclerotic margins and relative preservation of joint space until later stages. ## Differential diagnosis | Alternative | Clues | Action | |---|---|---| | Septic arthritis | Toxicity, bacteremia risk, positive culture; may coexist with crystals | Aspirate and culture; treat infection when suspected | | Calcium pyrophosphate deposition | Older age, knee/wrist disease, chondrocalcinosis, positive birefringent crystals | Crystal confirmation when possible | | Cellulitis | Skin-centered inflammation without true effusion | Assess for portal of entry and soft-tissue infection | | Rheumatoid arthritis | Chronic symmetric inflammatory polyarthritis | Inflammatory-arthritis workup | | Psoriatic arthritis | Psoriasis, nail disease, dactylitis, enthesitis | Rheumatology assessment | | Hemarthrosis | Trauma or anticoagulation; bloody aspirate | Identify bleeding trigger and structural injury | See [Rheumatoid Arthritis](rheumatoid-arthritis.md) and [Osteoarthritis](osteoarthritis.md). ## Acute flare management Treat early and continue established ULT through the flare unless a drug-specific adverse reaction requires discontinuation.[1] ### Treatment selection | Therapy | Typical role | Adult dose / approach | Major cautions | Monitoring | |---|---|---|---|---| | Colchicine | Early flare; oral therapy | 1.2 mg once, then 0.6 mg 1 hour later per U.S. label[3] | Renal/hepatic impairment, P-gp/CYP3A4 interactions, myopathy | GI toxicity, weakness, cytopenia, drug interactions | | NSAID | Effective when renal/GI/CV risk is acceptable | Full anti-inflammatory dose according to selected agent/local label | CKD, ulcer/GI bleed, HF, anticoagulation, uncontrolled hypertension | Renal function, BP, GI toxicity, fluid status | | Oral glucocorticoid | When NSAID/colchicine unsuitable; polyarticular flare | Short course individualized to severity/comorbidity | Hyperglycemia, infection, psychiatric effects | Glucose, infection risk, symptom response | | Intra-articular glucocorticoid | One or few accessible joints | Local procedure after infection is reasonably excluded | Do not inject a potentially infected joint | Local response, infection | | IL-1 inhibitor | Selected refractory/contraindicated cases | Product/jurisdiction-specific | Infection risk, access, cost | Infection and product-specific safety | ### Colchicine safety Current U.S. labeling uses **1.2 mg at the first sign of flare followed by 0.6 mg one hour later**, maximum **1.8 mg over one hour** for the acute regimen.[3] Colchicine toxicity can cause: - severe diarrhea and vomiting; - cytopenias; - neuromyopathy; - rhabdomyolysis; - multiorgan failure. Strong CYP3A4 or P-glycoprotein inhibitors can markedly increase colchicine exposure, particularly in renal or hepatic impairment. Use current product labeling for interaction-specific contraindications and dose adjustment.[3] ### NSAIDs Choose an anti-inflammatory NSAID regimen according to local labeling and stop after the flare resolves. Avoid or use cautiously with: - significant CKD; - active peptic ulcer or GI bleeding; - decompensated heart failure; - substantial cardiovascular risk; - anticoagulation; - marked volume depletion. ### Glucocorticoids Oral glucocorticoids are often the simplest option when NSAIDs and colchicine are unsuitable. Intra-articular injection is useful for one or a few joints once infection is adequately excluded. Do not delay septic-joint treatment in order to give a steroid injection. ## When to start urate-lowering therapy ACR strongly recommends ULT for:[1] - one or more subcutaneous tophi; - radiographic damage attributable to gout; - frequent flares, generally **2 or more per year**. After a first flare, ACR generally recommends against routine ULT but conditionally supports initiation when any of the following is present:[1] - CKD stage 3 or worse; - serum urate >9 mg/dL; - urolithiasis. ULT may be started during an active flare if anti-inflammatory treatment is also provided and the patient is ready to begin long-term therapy.[1] ## Treat-to-target urate lowering Use serial serum urate measurements and titrate ULT to target rather than leaving patients indefinitely on a fixed low dose.[1,2] ### Targets - **ACR:** <6 mg/dL (<360 micromol/L).[1] - **NICE:** <6 mg/dL; consider <5 mg/dL (<300 micromol/L) for tophi, chronic gouty arthritis, or ongoing frequent flares despite urate below 6 mg/dL.[2] NICE recommends monthly urate checks while titrating ULT until target is achieved.[2] Local monitoring intervals can be individualized once stable. > **Clinical pearl:** Continued flares early after ULT initiation do not prove treatment failure. The key long-term measure is sustained urate below target with progressive reduction in flare and tophus burden. ## Allopurinol Allopurinol inhibits xanthine oxidase and is ACR’s preferred first-line ULT, including in CKD.[1] ### Initiation and titration - Start **≤100 mg/day** in most adults.[1] - Use a lower initial dose in CKD when appropriate.[1,4] - Titrate progressively to serum urate target while monitoring tolerance and renal function. - Do not impose an arbitrary low maintenance ceiling solely because CKD is present; many patients require higher doses to reach target.[1] ### HLA-B*58:01 and hypersensitivity HLA-B*58:01 markedly increases risk of severe allopurinol hypersensitivity. ACR conditionally recommends testing before starting allopurinol in people of Southeast Asian ancestry with higher allele prevalence and in African American patients, while recommending against universal testing in lower-prevalence groups.[1] Current U.S. labeling advises considering screening in populations with high prevalence of HLA-B*58:01 and emphasizes permanent discontinuation if a serious hypersensitivity reaction occurs.[4] Potential severe reaction features include: - rash or mucosal lesions; - fever; - eosinophilia; - hepatitis; - [acute kidney injury](/library/acute-kidney-injury); - systemic illness. ## Febuxostat Febuxostat is another xanthine oxidase inhibitor and is used when allopurinol is not tolerated, contraindicated, or insufficient under the relevant national pathway. Cardiovascular evidence is nuanced: - **CARES** studied patients with established cardiovascular disease and found similar major cardiovascular composite outcomes but higher cardiovascular and all-cause mortality with febuxostat.[5] - **FAST** found febuxostat noninferior to optimized allopurinol for its cardiovascular composite and did not show increased death with febuxostat in its studied population.[6] Because trial populations and design differ, regulatory and guideline positions vary. ACR conditionally recommends switching to an alternative ULT when a patient on febuxostat has established cardiovascular disease or develops a new cardiovascular event and another suitable option is available.[1] U.S. labeling retains a cardiovascular boxed warning. Document the jurisdictional framework and shared decision when febuxostat is used in high-risk cardiovascular disease. ## Uricosuric therapy Uricosuric drugs increase renal urate excretion. Their usefulness is limited by: - reduced kidney function; - nephrolithiasis risk; - drug interactions; - jurisdictional availability. Probenecid can be used in selected patients but is generally not preferred over a xanthine oxidase inhibitor in moderate-to-severe CKD.[1] ## Pegloticase and refractory severe gout Pegloticase is an IV uricase for **severe uncontrolled gout** after failure, intolerance, or contraindication of standard oral ULT. It is not first-line therapy.[1,7] Current U.S. labeling uses **8 mg IV every 2 weeks** and recommends coadministration with weekly methotrexate when appropriate because immunomodulation improves sustained response and reduces infusion-reaction risk.[7] Key safety actions include: - screen for G6PD deficiency in patients at increased risk before treatment; - premedicate for infusion reactions; - check serum urate before infusions; - stop according to label-defined loss of urate response because rising urate is associated with anti-drug antibodies and infusion reactions.[7] Specialist management is required. ## Flare prophylaxis when ULT starts ACR strongly recommends anti-inflammatory prophylaxis during ULT initiation for **at least 3–6 months**, with continuation if flares remain active.[1] Options include: - colchicine; - low-dose NSAID when safe; - selected low-dose glucocorticoid when alternatives are unsuitable.[1] Current U.S. colchicine labeling uses **0.6 mg once or twice daily**, maximum 1.2 mg/day, for prophylaxis, with renal/hepatic and interaction-specific adjustment.[3] ## Monitoring ### During ULT titration Track: - serum urate after dose changes; - renal function; - adherence; - flare frequency; - tophus burden and function; - drug-specific adverse effects; - liver tests when clinically indicated. ### When target is not reached 1. Verify adherence and actual dose taken. 2. Review urate-raising drugs and alcohol/fructose burden where relevant. 3. Titrate the xanthine oxidase inhibitor as tolerated. 4. Reassess kidney function and drug interactions. 5. Confirm that persistent joint symptoms are truly gout rather than infection, osteoarthritis, or another inflammatory disease. 6. Consider rheumatology referral for combination therapy, refractory tophi, or pegloticase. ## CKD CKD both increases gout risk and restricts flare-treatment options. - Allopurinol remains preferred first-line ULT in ACR guidance.[1] - Start low and titrate carefully to target.[1] - NSAIDs are often unsuitable. - Colchicine exposure increases as renal clearance falls and can become hazardous with interacting drugs.[3] - Systemic or intra-articular glucocorticoids are commonly used when infection has been excluded. Use [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) and [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) for renal comorbidity management. ## Cardiovascular disease and heart failure Do not use NSAIDs reflexively in heart failure or high GI/cardiovascular risk. Preserve cardiovascular therapies that have a strong primary indication rather than stopping them solely for modest effects on urate. When febuxostat is considered in established cardiovascular disease, discuss the differing CARES and FAST findings and follow the applicable regulator and guideline.[5,6] ## Pregnancy and lactation Gout is uncommon in pregnancy. Acute monoarthritis during pregnancy still requires careful assessment for infection and other crystal disease. Medication choice should use pregnancy-specific prescribing guidance. NSAIDs, colchicine, glucocorticoids, and ULT each require individualized assessment according to gestation, comorbidity, and local labeling. Rheumatology plus obstetric input is appropriate when gout is active or chronic ULT is required. ## Lifestyle and comorbidity care Dietary change can modestly lower urate but rarely replaces ULT when ULT is clearly indicated. Useful measures include: - gradual weight reduction when appropriate; - limiting heavy alcohol intake; - reducing sugar/fructose-sweetened beverages; - moderating excessive purine-rich meat and seafood intake; - maintaining hydration; - treating hypertension, diabetes, CKD, dyslipidemia, heart failure, and sleep apnea according to their own indications.[1,2] Avoid stigmatizing counseling. Genetics and renal urate handling are major determinants of gout biology. ## Complications | Complication | Recognition | Action | |---|---|---| | Tophaceous joint destruction | Deformity, erosions, impaired motion | Intensify sustained urate lowering; rheumatology review | | Tendon involvement | Nodular deposits, pain, functional compromise | Imaging and surgical review when threatened | | Urolithiasis | Renal colic, hematuria | Stone evaluation plus urate management | | Severe allopurinol hypersensitivity | Rash/systemic illness/organ injury | Stop permanently; urgent care | | Colchicine toxicity | Severe GI symptoms, weakness, cytopenia, neuromyopathy | Stop; assess interactions and organ function | | Pegloticase infusion reaction | Reaction during infusion or rising serum urate | Stop/manage per label and infusion protocol | ## Practical decision pathways ### Acute hot joint **Acute red swollen joint** → assess infection risk → aspirate if septic arthritis is plausible → send culture and crystal analysis → treat gout with colchicine, NSAID, or glucocorticoid according to comorbidity → continue established ULT unless a drug reaction requires stopping → plan long-term urate strategy after acute stabilization. ### Long-term gout control **Tophus / radiographic gout damage / frequent flares** → start low-dose allopurinol unless unsuitable → add flare prophylaxis → serial serum urate → titrate to <6 mg/dL → consider <5 mg/dL in severe disease under NICE framework → address adherence and drug interactions if target is not reached → specialist escalation for persistent severe disease.[1,2] ## Related library topics - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Acute Kidney Injury](../nephrology/acute-kidney-injury.md) - [Rheumatoid Arthritis](rheumatoid-arthritis.md) - [Osteoarthritis](osteoarthritis.md) - [Septic Arthritis of a Native Joint](../orthopedics/septic-arthritis-native-joint.md) ## 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. https://pubmed.ncbi.nlm.nih.gov/32391934/ 2. National Institute for Health and Care Excellence. Gout: diagnosis and management (NG219). Published 2022; current recommendations accessed September 23, 2026. https://www.nice.org.uk/guidance/ng219 3. U.S. National Library of Medicine. Colchicine tablets — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/ 4. U.S. National Library of Medicine. Allopurinol tablets — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/ 5. White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. *N Engl J Med.* 2018;378:1200-1210. DOI: 10.1056/NEJMoa1710895. PMID: 29527974. https://doi.org/10.1056/NEJMoa1710895 6. Mackenzie IS, Ford I, Nuki G, et al; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. *Lancet.* 2020;396(10264):1745-1757. DOI: 10.1016/S0140-6736(20)32234-0. PMID: 33181081. https://pubmed.ncbi.nlm.nih.gov/33181081/ 7. U.S. National Library of Medicine. Pegloticase injection — prescribing information. DailyMed; current label accessed September 23, 2026. https://dailymed.nlm.nih.gov/dailymed/7:["$","$L16",null,{"article":{"id":"medical-gout","title":"Gout","slug":"gout","description":"Gout is an inflammatory crystal disease caused by deposition of monosodium urate (MSU) in joints and periarticular tissues. Hyperuricemia is necessary for crystal formation but is not itself diagnostic of gout. Serum…","aliases":[],"category":"Rheumatology","tags":["Rheumatology"],"updatedAt":"$undefined","body":"$17","headings":[{"id":"summary","text":"Summary","level":2},{"id":"disease-states","text":"Disease states","level":2},{"id":"pathophysiology","text":"Pathophysiology","level":2},{"id":"risk-factors-and-secondary-contributors","text":"Risk factors and secondary contributors","level":2},{"id":"clinical-features","text":"Clinical features","level":2},{"id":"typical-flare","text":"Typical flare","level":3},{"id":"atypical-patterns","text":"Atypical patterns","level":3},{"id":"tophi","text":"Tophi","level":3},{"id":"dangerous-alternative-septic-arthritis","text":"Dangerous alternative: septic arthritis","level":2},{"id":"diagnosis","text":"Diagnosis","level":2},{"id":"synovial-fluid","text":"Synovial fluid","level":3},{"id":"serum-urate","text":"Serum urate","level":3},{"id":"imaging","text":"Imaging","level":3},{"id":"differential-diagnosis","text":"Differential diagnosis","level":2},{"id":"acute-flare-management","text":"Acute flare management","level":2},{"id":"treatment-selection","text":"Treatment selection","level":3},{"id":"colchicine-safety","text":"Colchicine safety","level":3},{"id":"nsaids","text":"NSAIDs","level":3},{"id":"glucocorticoids","text":"Glucocorticoids","level":3},{"id":"when-to-start-urate-lowering-therapy","text":"When to start urate-lowering therapy","level":2},{"id":"treat-to-target-urate-lowering","text":"Treat-to-target urate lowering","level":2},{"id":"targets","text":"Targets","level":3},{"id":"allopurinol","text":"Allopurinol","level":2},{"id":"initiation-and-titration","text":"Initiation and titration","level":3},{"id":"hla-b5801-and-hypersensitivity","text":"HLA-B*58:01 and hypersensitivity","level":3},{"id":"febuxostat","text":"Febuxostat","level":2},{"id":"uricosuric-therapy","text":"Uricosuric therapy","level":2},{"id":"pegloticase-and-refractory-severe-gout","text":"Pegloticase and refractory severe gout","level":2},{"id":"flare-prophylaxis-when-ult-starts","text":"Flare prophylaxis when ULT starts","level":2},{"id":"monitoring","text":"Monitoring","level":2},{"id":"during-ult-titration","text":"During ULT titration","level":3},{"id":"when-target-is-not-reached","text":"When target is not reached","level":3},{"id":"ckd","text":"CKD","level":2},{"id":"cardiovascular-disease-and-heart-failure","text":"Cardiovascular disease and heart failure","level":2},{"id":"pregnancy-and-lactation","text":"Pregnancy and lactation","level":2},{"id":"lifestyle-and-comorbidity-care","text":"Lifestyle and comorbidity care","level":2},{"id":"complications","text":"Complications","level":2},{"id":"practical-decision-pathways","text":"Practical decision pathways","level":2},{"id":"acute-hot-joint","text":"Acute hot joint","level":3},{"id":"long-term-gout-control","text":"Long-term gout control","level":3},{"id":"related-library-topics","text":"Related library topics","level":2},{"id":"references","text":"References","level":2}],"readingMinutes":14},"linkedMarkdown":"$18","backlinks":[],"related":[],"previewBySlug":{"abcde-approach":{"title":"ABCDE Approach","description":"The ABCDE approach is a structured method for the immediate assessment and treatment of a deteriorating or critically ill patient: Airway, Breathing, Circulation, Disability, Exposure. 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