Musculoskeletal

Gout: acute attack and chronic management

Clinical Overview and When to Suspect Gout

— Most common inflammatory arthritis in US adults; prevalence ~4% (men >> premenopausal women).

— Peak incidence men 40–60; women typically post-menopausal.

— Rising prevalence tied to obesity, metabolic syndrome, CKD, and diuretic use.

— Underexcretion (~90%): CKD, thiazides/loop diuretics, low-dose aspirin, cyclosporine, tacrolimus, ethanol (especially beer).

— Overproduction (~10%): high cell turnover (tumor lysis, hemolysis, psoriasis), HGPRT deficiency (Lesch-Nyhan), fructose-rich diets.

— Middle-aged man, acute monoarthritis of the first MTP (podagra) waking him at 2 a.m., exquisite tenderness, erythema mimicking cellulitis.

— Post-op patient day 2–4 with sudden monoarthritis (surgery and fluid shifts precipitate attacks).

— Patient newly started on a thiazide for HTN or low-dose ASA for ASCVD developing podagra.

— Transplant recipient on cyclosporine with tophaceous polyarthritis.

— Recurrent attacks in knee, midfoot, ankle, olecranon bursa; tophi on helix of ear, Achilles, or DIPs in older women on diuretics.

Board pearl: Any acute monoarthritis in an adult should prompt arthrocentesis to rule out septic arthritis before assuming gout — the two can coexist, and missing infection is a tested patient-safety error. Empirically treating "cellulitis" of the great toe with antibiotics is a classic distractor when the real diagnosis is podagra.

Definition: Gout is a crystal-induced arthropathy caused by deposition of monosodium urate (MSU) crystals in joints and soft tissues, driven by chronic hyperuricemia (serum urate >6.8 mg/dL, the physiologic saturation point).

Epidemiology:

Pathophysiology drivers:

When to suspect on Step 3:

Triggers of acute flare: trauma, dehydration, alcohol binge, purine-rich meal (red meat, organ meat, shellfish), starting/stopping urate-lowering therapy (ULT), surgery, sepsis.

Presentation Patterns and Key History

— Abrupt onset, often nocturnal, reaching peak severity within 12–24 hours.

— Patient describes "can't bear a bedsheet on the toe" — exquisite hyperalgesia.

— Self-resolves over 7–14 days untreated; treated attacks resolve in 3–5 days.

— Podagra (1st MTP) is the inaugural joint in ~50%; lifetime involvement ~90%.

— Develops after ~10 years of poorly controlled disease.

— Painless, firm, sometimes ulcerating nodules with chalky exudate on helix of ear, olecranon, Achilles tendon, finger pads.

— Can mimic RA (symmetric polyarthritis with nodules) — distinguished by tophi composition and joint distribution.

— Diet: red meat, organ meats, shellfish, beer and spirits, sugar-sweetened beverages (fructose).

— Meds: thiazides, loop diuretics, low-dose ASA, niacin, cyclosporine, tacrolimus, pyrazinamide, ethambutol.

— Comorbidities: HTN, CKD, obesity, T2DM, CHF, psoriasis, hematologic malignancy.

— Family history: first-degree relative with gout (strong heritability of urate transport).

— Prior attacks, timing, joints, treatments tried, response to NSAIDs/colchicine.

Key distinction: Pseudogout (CPPD) more often targets knees and wrists in older patients and may be triggered by hospitalization or surgery; gout favors the first MTP and lower extremity. Both can coexist — only synovial fluid analysis reliably separates them.

Classic acute attack:

Other typical sites: midfoot, ankle, knee, wrist, olecranon bursa, finger DIPs (especially in elderly women with Heberden nodes + diuretics).

Intercritical period: asymptomatic between attacks; crystals still present in synovium. Untreated, attacks become more frequent, polyarticular, and prolonged.

Chronic tophaceous gout:

Targeted history to elicit:

Female-specific clues: post-menopausal, often on HCTZ, polyarticular DIP involvement, frequently misdiagnosed as osteoarthritis or RA.

Physical Exam Findings and Systemic Assessment

— Marked erythema, warmth, swelling, exquisite tenderness; overlying skin may desquamate as attack resolves.

— Pseudocellulitic appearance — erythema can extend beyond joint margins, mimicking soft tissue infection.

— Patient guards joint; even passive ROM is intolerable.

— Low-grade fever (≤38.5°C) common; high fever should prompt septic workup.

— Monoarticular in 80–90% of first attacks, lower extremity predominant.

— Polyarticular flares seen in long-standing disease, transplant patients, or post-ULT initiation without prophylaxis.

— Inspect helix/antihelix of ear, olecranon bursa, Achilles tendon, extensor surfaces, finger pads, first MTP.

— Firm, nontender, sometimes with chalky white discharge if ulcerated.

— Tophi can erode bone — palpate for underlying deformity.

— Vitals/BMI: hypertension and obesity are nearly universal comorbidities.

— Cardiovascular: gout is an independent CV risk factor; screen for ASCVD risk, check lipids, calculate 10-year ASCVD risk.

— Renal: evaluate volume status, look for signs of CKD (peripheral edema, pallor).

— Skin: psoriasis (high cell turnover → hyperuricemia).

— Medication reconciliation at the bedside: identify diuretics, low-dose ASA, niacin.

— Fever >38.5°C, rigors, hemodynamic instability → suspect septic arthritis.

— Multiple joints with morning stiffness >1 hour, symmetric small joint involvement → consider RA.

— Tense effusion with prior trauma or anticoagulation → hemarthrosis.

Step 3 management: Document a focused cardiometabolic exam at every gout visit — BP, BMI, waist circumference, foot/skin check. Gout is a sentinel for metabolic syndrome and underdiagnosed CKD; bundle these assessments into the longitudinal care plan.

Acute inflamed joint:

Joint distribution clues:

Tophi exam:

Systemic/comorbidity assessment (Step 3 emphasis):

Red flags suggesting alternative or concurrent diagnosis:

Diagnostic Workup — Initial Labs, Imaging, and Arthrocentesis

— Synovial fluid analysis: cell count with differential, Gram stain, culture, crystal analysis under polarized light microscopy.

— MSU crystals: needle-shaped, negatively birefringent (yellow when parallel to compensator axis).

— CPPD crystals: rhomboid, positively birefringent (blue when parallel).

— Inflammatory fluid: WBC 2,000–50,000/µL, neutrophil predominant; >50,000 raises septic concern but gout flares can reach this range.

— CBC (leukocytosis common in flare), CMP (baseline creatinine for drug dosing), uric acid level.

— Serum urate during acute attack can be falsely normal or low (IL-6–mediated uricosuria); recheck 2 weeks after flare resolution.

— Lipid panel, HbA1c, urinalysis — comorbidity screen.

— Consider blood cultures if febrile or septic features.

— Plain radiographs: early attacks usually normal; chronic disease shows "punched-out" erosions with overhanging edges, preserved joint space until late, tophi as soft tissue densities.

— Ultrasound: "double contour sign" (hyperechoic urate deposition on cartilage surface), tophi, erosions — increasingly used point-of-care.

— Dual-energy CT (DECT): color-codes urate deposits; useful when arthrocentesis is not possible or diagnosis uncertain.

CCS pearl: On a CCS case with acute monoarthritis, order "arthrocentesis with synovial fluid analysis — cell count, Gram stain, culture, crystals" before initiating definitive therapy. Empiric NSAIDs without ruling out septic arthritis is a classic patient-safety pitfall the simulation will flag.

Arthrocentesis is the gold standard for any acute monoarthritis when feasible — particularly the first attack or atypical presentation.

Basic labs:

Imaging:

2015 ACR/EULAR classification criteria can support diagnosis when aspiration not feasible: clinical pattern, serum urate, imaging (US double contour or DECT urate), and tophi.

Diagnostic Workup — Confirmatory and Longitudinal Studies

— Recheck serum urate 2–4 weeks after flare — acute inflammation lowers urate.

— Goal documentation: baseline and trended values; target <6 mg/dL (or <5 mg/dL with tophi) on ULT.

— Historically used to distinguish over-producers (>800 mg/24h on regular diet) from under-excretors.

— Now rarely needed clinically — does not change first-line drug choice (allopurinol is first-line regardless).

— Consider in young patients (<25) with severe disease, suspected HGPRT deficiency, or to assess uric acid nephrolithiasis risk (>1100 mg/24h → high stone risk, favor allopurinol over uricosurics).

— eGFR and urinalysis at baseline and annually — urate nephropathy, urate stones (radiolucent on plain film, visible on CT).

— Renal ultrasound if recurrent stones or hematuria.

— Strongly recommended before starting allopurinol in Han Chinese, Korean (CKD stage ≥3), Thai, and African American patients due to risk of allopurinol hypersensitivity syndrome (SJS/TEN).

— Positive result → avoid allopurinol; use febuxostat or pegloticase.

— Musculoskeletal ultrasound at baseline and to monitor tophus regression.

— DECT for tophus burden quantification and to differentiate from RA nodules or infection.

— Fasting lipids, HbA1c, BP, BMI, eGFR, hepatic panel.

— Screen for OSA in obese patients (independent hyperuricemia risk).

— Cardiovascular risk stratification (ASCVD score).

Board pearl: Pre-screen HLA-B*5801 in high-risk ethnic groups before allopurinol initiation. A test stem of a Han Chinese man started on allopurinol who develops a desquamating rash + mucositis is testing allopurinol hypersensitivity / SJS-TEN — discontinue immediately, admit, and never rechallenge.

Confirming hyperuricemia:

24-hour urinary uric acid (selective use):

Renal evaluation:

HLA-B*5801 testing:

Imaging in chronic/atypical disease:

Comorbidity workup at diagnosis:

Risk Stratification and Management Decision Framework

1. Abort the acute flare (anti-inflammatory).

2. Lower serum urate long-term to prevent recurrence and dissolve crystals (urate-lowering therapy, ULT).

— Mild–moderate: 1–few small joints, pain ≤6/10 → monotherapy (NSAID, colchicine, or glucocorticoid).

— Severe / polyarticular / large joint: combination therapy (e.g., colchicine + NSAID, or colchicine + steroid).

— Initiate within 24 hours of symptom onset for best response.

— ≥2 flares per year.

— Any tophus (clinical or imaging).

— Radiographic damage from gout.

— CKD stage ≥3, urolithiasis, or serum urate >9 mg/dL — conditional recommendation to start ULT.

— Single flare with comorbidities (CKD, stones) — shared decision-making.

— Can be initiated during an acute flare (with concurrent anti-inflammatory coverage) — this is a 2020 ACR change from older "wait until flare resolves" teaching. Improves adherence.

— Always pair with flare prophylaxis for 3–6 months (low-dose colchicine 0.6 mg daily/BID, or low-dose NSAID, or low-dose prednisone).

— Titrate ULT to serum urate <6 mg/dL (or <5 mg/dL if tophi/erosive disease) — not symptom-guided.

— Recheck urate every 2–5 weeks during titration, then every 6 months once at goal.

Step 3 management: A patient with 2 flares/year + CKD stage 3 should be started on allopurinol with colchicine prophylaxis at the index visit — don't defer ULT to "after the flare." Pair with lifestyle counseling and review of offending meds (consider switching HCTZ to losartan, which is mildly uricosuric).

Two parallel treatment goals:

Acute flare severity stratification (ACR 2020):

Indications for chronic ULT (ACR 2020 strong recommendations):

When to start ULT:

Treat-to-target principle:

Pharmacotherapy — Acute Flare and Urate-Lowering Therapy

— NSAIDs: naproxen 500 mg BID, indomethacin 50 mg TID, or ibuprofen 800 mg TID until 24h after resolution. Avoid in CKD, CHF, PUD, anticoagulation.

— Colchicine: 1.2 mg PO at onset, then 0.6 mg one hour later, then 0.6 mg BID until resolution. Most effective if started within 24 hours. Reduce dose in CKD; avoid with strong CYP3A4/P-gp inhibitors (clarithromycin, diltiazem, cyclosporine).

— Glucocorticoids: prednisone 30–40 mg daily × 5 days, or intra-articular triamcinolone for monoarticular flare. Preferred in CKD, anticoagulated patients, CHF.

— IL-1 inhibitors (anakinra, canakinumab): refractory cases or contraindications to all above.

— Allopurinol (first-line): xanthine oxidase inhibitor.

– Start ≤100 mg/day (50 mg/day if eGFR <60) to reduce flare and hypersensitivity risk.

– Titrate by 100 mg every 2–5 weeks to target urate <6 mg/dL; max 800 mg/day.

– Higher doses safe in CKD if titrated carefully — CKD is not a contraindication.

— Febuxostat: alternative XO inhibitor; consider with allopurinol intolerance or HLA-B*5801+.

– Black box: increased CV mortality vs allopurinol (CARES trial) — avoid in established CVD.

— Probenecid (uricosuric): alternative if eGFR >30 and no nephrolithiasis history; less commonly used.

— Pegloticase (IV recombinant uricase): refractory tophaceous gout; check G6PD before use (hemolysis risk).

— Low-dose colchicine 0.6 mg daily–BID (or NSAID, or low-dose prednisone) for 3–6 months, longer if tophi present.

Board pearl: Never start or stop ULT in isolation during an acute flare without anti-inflammatory cover — fluctuating urate destabilizes crystals and prolongs the attack. Continue established ULT through a flare; if newly starting, layer colchicine prophylaxis on day one.

Acute flare — three first-line options (choose based on comorbidities):

Urate-lowering therapy (ULT):

Anti-inflammatory prophylaxis with ULT initiation:

Expanded Pharmacology — Drug Interactions, Adjuncts, and Refractory Disease

— Major interaction with azathioprine and 6-mercaptopurine — xanthine oxidase inhibition raises 6-MP levels → marrow toxicity. Reduce thiopurine dose by 75% or avoid combination.

— Potentiates warfarin; monitor INR.

— Rash → stop immediately; allopurinol hypersensitivity syndrome (DRESS, SJS/TEN) carries 25% mortality.

— Renal dosing is for starting dose; titrate to effect, not eGFR.

— No HLA screening needed; hepatotoxicity — monitor LFTs.

— Same azathioprine/6-MP interaction.

— Avoid in ASCVD/CHF per FDA boxed warning.

— Ineffective if eGFR <30; contraindicated with nephrolithiasis or overproducer phenotype.

— Hydrate aggressively and alkalinize urine to prevent stones.

— Increases levels of penicillins, methotrexate, NSAIDs.

— 8 mg IV every 2 weeks; profound urate reduction.

— Check G6PD first — hemolytic anemia risk.

— Pre-medicate with antihistamine + steroid; infusion reactions common; loss of efficacy with anti-drug antibodies — stop if urate rises >6 between infusions.

— Often co-administered with methotrexate to reduce immunogenicity (emerging evidence).

— Losartan (mildly uricosuric) preferred over other ARBs in gout + HTN.

— Amlodipine vs thiazides for HTN.

— Fenofibrate lowers urate; useful in dyslipidemia.

— SGLT2 inhibitors lower urate ~0.5–1 mg/dL — favorable in T2DM/CKD/gout overlap.

— Thiazides, loop diuretics (if alternatives exist), low-dose aspirin (continue for ASCVD indication — benefit outweighs urate effect), niacin, cyclosporine.

Key distinction: Allopurinol is first-line regardless of over- vs under-excretor status. Febuxostat is second-line and contraindicated in established ASCVD. Pegloticase is reserved for refractory tophaceous disease and requires G6PD screening plus infusion-reaction precautions.

Allopurinol pearls:

Febuxostat:

Probenecid:

Pegloticase:

Adjunctive agents with uricosuric effect (consider in HTN/dyslipidemia):

Medications to avoid or reduce:

Special Populations — Elderly, CKD, and Hepatic Impairment

— Polyarticular presentations more common, often misdiagnosed as RA or OA flare.

— NSAIDs frequently contraindicated (CKD, CHF, anticoagulation, PUD risk) — prefer low-dose colchicine or glucocorticoids for flares.

— Polypharmacy: review for diuretics, low-dose ASA, and CYP3A4/P-gp interactions with colchicine.

— Start allopurinol at 50 mg/day with slow titration to minimize hypersensitivity and flare risk.

— Gout prevalence rises sharply with eGFR <60; CKD is the strongest comorbidity driver.

— Allopurinol IS appropriate in CKD — start low (50 mg/day if eGFR <60), titrate to urate <6. The old "ceiling dose by eGFR" approach is outdated and undertreats.

— Avoid NSAIDs if eGFR <60.

— Colchicine: dose-reduce; avoid if eGFR <30 or on dialysis except brief courses; never combine with strong CYP3A4/P-gp inhibitors in CKD (rhabdomyolysis, marrow toxicity).

— Glucocorticoids are usually safest acute flare option in advanced CKD.

— Probenecid ineffective if eGFR <30.

— Pegloticase acceptable; dialysis does not remove it significantly.

— Febuxostat — monitor LFTs; avoid in severe hepatic disease.

— Colchicine — reduce dose; avoid with concurrent CYP3A4 inhibitors.

— Acetaminophen preferred analgesic adjunct.

— Cyclosporine/tacrolimus drive hyperuricemia and tophaceous disease.

— Colchicine + cyclosporine = high toxicity risk (rhabdo, neuropathy, marrow suppression) — avoid combination or use very cautiously.

— Allopurinol + azathioprine → switch azathioprine to mycophenolate, or use febuxostat with same precaution.

Step 3 management: In a CKD-3 elderly patient with podagra on warfarin, the safest acute therapy is intra-articular triamcinolone (or oral prednisone 30 mg × 5 days). Avoid NSAIDs (renal/bleeding) and full-dose colchicine. Start allopurinol 50 mg with colchicine 0.3 mg daily prophylaxis once flare settles.

Elderly patients:

CKD (very high yield):

Hepatic impairment:

Transplant recipients:

Special Populations — Women, Pregnancy, and Pediatric Considerations

— Estrogen is uricosuric — gout is rare premenopausally; new gout in a young woman should prompt search for secondary cause (CKD, diuretics, genetic disorder, lead exposure — "saturnine gout").

— Post-menopausal women: often on HCTZ for HTN, present with polyarticular DIP/PIP disease mimicking erosive OA or RA.

— Heberden nodes can harbor tophi — ultrasound or DECT clarifies.

— Gout itself is rare in pregnancy.

— Avoid:

– Allopurinol and febuxostat (limited data, generally avoided).

– NSAIDs after 20 weeks (oligohydramnios/fetal renal dysfunction per FDA) and in third trimester (premature ductal closure).

– Colchicine — historically avoided but considered acceptable for FMF in pregnancy; for gout, use only if benefit clearly outweighs risk.

— Preferred acute therapy: low-dose prednisone or intra-articular steroid.

— Defer ULT initiation until postpartum.

— Lactation: prednisone compatible; colchicine generally acceptable; allopurinol excreted in milk — case-by-case.

— Very rare — investigate for inborn errors:

– Lesch-Nyhan syndrome (HGPRT deficiency): X-linked, severe hyperuricemia, self-mutilation, choreoathetosis, intellectual disability.

– PRPP synthetase overactivity.

– Glycogen storage disease type I (von Gierke): hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia.

— Secondary causes: tumor lysis syndrome, hematologic malignancy, sickle cell, CKD.

— Treatment: hydration, allopurinol (with HLA-B*5801 considerations), pediatric rheumatology referral.

Board pearl: A boy with self-mutilation, intellectual disability, and hyperuricemia = Lesch-Nyhan (HGPRT deficiency). A young woman with new gout on HCTZ + lead exposure history (renovated old home, ceramics) = saturnine gout — check blood lead level.

Women:

Pregnancy:

Pediatric/adolescent gout:

Adolescent athletes: dehydration and high-protein/creatine supplementation can unmask hyperuricemia.

Complications and Adverse Outcomes

— Develops after years of uncontrolled hyperuricemia.

— Tophi cause joint destruction, deformity, functional disability, and chronic pain.

— Skin ulceration over tophi → secondary infection, osteomyelitis.

— Tophi can compress nerves (carpal tunnel) or erode into joints/tendons (tendon rupture).

— Uric acid nephrolithiasis — radiolucent stones, low urine pH; treated with hydration, urinary alkalinization (potassium citrate to pH 6.5), and allopurinol.

— Chronic urate nephropathy — interstitial deposition; uncommon as isolated entity but contributes to CKD progression.

— Acute uric acid nephropathy — tumor lysis syndrome; prevent with allopurinol or rasburicase (check G6PD).

— Gout is an independent risk factor for MI, stroke, and CV mortality.

— Hyperuricemia correlates with HTN, metabolic syndrome, and CKD progression.

— Febuxostat carries excess CV mortality vs allopurinol in patients with established ASCVD.

— Allopurinol hypersensitivity syndrome (AHS/DRESS/SJS-TEN): fever, rash, eosinophilia, hepatitis, nephritis — 25% mortality; higher risk with HLA-B*5801, CKD, thiazides.

— Colchicine toxicity: GI distress, neuromyopathy, marrow suppression, rhabdomyolysis — especially with CYP3A4/P-gp inhibitors or CKD.

— NSAID complications: AKI, GI bleed, HTN, CHF exacerbation.

— Steroid complications: hyperglycemia, infection, BP elevation; intra-articular steroids can rarely seed infection if septic joint missed.

Key distinction: Acute uric acid nephropathy (tumor lysis, very high serum urate, oliguria, low urine pH) is treated with rasburicase + IV fluids, while chronic urate nephropathy is managed with long-term ULT and BP/CKD optimization. Knowing which to deploy in an oncology stem is high-yield.

Chronic tophaceous gout:

Renal complications:

Cardiovascular:

Drug-related adverse events:

Iatrogenic flare: initiating or rapidly titrating ULT without prophylaxis precipitates flares — major adherence killer; mitigated with colchicine prophylaxis ×3–6 months.

Escalation of Care — When to Admit, Consult, or Refer

— Cannot exclude septic arthritis pending culture data — admit for IV antibiotics until cultures finalize.

— Polyarticular flare with systemic toxicity, fever, or inability to ambulate/self-care.

— Severe AKI in setting of NSAIDs or tumor-lysis-related uric acid nephropathy.

— Allopurinol hypersensitivity syndrome / DRESS / SJS-TEN — admit to burn unit or ICU depending on TBSA and organ involvement; immediate drug discontinuation, supportive care, dermatology consult.

— Pegloticase infusion reaction or hemolysis (G6PD-deficient).

— Tophus ulceration with cellulitis or osteomyelitis.

— Septic arthritis with bacteremia/hemodynamic instability.

— Severe SJS/TEN with airway, hemodynamic, or fluid compromise.

— Tumor lysis syndrome with metabolic derangement.

— Rheumatology: refractory disease (failure of allopurinol titration to target), tophaceous disease, diagnostic uncertainty, suspected overlap with RA or CPPD, candidacy for pegloticase.

— Nephrology: CKD stage ≥3 with difficult ULT titration, uric acid stones, suspected urate nephropathy, dialysis planning.

— Orthopedics: suspected septic arthritis (joint washout), tophus debridement, tendon rupture, joint replacement for end-stage destructive disease.

— Dermatology: any allopurinol-associated rash or DRESS features.

— Genetics/pediatric rheumatology: early-onset gout, suspected HGPRT or PRPS1 disorders.

— Most gout is managed in primary care; refer when ≥2 ULT agents fail to reach target, tophi persist after 6 months of target urate, or recurrent flares despite prophylaxis.

CCS pearl: On a CCS case, arthrocentesis first, then empiric IV vancomycin + ceftriaxone if septic arthritis cannot be excluded — do not wait on synovial fluid analysis to start antibiotics in a toxic-appearing patient. Discontinue antibiotics once cultures and crystals confirm gout alone.

Admit (inpatient) when:

ICU criteria:

Specialty consultations:

Outpatient referral cadence:

Key Differentials — Same-Category (Crystal/Inflammatory Arthritis)

— Older patients, knees and wrists, often triggered by surgery, trauma, or acute illness.

— Synovial fluid: rhomboid, positively birefringent crystals.

— Imaging: chondrocalcinosis on plain films (linear calcium in cartilage).

— Associated with hemochromatosis, hyperparathyroidism, hypomagnesemia, hypophosphatasia, hypothyroidism — screen if early-onset or atypical.

— Treatment of acute attack mirrors gout (NSAIDs, colchicine, steroids); no urate-lowering equivalent.

— Must always be excluded in acute monoarthritis.

— Risk factors: prosthetic joint, IVDU, immunosuppression, recent intra-articular injection, bacteremia source.

— Synovial WBC often >50,000 with >90% PMNs, positive Gram stain/culture; gout can overlap in WBC count.

— Gonococcal arthritis in young sexually active adults — tenosynovitis, pustular rash, migratory polyarthralgia.

— Post-GU (Chlamydia) or post-GI (Shigella, Salmonella, Campylobacter, Yersinia) infection.

— Asymmetric oligoarthritis, enthesitis, conjunctivitis, urethritis, keratoderma blennorrhagicum.

— HLA-B27 associated.

— Symmetric small joint polyarthritis, MCP/PIP, morning stiffness >1 hour, positive RF/anti-CCP.

— Can be confused with chronic tophaceous gout in older women with diuretic-induced disease.

— DIP involvement, dactylitis, nail pitting, psoriasis plaques.

— Hyperuricemia common due to high skin turnover → may coexist with gout.

— Shoulder/knee destructive arthropathy in elderly women; non-birefringent crystals on alizarin red staining.

Key distinction: Polarized light microscopy is the decisive test: needle-shaped, negatively birefringent (yellow when parallel) = MSU/gout; rhomboid, positively birefringent (blue when parallel) = CPPD/pseudogout. Memorize the mnemonic and the colors will be exam-ready.

Pseudogout (CPPD deposition disease):

Septic arthritis:

Reactive arthritis:

Rheumatoid arthritis:

Psoriatic arthritis:

Hydroxyapatite (Milwaukee shoulder):

Key Differentials — Other-Category Mimics

— Overlying erythema in gout (especially podagra) closely mimics cellulitis.

— Cellulitis typically lacks the deep joint-line tenderness and the sharply-defined precipitating event of crystal arthritis.

— Failure to resolve on antibiotics, or recurrent "cellulitis" of the great toe, should prompt joint aspiration.

— Stress fracture of metatarsal can mimic podagra in runners; imaging clarifies.

— Bunion/hallux rigidus (osteoarthritis of 1st MTP) — chronic deformity, less inflammation.

— DIP/PIP involvement (Heberden, Bouchard nodes) — can be confused with tophaceous gout in older women; absence of crystals on aspiration distinguishes.

— Olecranon bursitis can be gouty, septic, or traumatic — aspirate to differentiate.

— Achilles tendinopathy can harbor tophus.

— Diabetic neuropathy → painless joint destruction; differs from painful gouty flare but coexisting diabetes makes overlap testable.

— Bilateral ankle arthritis, erythema nodosum, hilar adenopathy — mimics polyarticular gout; chest imaging clarifies.

— Anticoagulated patient with sudden joint swelling after minor trauma — aspirate shows blood without crystals.

— Persistent monoarticular pain unresponsive to therapy with constitutional symptoms — image and biopsy.

Board pearl: A diabetic patient on warfarin presenting with a hot, swollen knee after a fall could have hemarthrosis, septic arthritis, gout, or pseudogout simultaneously — only arthrocentesis with fluid analysis, Gram stain/culture, and crystal exam can sort them. Don't anchor on the most likely diagnosis without the tap.

Cellulitis:

Trauma / fracture:

Osteoarthritis flare:

Bursitis/tenosynovitis:

Charcot arthropathy:

Sarcoidosis (Löfgren syndrome):

Calciphylaxis / vascular ulcers in CKD patients can be mistaken for ulcerated tophi — biopsy clarifies.

Hemarthrosis:

Bone/joint malignancy:

Secondary Prevention, Discharge Plan, and Long-Term ULT

— Complete anti-inflammatory course (NSAID/colchicine/steroid) until 24h after symptom resolution.

— Initiate or continue ULT — do not stop allopurinol during a flare.

— Prescribe flare prophylaxis (low-dose colchicine 0.6 mg daily or BID, or low-dose NSAID, or prednisone 5 mg daily) for 3–6 months if recently started ULT; longer if tophi.

— Educate on signs of allopurinol hypersensitivity (rash, fever, mucositis) → stop and call.

— Allopurinol uptitrated every 2–5 weeks by 100 mg until serum urate <6 mg/dL (or <5 with tophi).

— Once at target, recheck urate every 6 months.

— Continue ULT indefinitely in most patients — discontinuation leads to recurrence.

— Limit: red meat, organ meats, shellfish, beer and spirits, high-fructose corn syrup beverages.

— Encourage: low-fat dairy (uricosuric effect), cherries (modest urate reduction), coffee, vitamin C (modest effect), weight loss, hydration.

— DASH-style or Mediterranean diet improves both gout and CV risk.

— Switch HCTZ → losartan for HTN when feasible.

— Continue low-dose ASA for ASCVD indication (CV benefit > urate effect).

— Consider SGLT2 inhibitor in T2DM/CKD (urate-lowering and CV/renal protective).

— Fenofibrate for combined dyslipidemia/hyperuricemia.

— Optimize BP (<130/80), LDL per ASCVD risk, HbA1c, weight, OSA screening.

— Annual eGFR and urinalysis; cardiovascular risk reassessment.

Step 3 management: Frame gout as a chronic disease requiring lifelong ULT with treat-to-target (urate <6), bundled with CV/CKD/metabolic risk reduction. Lifestyle alone almost never reaches target; setting realistic expectations at discharge prevents the "I'll diet instead" non-adherence trap.

Discharge after acute flare:

Treat-to-target ULT plan:

Lifestyle modification (adjunct, not substitute for ULT):

Medication reconciliation:

Comorbidity bundle:

Follow-Up, Monitoring, and Patient Counseling

— 2–4 weeks after starting/uptitrating ULT — recheck serum urate, eGFR, LFTs (febuxostat), CBC (colchicine).

— Continue every 2–5 weeks during titration until target reached.

— Once at target urate <6, recheck every 6 months; annual comorbidity reassessment.

— Flare diary — frequency, joints, triggers, response.

— Serum urate — primary target.

— eGFR, CBC, LFTs — drug safety.

— BP, lipids, HbA1c, BMI — cardiometabolic comorbidities.

— Annual foot exam (tophi, ulceration, joint deformity).

— Repeat ultrasound or DECT in tophaceous disease at 12–24 months to document regression.

— Education that ULT prevents future flares but may precipitate flares early — explain prophylaxis rationale to prevent self-discontinuation.

— Single daily dosing improves adherence.

— Pharmacist-led titration protocols and shared decision-making increase target attainment.

— Hydration: 2 L/day if no CHF/CKD contraindication.

— Alcohol: beer worst (purines + ethanol), spirits next, wine least; eliminate during flares.

— Diet: reduce red meat/organ meat/shellfish; emphasize low-fat dairy, coffee, cherries; avoid sugary drinks.

— Weight loss: gradual — rapid weight loss/ketogenic diets can precipitate flares.

— Exercise: low-impact during flares; resumption when joint cool and pain-free.

— Sick-day rules: continue ULT during illness; flare prophylaxis if scheduled surgery/contrast.

Board pearl: A patient who reaches urate <6 but stops allopurinol "because I feel better" predictably relapses within 12 months — re-engage with motivational interviewing and reinforce that crystals persist in tissues for years even after symptoms resolve; ongoing ULT dissolves the reservoir.

Visit cadence:

Monitoring parameters:

Adherence support:

Counseling content:

Vaccinations and preventive care: standard adult schedule; influenza, pneumococcal, shingles given comorbidity profile.

Ethical, Legal, and Patient Safety Considerations

— Document HLA-B*5801 screening discussion in Han Chinese, Korean (CKD ≥3), Thai, and African American patients before initiation.

— Explain SJS-TEN risk in plain language; provide written rash precautions; document teach-back.

— Mandatory pre-treatment G6PD assay — administering without screening to a G6PD-deficient patient can precipitate fatal hemolysis and methemoglobinemia. Documented as a patient-safety never-event in rheumatology practice.

— Hospital discharge is the highest-risk window for gout mismanagement:

– Stopping home allopurinol during admission triggers rebound flares — reconcile and continue ULT unless contraindicated.

– Newly started thiazides/loop diuretics on discharge frequently precipitate flares — flag at med rec.

– Communicate ULT titration plan to PCP in discharge summary with specific urate target and recheck date.

— Closed-loop communication with the primary care team for ULT titration responsibility — common gap that leaves patients on suboptimal doses for years.

— Empirically treating presumed cellulitis without aspiration risks missed septic arthritis or untreated gout — joint aspiration is the safer default in monoarthritis.

— Acute gout pain is severe but time-limited; avoid opioid prescriptions when NSAIDs/colchicine/steroids are available — supports CDC chronic pain and opioid prescribing guidelines.

— Gout disproportionately affects lower-income patients with poor specialty access; ensure affordable formulary choices (allopurinol is generic and inexpensive).

— Address food access in dietary counseling.

— Crystal-confirmed diagnosis when possible improves coding and future care continuity.

Step 3 management: Before discharging a newly diagnosed gout patient on allopurinol, ensure (1) HLA-B*5801 considered in high-risk groups, (2) prophylactic colchicine prescribed, (3) urate recheck scheduled at 2–4 weeks, (4) PCP notified with target urate, and (5) written rash-warning instructions given. This is the bundle that prevents the tested complications.

Informed consent for allopurinol in high-risk populations:

Pegloticase G6PD screening:

Transition-of-care risks:

Avoiding diagnostic anchoring:

Opioid stewardship:

Health-systems and equity:

Documentation:

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: If a stem mentions a renal transplant patient on cyclosporine with tophaceous gout, the answer set will test drug interactions — avoid colchicine + cyclosporine, swap azathioprine for mycophenolate before allopurinol, and consider febuxostat or pegloticase if standard ULT fails.

Podagra = 1st MTP joint inflammation; 50% of first attacks, 90% lifetime.

MSU crystals: needle-shaped, negatively birefringent, yellow parallel to compensator.

CPPD crystals: rhomboid, positively birefringent, blue parallel.

Serum urate during acute flare is often normal or low — recheck after resolution.

First-line ULT: allopurinol, start ≤100 mg/day (50 mg if eGFR <60), titrate to urate <6 (<5 with tophi).

HLA-B*5801 screen: Han Chinese, Korean (CKD ≥3), Thai, African American.

Allopurinol + azathioprine/6-MP = marrow toxicity (reduce thiopurine 75% or avoid).

Febuxostat carries CV mortality warning — avoid in established ASCVD.

Pegloticase — refractory tophaceous gout; check G6PD first.

Probenecid ineffective if eGFR <30; avoid in stone-formers.

Losartan = mildly uricosuric ARB — preferred in gout + HTN.

HCTZ, loop diuretics, low-dose ASA, niacin, cyclosporine, pyrazinamide, ethambutol raise urate.

Diet triggers: red/organ meat, shellfish, beer, spirits, high-fructose corn syrup.

Protective: low-fat dairy, coffee, cherries, vitamin C.

Lesch-Nyhan: HGPRT deficiency, X-linked, self-mutilation + hyperuricemia.

Saturnine gout: chronic lead exposure (moonshine, old plumbing, ceramics).

Tumor lysis nephropathy: allopurinol or rasburicase (check G6PD).

Chondrocalcinosis + arthritis → think CPPD + look for hemochromatosis, hyperparathyroidism, hypomagnesemia, hypothyroidism.

Initiate ULT during flare is acceptable (ACR 2020), with anti-inflammatory cover.

Flare prophylaxis with ULT: colchicine 0.6 mg daily/BID × 3–6 months (longer if tophi).

Target urate: <6 mg/dL, or <5 mg/dL with tophi/erosions.

Tophus locations: ear helix, olecranon, Achilles, finger pads, 1st MTP.

Double contour sign on US = pathognomonic urate deposition.

DECT color-codes urate — confirms diagnosis when aspiration impossible.

Board Question Stem Patterns

Step 3 management: When a stem mentions multiple comorbidities (CKD, CHF, anticoagulation), the right acute flare answer is almost always glucocorticoid (oral or intra-articular), not NSAID or full-dose colchicine. Match drug choice to the contraindication profile, not pattern-matching to "first-line NSAID."

Classic podagra stem: 55-year-old man wakes at 2 a.m. with severe right great toe pain after a steak-and-beer dinner; exam shows erythematous, exquisitely tender 1st MTP. Best next step? → Arthrocentesis with crystal analysis (not empiric antibiotics, not MRI).

Diuretic-induced gout: Hypertensive woman started on HCTZ 3 months ago presents with podagra. Best long-term management? → Switch HCTZ to losartan + treat flare + initiate ULT if recurrence criteria met.

Tumor lysis prevention: Patient with high-grade lymphoma starting chemo. Prophylaxis? → IV hydration + allopurinol (or rasburicase if high tumor burden — check G6PD first).

Allopurinol hypersensitivity: Han Chinese man with CKD-3 started on allopurinol develops fever, diffuse rash, mucositis, eosinophilia. Diagnosis/management? → AHS/SJS-TEN — stop allopurinol, admit, supportive care, dermatology consult, never rechallenge; HLA-B*5801 likely positive.

Allopurinol-azathioprine interaction: IBD patient on azathioprine started on allopurinol presents with pancytopenia. → Marrow suppression from xanthine oxidase inhibition; reduce 6-MP/AZA dose 75% or stop allopurinol.

Pseudogout in elderly: 78-year-old post-hip surgery develops acute knee swelling; aspirate shows rhomboid positively birefringent crystals + chondrocalcinosis on X-ray. → CPPD; screen for hemochromatosis, hyperparathyroidism.

Refractory gout: Patient on max allopurinol with urate 8 mg/dL and progressive tophi. → Add probenecid (if eGFR adequate) or switch to pegloticase (check G6PD).

Pregnant patient with flare: → Intra-articular or oral glucocorticoid (avoid NSAIDs after 20 weeks, avoid ULT in pregnancy).

Young man with self-mutilation + hyperuricemia → Lesch-Nyhan.

Transition-of-care stem: Discharged patient stops allopurinol "because flare is over" and returns in 2 months with severe attack. → Counsel on lifelong ULT, restart with colchicine prophylaxis.

One-Line Recap

Gout is a chronic crystal-deposition disease driven by hyperuricemia in which acute flares are aborted with NSAIDs, colchicine, or glucocorticoids (matched to comorbidities), and long-term outcomes depend on lifelong urate-lowering therapy — almost always allopurinol — titrated to a serum urate <6 mg/dL (<5 with tophi) under cover of 3–6 months of flare prophylaxis, while simultaneously addressing the metabolic, renal, and cardiovascular comorbidities that travel with the disease.

Board pearl: The two highest-yield tested decisions are (1) aspirate before treating any acute monoarthritis and (2) start ULT with prophylaxis and treat to target, not to symptoms — every other detail flows from those two principles.

Diagnosis: confirm with arthrocentesis showing needle-shaped, negatively birefringent MSU crystals; rule out septic arthritis in every acute monoarthritis; recheck serum urate after the flare since it can be falsely normal during inflammation.

Acute flare: NSAID, colchicine, or steroid — start within 24 hours; pick by comorbidity (steroid for CKD/CHF/anticoagulation); don't stop existing ULT during a flare.

Chronic management: start allopurinol low and titrate to target (HLA-B*5801 screen in high-risk groups); pair with colchicine prophylaxis ×3–6 months; treat to urate <6 with periodic monitoring every 6 months once at goal; lifelong therapy.

Step 3 wrap-around: switch HCTZ to losartan, consider SGLT2 inhibitors in T2DM/CKD, counsel on alcohol/fructose/red meat, optimize BP/lipids/weight, and ensure closed-loop PCP follow-up — gout is a marker of cardiometabolic risk, not just a sore toe.