Gout Carlson

What is the source of serum uric acid (SUA), and how is it eliminated?

SUA comes ~2/3 from endogenous purine synthesis and ~1/3 from dietary purines. Eliminated ~2/3 via renal excretion and ~1/3 via the gut.

What is the pathophysiologic sequence from purine metabolism to gout?

Dietary + endogenous purines → elevated SUA → urate supersaturation → monosodium urate (MSU) crystal deposition → inflammatory response → gout flare.

Does asymptomatic hyperuricemia require treatment?

No — in the absence of gout, asymptomatic hyperuricemia does NOT require treatment.

What is the gold standard for diagnosing gout?

Identification of monosodium urate (MSU) crystals in synovial fluid via joint aspiration. Often made clinically without aspiration.

How do MSU crystals appear under polarized light microscopy?

Needle-shaped crystals with NEGATIVE birefringence. (Compare: CPPD crystals are positively birefringent.)

What are the classic signs and symptoms of an acute gout flare?

Rapid-onset monoarticular arthritis, exquisite joint pain (often at night or after a trigger), redness, swelling, warmth, fever, leukocytosis, and elevated SUA. Classic location: MTP1 (big toe = podagra).

List the main medication classes that are risk factors for gout.

Diuretics (loop, thiazide), low-dose aspirin (<2 g/day), cyclosporine, tacrolimus, cytotoxic chemotherapy, niacin, pyrazinamide, ethambutol.

Which two of RT's medications are medication-related risk factors for gout?

Furosemide (loop diuretic) and aspirin 81 mg (low-dose salicylate) — both raise SUA.

List conditions that cause uric acid OVERproduction.

Myeloproliferative/lymphoproliferative disorders, malignancy, hemolytic disorders, psoriasis, glycogen storage diseases (types III, V, VII), Down syndrome, HGPRT deficiency, PRPP overactivity.

List conditions that cause uric acid UNDERexcretion.

Chronic renal insufficiency, lead nephropathy, volume depletion, DM/starvation ketoacidosis, lactic acidosis, obesity, hypothyroidism, hyperparathyroidism, sarcoidosis.

What guideline governs gout management in these slides?

2020 American College of Rheumatology (ACR) Guidelines.

What are the three treatment goals for acute gout?

(1) Rapid symptom relief, (2) prevent recurrent attacks, (3) prevent complications of chronic urate crystal deposition.

How long should acute gout therapy be continued, and when should it start?

Started within 24 hours of symptom onset; continued for 1–2 weeks. Acute flares are self-limiting.

Should urate-lowering therapy (ULT) be discontinued during an acute gout flare?

NO — do not stop ULT during an acute flare (Evidence C, ACR).

What are the three first-line treatment classes for an acute gout flare?

NSAIDs (or COX-2 inhibitors), colchicine, and corticosteroids.

List the NSAIDs used for acute gout and their dosing.

Ibuprofen 400–800 mg PO q6h; Indomethacin 50 mg PO q8h then taper; Naproxen 750 mg PO x1 then 250 mg PO q8h; Sulindac 150–200 mg PO q12h x7–10d; Celecoxib 800 mg then 400 mg on Day 1, then 400 mg q12h x7d.

What are the major adverse effects and contraindications of NSAIDs in gout?

ADEs: elevated BP (~5 mmHg), sodium/water retention, GI bleeding/ulcers, AKI, bronchoconstriction. Avoid/use caution in: CKD, CHF, HTN, ASCVD, PUD, liver disease, anticoagulation, geriatric patients (especially indomethacin → CNS ADEs).

Why is indomethacin particularly cautioned in elderly gout patients?

It has prominent CNS adverse effects (dizziness, confusion, headache) that are poorly tolerated in older adults.

What is the FDA-approved colchicine dosing for an ACUTE gout flare?

1.2 mg PO x1, then 0.6 mg PO 1 hour later (max 1.8 mg). In real life: repeat prophylaxis dose (0.6 mg daily or BID) starting 12 hours after the loading dose until flare resolves.

What is the colchicine dosing for PROPHYLAXIS of gout flares?

0.6 mg PO once or twice daily (max 1.2 mg/day). Dose reduce to 0.3 mg daily in severe renal impairment (CrCl <30 mL/min); 0.3 mg twice weekly in HD.

What are the major adverse effects of colchicine?

GI: diarrhea, N/V, abdominal cramping (most common). Blood dyscrasias: myelosuppression, leukopenia, thrombocytopenia. Neuromuscular: myopathy, rhabdomyolysis.

What is the major drug interaction concern with colchicine?

P-glycoprotein (PGP) and strong CYP3A4 inhibitors — contraindicated with renal or hepatic impairment. Also: statins and fibrates (↑ myopathy risk), cyclosporine/tacrolimus.

Why must colchicine be used cautiously with statins?

Pharmacodynamic interaction: both colchicine and statins increase risk of myopathy/rhabdomyolysis. Rosuvastatin is lower risk than other statins.

What fruit should patients avoid while taking colchicine, and why?

Grapefruit — it inhibits CYP3A4 and can significantly increase colchicine levels.

What is the prednisone dosing for an acute gout flare?

0.5 mg/kg/day x5–10 days then stop (Evidence A), OR 0.5 mg/kg/day x2–5 days then taper over 7–10 days (Evidence C).

What are the acute and chronic adverse effects of corticosteroids in gout?

Acute: hyperglycemia, leukocytosis, fluid retention, hypertension, GI upset, insomnia, impaired wound healing. Chronic: HPA suppression, osteoporosis, cataracts.

Why are corticosteroids problematic in a patient with diabetes?

Corticosteroids cause significant hyperglycemia — blood glucose must be closely monitored in diabetic patients.

What are IL-1 antagonists used for in gout, and which agents are available?

Used for refractory acute gout flares not responsive to first-line agents. Anakinra (100 mg SC daily x3 days, Evidence B), Canakinumab (150 mg SC single dose, Evidence A), Rilonacept (not studied in acute flares).

What is the biggest barrier to IL-1 antagonist use in gout?

Cost — Canakinumab (Illaris) is ~$201,806 per dose.

For patient RT (HTN, CHF, DM, CAD), which acute gout agent is preferred and why?

Colchicine — NSAIDs worsen CHF (sodium/water retention) and HTN (↑BP); corticosteroids worsen hyperglycemia. Colchicine avoids these issues (monitor given rosuvastatin co-administration).

What is a "mobilization flare" and why does it occur?

When ULT is started, rapid reduction in SUA mobilizes urate crystals from tissue deposits into joints, triggering a gout flare. This is why prophylaxis is ALWAYS started before or with ULT.

How long should mobilization flare prophylaxis be continued?

At least 3–6 months after ULT initiation; longer if mobilization flares continue.

What are the first-line agents for mobilization flare prophylaxis?

Low-dose colchicine 0.6 mg daily or BID (preferred), low-dose NSAIDs ± PPI (e.g., naproxen 250 mg BID), or low-dose corticosteroids (≤10 mg/day prednisone).

What are the ACR 2020 indications for initiating ULT?

≥2 gout flares/year (highly recommended), tophaceous gout, CKD stage ≥3, urolithiasis, or SUA >9 mg/dL. Conditional recommendation for first or infrequent flares.

What is the SUA target goal when on ULT?

SUA <6 mg/dL (treat-to-target approach, analogous to goal A1c or BP).

What is the mechanism of action of allopurinol?

Xanthine oxidase inhibitor (XOI) — blocks conversion of hypoxanthine → xanthine → uric acid, reducing uric acid synthesis.

What is the starting dose and titration for allopurinol?

Start 50 mg/day (CKD stage ≥4) or 100 mg/day (all others) PO daily; titrate 50–100 mg every 2–5 weeks until SUA <6 mg/dL. Max dose = 800 mg/day.

Can allopurinol be titrated above 300 mg/day in patients with renal impairment?

Yes — with adequate patient education and monitoring (pruritis, rash, elevated LFTs). Patients with CKD may need >300 mg/day to reach SUA goal (ACR 2020).

What is allopurinol hypersensitivity syndrome (AHS), and who is at highest risk?

Rare but potentially fatal reaction: fever, rash (can progress to SJS/TEN), eosinophilia, hepatitis, renal failure. Highest risk: Han Chinese, Korean, Thai, and African American patients who are HLA-B*5801 positive — screen before initiating.

What are the key drug interactions with allopurinol?

CRITICAL: Azathioprine and 6-MP — allopurinol inhibits their metabolism; MUST reduce 6-MP/azathioprine dose by ~67–75%. Others: didanosine, theophylline, loop/thiazide diuretics, pegloticase.

What is the mechanism of action of febuxostat?

Selective, non-purine XOI — inhibits xanthine oxidase more selectively than allopurinol, reducing uric acid synthesis.

How is febuxostat dosed, and what are its renal/hepatic adjustments?

Start 40 mg PO daily; increase to 80 mg daily if SUA not at goal after 2 weeks (US max = 80 mg). No adjustment for mild-moderate impairment; max 40 mg with severe renal impairment.

When should febuxostat be avoided?

In patients with established ASCVD or a recent CV event — the CARES trial showed increased CV mortality vs. allopurinol. ACR conditionally recommends switching to alternative ULT in these patients.

What drug interaction is shared by BOTH allopurinol and febuxostat?

Both are contraindicated with azathioprine and 6-mercaptopurine (6-MP) — toxic accumulation of these immunosuppressants can cause fatal myelosuppression.

What is allopurinol's place in therapy vs. febuxostat per ACR 2020?

Allopurinol = preferred first-line XOI for ALL patients (more cost-effective, safer CV profile). Febuxostat = alternative if allopurinol not tolerated or SUA goal not reached — AVOID in ASCVD.

What is the mechanism of action of probenecid?

Uricosuric agent — blocks renal tubular reabsorption of urate (inhibits URAT1 transporter), increasing urinary uric acid excretion.

When is probenecid contraindicated?

History of urolithiasis (nephrolithiasis), uric acid overproducers, CrCl <50 mL/min (ineffective), G6PD deficiency, blood dyscrasias, salicylate therapy, age <2 years.

What is probenecid's place in therapy?

Second-line to XOIs. May be added as adjunct when patient is not at SUA goal on XOI alone (or used if XOI is not tolerated). Ineffective with renal impairment (CrCl <50 mL/min).

What is the mechanism of action of pegloticase (Krystexxa)?

Pegylated recombinant uricase — converts uric acid to allantoin (much more soluble), dramatically lowering SUA. Humans lack endogenous uricase.

What are the dosing and administration requirements for pegloticase?

8 mg IV infusion over ≥2 hours every 2 weeks. Requires premedication with corticosteroids and antihistamines. Administered only in a healthcare setting (anaphylaxis risk — boxed warning).

When should pegloticase be discontinued?

If 2 consecutive SUA values >6 mg/dL — indicates loss of response (anti-drug antibody formation) and signals high risk for infusion reactions.

Who should NOT receive pegloticase?

Patients with G6PD deficiency (risk of hemolysis). Screen African and Mediterranean ancestry patients prior to initiation.

What is pegloticase's place in therapy?

Reserved for chronic tophaceous gout with SUA >6 mg/dL and either ≥2 flares/year OR nonresolving tophi, after failing all other ULT. All other ULT must be DISCONTINUED before use.

What is the role of losartan in gout management?

Has mild uricosuric properties. ACR conditionally recommends it as the preferred antihypertensive agent for gout patients who need BP control — consider switching from HCTZ to losartan.

What does the ACR recommend regarding hydrochlorothiazide (HCTZ) in gout patients?

Consider switching to an alternative antihypertensive when feasible — HCTZ raises SUA.

What does the ACR recommend about low-dose aspirin in gout patients?

Conditionally recommends AGAINST stopping low-dose aspirin even though it raises SUA — cardiovascular benefit outweighs the gout risk.

What are the HLA genetic screening recommendations in gout pharmacotherapy?

HLA-B*5801 positive (Han Chinese, Korean, Thai, African American) → AVOID allopurinol (risk of AHS). G6PD deficiency → AVOID probenecid and pegloticase (risk of hemolysis).

For patient RT (CHF, HTN, DM, CAD), why is allopurinol preferred over febuxostat for ULT?

Allopurinol is first-line per ACR, more cost-effective, and has a safer CV profile. Febuxostat is conditionally avoided with established CVD (RT has CAD) due to increased CV mortality risk (CARES trial).

Why is probenecid not ideal for RT?

Probenecid is less effective than XOIs, requires CrCl ≥50 mL/min, and RT is on aspirin — salicylates antagonize probenecid's uricosuric effect (contraindicated together).

When should mobilization flare prophylaxis be stopped?

After ≥3–6 months of ULT AND the patient is flare-free. If SUA is still above goal, continue prophylaxis and keep titrating the ULT dose.

How often should SUA be monitored during ULT initiation vs. maintenance?

Every 2–5 weeks during dose titration; every 6 months once SUA is stable at goal.

What non-pharmacologic interventions can reduce SUA by ~10–18%?

Weight loss, dietary modification (reduce purines, alcohol, HFCS), hydration, exercise, and avoidance of uricogenic medications when feasible.

What dietary items should gout patients AVOID or LIMIT?

High-purine foods (organ meats, shellfish, red meat), alcohol (especially beer), high-fructose corn syrup beverages, and fasting/crash dieting.

What dietary items may be BENEFICIAL in gout?

Low-fat dairy, coffee, adequate hydration, and vitamin C (modest uricosuric effect).

What is the overall treatment timeline integrating all phases of gout management?

(1) Acute flare: anti-inflammatory x1–2 weeks. (2) Start ULT + prophylaxis simultaneously (prophylaxis ≥3–6 months). (3) Titrate ULT every 2–5 weeks to SUA <6 mg/dL. (4) ULT is lifelong. (5) Non-pharm therapy throughout. Monitor SUA, flares, tophi, and drug-specific parameters.

How does gout differ from CPPD (pseudogout) on synovial fluid analysis?

Gout: needle-shaped, negatively birefringent MSU crystals. CPPD/pseudogout: rhomboid-shaped, positively (weakly) birefringent calcium pyrophosphate crystals. CPPD prefers knees/wrists; gout prefers MTP1.

Why can gout NOT be ruled out if septic arthritis is suspected?

Gout and septic arthritis can COEXIST. Observing crystals in synovial fluid does NOT exclude infection — Gram stain and culture are still needed.