What it is:Gout is an inflammatory arthritis caused by monosodium urate (MSU) crystals precipitating out of supersaturated serum and depositing in joints and soft tissue. It used to be called the "disease of kings" because rich diets and alcohol drive it, but it's really a disease of purine metabolism gone wrong.
The core problem:Serum uric acid climbs above its solubility limit (>6.8 mg/dL), crystals form, and the immune system reacts to those crystals like they're an infection: it isn't one, but the joint doesn't know that. Every acute flare is basically your own immune system overreacting to salt crystals sitting in a joint.
What you do about it:Two completely separate jobs that use different drugs. Job 1:put out the fire of an acute attack (NSAID, colchicine, or steroid; never a urate-lowering drug). Job 2:once the joint is calm, decide if this patient needs lifelong urate-lowering therapy (ULT) to stop it from happening again.
Keep these two jobs mentally separate for your whole career: treat the flare with anti-inflammatories, treat the disease with urate-lowering therapy.Starting or changing a ULT dose during an active flare doesn't help the flare and can make it worse by yanking urate crystals out of tissue deposits, so ULT is either continued at a steady dose or started with anti-inflammatory cover, never adjusted acutely to "fix" the attack.
Uric acid is the end product of purine breakdown, and humans can't degrade it further the way most mammals can (we lost the uricase enzyme somewhere in evolution). Purines come from three places: diet, turnover of the body's own nucleic acids, and de novo synthesis. Diet alone almost never causes gout; you need an underlying defect in production or excretion first.
| Mechanism | Drivers |
|---|---|
| Overproduction(~10% of patients) | Enzyme abnormalities (↑ PRPP synthetase activity, HGPRT deficiency), myelo/lymphoproliferative disease with high cell turnover, cytotoxic chemo lysing cells |
| Underexcretion(~90% of patients) | The kidney normally dumps about two-thirds of daily uric acid; the rest goes out via GI degradation by colonic bacteria. When renal clearance falls below production, urate accumulates. This is by far the more common mechanism. |
Xanthine oxidase inhibitors (allopurinol, febuxostat) block the enzyme that makes uric acid in the first place, so they work regardless of whether the patient is an overproducer or underexcretor. That's why they're first-line for everyone. Uricosurics (probenecid) only push the kidney to excrete more urate, so they're useless in an overproducer and useless if the kidneys already can't do the job (moderate-to-severe CKD).
Once serum urate crosses its solubility ceiling, MSU crystals precipitate in synovial fluid. Neutrophils try to phagocytose the crystals, rupture in the process, and dump proteolytic enzymes and inflammatory mediators into the joint. That cascade, complement activation, vasodilation, increased vascular permeability, chemotaxis, is what produces the classic hot, red, swollen, exquisitely painful joint within hours.
About 10% of gout patients develop uric acid nephrolithiasis(worse with acidic urine pH <6, concentrated urine, high urinary uric acid excretion). Massive acute crystal precipitation in collecting ducts can cause acute uric acid nephropathy(an AKI). Long-term deposition in the renal parenchyma causes chronic urate nephropathy. Kidney disease and gout feed each other: bad kidneys can't clear urate, and urate crystals damage kidneys.
Tophiare urate deposits that show up late, after years of untreated or undertreated hyperuricemia. Classic locations: base of the fingers, olecranon bursae, ulnar forearm, Achilles tendon, knees, wrists, hands, and the pinna of the ear. Their presence automatically means the patient needs lifelong ULT, no debate.
The textbook acute attack: excruciating pain, swelling, warmth, and erythema that comes on rapidly, often overnight, so the patient literally wakes up from the pain. It's almost always monoarticularat first.
| Joint | Frequency note |
|---|---|
| First MTP joint (big toe) | Classic presentation, called podagra. Most common site by far. |
| Instep, ankle, heel | Next most common |
| Knee, wrist, fingers, elbow | Less common, more typical in recurrent/chronic disease |
Systemic signs like fever and leukocytosisare common and can mimic septic arthritis or cellulitis, which is exactly why joint aspiration matters when the diagnosis is in question. Untreated, an attack runs 3 to 14 daysbefore it burns itself out.
Attacks are triggered by stress, trauma, surgery, alcohol, infection, and, counterintuitively, starting or rapidly changing urate-lowering therapy. Dropping serum urate quickly destabilizes existing crystal deposits and can trigger a flare, which is exactly why anti-inflammatory prophylaxis is layered on top of ULT initiation instead of skipped.
A classic teaching case is a 68-year-old with sudden, severe, monoarticular first-MTP pain, redness, and swelling, first episode ever, on a statin with no other meds. No fever needed, no prior gout history needed. The abrupt onset and joint location alone should put gout at the top of the differential even before labs come back.
| Test | Role |
|---|---|
| Joint aspiration (arthrocentesis) | The definitive test.Intracellular needle-shaped MSU crystals inside synovial leukocytes confirms it. Also lets you rule out septic arthritis by culture/gram stain, which matters because septic joints can look identical clinically. |
| Serum uric acid | Not diagnostic.Can be normal during an acute attack (urate often shifts into the inflamed tissue) and plenty of people walk around hyperuricemic without ever having gout. Useful for tracking ULT response, not for diagnosing the flare. |
| X-ray | Normal early in disease. Useful later to show erosive changes or confirm chronic tophaceous disease. |
| Ultrasound / CT (dual-energy CT) | Can visualize urate deposition when aspiration isn't feasible. |
| CBC, renal function | Supportive workup, not diagnostic; also needed before starting most gout drugs. |
If joint fluid can't be obtained, diagnosis becomes presumptive, based on the classic clinical picture (sudden monoarticular pain, podagra, risk factors) plus response to treatment. This is common in practice but always a step down in certainty from crystal confirmation.
Goals:terminate the attack, and do it fast, before moving on to any conversation about prevention. Start therapy as early as possible after symptom onset, ideally within 24-36 hours; earlier treatment means faster, more complete relief.
NSAIDs, colchicine, and corticosteroids all have roughly equivalent efficacyfor a first-line monotherapy attack. The choice comes down to the patient in front of you: renal function, GI bleed risk, cardiovascular disease, diabetes, drug interactions, and how many joints are involved.
Indomethacin, naproxen, sulindac are FDA-approved for gout specifically, but most NSAIDs work.
Best when started within the first 24-36 hours. About two-thirds of patients respond within hours if timed right.
Oral, IM, or intra-articular. Efficacy equivalent to NSAIDs. Good choice when NSAIDs/colchicine are contraindicated.
Monotherapy first. If pain doesn't respond, you can combineNSAID + low-dose colchicine + corticosteroid. If first-line options are ineffective, poorly tolerated, or contraindicated, the next step is an IL-1 inhibitor(canakinumab or anakinra), reserved for refractory cases because of cost and infection risk, not a first-line choice.
| NSAIDs (initial dose → continue until attack resolves) | ||
| Indomethacin | 50 mg TID | Reduce as pain improves, then stop |
| Naproxen | 750 mg once | then 250 mg Q8h until resolved |
| Ibuprofen | 400 mg TID | 400-800 mg TID-QID |
| Sulindac | 200 mg BID | 150-200 mg BID for 7-10 days |
| Meloxicam | 5 mg daily | 7.5-15 mg daily |
| Celecoxib | 800 mg then 400 mg day 1 | 400 mg BID x 1 week |
| Colchicine | ||
| Colcrys (0.6 mg tabs) | 1.2 mg (2 tabs) | then 0.6 mg 1 hour later; may resume 0.6 mg once-twice daily 12h after loading dose per ACR |
| Corticosteroids | ||
| Prednisone/prednisolone | 0.5 mg/kg/day | 5-10 days then stop, or 2-5 days then taper 7-10 days |
| Methylprednisolone dose pack | 24 mg day 1 | taper by 4 mg/day over 6 days |
| Triamcinolone IA | 10-40 mg (large joint) | 5-20 mg (small joint); pair with an oral NSAID/colchicine/steroid |
| Triamcinolone IM | 60 mg once | useful when oral therapy isn't possible or multiple joints involved |
| IL-1 inhibitors (refractory / first-line failure) | ||
| Canakinumab | 150 mg SC once | |
| Anakinra | 100 mg SC daily x 5 days | |
Colchicine's efficacy is time-dependent: started within the first 24-36 hours, roughly two-thirds of patients get relief within hours. Wait too long and it barely helps, so this is not a "start whenever" drug.
Nausea, vomiting, and diarrhea scale directly with dose, which is why modern dosing (1.2 mg then 0.6 mg) replaced older high-dose regimens that basically dosed to diarrhea. Non-GI toxicity includes neutropeniaand axonal neuromyopathy, both worsened by other myopathic drugs (statins are the classic interacting culprit) or impaired renal function.
Drugs like clarithromycin(strong CYP3A4 inhibitor) raise colchicine plasma levels and can cause serious, sometimes fatal toxicity. Dose reductions are required with concurrent use, and caution applies broadly with P-gp inhibitors, statins, and impaired hepatic or renal function. This is a high-yield drug interaction to have memorized cold.
Use with caution in renal or hepatic impairmentsince colchicine clearance depends on both.
Not every gout patient needs lifelong ULT. This is a distinct clinical decision made after the acute attack is under control, and it's frequently tested because students want to start ULT on everyone with a first flare.
| Indication for ULT | Note |
|---|---|
| ≥2 attacks per year | Even if serum uric acid is normal or only mildly elevated |
| Presence of tophi | Automatic indication, no debate |
| Radiographic joint damageattributable to gout | Evidence of chronic disease |
| CKD | Recognized indication |
| Past urolithiasis(uric acid stones) | Recognized indication |
Asymptomatic hyperuricemia is NOT treated.A high serum uric acid on a routine metabolic panel, with no history of gout attacks, is not itself an indication to start allopurinol. Treat the patient, not the number.
Before or alongside starting ULT, look for drugs that are quietly driving urate up and swap them if clinically reasonable:
Nonpharmacologic measures also help: weight loss, limiting alcohol (strongly associated with attack risk), and cutting high-fructose corn syrup and purine-dense foods (organ meats, certain seafood like anchovies/sardines/mussels/scallops, red meat, game meat). The DASH diet can lower serum urate by roughly 1 mg/dL if the patient actually sticks with it.
Target:serum uric acid <6 mg/dL, and it's meant to be maintained indefinitely once started, this is a lifelong drug in most patients, not a short course.
First-line: xanthine oxidase inhibitors (XOIs).They block the conversion hypoxanthine → xanthine → uric acid, so they work in both overproducers and underexcretors, which is why they're the default for essentially everyone.
Starting ULT can itself trigger an attack because it mobilizes existing urate crystal deposits as the serum level drops. That's why anti-inflammatory prophylaxis(low-dose colchicine, low-dose NSAID, or low-dose prednisone) is started alongside ULT initiation, typically for 3-6 months, and why ULT is fine to start duringan acute attack as long as anti-inflammatory therapy is already on board.
XOI first-line → titrate to the max tolerated dose → if urate target not met, consider add-on uricosuric (probenecid or lesinurad) → if still refractory, pegloticase. Uricosurics alone are reserved for patients who can't tolerate or have a contraindication to XOIs.
| Xanthine oxidase inhibitors (first-line) | ||
| Allopurinol | ≤100 mg/day (≤50 mg/day if CKD stage 4+) | Titrate slowly by serial uric acid up to max 800 mg/day |
| Febuxostat (Uloric) | 40 mg daily | Titrate to max FDA-approved 80 mg daily; reserve for allopurinol failure/intolerance |
| Uricosurics | ||
| Probenecid | 250 mg BID x 1-2 wks | then 500 mg BID x 2 wks, increase by 500 mg increments q1-2wks to max 2 g/day |
| Lesinurad (Zurampic) | 200 mg once daily AM, with food/water, only in combo with a XOI (not marketed currently in the US) | |
| Uricase (refractory disease) | ||
| Pegloticase (Krystexxa) | 8 mg IV over ≥2h every 2 weeks; premedicate with antihistamine + corticosteroid | |
| Adjunct urate-lowering (comorbidity-driven, not primary ULT) | ||
| Losartan | Preferred antihypertensive choice in gout patients when feasible | |
| Fenofibrate | 20-30% urate reduction, but not recommended solely as a lipid-drug swap for this purpose | |
Lowers uric acid in a dose-dependentmanner, which is why it's titrated to a target rather than fixed at one dose. Start low (≤100 mg/day, even lower in advanced CKD) specifically to reduce the risk of triggering both an acute gout flare and the rare-but-serious hypersensitivity reaction, then titrate up using serial serum uric acid checks toward the max of 800 mg/day.
Rare but carries a 20-25% mortality rate. Features severe rash (toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis), hepatitis, interstitial nephritis, and eosinophilia. Risk is higher in certain populations (Southeast Asian, particularly Han Chinese, Korean, and Thai ancestry) carrying the HLA-B*5801allele; guidelines recommend testing for it in high-risk populations before starting. Mild adverse effects (rash, leukopenia, GI upset, headache) are far more common and don't require stopping the drug outright.
Also dose-dependent, starting at 40 mg daily and titrating to a max FDA-approved 80 mg daily. Adverse effects are generally mild: nausea, arthralgias, minor LFT elevations.
A large cardiovascular outcomes trial showed increased all-cause and cardiovascular mortalitycompared with allopurinol, which is why FDA labeling now restricts febuxostat to patients who can't tolerate or don't respond to allopurinol. Don't reach for it first.
Flare prevention at initiation:because febuxostat mobilizes urate deposits quickly, give concomitant colchicine or an NSAID for at least the first 8 weeks of therapy.
Works by blocking postsecretory renal tubular reabsorption of uric acid, so more gets excreted in urine. Because that transiently increases the urine's uric acid concentration, it raises the risk of new stone formation, so it's started low and pushed up slowly, and patients need to maintain good fluid intake and urine alkalinization during the first several days.
Do not use in patients with a history of urolithiasis. Not generally recommended in moderate-to-severe CKDeither, since a compromised kidney can't excrete the extra uric acid load effectively, which defeats the mechanism entirely. Other side effects: GI irritation, rash/hypersensitivity, and it can actually precipitate an acute gouty flare if urate mobilizes too fast.
Lesinuradworks similarly (URAT1 transporter inhibition) but must always be combined with a XOI, never used alone, because of a black box warning for acute renal failure when used as monotherapy.
A pegylated recombinant uricase, an enzyme humans don't naturally have, that converts uric acid directly into water-soluble allantoin for excretion. Reserved for refractory gout: patients who've failed or can't tolerate all other ULT options.
Infusion-related allergic reactions are common enough that patients are premedicated with antihistamines and steroids before every dose. Efficacy can wane over time as patients develop anti-drug antibodies, and it's substantially more expensive than oral options, which is part of why it's a last resort rather than an early option.
Starting or up-titrating ULT causes remodeling of urate crystal deposits already sitting in joints, and that remodeling can trigger a flare even while the serum level is dropping toward goal. This is genuinely confusing to patients ("why am I flaring on the medicine that's supposed to fix this?"), so counseling on it up front matters.
| Line | Regimen |
|---|---|
| First-line | Low-dose colchicine (0.6 mg once or twice daily) or low-dose NSAID (e.g., naproxen 250 mg BID) |
| Second-line | Low-dose prednisone/prednisolone (e.g., 10 mg daily) |
Duration is typically the first 3-6 monthsof ULT, and longer if flares are still occurring. If a patient stays on NSAID prophylaxis long-term, add a PPIto protect the GI tract.
For patients who can reliably recognize their own attack symptoms, give them a standing prescription for a first-line acute agent (NSAID or colchicine) to keep on hand and start immediately at the first sign of a flare. Earlier treatment means faster, more complete resolution, so this self-treatment plan is genuinely part of good gout management, not just convenience.
| Parameter | When | Watching for |
|---|---|---|
| Serum uric acid | At acute attack (esp. if recurrent), then serially during ULT titration, then every 6-12 months once at target | Confirms trend toward the <6 mg/dL goal; not diagnostic acutely |
| Pain/inflammation resolution | Within 8 hours of starting acute therapy, full resolution by 48-72 hours | Treatment failure if not improving on that timeline |
| Renal function, LFTs, CBC, electrolytes | Baseline before starting ULT, then every 6-12 months | Renal or hepatic impairment changing drug choice/dose; cytopenias |
| Skin (rash) | Especially first weeks of allopurinol | Early sign of allopurinol hypersensitivity syndrome, don't dismiss it |
| Attack frequency | Ongoing | Whether current regimen (ULT dose, prophylaxis) is adequate |
| Comorbidity screen | At diagnosis and periodically | Diabetes, CKD, hypertension, obesity, CAD, HF, stroke, all cluster with gout |