Part 1 · The disease
A flare, hour by hour
A gout flare starts when immune cells in the joint swallow urate crystals and fire the NLRP3 inflammasome, which releases the alarm signal IL-1β. That alarm floods the joint with neutrophils. Scrub through fourteen days: the first 24 hours take half the track, because that is when most of the biology happens.
Teaching sketch. The hour boundaries are schematic. Human data give only a few fixed points: maximal pain within 24 hours, resolution within 14 days, synovial fluid sampled at 0–48 hours, days 3–4 and days 5–7, and skin blisters at 16 and 40 hours. The 4-hour and 24-hour neutrophil anchors come from mice and rabbits. The pain and CRP curves are drawn shapes, not measured averages. 33,290,349,437
Where each flare drug acts
| Drug | Where it is drawn | What the trials show |
|---|---|---|
| Colchicine | Microtubules: NLRP3 assembly inside the macrophage, and neutrophil sticking and migration at the vessel wall 68,229,263 | Low dose (1.2 mg then 0.6 mg 1 h later): ≥ 50% pain reduction at 24 h in 37.8% vs 15.5% on placebo, with diarrhoea in 23.0% vs 76.9% on the high dose 406. EULAR 2016 recommends starting within 12 h of onset 331. |
| NSAID | Cyclo-oxygenase in the inflamed tissue, downstream of the inflammasome. Non-selective NSAIDs and COX-2 inhibitors relieve flare pain about equally 418 | Naproxen and low-dose colchicine gave the same pain change over 7 days in CONTACT, with less diarrhoea on naproxen (20.0% vs 45.9%) 338. |
| Glucocorticoid | Inflammatory gene activity in the nucleus. This placement is a simplification: glucocorticoids act broadly | Prednisolone 35 mg once daily for 5 days matched naproxen 500 mg twice daily 179. Across 6 trials, pain was no different from NSAIDs, with less indigestion, nausea and vomiting 24. |
| IL-1 blocker | IL-1β and its receptor, the step that tells the vessel wall to let neutrophils in 38 | Canakinumab 150 mg: 72-hour pain 25.0 vs 35.7 mm on triamcinolone 40 mg 355. ACR 2020 conditionally recommends IL-1 inhibition when the other options are ineffective, poorly tolerated or contraindicated 135. |
ACR 2020 strongly recommends colchicine, NSAIDs or glucocorticoids as first-line flare treatment, chosen by the person's other conditions; the network meta-analysis found similar efficacy, so none is ranked above another 135. Treatment choices are covered in Treating a flare.
Clues in the timing
Flares start at night
724 people with 1,433 flares. Sector area is proportional to the number of flares. Overnight odds ratio 2.36 (95% CI 2.05–2.73) against the daytime; evening 1.26. 58
Serum urate can look normal
41 people: urate was lower during the flare than between flares (p < 0.0001), and the fall tracked CRP and IL-6 and a rise in urate excretion 416. In 339 people from two flare trials, 14% had urate ≤ 6 mg/dL at the flare 354.