Don’t start uric-acid–lowering drugs just because a check-up found high uric acid and you have never had pain

For people whose uric acid is over the limit but who have never had a gout attack or tophi, the American College of Rheumatology advises not starting uric-acid–lowering drugs yet. Treat 24 people for 3 full years and you prevent only one gout attack. Hoping it protects the kidneys also fails: kidney patients on the drug still lose kidney function as fast as those on placebo. Treat only after a real attack.

Cost

No money, and you also save long-term drug costs and money for regular follow-up labs, and you skip one unnecessary drug risk.

Benefit

The American College of Rheumatology 2020 gout guideline covers asymptomatic hyperuricemia: blood uric acid >6.8 mg/dL, with no prior gout attack and no subcutaneous tophi. The guideline conditionally recommends that these people not start any uric-acid–lowering drug. Drugs include allopurinol, febuxostat, and probenecid. Evidence certainty is rated “high.” A table footnote states that “by attributable risk, 24 patients must be treated for 3 years to prevent one gout attack.” The CKD-FIX randomized controlled trial enrolled 363 people with stage 3 or 4 chronic kidney disease, no gout history, but risk of worsening. One group took 100–300 mg allopurinol daily; one took placebo. The trial ran 104 weeks. eGFR is a kidney-function marker in mL/min/1.73 m². One group changed −3.33 per year (95% CI −4.11 to −2.55). The other −3.23 (−3.98 to −2.47). The difference was −0.10 (−1.18 to 0.97), P=0.85 — kidney function fell at the same speed. Serious adverse events 46% versus 44%. The PERL randomized controlled trial enrolled 530 people with type 1 diabetes and early-to-mid diabetic kidney disease; they took allopurinol for 3 years, then stopped for 2 months to wash out the effect. Allopurinol did lower blood uric acid from 6.1 to 3.9 mg/dL. After washout, the two groups’ GFR differed by only 0.001 mL/min/1.73 m². The credible range for that difference is 95% CI −1.9 to 1.9, P=0.99. Urinary albumin was 40% higher on allopurinol (0 to 80). It looks worthwhile because the intuition “the marker is high so take a drug to push it down” is smooth.

Notes

What to reject is “start lifelong uric-acid–lowering drugs when you have never had an attack,” not “high uric acid does not matter.” The same guideline lists exceptions. The cases below may warrant starting. First: a first attack plus stage 3 or higher chronic kidney disease. Second: blood uric acid >9 mg/dL (about 535 µmol/L). Third: a history of urinary stones. People with tophi, bone erosion on imaging, or 2 or more attacks a year get a strong recommendation to take drugs; those with more than one attack but under 2 a year get a conditional recommendation. Details: Section 16, Item 9 (once gout is confirmed, take uric-acid–lowering drugs long term). About 7.4% of Han Chinese carry the HLA-B*5801 genotype versus 0.7% of White people. Carriers on allopurinol are more likely to get life-threatening severe drug rash; Asian risk of hypersensitivity syndrome is 3 times that of White people. This is a drug you can skip for now; there is no need to take that extra risk. Before starting, test for the genotype — Section 16, Item 9. The two kidney trials were in chronic kidney disease and type 1 diabetes; they cannot be stretched to “high uric acid is wholly harmless to kidneys.” They only reject “lowering uric acid with drugs protects the kidneys.”

Sources · 3

1. FitzGerald JD, Dalbeth N, Mikuls T, et al. (2020). 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care & Research, 72(6), 744-760（表 1 及其脚注）. doi.org/10.1002/acr.24180
2. Badve SV, Pascoe EM, Tiku A, et al. (2020). Effects of Allopurinol on the Progression of Chronic Kidney Disease. New England Journal of Medicine, 382(26), 2504-2513. doi.org/10.1056/NEJMoa1915833
3. Doria A, Galecki AT, Spino C, et al. (2020). Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 Diabetes. New England Journal of Medicine, 382(26), 2493-2503. doi.org/10.1056/NEJMoa1916624