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HY points followed by a quiz at the end
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A 54-year-old man with a history of chronic renal disease secondary to granulomatosis with polyangiitis presents with a large, painful, ulcerated tophus located on the first metatarsophalangeal joint. He has a 36-pack-year history of smoking. Which of the following is the most appropriate initial pharmacologic therapy for this patient?
A) Allopurinol
B) Colchicine
C) Corticosteroids
D) Febuxostat
E) Indomethacin
F) Probenecid
G) Rasburicase
H) Sulfinpyrazone
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This is a classic USMLE “trick” question.
Indomethacin, colchicine, and corticosteroids are all acceptable and comparably effective first-line treatments for acute gout.1, 2
In the United States, indomethacin, an NSAID, is the standard choice for acute gout attacks.1
On the USMLE, most questions on acute gout will have indomethacin as the answer.
However this patient has a history of renal insufficiency, making NSAIDs and colchicine inferior selections compared to steroids.
Stages of renal failure3:
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Stage 1 with normal or high GFR (GFR > 90 mL/min)
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Stage 2 Mild CKD (GFR = 60-89 mL/min)
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Stage 3A Moderate CKD (GFR = 45-59 mL/min)
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Stage 3B Moderate CKD (GFR = 30-44 mL/min)
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Stage 4 Severe CKD (GFR = 15-29 mL/min)
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Stage 5 End Stage CKD (GFR <15 mL/min)
Regarding NSAIDs (e.g., indomethacin) for acute gout:4
- CrCl 30 to 59 mL/min: avoid or use with caution depending on the kidney disease
- CrCl <30 mL/min: relatively contraindicated
Regarding colchicine for acute gout:4
- CrCl ≥30 mL/min: dosage adjustment not required
- CrCl <30 mL/min: consider dosage reduction
Regarding steroids for acute gout:4
- Dosage adjustment for CKD not required
What the USMLE wants
- If the patient has no apparent contraindications to any medications and indomethacin, steroids, and colchicine are all listed, choose indomethacin.
- If indomethacin and steroids are not listed, colchicine will be the answer they want for acute attacks.
- If the patient has renal insufficiency or history of renal transplant, choose corticosteroids.
Colchicine is a microtubule inhibitor.5 This is a high-yield MOA for USMLE.
Allopurinol and febuxostat are xanthine oxidase inhibitors used in the treatment of chronic gout, not acute flares.6 These are not to be used in patients taking 6-mercaptopurine (6-MP), since the latter requires xanthine oxidase for breakdown (i.e., allopurinol or febuxostat can cause ↑ serum 6-MP levels → 6-MP toxicity).7
Probenecid and sulfinpyrazone are a uricosurics (i.e., increase urinary excretion of uric acid) used in the treatment of chronic gout, not acute flares.6 They inhibit organic anion transporter (OAT) in the proximal tubules of the kidney, which normally functions to reabsorb uric acid (i.e., ↓ OAT activity → ↓ uric acid reabsorption).
Another high-yield point for USMLE is that OAT functions to secrete beta-lactam antibiotics. In addition to being used as a gout drug, probenecid can sometimes be added to beta-lactam regimens to help maintain serum levels.8 USMLE likes this point.
Probenecid and sulfinpyrazone should not be used in patients with history of uric acid stones or in those who are uric acid over-producers (i.e., tumor lysis syndrome; Lesch-Nyhan syndrome). Since these drugs are uricosurics, they increase uric acid in the urine and therefore risk of stones. 90% of patients with gout are under-excreters; 10% are over-producers. These drug are used in under-excreters who do not respond to, or who cannot take, xanthine oxidase inhibitors.9
Rasburicase and pegloticase are urate oxidase analogues that directly cleave uric acid. They are used in the prevention and treatment of tumor lysis syndrome.10
Bottom line: Indomethacin, corticosteroids, and colchicine are all acceptable and comparably effective first-line treatments for acute gout. On the USMLE, indomethacin is usually the answer, however if the patient has renal insufficiency, choose corticosteroids. Colchicine will be the answer if indomethacin and corticosteroids are not listed.
1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539261/
2) https://annals.org/aim/fullarticle/2578528/
3) https://www.davita.com/education/kidney-disease/stages
4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572666/
5) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4656054/
6) https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858
7) https://www.sciencedirect.com/book/9780721694917/peripheral-neuropathy
8) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3535968/
9) https://www.sciencedirect.com/book/9780323316965/kelley-and-firesteins-textbook-of-rheumatology
10) https://www.sciencedirect.com/science/article/abs/pii/S1543291213600090?via%3Dihub
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