Gouty pitfalls

For classic presentations of gout and diagnosis please see: Shojania K, Amiri N. Part 1: Diagnosing gout in primary care settings: do we have to tap? This Changed My Practice, UBC CPD. March 31, 2015. Accessed January 24, 2024. (View)

Authors

Dr. Carson Chin (biography, no disclosures), Dr. Nathan Hitchman (biography, no disclosures), and Dr. Jordan Friedmann (biography, no disclosures)

What care gaps or frequently asked questions we have noticed

Guidelines recommend that urate-lowering therapy (ULT) be directed by serum uric acid levels (SUA), but interpretation of such differs in acute and chronic phases of gout.¹ Furthermore, although treatment is simplified by the small number of pharmacotherapies available, these therapies require renal dose adjustment and can lead to serious and even fatal adverse events. Although the risk for such adverse events is predicted by the presence of HLA-B*58:01, preventable adverse events continue to occur in British Columbia due to underutilization of testing.² Finally, many practitioners have questions around the timing of allopurinol initiation and therapeutic options for chronic or refractory gout cases.

We will review the following commonly encountered issues:

1. Interpretation of serum uric acid
2. Risks for allopurinol hypersensitivity syndrome (AHS)
3. Use of allopurinol in CKD
4. Timing of allopurinol initiation and prophylaxis
5. Therapeutic options for chronic or refractory gout

Data that answer these topics

1. Interpretation of serum uric acid
   1. Asymptomatic hyperuricemia — The specificity of hyperuricemia for the diagnosis of gout is only 53–61%, and in one study only 22% of asymptomatic patients with SUA levels >535 µmol/L developed incident gout over a 5-year period.³ Accordingly, European Alliance of Associations for Rheumatology (EULAR) guidelines recommend against treating asymptomatic hyperuricemia.¹
   2. SUA during acute gout flares — During the acute phase of a gout flare, renal excretion of uric acid increases, so SUA may be normal or low in as many as half of patients.^4,5,6 The 2018 EULAR recommendations suggest that the diagnosis of gout should not be made based on hyperuricemia alone, and by the same token, the diagnosis should not be excluded based on normal SUA levels during an acute flare.³ Joint aspiration is the gold standard for diagnosis of gout and can be helpful to rule out other etiologies, although classic presentations of gout can be diagnosed clinically or with clinical scoring tools (View TCMP aricle on diagnosing gout).
   3. Target uric acid with ULT — Upper limit of normal SUA levels range from 360 to 420 µmol/L depending on the jurisdiction; however, EULAR recommendations suggest that SUA level should be maintained <360 µmol/L for most patients on ULT (a lower SUA target of <300 µmol/L is recommended for patients with severe gout until total crystal dissolution).¹
2. Risks for allopurinol hypersensitivity syndrome (AHS) — The HLA-B*5801 haplotype is most common among patients of Korean, Chinese, Thai, or African genetic ancestry, and is the strongest risk factor for allopurinol-induced serious cutaneous adverse reactions (SCARs), which include Stevens-Johnson Syndrome (SJS), Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Toxic Epidermal Necrolysis (TEN).¹ In the largest review of allopurinol-induced SCARs to date, HLA-B*5801 was present in 99% of cases, indicating that their occurrence is almost entirely preventable by appropriate testing for this haplotype prior to allopurinol initiation.⁷ This is particularly important as mortality rate for such SCARs can exceed 25% (Richette et al, 2016). Current guidelines recommend testing HLA-B*5801 prior to allopurinol initiation among populations at high risk for SCARs (patients of Korean, Chinese, Thai, or African genetic ancestry).^1,8,9 In patients who test positive for HLA-B*5801, we recommend febuxostat as an alternate ULT to allopurinol.
3. Use of allopurinol in CKD – Allopurinol is the preferred first-line ULT even in those with moderate to severe kidney disease.⁸ The risk of allopurinol-induced SCARs is increased in patients with renal failure due to increased levels of toxic metabolites.¹ In patients with normal renal function, allopurinol should be started at 100mg/day and titrated by 100mg every 2–4 weeks until the target uric acid reached.³ In patients with renal impairment (CrCl ≤30 mL/min), the allopurinol dosage should be started even lower at 50mg and titrated by 50mg every 2–4 weeks until target uric acid is reached and with close monitoring of adverse effects. Starting with lower doses of allopurinol reduces the risk of gout flares and serious adverse reactions. If target SUA <360 µmol/L cannot be achieved with allopurinol, febuxostat should be considered as an alternative, second-line agent.¹ Although recent evidence suggests that the risk of adverse cardiovascular outcomes associated with febuxostat may be less than previously believed, we recommend an informed discussion of potential risks prior to febuxostat initiation.¹⁰
4. Lab monitoring while on allopurinol – Although there are no guidelines on this topic, we recommend that practitioners monitor labs (CBC, Cr, eGFR, ALT, uric acid, CRP) monthly during allopurinol dose titration, and then every three to six months once a stable dose has been reached.
5. Timing of allopurinol initiation and prophylaxis — Historically there has been concern that initiation of allopurinol during an acute flare may prolong or worsen flares. However, there have now been two randomized controlled trials demonstrating that initiation of allopurinol during an acute gout flare concomitantly with colchicine/NSAIDs does not prolong or otherwise exacerbate flares.^11,12 Accordingly, we recommend that allopurinol initiation does NOT need to be delayed until after acute flare resolution, however, it should be accompanied with daily prophylaxis (colchicine, NSAIDs, or low dose prednisone) for 3–6 months or until normal SUA levels are achieved to prevent remobilization symptoms. Of note, prophylaxis is recommended in ALL patients who are starting on ULT, even those who are not flaring, and should be continued for at least 3–6 months to reduce the risk of flares.⁸
6. Treatment of chronic or refractory gout — If gout flares become chronic despite appropriate urate-lowering therapy, prophylactic colchicine (0.6 mg daily) can be initiated and continued indefinitely as needed. More aggressive serum urate-lowering can also be pursued, with EULAR recommending SUA levels <300 µmol/L in patients with chronic gout activity, frequent attacks, or tophi.¹

What we recommend (practice tips)

1. Asymptomatic hyperuricemia should not be diagnosed as gout or treated as such, although it may predate the eventual development of gout in some individuals.
2. SUA levels may be normal or low during an acute gout flare in up to half of cases, so the diagnosis of gout should not be ruled out based on SUA levels alone and acute treatment should not be delayed
3. Populations at high risk for SCARs (patients of Korean, Chinese, Thai, or African genetic ancestry) should be tested for HLA-B*5801 prior to allopurinol initiation. This testing can be ordered by any practitioner.
4. Allopurinol is first-line serum urate-lowering therapy, even in those with CKD. It should be initiated at doses of 100mg daily and up-titrated every 2–4 weeks until SUA <360 µmol/L is achieved, up to a maximum dose of 800mg/day.
5. Allopurinol should be dose reduced (50 mg daily) in patients with decreased renal function, and if target SUA cannot be achieved at tolerated doses, it should be switched to febuxostat.
6. For patients on allopurinol, monitoring labs (CBC, Cr, eGFR, ALT, uric acid, CRP) should be monthly during up-titration, and then every three to six months once a stable dose has been reached.
7. Allopurinol initiation does NOT need to be delayed until flare resolution, so long as it is administered concomitantly with appropriate prophylactic colchicine.
8. ALL patients should be on prophylaxis (colchicine, NSAIDs, low dose prednisone) when starting ULT for at least 3–6 months.
9. Prophylactic colchicine and more aggressive serum urate-lowering therapy should be initiated in patients with frequent gout attacks or chronic gout activity.

Resources

1. 2018 EULAR recommendations for the diagnosis of gout: view
2. 2016 EULAR recommendations for the treatment of gout: view
3. 2020 American College of Rheumatology guideline for the management of gout: view

Handouts for patients

1. Rheuminfo allopurinol patient handout (view PDF)
2. Rheuminfo gout patient handout (view PDF)

References

1. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42. doi:10.1136/annrheumdis-2016-209707 (View)
2. Ponzo MG, Miliszewski M, Kirchhof MG, Keown PA, Dutz JP. HLA-B*58:01genotyping to prevent cases of DRESS and SJS/TEN in East Asians treated with allopurinol-a Canadian missed opportunity. J Cutan Med Surg. 2019;23(6):595-601. doi:10.1177/1203475419867599 (Request with CPSBC or view with UBC)
3. Richette P, Doherty M, Pascual E, et al. 2018 updated EULAR evidence-based recommendations for the diagnosis of gout. Ann Rheum Dis. 2020;79(1):31-38. doi:10.1136/annrheumdis-2019-215315 (View)
4. Schlesinger N, Norquist JM, Watson DJ. Serum urate during acute gout [published correction appears in J Rheumatol. 2009 Aug;36(8):1851]. J Rheumatol. 2009;36(6):1287-1289. doi:10.3899/jrheum.080938 (View with CPSBC or UBC)
5. Urano W, Yamanaka H, Tsutani H, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol. 2002;29(9):1950-1953 (View with CPSBC or UBC)
6. Zhang J, Sun W, Gao F, et al. Changes of serum uric acid level during acute gout flare and related factors. Front Endocrinol (Lausanne). 2023;14:1077059. Published 2023 Feb 21. doi:10.3389/fendo.2023.1077059 (View)
7. Ramasamy SN, Korb-Wells CS, Kannangara DR, et al. Allopurinol hypersensitivity: a systematic review of all published cases, 1950-2012. Drug Saf. 2013;36(10):953-980. doi:10.1007/s40264-013-0084-0 (Request with CPSBC or view with UBC)
8. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180 (View)
9. Vancouver Coastal Health. Preventing allopurinol-induced severe cutaneous adverse reactions in patients with gout: a brief review for physicians and pharmacists. Vancouver Coastal Health Research Institute. March 2020. Accessed August 18, 2023. (View)
10. Mackenzie IS, Ford I, Nuki G, Hallas J, Hawkey CJ, Webster J, Ralston SH, Walters M, Robertson M, De Caterina R, Findlay E. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. The Lancet. 2020 Nov 28;396(10264):1745-57.
11. Hill EM, Sky K, Sit M, Collamer A, Higgs J. Does starting allopurinol prolong acute treated gout? A randomized clinical trial. J Clin Rheumatol. 2015;21(3):120-125. doi:10.1097/RHU.0000000000000235 (View with CPSBC or UBC)
12. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med. 2012;125(11):1126-1134.e7. doi:10.1016/j.amjmed.2012.05.025 (View with CPSBC or UBC)

Vote

Please indicate how this article will change your practice:

Gouty pitfalls

• I disagree with this approach
• I will consider changing my practice, but need more information/time
• I will likely change my practice
• I will definitely change my practice
• I already do this

View Results

 Loading ...