How Should You Approach This Difficult Gout Management Problem?

Author: 

Theodore R. Fields, MD

Hospital for Special Surgery

Weill Cornell Medical College

A 67-year-old man presents for follow-up of his gout and kidney disease. His mother and brother had renal insufficiency, told to be due to hypertension, and the patient advises you that his nephrologist has recently told him he may soon need dialysis.  

The patient—who is of Chinese background—had presented with tophaceous gout 7 years prior. His creatinine level at that time was 2.3 mg/dL, and his rheumatologist at that time decided to start him on febuxostat rather than allopurinol. This choice was made because febuxostat does not require dosage adjustment with decreased renal function, whereas allopurinol needs to be initiated slowly and gradually increased in that setting. This decision might not have been made after the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial of allopurinol vs febuxostat was published in The New England Journal of Medicine in March 2018,¹ which suggested that there might be a higher mortality rate among patients receiving febuxostat than among those receiving allopurinol. To qualify for entry into the CARES study, a patient needed to have certain cardiac risk factors, such as prior myocardial infarction or stroke. This patient did not have any of these risk factors and was doing well on febuxostat. He was kept on this medication after the study came out. 

The decision to continue febuxostat was further supported with the publication of the Febuxostat Versus Allopurinol Streamlined Trial (FAST), published in The Lancet in November 2020.² This trial was similar to the CARES trial but had 95% patients remaining in the study rather than the less than 50% in the CARES trial. In FAST, there was no significant difference in any cardiovascular outcomes or mortality rate between allopurinol and febuxostat.  

However, our patient now has a creatinine level of 6.9 mg/dL and an estimated glomerular filtration rate (eGFR) of 9 and has been told of imminent dialysis. While allopurinol has been studied among patients on hemodialysis and has been shown to be removed during hemodialysis, febuxostat has only been studied down to an eGFR of 15. His present urate level is 6.3.  

Answer: Check him for the genetic marker HLA–B*5801, then consider starting him on allopurinol, 50 mg. 

Discussion: 

Febuxostat has remained a reasonable option for this patient, but now that his eGFR has dropped below 15 and dialysis is imminent, it is reasonable to consider switching him to allopurinol. We do not have published data on the use of febuxostat below an eGFR of 15, nor do we have data on its use in hemodialysis. Also, once the patient is on hemodialysis, his urate-lowering needs may change, and allopurinol gives us more flexibility. We also know that allopurinol itself is dialyzed, and that can be taken in consideration in allopurinol dosing.  

Caution is needed, however, because it is known that allopurinol hypersensitivity syndrome (Stevens-Johnson syndrome [SJS]) is a higher risk among patients with renal insufficiency. Fortunately, it is also known that starting slow with allopurinol and gradually building up the dose as needed leads to a lower risk of SJS. Therefore, even though we would predict that he might need allopurinol, 300 mg, since this is roughly equivalent to the urate-lowering power of febuxostat, 40 mg, we need to start with only allopurinol, 50 mg, and increase no faster than 50 mg every 2 to 5 weeks. Also, when he goes on dialysis, his urate-lowering requirements can drop since urate is dialyzable. Once he is in on dialysis, the urate level should be checked just before the next dialysis to see where the levels have returned to after the removal from the prior dialysis. It is this urate level that can drive the dosing of allopurinol in a hemodialysis patient. 

Another issue related to allopurinol SJS relevant to this patient is that SJS is more common among patients with the genetic marker HLA–B*5807. The 2020 American College of Rheumatology gout guideline³ advises testing for this marker among patients of Southeast Asian descent (e.g., Han Chinese, Korean, Thai) as well as among African American patients. This is because Southeast Asians have a 7.4% prevalence of HLA–B*5801 and African Americans have a 3.8% prevalence, whereas Whites and Hispanics each have a prevalence of 0.7%.³ 

Therefore, for our patient, it is appropriate to test him for the HLA–B*5801 allele. As it turned out, he was negative for HLA–B*5801; his febuxostat was stopped, and he was started on allopurinol, 50 mg.  

References: 

1. White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Eng J Med. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895

2. Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396(10264):1745-1757. doi:10.1016/S0140-6736(20)32234-0

3. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Rheumatol. 2020;72(6):879-895. doi:10.1002/art.41247

Theodore R. Fields, MD, is an attending rheumatologist at the Hospital for Special Surgery in New York, New York; a professor of clinical medicine at Weill Cornell Medical College; and a medical advisor to CreakyJoints, where he contributes to “The Gout Show,” a new podcast for patients.