Update on Gout Management: What Is Old and What Is New

Yuliya Afinogenova; Abhijeet Danve; Tuhina Neogi


Curr Opin Rheumatol. 2022;34(2):118-124. 

In This Article

Specific Conditions or Treatment Considerations

Allopurinol Hypersensitivity Syndrome

Allopurinol hypersensitivity syndrome, AHS, is a rare, but highly fatal, adverse reaction to allopurinol. Starting dose is an important risk factor for AHS;[26,27] as such, allopurinol should be started at 100 mg/day for those with normal or mildly impaired renal function (up to CKD stage 3), or at 50 mg/day for those with CKD stage 4 or worse; this lower starting dose approach also mitigates risk of flares.[12] Another important risk factor for AHS is the HLA-B*58 : 01 allele, which is associated with a 80 to 580-fold increased likelihood of AHS.[28,29] Prevalence of HLA-B*58 : 01 allele is nearly 7.4% in Han Chinese, Korean and Thai populations, nearly 3.8% in African–Americans and 0.7% in whites.[30] However, numerous ethnic groups have not had prevalence of HLA-B*58 : 01 reported. Nonetheless, testing for HLA-B*58 : 01 allele is conditionally recommended in Southeast Asian and African–American patients.[12]

In settings wherein HLA-B*5801 testing is not available or cost-prohibitive to patients, starting at a low dose and slowly titrating up with close monitoring is a feasible approach.[12] It should also be recognized that febuxostat is associated with drug rash with eosinophilia and systemic symptoms (DRESS), through a different mechanism than HLA-B*5801.

Management of Gout in Chronic Kidney Disease

In addition to the dosing recommendations regarding allopurinol in CKD summarized above, patients on haemodialysis or peritoneal dialysis can also safely receive allopurinol.[31] Febuxostat does not require dose adjustments for CrCl at least 30 ml/min; for CrCl 15–29 ml/min, it is recommended to use no more than 40 mg/day according to the FDA label. RCT data suggest that febuxostat may be well tolerated to use in patients with GFR at least 15 ml/min,[32] but there are limited data on its use in advanced CKD, dialysis and transplant.[31,33] Uricosurics are not effective at low CrCl levels; probenecid is not recommended for those with CrCl less than 30 ml/min.[12] Pegloticase can be used in patients with advanced CKD, including patients on dialysis, without dose adjustment.[31] For prophylaxis while initiating ULT, NSAIDs and often colchicine may not be an option for patients with CKD; in such case, low-dose steroids may need to be used, though not ideal; consideration of anti-IL-1β therapy may be reasonable.

There has been substantial interest in whether ULT may have a beneficial effect on renal function among people with CKD outside of the context of gout. However, two recent RCTs suggested that allopurinol use was not associated with reduction in renal disease progression in patients with CKD who were at high risk, though questions remain about appropriateness of study sample given the underlying cause of CKD in one RCT (type 1 diabetes) and potential issues with power in the other RCT.[34,35]

Cardiovascular Risk and XOI

Although there are biologic hypotheses supporting potential detrimental effects of serum urate on CVD, ULT RCTs have not supported these hypotheses and have in fact raised concerns about potential adverse cardiovascular consequences of febuxostat in particular. The FDA-mandated postmarketing Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities Trial, CARES, raised concerns about potential higher all-cause and cardiovascular mortality with febuxostat compared with allopurinol.[36] However, valid interpretation of these findings is challenging due to 57% dropout, 45% lost-to-follow-up and 85% of events occurring after drug discontinuation, including 23–28% of deaths occurring within 30 days of drug discontinuation.[37] In contrast, the EMA-mandated postmarketing Febuxostat versus Allopurinol Streamlined Trial, FAST, did not find an elevated risk of cardiovascular events in the febuxostat group compared with allopurinol and had excellent follow-up and much lower drug discontinuation.[38] The FDA placed a black box warning on febuxostat in light of the results of the CARES trial. The 2020 ACR gout guideline took the CARES trial results and the FDA black box warning into account and made a conditional recommendation to switch therapy in patients on febuxostat with a history of CVD or a new cardiovascular event.[12] Subsequently, with the FAST trial results providing some reassurance about lack of elevated risk with febuxostat, it is anticipated that the next treatment guideline will take these newer data into consideration.[39]

Pegloticase and Immunogenicity

A challenge in the use of pegloticase is the development of antidrug antibodies with resultant risk for infusion reactions and anaphylaxis.[16,40] A rise in serum urate levels in between pegloticase infusions above 6 mg/dl signals a risk for infusion reaction or anaphylaxis. Only about 42% of patients maintain serum urate levels below 6 mg/dl over a 6-month treatment course with pegloticase.[16] A prospective clinical trial enrolled 14 patients who were treated with methotrexate 15 mg per week for 4 weeks prior to and during pegloticase treatment and reported that 79% of patients maintained therapeutic response at 6 months.[41] Mycophenolate mofetil (MMF) was also demonstrated to be effective in mitigating immunogenicity of pegloticase: at 12 weeks, serum urate below 6 mg/dl was achieved in 86% of participants in the MMF group as compared to 40% in placebo; maintenance of serum urate below 6 mg/dl at 24 weeks was achieved in 68 versus 30% in the MMF and placebo groups, respectively.[42] The optimal immunosuppressive regimen with pegloticase to prevent antidrug antibody formation remains to be determined.