Background/Purpose: Allopurinol can lead to skin toxicity. Minor skin reactions are reported in 2-4% of patients and life threatening severe cutaneous reactions (SCARs) in 0.1-0.4%. SCARs are more frequent in patients with a history of minor reaction to allopurinol, precluding re-challenge with the drug. Febuxostat is structurally distinct from allopurinol and could be an interesting option in patients who developed skin reaction to allopurinol. However, the frequency of skin reactions to febuxostat has been suggested to be increased in patients with  skin intolerance to allopurinol, therefore challenging the value of this option. The aim of our study was to investigate the cutaneous tolerance of febuxostat in gouty patients who had experienced skin intolerance to allopurinol as compared to those who had not.

Methods: We exhaustively identified gouty patients who had sequentially received allopurinol and febuxostat in the Rheumatology departments of 4 French university hospitals and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician at least two months after the initiation of febuxostat were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients who had a cutaneous reaction to allopurinol as compared to those who had not, was calculated. For estimating the 95% confidence interval (CI) we used two methods: Miettinen’s method and a bootstrap method. For bootstrapping, 5000 random subsamples having the same size than the study population were drawn with replacement. An OR was calculated for each replicate. The limits of the 95% CI correspond to the antilog of the 2.5^th and 97.5^thof log(OR) considered as a randomly distributed variable. 

Results:   The hospital files of 554 gouty patients were examined. 113 had sequentially been treated with allopurinol and febuxostat. Among them 12 did not visit the prescribing physician after the initiation of febuxostat and were excluded from analysis. The analyzed population therefore included 101 patients (86 males, mean age 61±14 years). 22 patients had a history of cutaneous adverse event to allopurinol (16 minor reactions and 6 severe reactions including 2 systemic epidermal necrosis, 1 DRESS, 2 severe drug-induced skin rash and 1 angioedema). 2 (9.1%) of these 22 patients experienced skin reactions to febuxostat (one diffuse rash in a patient with a history of systemic epidermal necrosis and one localised pruritus in a patient who had the same reaction with allopurinol). Among the 79 patients without history of skin reaction to allopurinol, 2 (2.5%) had a minor skin reaction to febuxostat (one localized vesicular eruption and one pruritus). OR was statistically not significant: 3.85 [0.51-29.04] with the Miettinen’s method and 3.86 [0.80-18.74] with the bootstrap method. In addition, renal failure did not modify the risk of skin reaction to febuxostat (P=0.97 in univariate analysis and 0.98 in a multivariate model combining renal failure and intolerance to allopurinol).

Conclusion: These results suggest that the risk of skin reaction to febuxostat is moderate and not significantly increased by a history of cutaneous adverse event to allopurinol nor by renal failure.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/is-the-rate-of-skin-reactions-to-febuxostat-increased-in-patients-with-a-history-of-skin-intolerance-to-allopurinol-a-retrospective-hospital-based-study-involving-101-patients-consecutively-treated/