Allopurinol hypersensitivity syndrome L51.1

Allopurinol hypersensitivity syndrome is a rare (04% of cases) hypersensitivity syndrome (AHS) that includes the following clinical pictures: Stevens-Johnson syndrome, toxic epidermal necrolysis and morbilliform or multiforme drug reactions with eosinophilia and systemic symptoms.

This affects 1:1000 patients who are prescribed allopurinol.

Patients typically present with an acute exanthema (morbilliform exanthema, erythema multiforme, exfoliative dermatitis) associated with renal dysfunction, hepatic impairment and eosinophilia. The syndrome can occur within weeks to months after drug exposure, but most cases occur within 8-9 weeks.

Treatment includes discontinuation of allopurinol and supportive measures.

Systemic steroids and immunomodulatory therapies may be useful. Specific treatment depends on whether the patient has Stevens-Johnson syndrome, toxic epidermal necrolysis or a drug reaction with eosinophilia and systemic symptoms. Patients who develop AHS should not be re-exposed to allopurinol; however, alternative therapies to lower uric acid (e.g. febuxostat) may be considered(Khanna D et al. 2012).

The reported mortality rate is between 20 % and 25 % (Yaseen W et al. 2023).

The guidelines recommend screening for the HLA-B*58:01 allele in high-risk populations before starting allopurinol treatment. The risk of AHS is almost 100 times higher in carriers of the HLA-B*58:01 allele than in non-carriers. Populations with high allele frequencies include people of Han Chinese (6%-8%), Korean (12%) and Thai (6%-8%) descent. Testing for the allele is widespread in Canada. In people with a negative test result for the HLA-B*58:01 allele, the risk of AHS is low unless other risk factors are present (Yaseen W et al. 2023).

Chronic kidney disease and cardiovascular disease are clinical risk factors for AHS. Population-based studies have shown that patients with chronic kidney disease and cardiovascular disease treated with high doses of allopurinol (> 100 mg/day) have an 11-fold increased risk of hospitalization for AHS (Yokose C et al.(2019) Heart disease and the risk of allopurinol-associated severe cutaneous adverse reactions: a general population-based cohort study. (Yokose C et. al. 2019) Slow titration of low-dose allopurinol could reduce the risk of AHS.

Although the relationship between maintenance dose and AHS risk is controversial, allopurinol should be started at a low dose (≤ 100 mg/day) and an even lower dose (≤ 50 mg/day) in patients with stage 4 or higher chronic kidney disease.

1. Khanna D et al. (2012) American College of Rheumatology. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic non-pharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 64:1431-1446.
2. Yaseen W et al. (2023) Allopurinol hypersensitivity syndrome. CMAJ 195:E483.
3. Yokose C et al.(2019) Heart disease and the risk of allopurinol-associated severe cutaneous adverse reactions: a general population-based cohort study. CMAJ 191: E1070-1077.)