Allopurinol-induced serious cutaneous adverse reactions and the role of genotyping

HSA, together with the Ministry of Health (MOH), have jointly issued a Dear Healthcare Professional Letter (DHCPL) on 23 March 2016 to remind healthcare professionals of the risk of allopurinol-induced serious cutaneous adverse reactions (SCAR), and inform on the role of genotyping prior to the initiation of allopurinol. This article shares the summary of evidence presented on allopurinol-induced SCAR, genetic associations reported and the role of genotyping prior to therapy initiation.

Allopurinol is an efficacious urate-lowering therapy (ULT) which has been registered in Singapore since 1989 and is recommended as first-line therapy for gout patients who have two or more gouty attacks per year, presence of tophus, radiographic changes of gout, and urolithiasis.¹Globally, increasing incidence but sub-optimal management of gout has been reported.^2,3

Allopurinol, while effective in treating chronic gout, is associated with rare and potentially fatal SCAR, such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Allopurinol is one of the leading causes of drug-induced SCAR reported to HSA. From 2010 to 2014, HSA received 70 cases of allopurinol-induced SCAR, seven of which were fatal. A review of local SCAR reports received by HSA and the published local and international studies found that the majority of SCAR occurred within three months, with a median onset of 3-4 weeks upon the initiation of therapy.^4--7 Risk factors of allopurinol-induced SCAR include HLA-B*5801 allele, starting dose of allopurinol and renal impairment. A low starting dose, no greater than 100mg per day, for gout has been recommended to minimise the risk of allopurinol-induced SCAR.¹

Summary of evidence on HLA-B*5801 and allopurinol-induced SCAR

The recommendations on the use and monitoring of allopurinol and the consideration for HLA-B*5801 allele genotyping are based on the findings listed below.

• A HSA-initiated, local, multi-centre, case-control study conducted at Singapore General Hospital, National University Hospital, Changi General Hospital and the National Skin Centre found a strong association between HLA-B*5801 allele and allopurinol-induced SCAR (Odds ratio=100, p=0.0004) i.e. patients carrying the HLA-B*5801 allele have higher risk of developing allopurinol-induced SCAR (100 times) compared to one who does not have the allele. This is consistent with international data which showed that HLA-B*5801 carriers have an elevated risk of developing SCAR when taking allopurinol.

• The PPV is low at 2% and the Negative Predictive Value (NPV) of the genotyping test is nearly 100%. This means that among 100 allopurinol users with positive HLA-B*5801, two patients may develop SCAR, while among 100 patients tested negative, almost all patients are unlikely to develop SCAR, provided there are no other non-genetic factors involved.

• The frequency of HLA-B*5801 prevalence is estimated at 18.5% in Singapore (approximately 1 in 5 Singaporeans or 1 in 5 Chinese, 1 in 15 Malays and 1 in 25 Indians).

• There are limited alternative ULTs available locally. Uricosuric agents such as probenecid and benzbromarone are only effective in preserved renal function (creatinine clearance > 50ml/minute for probenecid or >20ml/min for benzbromarone). Both are contraindicated in patients with a history of urolithiasis and hepatotoxicity has been reported with benzbromarone.¹ A new ULT, febuxostat, has been recently approved in Singapore in February 2016. Rare but serious cases of hypersensitivity reactions to febuxostat, including SJS and acute anaphylactic shock, have been reported overseas. In some cases, the reactions occurred in patients with a prior history of hypersensitivity to allopurinol and/or pre-existing renal disease.

• Patients tested negative for HLA-B*5801 may still be at risk of developing allopurinol-induced SCAR. Other non-genetic risk factors associated with SCAR, such as renal impairment and starting dose of allopurinol have been reported.⁸

• A cost-effectiveness analysis by Duke-NUS Graduate Medical School, in collaboration with HSA and National University Health System (NUHS), concluded that genotyping all gout patients prior to initiation of allopurinol is currently not cost-effective for Singapore’s overall population from a health systems perspective.⁹

HSA’s advisory

HSA has received nine allopurinol-induced SCAR reports between March and August 2016, since the issuance of the DHCPL. Majority of these cases reported the use of allopurinol for gout in Chinese patients.

In view of the seriousness and fatalities reported with allopurinol-induced SCAR, healthcare professionals are advised to use allopurinol with caution; start at a low dose, titrate and monitor accordingly based on clinical indications.

As early signs of rash and skin reactions may be indicative of a more serious reaction such as SCAR, healthcare professionals are advised to educate their patients on early recognition of allergic reactions, the importance of prompt withdrawal of the drug at the first sign of rash and to seek medical advice.

While genotyping is not required as standard of care for new patients starting allopurinol, doctors may consider genotyping patients who have other pre-existing risk factors for allopurinol-induced SCAR such as renal impairment and to identify the patients who are at a greater risk of allopurinol-induced SCAR. While it is likely that patients who have tested negative for this allele may not develop allopurinol-induced SCAR, the possibility of developing allopurinol-induced SCAR due to other risk factors cannot be ruled out. Genetic testing, when ordered for at-risk patients, should not substitute for appropriate clinical vigilance and patient management.

Healthcare professionals are encouraged to continue reporting suspected adverse drug reactions associated with allopurinol to the Vigilance and Compliance Branch of HSA and include information on indication of gout, renal function, starting dose and genotype status of the patient, to facilitate close monitoring of this safety issue.

Where to test

The HLA-B*5801 test is available at KK Women’s and Children’s Hospital (KKH) DNA Diagnostic and Research Lab at $200 per test (excluding GST) and is not subsidised. The estimated turnaround time is one to two working days. For this test, 3ml of blood must be collected in an EDTA sample tube and kept at 4°C before despatch.

Table 1: Information on DNA testing at KKH DNA Diagnostic and Research Laboratory

We would like to thank Dr Bernard Thong and Dr Teng Gim Gee for their inputs to this article.

References

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2. Nat Rev Rheumatol. 2015; 11: 649-62

3. Annals of the rheumatic diseases. 2014; 74: 661-7

4. SMJ. 2008; 49: 384-7.

5. Acta derm Venereol. 2012;92: 62-6.

6. Expert Rev Clin Immunol. 2011; 7: 803-13

7. Drug Safety. 2013; 36: 953-80.

8. Arthritis Rheum. 2012; 64: 2529-36.

9. Pharmacogenomics. 2015; 16: 1781-93.