Allopurinol Hypersensitivity (AHS)

Description

Allopurinol hypersensitivity syndrome (AHS) is a severe and sometimes life-threatening adverse drug reaction. Although AHS is rare, the number of patients with gout requiring allopurinol is high, and there are sufficient overall cases of AHS to warrant consideration of preventive measures.

Allopurinol hypersensitivity syndrome typically occurs in persons with preexisting kidney failure. Weeks to months after allopurinol is begun, the patient develops a morbilliform eruption or, less commonly, develops one of the far more serious and potentially lethal severe cutaneous adverse reactions viz., the DRESS syndrome, Stevens Johnson syndrome, or toxic epidermal necrolysis.

Allopurinol is the most commonly prescribed drug to treat gout, a disease characterized by the buildup of uric acid crystals in certain body tissues, as well as hyperuricemia.  It inhibits the action of a key enzyme involved in uric acid formation, xanthine oxidase.  However, in some individuals, allopurinol can cause severe cutaneous adverse reactions (SCAR, also known as allopurinol hypersensitivity reaction).

The symptoms of SCAR include rash with eosinophilia, fever, leukocytosis, progressive kidney failure, hepatitis, and the development of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS).  Allopurinol-induced SCAR can be life-threatening, with up to 25% mortality, and can develop within a few weeks or months after commencement of allopurinol treatment.

Clinical Utility

Allopurinol hypersensitivity is strongly associated with the presence of the HLA-B*58:01 allele, most commonly found in patients of Asian and African ancestry.  Because allopurinol hypersensitivity can cause such severe reactions, Clinical Pharmacogenomics Implementation Consortium guidelines recommend testing for the presence of the HLA-B*58:01 allele prior to initiating allopurinol therapy.  If the HLA-B*58:01 allele is detected, use of allopurinol is contraindicated, and an alternative therapy should be considered. Note that the absence of the HLA-B*58:01 allele does not exclude a patient from possessing sensitivity to allopurinol, especially since less severe rashes can occur in 2 to 3% of patients and are not associated with the HLA-B*58:01 allele.  In these cases, FDA guidelines recommend discontinuing allopurinol treatment, even if the patient is negative for the HLA-B*58:01 allele.

Scientific References

• Hershfield MS, Callaghan JT, Tassaneeyakul W, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther. 2013;93(2):153-8.
• Saito Y, Stamp LK, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther. 2016;99(1):36-7.
• Yu KH, Yu CY, Fang YF. Diagnostic utility of HLA-B*5801 screening in severe allopurinol hypersensitivity syndrome: an updated systematic review and meta-analysis. Int J Rheum Dis. 2017;20(9):1057-1071..