Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening

• Published in: Canadian Medical Association journal (CMAJ) 2010-03, Vol.182 (5), p.476-480
• Main Authors: Fernando, Suran L, Broadfoot, Andrew J
• Format: Article
• Language: English
• Subjects: Adult; Adverse and side effects; Alleles; Allopurinol - adverse effects; Anticonvulsants - adverse effects; Asian Continental Ancestry Group - genetics; Asian people; Carbamazepine - adverse effects; China; Cyclosporine - therapeutic use; Disease; Drug Hypersensitivity - genetics; Drugs; Genes; Genetic Predisposition to Disease; Genetic Testing; Gout Suppressants - adverse effects; HLA-B Antigens - genetics; Humans; Immunization, Passive; Immunosuppressive Agents - therapeutic use; Keratoconjunctivitis - chemically induced; Keratoconjunctivitis - drug therapy; Male; Practice; Risk factors; Stevens-Johnson syndrome; Stevens-Johnson Syndrome - chemically induced; Stevens-Johnson Syndrome - drug therapy; Stevens-Johnson Syndrome - etiology; Urethritis - chemically induced; Urethritis - drug therapy
• ISSN: 0820-3946; 1488-2329
• DOI: 10.1503/cmaj.090401

Stevens-Johnson syndrome and toxic epidermal necrolysis are considered two forms of the same disease. They are distinguished arbitrarily by the extent of epidermal detachment (i.e., less than 10% in Stevens-Johnson syndrome, 10%-30% in overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis, and greater than 30% in toxic epidermal necrolysis).2 Blistering erosions of the skin and mucous membranes result from apoptosis of keratinocytes.3 The reaction usually begins one to three weeks after treatment is started.4 Incidence of overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis is low and estimated to be one to two patients per million inhabitants per year.5 Mortality, however, is high at 10% for Stevens-Johnson syndrome and 50% for toxic epidermal necrolysis.6 The most commonly offending drugs vary among different ethnic populations. In Western countries, the most commonly implicated agents of overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis are nonsteroidal antiinflammatory drugs (NSAIDs) and sulphonamides.8 By contrast, carbamazepine is the leading cause of Stevens-Johnson syndrome in Southeast Asian countries, including India, Malaysia, Singapore, Taiwan and Hong Kong.9 Carbamazepine in Western countries causes more instances of drug-induced hypersensitivity syndrome than overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis. Allopurinol is also a frequent cause of overlapping Stevens- Johnson syndrome and toxic epidermal necrolysis and of drug-induced hypersensitivity syndrome, but it does not appear to have an ethnic bias.10 Health Canada and the United States Food and Drug Administration (FDA) have issued warnings for carbamazepine, stating that persons with ancestry in genetically atrisk populations should be screened for the presence of HLAB* 1502 before initiating treatment.18,19 Genetic screening for HLA-B*1502 in a high-risk population such as the Han Chinese has a 100% sensitivity and 97% specificity and its presence confers a 7.7% positive predictive value for carbamazepine- induced overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis, whereas its absence has a 100% negative predictive value.9 The odds ratio of carbamazepine- induced overlapping Stevens-Johnson syndrome and toxic epidermal necrolysis in test-positive Chinese patients to test-negative patients is > 3200. In 3% of patients who are test-positive, the disease may never develop with exposure to carbamazepine.