Phenytoin (diphenylhydantoin) is a widely prescribed antiepileptic drug and remains the most frequently used first-line antiepileptic drug in hospitalized patients.^1,2 Although effective for treating neurological diseases, phenytoin can cause cutaneous adverse reactions ranging from mild rash (maculopapular exanthema) to life-threatening severe cutaneous adverse reactions.^3-6 Phenytoin-related severe cutaneous adverse reactions include drug reactions with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).^4-6 Stevens-Johnson syndrome and TEN are variants of the same mucocutaneous blistering reaction disease and carry high morbidity and mortality (10%-50%).^4-6 DRESS, also known as drug-induced hypersensitivity syndrome, is characterized by generalized maculopapular eruptions, high fever, eosinophilia, atypical lymphocytes, and visceral involvement and has a mortality rate of approximately 10%.^6,7 Phenytoin-related severe cutaneous adverse reactions frequently impair the internal organs, leading to the highest mortality among the different antiepileptic drug–related cutaneous reactions.⁵

BACKGROUND. Cytotoxic T lymphocyte–mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. METHODS. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. RESULTS. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%–62.5% decrease after treatment; all P < 0.05) and increased the Treg population (2-fold percentage increase after treatment; P = 0.002), which was related to mortality in severe SJS-TEN. CONCLUSIONS. The anti–TNF-α biologic agent etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. TRIAL REGISTRATION. ClinicalTrials.gov NCT01276314. FUNDING. Ministry of Science and Technology of Taiwan.

Allopurinol was approved by the US Food and Drug Administration in 1966 for treating gout and remains a cornerstone of the treatment of uric acid nephrolithiasis and hyperuricemia caused by cancer or chemotherapy.^1,2 Although it is generally well tolerated, allopurinol is one of the most common drugs associated with life-threatening hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms.^3-8 Stevens-Johnson syndrome and toxic epidermal necrolysis are variants of the same mucocutaneous blistering reaction disease and carry high morbidity and mortality.³ Drug rash with eosinophilia and systemic symptoms is a nonblistering cutaneous adverse reaction with systemic manifestations, including eosinophilia, leukocytosis, fever, hepatitis, and renal dysfunction.^8,9 In previous studies,^3,4,7 allopurinol hypersensitivity was found in 1 of 260 patients (approximately 0.4% of new users of allopurinol) and was a leading cause of severe cutaneous adverse reactions in several countries. Allopurinol hypersensitivity–related mortality was reported to be as high as 18% to 32%, and its long-term complications (eg, renal failure and eye sequelae) are frequently observed in survivors.^3,7,10,11

Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 ofHLA-Bgene (termsHLA-B∗57:01). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles:HLA-B∗38:02andHLA-DRB1∗08:03. In addition,HLA-B∗15:02allele was reported to be related to carbamazepine-induced SJS/TEN, andHLA-B∗57:01in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.