Rosaline Chung-Yee Hui

Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese.

AIMS Compared with other categories of drugs, such as antibiotics and NSAIDs, antiepileptic therapies are associated with a high incidence of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We previously reported that carbamazepine (CBZ)-SJS/TEN is strongly associated with the HLA-B*1502 in Han Chinese, which has been confirmed in other Southeast Asian countries where the allele is prevalent. Here, we extend the study of HLA susceptibility to three different antiepileptic drugs, phenytoin (PHT), lamotrigine (LTG) and oxcarbazepine (OXC), which have structure similarity to CBZ. MATERIALS & METHODS We carried out a case-control association study. We enrolled 26 PHT-, six LTG- and three OXC-induced SJS/TEN patients, 113 PHT-tolerant and 67 LTG-tolerant subjects who were on the drug, respectively, for more than 3 months without the adverse reactions, and 93 normal subjects from the general population. The HLA-A, B, C and DRB1 genotypes were determined. RESULTS We found that HLA-B*1502 was present in eight out of 26 (30.8%) PHT-SJS/TEN (OR: 5.1; 95% CI: 1.8-15.1; p = 0.0041), two out of six (33%) LTG-SJS (odds ratio [OR]: 5.1; 95% CI: 0.8-33.8; p = 0.1266) and three out of three (100%) OXC-SJS (OR: 80.7; 95% CI: 3.8-1714.4; p = 8.4 x 10(-4)) patients. In addition, HLA-B*1301, Cw*0801 and DRB1*1602 also showed an association with PHT-SJS/TEN (p = 0.0128-0.0281; OR: 3.0-4.3). CONCLUSION Our results indicate that OXC, PHT and LTG, which possess an aromatic ring just as CBZ does, when causing SJS/TEN, share a common risk allele. Aromatic antiepileptic drugs causing SJS/TEN in HLA-B*1502 carriers may act on a similar pathogenetic mechanism, although other genetic/nongenetic factor(s) may also contribute to the pathomechanism of the disease. We suggest that aromatic antiepileptic drugs, including CBZ, OXC and PHT, should be avoided in the B*1502 carrier and caution should also be exercised for LTG.

Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions

IMPORTANCE The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background  The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations.

Genotype-phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: strength and clinical correlations.

BACKGROUND Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). OBJECTIVE To carry out a comprehensive analysis on the clinical spectrum and HLA genotype-phenotype correlations in CBZ-induced hypersensitivity reactions. METHODS We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. RESULTS CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10(-43); odds ratio (OR) (95% CI)=97.6(42.0-226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10(-5); OR (95% CI)=0.22(0.1-0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10(-3); OR (95% CI)=6.86(2.4-19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0-10.5)). No gene dosage or CBZ dosage effects was observed. CONCLUSION This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype-phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.

Risk and association of HLA with oxcarbazepine-induced cutaneous adverse reactions in Asians

Objective: To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in Asian populations (Chinese and Thai). Methods: We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database. Results: We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6  drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10−10; odds ratio 27.90; 95% confidence interval [CI] 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584). Conclusions: Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.

Identifying prognostic factors for drug rash with eosinophilia and systemic symptoms (DRESS)

Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous drug reaction. Although the severity-of-illness score (SCORTEN) has been proposed for toxic epidermal necrolysis (TEN) for 10 years, a prognostic score for DRESS is still lacking. To identify prognostic factors of DRESS patients during hospitalization in one medical health system in Taiwan. We retrospectively reviewed all patients with DRESS diagnosed by dermatologists in Chang Gung Memorial Hospital (CMGH) Health System from 2001 to 2010. To study prognostic factors, we collected data at early disease and maximal disease stages. 91 individuals, including 13 dead patients, were evaluated. Five independent prognostic factors of death were found: heart rate > 90/min, white blood cells >12,000/mm(3) and respiratory rate >20/min (at early disease stage), coagulopathy and gastrointestinal bleeding (at maximal disease stage). In addition, systemic inflammatory response syndrome (SIRS) occurred at a much higher percentage among non-survivors throughout hospitalization. We found tachycardia, leukocytosis, tachypnea, coagulopathy, gastrointestinal bleeding and SIRS were associated with a poor outcome in DRESS patients. DRESS patients with persistent SIRS during hospitalization were also associated with a higher mortality risk. Early recognition and prompt intervention in these factors may improve outcome.

Histopathological analysis and clinical correlation of drug reaction with eosinophilia and systemic symptoms (DRESS)

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe cutaneous adverse drug reaction. However, its histopathological features have not been well defined.

Prurigo pigmentosa: a clinicopathological study and analysis of associated factors.

Background  Prurigo pigmentosa (PP), a rare inflammatory disease of the skin, is mostly reported in the ethnic Japanese population. Its pathogenesis remains unclear. The chronic and recurrent nature of PP implies a possible role of viral infection in the pathogenesis. The anti‐inflammatory mechanism of doxycycline, which is well documented as a good treatment for PP, is related to the suppression of interleukin expression.

Long-term follow-up study of clear cell papulosis

BACKGROUND Clear cell papulosis (CCP) was described as a new entity in 1987. Since then, only case reports or small case series have appeared in the literature and the long-term outcome of CCP remains unknown. OBJECTIVES The aim of this study was to review cases of CCP diagnosed at our institution and to investigate their outcome. METHODS Nineteen patients given a diagnosis of CCP more than 6 years previously were identified. Their medical records and histopathologic findings were reviewed. RESULTS With a median follow-up duration of 11.5 years, regression of skin lesions was observed in 85.7% of patients. Persistence of skin lesions 11.5 years after diagnosis was confirmed histopathologically in one case, with a reduction in clear cell density. LIMITATIONS Retrospective nature of the study is a limitation. CONCLUSION No treatment is necessary for CCP because the skin lesions are asymptomatic and most patients experience at least partial regression.

Fas/Fas Ligand Mediates Keratinocyte Death in Sunitinib-Induced Hand-Foot Skin Reaction

Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.