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Epidermal growth factor (EGFR)-inhibitors have emerged as the primary therapy in advanced solid tumor malignancies because of improvement in survival with overall favorable side effect profile. However, 50–90% of patients treated with EGFR-inhibitors develop a follicular or acneiform rash, which can be symptomatic and source of psychosocial distress, negatively impacting quality of life. As this acneiform rash is a well-recognized cutaneous toxicity of EGFR-inhibitors, a treatment algorithm has been proposed for management based on severity. However, treatment options for EGFR-inhibitor induced rash may not be generalizable to African Americans whose differences in skin biology and sensitivity present pathophysiologic challenges. Herein, we present a case of an African American patient who developed this acneiform rash while on cetuximab. We also review the few cases that have been reported in the literature of EGFR-inhibitor rash in African Americans, highlighting important management considerations in this patient population. J Drugs Dermatol. 2020;19(9):894-896. doi:10.36849/JDD.2020.5275.

Objectives: To examine associations of race/ethnicity and purported risk factors with hospitalised allopurinol-associated severe cutaneous adverse reactions (AASCARs)., Methods: We used US Medicaid data to identify incident allopurinol users between 1999 and 2012. We examined the risk of hospitalised AASCARs according to race/ethnicity and purported key risk factors and calculated relative risks (RR)., Results: Among 400 401 allopurinol initiators, we documented 203 hospitalised AASCAR cases (1 in 1972 initiators). The average AASCAR hospitalisation was 9.6 days and 43 individuals (21%) died. The multivariable-adjusted RRs for AASCARs among blacks, Asians and Native Hawaiians/Pacific Islanders compared with whites or Hispanics were 3.00 (95% CI 2.18 to 4.14), 3.03 (95% CI 1.72 to 5.34) and 6.68 (95% CI 4.37 to 10.22), respectively. Female sex, older age (≥60 years), chronic kidney disease and initial allopurinol dose (>100 mg/day) were independently associated with a 2.5-fold, 1.7-fold, 2.3-fold and 1.9-fold higher risk of AASCAR, respectively. In our combined demographic analysis, older women (≥60 years) of a high-risk race/ethnicity (blacks, Asians or Native Hawaiians/Pacific Islanders) had over a 12-fold higher risk of hospitalised AASCARs than younger men of a low-risk race/ethnicity (whites or Hispanics) (multivariable-adjusted RR, 12.25; 95% CI 6.46 to 23.25)., Conclusions: This racially diverse (yet mostly white) cohort study indicates that the risk of hospitalised AASCAR is rare overall, although blacks, Asians and Native Hawaiians/Pacific-Islanders have a substantially higher risk of hospitalised AASCARs, particularly among older women. These data also support the practice of initiating allopurinol at a low dose (eg, ≤100 mg/day)., Competing Interests: Competing interests: HKC has received research grants from Pfizer and Astra-Zeneca to Massachusetts General Hospital for unrelated studies and served as a consultant for Takeda Pharmaceuticals, Selecta, Horizon and Ironwood. SCK has received research grants to the Brigham and Women’s Hospital from Pfizer, AstraZeneca, Bristol-Myers Squibb and Roche for unrelated studies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs., Methods: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed., Results: We report an association between a rare variant in the complement factor H-related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10 -11 ; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients., Conclusions: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Allopurinol is widely used for hyperuricemia and gouty arthritis, but is associated with cutaneous adverse drug reactions (CADRs). Recently, HLA-B*58:01 allele was identified as a strong genetic marker for allopurinol-induced CADRs in Han Chinese. However, the magnitude of association and diagnosis value of HLA-B*58:01 in allopurinol-induced CADRs remain inconclusive. To investigate this inconsistency, we conducted a meta-analysis of 21 pharmacogenetic studies, including 551 patients with allopurinol-induced CADRs, and 2,370 allopurinol-tolerant controls as well as 9,592 healthy volunteers. The summary OR for allopurinol-induced CADRs among HLA-B*58:01 carriers was 82.77 (95% CI: 41.63 - 164.58, P < 10-5) and 100.87 (95% CI: 63.91 - 159.21, P < 10-5) in matched and population based studies, respectively. Significant results were also observed when stratified by outcomes and ethnicity. Furthermore, the summary estimates for quantitative analysis of HLA-B*58:01 allele carriers in allopurinol-induced CADRs screening were as follows: sensitivity, 0.93 (95% CI: 0.85 - 0.97); specificity, 0.89 (95% CI: 0.87 - 0.91); positive likelihood ratio, 8.24 (95% CI: 6.92 - 9.81); negative likelihood ratio, 0.084 (95% CI: 0.039 - 0.179); and diagnostic odds ratio, 98.59 (95% CI: 43.31 - 224.41). The AUSROC was 0.92 (95% CI: 0.89-0.94), indicating the high diagnostic performance. Our results indicated that allopurinol-SCAR is strongly associated with HLA-B*58:01, and HLA-B*58:01 is a highly specific and effective genetic marker for the detection allopurinol-induced CADRs, especially for Asian descents.

Purpose: To describe the clinical characteristics and genetic background of allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in South Korea., Methods: This is a prospective, noncomparative case series. Visual acuity, detailed medical history, ocular findings, and systemic manifestations of 5 patients (10 eyes) with allopurinol-induced SJS/TEN were recorded. The acute ocular involvement score and the chronic ocular manifestation score were graded on scales of 0-3 and 0-39, respectively, based on severity. Human leukocyte antigen (HLA) genotyping was also performed during the hospitalization., Results: Three patients were diagnosed with SJS, and 2 with TEN. Mild ocular involvement with only conjunctival hyperemia (acute ocular involvement score ≤ 1) was present in all 10 eyes during the acute stage. Patients were treated with systemic steroids and topical antibiotics, steroids, and preservative-free artificial tears, with rinsing of the ocular surface, in the acute stages of SJS/TEN. In the final follow-up, none of the patients had developed severe chronic ocular complications (chronic ocular manifestation score ≤ 8), including keratinization, corneal conjunctivalization, mucocutaneous junction involvement, or symblepharon. One patient developed bilateral persistent epithelial defects 3 months after the disease onset, which healed after conservative treatment, leaving a bilateral central corneal haze. HLA genotyping showed that 4 of the 5 patients (80%) were positive for HLA-B*58:01., Conclusions: Allopurinol-induced SJS/TEN might not cause serious acute or chronic complications of the ocular surface. In addition, our HLA genotyping results are consistent with previous studies reporting a strong association between HLA-B*58:01 and allopurinol-induced SJS/TEN among Koreans.

In March 2012, a Salvadoran-American boy aged 7 years living in Maryland developed three slightly painful, well-demarcated, flat, gray-brown patches on his torso. A dermatologist in Washington, DC, suspected a fixed drug eruption (an erythema multiforme-like adverse drug reaction that occurs in the same location each time the person uses a particular medication). The child had recently taken a cough and cold remedy, Baczol Antigripal, which was made in El Salvador and purchased in a Maryland suburb of Washington, DC, without a prescription. The Baczol Antigripal ingredients included the sulfonamide-containing antibiotic trimethoprim-sulfamethoxazole (TMP/SMX), which is a common cause of fixed drug eruption. In June 2013, another Salvadoran-American child, a girl aged 14 years living in northern Virginia, was evaluated for a similar fixed drug eruption likely caused by a Baczol product purchased near her home. In August 2013, staff members from the Children's National Medical Center investigated the availability of Baczol products in grocery stores in Salvadoran neighborhoods of Washington, DC, and neighboring suburbs. TMP/SMX-containing products were found in seven of 19 stores.

Infection with human immunodeficiency virus (HIV) remains a significant problem globally. Early diagnosis and treatment with antiretroviral drugs has considerably improved health outcomes and decreased disease-related morbidity. HIV infection is associated with a wide range of skin disorders enabling dermatologists to diagnose HIV as well as associated opportunistic infections early in the course of disease. Despite concerted efforts by international health organizations to limit disease incidence, the prevalence of HIV infection remains high and is highest in sub-Saharan Africa. The diagnosis of HIV-related skin diseases is challenging as immunosuppression often results in atypical disease presentation. In addition, the clinical presentation will vary in pigmented skin types. The aim of this article is to describe disease variation in pigmented skin types., (© 2013 The Author BJD © 2013 British Association of Dermatologists.)

Background: Allopurinol has been reported as a common cause of severe cutaneous adverse reactions (SCARs). Recent studies in various populations suggest that HLA-B*58:01 is a strong genetic marker for allopurinol-induced SCAR, especially in populations with a high frequency of HLA-B*58:01., Objectives: To confirm the association link between HLA-B*58:01 and hypersensitivity reactions attributed to allopurinol use in Han Chinese patients in Hong Kong., Methods: We performed a case-control study to investigate whether the HLA-B*58:01 allele predisposes to allopurinol-induced SCAR in Han Chinese patients in Hong Kong. The HLA-B*58:01 genotyping was performed in 20 patients with allopurinol-induced SCAR or erythema multiforme major (EMM; n = 1) and in 30 patients tolerant to allopurinol., Results: All of the 19 patients with allopurinol-induced SCAR examined but not the patient with EMM carried HLA-B*58:01 whereas only four (13%) of the control patients had this allele. The positive rate of the HLA-B*58:01 was significantly higher in the cases than in the allopurinol-tolerant control group [odds ratio (OR) 123·5, 95% confidence interval (CI) 12·8-1195·1; P < 1 × 10(-4) ] and was even higher after removal of the patient with EMM (OR 229·7, 95% CI 11·7-4520·4). The sensitivity and specificity of the HLA-B*58:01 allele for prediction of allopurinol-induced SCAR were 100% and 86·7%, respectively., Conclusions: This study confirmed the strong association between the HLA-B*58:01 and allopurinol-induced SCAR in Hong Kong Han Chinese patients. A screening test for the HLA-B*58:01 allele should effectively reduce the risk for allopurinol-induced SCAR in Chinese populations., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Although the US FDA recommends screening for HLA-B*1502 allele in most of Asian ancestry before initiating carbamazepine therapy, the HLA associations with carbamazepine hypersensitivity in non-Chinese Asian populations remain unclear. This study investigated the association between the HLA class I genotype and carbamazepine-induced severe cutaneous adverse reaction (SCAR) in Koreans., Methods: Twenty-four patients who had developed carbamazepine-induced SCAR (7 Stevens-Johnson syndrome (SJS), 17 drug hypersensitivity syndrome (HSS)), 50 carbamazepine-tolerant controls from the Korean Pharmacogenetic Adverse Drug Reaction Research Network and data of 485 Korean general population from a previously published study were recruited. HLA-A, -B, and -C genotyping was performed by direct DNA sequence analysis., Results: Only one of the seven SJS patients was positive for the B*1502 allele, but the frequency of B*1511 was much higher in the patients with CBZ-SJS than in the CBZ-tolerant control patients (P=0.011, P(c)=not significant; OR=18.0(2.3-141.2)). The frequencies of A*3101 in carbamazepine-induced HSS and SCAR were significantly higher than those in carbamazepine-tolerant controls (P(c)=0.011, OR=8.8(2.5-30.7) and P(c)=0.013, OR=7.3(2.3-22.5), respectively). The frequencies of B*1511 in carbamazepine-SJS and A*3101 in carbamazepine-HSS/SCAR were significantly higher than those in the general population., Conclusions: HLA-B*1502 does not seem to be an effective predictive marker for carbamazepine-induced SCAR, while HLA-B*1511 and A*3101 was associated with carbamazepine-induced SJS and HSS/SCAR respectively in the Korean population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Skin lesions are often associated with human immunodeficiency virus (HIV) infection, reflecting the immunocompromised status of the individual. We investigated the relationship between skin lesions and immune function in a retrospective study of 796 Chinese HIV patients with and without highly active antiretroviral therapy (HAART). Of the 651 patients who had not received HAART, we found that 531 (81.6%) had apparent skin lesions. The incidence of infectious skin diseases (fungi, viruses, bacteria, spirochetes and parasites) and non-infectious skin diseases (excluding skin cancer) was 68.8% and 34.9%, respectively. Mean CD4(+) T-cell counts and CD4(+)/CD8(+) ratios were lower in patients with skin lesions than in patients without lesions (178 ± 96/µl vs. 306 ± 189/µl (p < 0.05) and 0.22 vs. 0.34 (p < 0.01), respectively). Candidiasis (25.8%), eczema (19.2%), nodular prurigo (13.8%), dermatophyte infections (10.6%) and herpes zoster (9.4%) were most common in Chinese patients with HIV. Among the 145 patients who had started HAART, there was a significantly lower prevalence of skin diseases (29.0%), although drug eruptions (12.4%) were more commonly observed. These findings indicate that HAART often reduces the incidence of infectious and non-infectious skin lesions in patients with HIV, but can itself be the cause of drug eruptions.

Previous studies have found a strong association between HLA-B*1502 and carbamazepine-induced Stevens-Johnson syndrome in Asian areas including Taiwan, Hongkong and Thailand. This study explores the association between HLA-B*1502 allele and carbamazepine-induced cutaneous adverse reactions in Han Chinese of southern China mainland, and find the genetic marker that can predict carbamazepine-induced cutaneous adverse reactions. HLA-B*1502 allele genotyping was performed by a polymerase chain reaction-sequence specific primers (PCR-SSP) method in 48 Han Chinese subjects who had carbamazepine-induced cutaneous adverse reactions, including 9 severe cutaneous adverse reaction patients with Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) and 39 cutaneous adverse reaction patients with maculopapular eruption (MPE). Meanwhile 80 carbamazepine-tolerant controls and 62 healthy individuals were also tested. The frequency of HLA-B*1502 allele among SJS/TEN patients (100%) is significantly higher than carbamazepine-tolerant controls (13.75%, P<0.001) and healthy individuals (17.74%, P<0.001). But the frequency between MPE patients and carbamazepine-tolerant controls (25.64% vs.13.75%, P=0.110) did not have any significant difference. The data showed that HLA-B*1502 allele is strongly associated with carbamazepine-induced SJS/TEN but not MPE in Han Chinese of southern China mainland., (Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Drug-induced hypersensitivity reactions are of major medical concern because they are associated with high morbidity and high mortality. In addition, individual patients' reactions are impossible to predict in each patient. In the field of severe cutaneous adverse drug reactions (cutaneous ADR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DHIS) or drug rash with eosinophilia and systemic symptoms (DRESS), major advances have recently been gained through studies of an association between HLA alleles and drug hypersensitivity induced by specific drugs. The results of these pharmacogenomic studies allow prediction of the risk of adverse reactions in patients treated with certain drugs, including carbamazepine and other aromatic antiepileptic drugs, allopurinol and abacavir. However, different ethnic populations show variations in the genetic associations. A strong association between carbamazepine-induced SJS/TEN and HLA-B*1502 has been found in Southeast Asian patients but not in Caucasian and Japanese patients. Moderate associations between aromatic amine anticonvulsants and other HLA alleles have been proposed in Japanese patients. In contrast, HLA-B*5801 was found to be associated with allopurinol-induced cutaneous ADR, including SJS/TEN and DIHS/DRESS, in Caucasian and Asian patients, including the Japanese. These differences may, at least in part, be due to the differences in allele frequency in different ethnic populations. This article reviews the progress in pharmacogenomics, associated mainly with carbamazepine and allopurinol in different ethnic populations. Pharmacogenetic screening based on associations between adverse reactions and specific HLA alleles helps to avoid serious conditions associated with drug hypersensitivity., (© 2011 Japanese Dermatological Association.)

A previous study conducted in Taiwan found a 100% association between HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals.

Setting: United Kingdom, 1978-1992., Objective: To assess the incidence and type of reactions to antituberculosis drugs in an unselected series of patients., Design: All patients treated for tuberculosis had details of drug treatment, durations and side-effects requiring alteration of treatment available. The data was compiled retrospectively for 1978-1980 patients and prospectively thereafter. Analysis of drug reactions was by drug, total months drug use, by age, sex and ethnic group, and reaction type., Results: Of 1317 patients 67 (5.1%) had 70 reactions to antituberculosis drugs requiring modification of treatment. The frequency of drug reactions increased from 2.3% at age 0-19 to 4.6% at age 20-39, 7.1% for age 40-59 and to 8.4% for those aged 60 and over. Females had significantly higher reactions rates than males. White patients had higher reaction rates than Pakistani and Indian patients, mainly due to the average age being greater., Conclusion: The drug reaction rate of 5.1% in this largely prospective study is lower than that reported in other unselected series in the UK and other countries.

All patients seen in the Contact Dermatitis Clinic of the National Skin Centre, Singapore (and the former Middle Road Hospital) between January 1986 and December 1990 were analysed retrospectively. 5557 patients comprising 2634 (47.4%) males and 2923 (52.6%) females were patch tested. 3154 (56.8%) patients had 1 or more positive reactions. The majority of the patients were Chinese (78.0%), followed by Malays (11.5%), Indians (8.1%) and other minority races (2.4%). The majority of positive reactions belonged to the 21-40 age group. The incidence of positivity decreased after 60 years. The commonest allergens responsible were nickel (17.7%), fragrance (13.3%), neomycin (6.9%), colophony (6.6%) and proflavine (6.5%). Both neomycin and proflavine were commonly used as over-the-counter medicaments. Compared to an earlier report in 1988, there were differences in the incidence of contact sensitivity to some allergens. Potassium dichromate, which used to be a common allergen, was less common. Some allergens (carba-mix, naphthyl-mix, caine-mix and PCMX) have been removed from our standard series as they were uncommon causes of contact allergy. Thimerosal and Amerchol L-101 were added in their place.

Of patients patch tested at a contact dermatitis clinic between 1985 and 1986, 22.5% (379/1685) had medicament sensitivity. The prevalence in men was 22.8% (193/847) and in women, 22.1% (186/838) (difference not significant). The rate appears to increase with age, 17.9% (216/1205) for patients less than 40 years old and 34.0% (163/480) for patients over 39 years old (difference, p less than 0.001). The differences in prevalence between Chinese (22.8%), Malay (21.3%), Indians (20.4%), and others (33.3%) were not statistically significant. Common sensitizers included neomycin (7.8%), proflavine (7.1%), clioquinol (4.3%), colophony (3.3%), and wool alcohol (2.7%). Proflavine sensitivity was significantly more common in men (9.9%) than women (4.2%) (p less than 0.001). Most dermatitis occurs on the limbs (upper limbs, 44.3%; lower limbs, 43.0%). Facial dermatitis was more common in women (37.4%) than men (19.2%) (difference not significant).

Chinese patients with cutaneous eruption due to antibiotics were found to be positively associated with HLA-BW46 (RR = 2.5; 95% confidence limit 1.2-4.9) and negatively associated with HLA-B40 (RR = 0.46; 95% confidence limit 0.22-0.98). The association with HLA-BW46 was even higher in patients with ampicillin sensitivity (RR = 3.5; 95% confidence limit 1.4-9.0).