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Extensive scientific evidence consistently demonstrates the clinical validity and utility of HLA-B*15:02 pre-screening in averting severe cutaneous adverse reactions (SCARs), namely Stevens-Johnson syndrome and toxic epidermal necrolysis, associated with carbamazepine or oxcarbazepine usage. Current practice guidelines and drug labeling actively advocate for pharmacogenetic pre-screening before initiating these antiepileptic drugs (AED), with particular emphasis on patients of Asian descent. However, there is a potential need to strengthen compliance with these recommendations. This retrospective study aimed to describe the pharmacogenetic pre-screening, documentation, and SCARs incidence for patients of Asian ancestry initiated on carbamazepine or oxcarbazepine at a large Northeastern USA healthcare system. Between 1 July 2016 and August 1, 2021, 27 patients with documented Asian heritage in the electronic health record (EHR) were included. The overall rate of HLA-B*15:02 pre-screening before carbamazepine or oxcarbazepine initiation was 4%. None who underwent pharmacogenetic pre-screening carried the associated HLA-B risk allele, and no SCARs were reported. Notably, pharmacogenetic results were not discretely entered into the EHR, and the results were only found as attached documents in the miscellaneous section of the EHR. There remains a significant opportunity for improving HLA-B*15:02 pre-screening for patients starting carbamazepine and oxcarbazepine to prevent SCARs in the USA., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: HLA-B*58:01 is strongly associated with allopurinol-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Vietnam. This study assessed the cost-effectiveness of this testing to prevent SJS/TEN. Methods: A model was developed to compare three strategies: no screening, use allopurinol; HLA-B*58:01 screening; and no screening, use probenecid. A willingness-to-pay of three-times gross domestic product per capita was used. Results: Compared with 'no screening, use allopurinol', 'screening' increased quality-adjusted life-years by 0.0069 with the incremental cost of Vietnam dong (VND) 14,283,633 (US$617), yielding an incremental cost-effectiveness ratio of VND 2,070,459,122 (US$89,398) per quality-adjusted life-year. Therefore, 'screening' was unlikely to be cost-effective under the current willingness-to-pay. Testing's cost-effectiveness may change with targeted high-risk patients, reimbursed febuxostat or lower probenecid prices. Conclusion: The implementation of nationwide HLAB*58:01 testing before the use of allopurinol is not cost-effective, according to this analysis. This may be due to the lack of quality data on the effectiveness of testing and costing data in the Vietnamese population.

What Is Known and Objective: Allopurinol, the first-line medication for hyperuricemia is well-known for its association with severe cutaneous adverse reactions, especially Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In the current study, we analysed the Vietnamese spontaneous reporting database to identify signals and preventability of allopurinol-induced SJS/TEN in Vietnam from 2010 to 2019., Methods: Signal generation was assessed using the case/non-case method. Reporting odds ratios (RORs) and 95% confidence intervals (95% CI) were calculated., Results: Among 72,822 spontaneous ADR reports submitted to the Vietnam National Drug Information and Adverse Drug Reaction Monitoring Centre, 392 reports were on SJS/TEN, of which, 65 cases (16.6%) were related to allopurinol. The signals of allopurinol-induced SJS/TEN in Vietnam started in 2014 (ROR of 3.531, 95% CI: 1.830-6.810) and annually increased until 2019 (ROR of 11.923, 95% CI: 8.508-16.710). The preventability assessment showed that no allopurinol-induced SJS/TEN case was definitely unpreventable. 61.6% of the SJS/TEN cases were avoidable because they were associated with inappropriate prescribing such as unapproved indications, too high initial dose and even rechallenging in patients with a history of allopurinol allergy., What Is New and Conclusion: The signals of allopurinol-induced SJS/TEN in Vietnam started in 2014 and annually increased until 2019. Our first report specifically focusing on the ADR preventability of allopurinol showed that correction of medical errors relating to prescription could prevent more than 60% of SJS/TEN cases in Vietnamese allopurinol users. This is a feasible and practical solution, provided that there would be a systematic change in both healthcare systems and public awareness., (© 2022 John Wiley & Sons Ltd.)

Stevens-Johnson Syndrome (SJS) is a rare life-threatening condition characterized by severe mucocutaneous epidermal necrolysis and detachment of the epidermis. The condition centers around a delayed-type hypersensitivity reaction with a complex etiology stemming from a variety of causes. The number one cause is medication-related-common ones including sulfonamides, antiepileptics, allopurinol, and nonsteroidal anti-inflammatory drugs. Genetics also play a role as several human leukocyte antigen (HLA) genotypes within certain ethnic groups have been implicated in adverse reactions to specific drugs. HLAB*15:02 has been identified in the Chinese and others of Southeast Asian origin to increase susceptibility to lamotrigine and carbamazepine-induced SJS. Furthermore, patients of Japanese origin with HLAB*31:01 and Koreans with HLA-B*44:03 are also at increased risk of SJS after receiving the same two drugs. Of the antiepileptics, one most commonly associated with SJS is lamotrigine, a pre-synaptic voltage-gated sodium channel inhibitor. Lamotrigine is an antiepileptic drug of the phenyltriazine class that is indicated for the prevention of focal and generalized seizures in epileptic patients as well as monotherapy or adjunctive maintenance treatment for Bipolar disorder. The occurrence of SJS is not a rigid contraindication to lamotrigine reintroduction in the same patient. To facilitate this, manufacturers have developed a strict re-challenge dosing regimen to facilitate successful reintroduction of lamotrigine. In order to prevent the recurrence of SJS during a re-challenge, timing of re-dose and initial rash severity must be considered. Therefore, to prevent SJS recurrence, prime lamotrigine re-challenge patients are those with mild initial rash that has not occurred within the previous 4 weeks. The Federal Food and Drug Administration recommends the testing HLA subtypes for those associated with SJS prior to starting lamotrigine., (Copyright © 1964–2021 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.)

Background and Objective: East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Screening is recommended in patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation to avoid these complications. Utilization rates of the HLA-B*58:01 predictive screening test within the Greater Vancouver area, which has a population composed of 40.1% people of East Asian descent, are unknown., Measures: We identified cases of DRESS or SJS/TEN due to allopurinol using the Vancouver General Hospital dermatology consult service database. We next compared the frequency in which the HLA-B*58:01 screening test was ordered since 2012 to the estimated frequency of new prescriptions for allopurinol prescribed for the management of gout among the East Asians., Results: We report 5 cases of East Asian patients exposed to allopurinol for management of gout between 2012 and 2016, who developed DRESS (4 patients) or SJS/TEN (1 patient). All were of HLA-B*58:01 genotype, representing preventable cases. The HLA-B*58:01 test was ordered 6 times in 2012, whereas the estimated number of new cases of allopurinol-prescribed gout among patients of East Asian descent during that time period was 13. For 2012, testing was ordered for only 46% of at-risk patients., Conclusion: We continue to observe cases of severe cutaneous drug reactions among high-risk individuals due to allopurinol exposure. The HLA-B*58:01 screening test for allopurinol hypersensitivity is underutilized in our geographic area.

Drug re-exposure resulting in Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) is a rare phenomenon and has scarcely been reported. With an aging population, polypharmacy, and a lack of a unified electronic medical record, standard recommendations to prevent or minimize the risk of re-exposure are necessary. We identified five patients, with diagnosis confirmed SJS/TEN, and determined the clinical characteristics and contributing risk factors leading to re-exposure. Polypharmacy, multiple prescribers, advanced age, medical illiteracy, retention of discontinued medications and self-prescribing all contributed to re-exposure in this cohort of patients. This case series demonstrates the potentially deadly effect of drug re-exposure, and the need for both streamlined and integrated medication allergy documentation systems. J Drugs Dermatol. 2019;18(10):1049-1052.

Background: Drug-induced skin reactions present with a range of clinical symptoms, from mild maculopapular skin rashes to potentially fatal blistering skin rashes - such as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) - which may result in death. Milder reactions may be troublesome and lead to low drug compliance. The pathogenesis of these drug reactions is not yet fully understood; however, there is evidence that pretreatment genetic testing may help to predict and prevent these reactions in some cases., Objectives: To assess the effects of prospective pharmacogenetic screening to reduce drug-associated skin reactions in a patient population., Search Methods: We searched the following databases up to July 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase and LILACS. We also searched five trials registers, and checked the reference lists of included studies and relevant reviews for further references to relevant randomised controlled trials (RCTs)., Selection Criteria: We included RCTs of participants who had prospective pharmacogenetic screening to determine genetic variants associated with hypersensitivity reactions, compared with those who did not have prospective pharmacogenetic screening. We included participants in any setting, who were of any age, gender, and ethnicity, who had been prescribed drugs known to cause delayed type hypersensitivity reactions., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane. To assess studies for inclusion, two review authors independently screened all of the titles and abstracts of publications identified by the searches. Because there was only one included study, many of the planned data analyses were not applicable to the review. We used GRADE to assess the quality of the included study.The review's primary outcomes were the incidence of severe skin rashes with systemic symptoms (such as fever and multiple organ involvement), and long-term effects (such as scarring of eyelids or lung tissue). Secondary outcomes were hospitalisation for drug-induced skin reactions, blistering skin reactions (such as SJS, hypersensitivity (HSS) syndrome), and death., Main Results: One study, which was a randomised, double-blind, controlled, multicentre trial, fulfilled our inclusion criteria. The trial included 1956 adult participants (74% men, with a mean age of 42 years) across 265 centres (medical centres, hospitals, outpatient clinics) in 19 countries around the world who were infected with HIV-type 1 and who had not received abacavir previously. The participants, who had a clinical need for treatment with an antiretroviral-drug regimen containing abacavir, were randomly assigned to undergo prospective human leukocyte antigen (HLA) Class I, locus B, allele 57:01 (HLA-B*57:01) screening (prospective-screening group) before this treatment, or to undergo a standard-care approach of abacavir use without prospective HLA-B*57:01 screening (control group). Participants who tested positive for HLA-B*57:01 were not given abacavir; instead, they received antiretroviral therapy that did not include abacavir. The control group did have retrospective HLA-B*57:01 pharmacogenetic testing. The trial duration was six months. Each participant was observed for six weeks. Assessments were performed at the time of study entry, at baseline (day one of abacavir treatment), and at weeks one, two and six. This study was funded by the manufacturer of abacavir, GlaxoSmithKline.The study did not assess any of our primary outcomes, and it measured none of our secondary outcomes in isolation. However, it did assess an outcome of (characteristically severe) hypersensitivity reaction which included (but was not limited to) our secondary outcomes of HSS and SJS/TEN.The study demonstrated that prospective HLA-B*57:01 screening probably reduces the incidence of hypersensitivity reaction to abacavir. The incidence of clinically diagnosed HSS reaction to abacavir was lower in the screening arm (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.28 to 0.67; 1650 participants; moderate-quality evidence), as was immunologically confirmed HSS reaction (RR 0.02, 95% 0.00 to 0.37; 1644 participants; moderate-quality evidence). A positive result from an epicutaneous patch test performed six to ten weeks after clinical diagnosis provided immunological confirmation.Overall, the study demonstrates a low risk of bias across five out of seven domains. There was a high risk of detection bias because hypersensitivity reactions were diagnosed by the principal investigator at the recruitment site without the use of predefined clinical criteria. Although there was also high risk of attrition bias due to excluding participants with incomplete follow-up from analyses, the authors did undertake a series of sensitivity analyses based on the intention-to-treat population, which demonstrated consistent results with the primary analysis. We rated the study quality as moderate-quality using GRADE criteria., Authors' Conclusions: Prospective screening for HLA-B*57:01 probably reduces severe hypersensitivity skin reactions to abacavir in patients positive for HIV-type 1. However, these results are only based on one study, which was at high risk of attrition and detection bias.Our primary outcomes (incidence of severe skin rashes with systemic symptoms, and long-term effects) were not assessed by the trial, and only one of the review's secondary outcomes was measured (hypersensitivity reaction); thus, we found no evidence relating to hospitalisation, death, or long-term conditions resulting from drug injury.We found no eligible evidence on genetic testing for severe drug-induced skin rash in relation to different drugs and classes of drugs. Further clinical trials based on other drugs, and in different patient populations, would be useful for advising policy changes for improving the prevention of adverse skin reactions to drug treatments.

Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated., Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs., Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016., Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01., Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs., Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001)., Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice.

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: A strong association has been documented between HLA-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Human leucocyte antigen testing is potentially valuable in many countries to facilitate early recognition of patient susceptibility to SCARs., Objectives: To determine the cost-effectiveness of universal HLA-B*15:02 screening in preventing carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in an ethnically diverse Malaysian population., Methods: A hybrid model of a decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed epilepsy among adults: (i) carbamazepine initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to carbamazepine initiation; and (iii) alternative treatment [sodium valproate (VPA)] prescribing without HLA-B*15:02 screening. Base-case analysis and sensitivity analyses were performed over a lifetime time horizon. Incremental cost-effectiveness ratios were calculated., Results: Both universal HLA-B*15:02 screening and VPA prescribing were dominated by current practice. Compared with current practice, universal HLA-B*15:02 screening resulted in a loss of 0·0255 quality-adjusted life years (QALYs) at an additional cost of 707 U.S. dollars (USD); VPA prescribing resulted in a loss of 0·2622 QALYs at an additional cost of USD 4127, owing to estimated differences in antiepileptic treatment efficacy., Conclusions: Universal HLA-B*15:02 screening is unlikely to be a cost-effective intervention in Malaysia. However, with the emergence of an ethnically diverse population in many other countries, this may render HLA-B*15:02 screening a viable intervention when an increasing proportion of the population is at risk and an equally effective yet safer antiepileptic drug is available., (© 2017 British Association of Dermatologists.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse reactions to drugs that cause a life-threatening eruption of mucocutaneous blistering and epithelial sloughing. While the acute complications of SJS/TEN are well described, it is increasingly recognized that survivors may develop delayed sequelae, some of which can be associated with significant morbidity. Studies of long-term SJS/TEN outcomes mostly focus on mucocutaneous and ocular complications. However, other internal organs, such as the respiratory tract and gastrointestinal tract, can be affected. Psychological sequelae are also frequent following the trauma of widespread epidermal necrolysis. An appreciation of the 'chronic' phase of SJS/TEN is needed by clinicians caring for individuals who have survived the acute illness. This review aims to provide an update on the breadth and range of sequelae that can affect patients in the months and years following an acute episode of SJS/TEN., (© 2017 British Association of Dermatologists.)

Cutaneous idiosyncratic drug reactions (CIDRs) are usually unpredictable, ranging from mild maculopapular exanthema (MPE) to severe cutaneous adverse drug reactions (SCARs) such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Increasing evidence suggests that HLA alleles are strongly associated with drug-induced-CIDRs. The pathomechanisms for CIDRs include genetic polymorphisms affecting complex immune-specific HLA/drug antigen/T-cell receptor interactions and drug metabolism. Pharmacogenomic tests to prevent CIDRs have been widely implemented in clinical practice in recent years., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Objective: Positive HLA-B*5801 carriers are at greater risk of experiencing rare but severe allopurinol hypersensitivity syndrome (AHS) [i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)]; however, HLA-B*5801 prevalence and AHS risk vary by race/ethnicity. We evaluated the cost-effectiveness of HLA-B*5801 testing according to race/ethnicity in the United States., Methods: We determined the cost-effectiveness of universal testing for HLA-B*5801 compared to no testing prior to the initiation of allopurinol per US major race/ethnicity groups. Using US-specific data, SJS/TEN risks and HLA-B*5801 prevalences were modeled per race/ethnicity (i.e., 1/3846 and 0.7% among Caucasians and Hispanics, 1/735 and 3.8% among African Americans, and 1/336 and 7.4% among Asians, respectively). Those who tested positive for HLA-B*5801 received febuxostat. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime., Results: Compared to no testing, universal testing for HLA-B*5801 costs more and was more effective for all races/ethnicities. The ICERs varied substantially across racial/ethnic groups, following their HLA-B*5801 prevalences. HLA-B*5801 testing was cost-effective for African Americans (ICER $83,450) and Asians (ICER $64,190), but not for Caucasians or Hispanics (ICER $183,720), using accepted US willingness-to-pay threshold ($109,000/QALY). Results were robust in sensitivity analyses, except that reducing the risk of SJS/TEN by a half made testing not cost-effective for all races/ethnicities., Conclusion: Testing for HLA-B*5801 prior to allopurinol initiation is cost-effective for Asians and African Americans, but not for Caucasians or Hispanics in the United States. Reducing AHS risk by other predictive measures could make HLA-B*5801 testing not cost-effective even among Asians and Blacks., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: HLA-B*15:02 is a known biomarker for carbamazepine (CBZ)-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) in some ethnic populations. The US FDA recommends B*15:02 screening for Asian and other populations with a high prevalence of B*15:02 prior to treatment with CBZ to prevent drug-related SJS/TEN., Materials and Methods: A total of 1607 blood samples were collected from volunteer blood donors who were ethnic minorities living in the Yunnan province of southwestern China, including 153 Yi, 193 Naxi, 167 Miao, 156 Lisu, 166 Derung, 211 Bai, 184 Hani, 198 Dai, and 179 Zhuang. The genetic diversity of the HLA-B*15:02 genes in the ethnic minority samples was examined using sequence based typing at high resolution., Results: The allele frequencies of HLA-B*15:02 in the Yi, Naxi, Miao, Lisu, Derung, Bai, Hani, Dai, and Zhuang populations were 4.25%, 4.4%, 5.09%, 5.77%, 6.33%, 7.82%, 8.15%, 9.6%, and 15.36%, respectively. The frequencies of HLA-B*15:02 carriers in the Yi, Naxi, Miao, Lisu, Derung, Bai, Hani, Dai, and Zhuang populations were 8.5%, 8.8%, 9.58%, 10.9%, 12.65%, 15.64%, 16.3%, 18.69%, and 28.49%, respectively., Conclusion: The HLA-B*15:02 allele frequencies indicated that the prevalence of B*15:02 was different among the different ethnic populations. Because the number of carriers of B*15:02 was high in some ethnic populations, larger studies are required to confirm these findings. The Zhuang population had the highest frequency of B*15:02 in this study. More attention should be paid to CBZ-induced SJS/TEN in Chinese minority populations., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: Screening for the HLA-B*15:02 allele has been recommended to prevent carbamazepine (CBZ) - induced Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) in individuals with Asian ancestry. We aimed, therefore, to develop and validate a robust and inexpensive method for detection of the HLA-B*15:02 allele., Methods: Real-time PCR using TaqMan® probes followed by SYBR® Green was used to detect the HLA-B*15:02 allele prior to treatment with CBZ therapy., Results: A total of 121 samples were tested. The assay has a sensitivity of 100% (95% CI: 76.84-100.0%), a specificity of 100% (95% CI: 96.61-100%), a positive predictive value of 100% (95% CI: 76.84-100%) and a negative predictive value of 100.0% (95% CI: 96.61-100.0%), respectively. There was 100% agreement between our results and genotyping using Luminex SSO/SBT/SSP. The lowest limit of detection of the TaqMan® probe is 0.05ng/μl and the SYBR® Green is 0.5ng/μl of DNA. The unit cost of using the TaqMan® probe followed by SYBR® Green is only $4.7 USD., Conclusion: We developed a novel assay for the detection of the HLA-B*15:02 allele, which is robust, inexpensive and suitable for screening individuals of Asian ancestry in the prevention of CBZ-induced SJS/TEN., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Background: Stevens-Johnson syndrome and toxic epidermal necrolysis are severe mucocutaneous adverse drug reactions characterized by extensive epidermal detachment. The mortality rates have been reported to vary between 1% and 5% for Stevens-Johnson syndrome and 25% and 35% for patients with toxic epidermal necrolysis. Studies have shown that early recognition and prompt withdrawal of the causative agent leads to increased patient survival., Methods: A retrospective chart review was conducted on 64 patients admitted to Vancouver General Hospital with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis from 2001 to 2011. The aim of this study was to identify the medications most often implicated in triggering Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as to delineate the timeline of identification and removal of these triggers., Results: A trigger was identified in 75% of cases. Allopurinol was the single most common offending agent (20% of cases). Anticonvulsants and antibiotics were common triggers. The offending agent was often removed at time of hospital admission/diagnosis but not at onset of symptoms. A history of prior culprit drug exposure with previous mucocutaneous adverse reaction was noted in 19% of cases with identified triggers. Asians and Native North Americans had a higher mortality than whites, and Asians more frequently had allopurinol as a trigger., Conclusions: The onset and high mortality rate of Stevens-Johnson syndrome/toxic epidermal necrolysis may be related to unawareness of the early signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis, the common drug triggers that cause it, and what investigations (human leukocyte antigen typing in Asians) can be done to prevent it., (Copyright © 2016. Published by Elsevier Inc.)

Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASE™). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events., (Copyright © 2016. Published by Elsevier B.V.)

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long-term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms 'erythema multiforme major' (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term 'epidermal necrolysis' (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA-B*1502 with carbamazepine-induced TEN) and understanding of the pathogenic roles of drug-specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas-ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition., (© 2015 British Association of Dermatologists.)

Allergic reactions to drugs are a serious public health concern. In 2013, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop on drug allergy. International experts in the field of drug allergy with backgrounds in allergy, immunology, infectious diseases, dermatology, clinical pharmacology, and pharmacogenomics discussed the current state of drug allergy research. These experts were joined by representatives from several National Institutes of Health institutes and the US Food and Drug Administration. The participants identified important advances that make new research directions feasible and made suggestions for research priorities and for development of infrastructure to advance our knowledge of the mechanisms, diagnosis, management, and prevention of drug allergy. The workshop summary and recommendations are presented herein., (Published by Elsevier Inc.)

Epilepsy affects 50 million persons worldwide, a third of whom continue to experience debilitating seizures despite optimum anti-epileptic drug (AED) treatment. Twelve-month remission from seizures is less likely in female patients, individuals aged 11-36 years and those with neurological insults and shorter time between first seizure and starting treatment. It has been found that the presence of multiple seizures prior to diagnosis is a risk factor for pharmacoresistance and is correlated with epilepsy type as well as intrinsic severity. The key role of neuroinflammation in the pathophysiology of resistant epilepsy is becoming clear. Our work in this area suggests that high-mobility group box 1 isoforms may be candidate biomarkers for treatment stratification and novel drug targets in epilepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance, which may also provide new insights into disease stratification. Some of the rare genetic epilepsies enable treatment stratification through testing for the causal mutation, for example SCN1A mutations in patients with Dravet's syndrome. Up to 50% of patients develop adverse reactions to AEDs which in turn affects tolerability and compliance. Immune-mediated hypersensitivity reactions to AED therapy, such as toxic epidermal necrolysis, are the most serious adverse reactions and have been associated with polymorphisms in the human leucocyte antigen (HLA) complex. Pharmacogenetic screening for HLA-B*15:02 in Asian populations can prevent carbamazepine-induced Stevens-Johnson syndrome. We have identified HLA-A*31:01 as a potential risk marker for all phenotypes of carbamazepine-induced hypersensitivity with applicability in European and other populations. In this review, we explore the currently available key stratification approaches to address the therapeutic challenges in epilepsy., (© 2014 The Association for the Publication of the Journal of Internal Medicine.)

Adverse effects of antiepileptic drugs are classified into idiosyncratic adverse effects, pharmacology-related adverse effects and biological effect after modification of seizure frequencies. Pharmacology-related adverse effects include those by administered AED and those by mutual interactions. Stevens-Johnson syndrome, one of the idiosyncratic adverse effects, may be predicted by the intrinsic HLA type (e.g., A*31:01 for CBZ). In epileptic patients after acute encephalitis, cutaneous adverse reactions usually occur in a month after encephalitis, but some patients will tolerate the causative AED by the extremely slow re-introduction. Prevention of pharmacology-related adverse effects needs therapeutic drug monitoring, and slow introduction considering dose-response curves for AEDs. Genotype examination of CYP2C9 and 2C19 can contribute to the safe introduction of PHT.

Background: Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), caused by allopurinol therapy, are strongly associated with the human leukocyte antigen (HLA), HLA-B*5801. Identification of HLA-B*5801 genotype before prescribing allopurinol offers the possibility of avoiding allopurinol-induced SJS/TEN. As there is a paucity of evidence about economic value of such testing, this study aims to determine the cost-effectiveness of HLA-B*5801 testing compared with usual care (no genetic testing) before allopurinol administration in Thailand., Methods and Finding: A decision analytical and Markov model was used to estimate life time costs and outcomes represented as quality adjusted life years (QALYs) gained. The model was populated with relevant information of the association between gene and allopurinol-induced SJS/TEN, test characteristics, costs, and epidemiologic data for Thailand from a societal perspective. Input data were obtained from the literature and a retrospective database analysis. The results were expressed as incremental cost per QALY gained. A base-case analysis was performed for patients at age 30. A series of sensitivity analyses including scenario, one-way, and probabilistic sensitivity analyses were constructed to explore the robustness of the findings. Based on a hypothetical cohort of 1,000 patients, the incremental total cost was 923,919 THB (USD 29,804) and incremental QALY was 5.89 with an ICER of 156,937.04 THB (USD 5,062) per QALY gained. The cost of gout management, incidence of SJS/TEN, case fatality rate of SJS/TEN, and cost of genetic testing are considered very influential parameters on the cost-effectiveness value of HLA-B*5801 testing., Conclusions: The genetic testing for HLA-B*5801 before allopurinol administration is considered a highly potential cost-effective intervention in Thailand. The findings are sensitive to a number of factors. In addition to cost-effectiveness findings, consideration of other factors including ethical, legal, and social implications is needed for an informed policy decision making.

Toxic epidermal necrolysis (TEN) is a life-threatening, typically drug-induced, mucocutaneous disease. TEN has a high mortality rate, making early diagnosis and treatment of paramount importance. New but experimental diagnostic tools that measure serum granulysin and high-mobility group protein B1 (HMGB1) offer the potential to differentiate early TEN from other, less serious drug reactions, but these tests have not been validated and are not readily available. The mainstay of treatment for TEN involves discontinuation of the offending drug, specialized care in an intensive care unit or burn center, and supportive therapy. Pharmacogenetic studies have clearly established a link between human leukocyte antigen allotype and TEN. Human leukocyte antigen testing should be performed on patients of East Asian descent before the initiation of carbamezapine and on all patients before the initiation of abacavir. The effectiveness of systemic steroids, intravenous immunoglobulins, plasmapheresis, cyclosporine, biologics, and other agents is uncertain., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: Carbamazepine (CBZ) is broadly used for the treatment of epilepsy, neuropathic pain and other neurological diseases, owing to its effectiveness and low price. CBZ can induce Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). There are several studies that found an association between HLA-B*1502 and CBZ-induced SJS/TEN, especially in people of Thai origin. In Thailand the prevalence of HLA-B*1502 was found to be in the range 8.1-14 %., Objective: This study aimed to determine if screening for HLA-B*1502 in Thai patients who were to receive CBZ is cost effective. Setting Srinagarind Hospital, Khon Kaen University, Thailand., Method: A comparison between treatment cost of CBZ induced SJS/TEN and the HLAB*1502 screening costs in the Thai population., Main Outcome Measure: Comparison of the costs of treatment of CBZ induced SJS/TEN and costs of HLA-B*1502 screening test. Results When persons having the HLA-B*1502 allele receive CBZ, the chance of developing SJS/TEN is as high as 88.1 %, while persons without the HLA-B*1502 allele do not develop SJS/TEN. Therefore, a model was calculated to compare the cost of treatment between HLA-B*1502 testing before giving CBZ and if the patients were not tested for HLAB*1502. It was found that screening 100 patients before giving CBZ would save an amount of 98,549.94 baht per 100 cases of CBZ-prescribed patients., Conclusion: The screening for HLA-B*1502 allele before giving carbamazepine is cost effective. The results of the present study may also apply to other populations if the HLA-B*1502 frequency is high enough.

Purpose of Review: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe adverse drug reactions. Once thought to be idiosyncratic and unpredictable, there has been significant progress made in the understanding of the pathomechanism and pharmacogenetics of such reactions. These advances together with their clinical implications will be elaborated in this review., Recent Findings: It is now known that the human leukocyte antigen (HLA) association in SJS/TEN is more than just a genetic marker and has a functional role as well. This reaction is mediated by cytotoxic T lymphocytes (CTLs) in an HLA-restricted fashion. Certain drugs may bind directly to the HLA complex and facilitate the development of self-reactivity due to drug-modified HLA-peptide repertoire. The role of the drug-specific T cells and their T-cell receptors has also been clarified. Downstream cytotoxic signals have been elucidated with granulysin, a cytotoxic protein produced by CTLs or natural killer cells deemed to be the key mediator in the reaction., Summary: Pharmacogenetic screening of HLA alleles prior to drug initiation has already been shown useful in the prevention of such reactions. The other advances in the disease mechanism will form the basis for better preventive and therapeutic strategies.

Gout is a common condition which is mainly treated with the hypo-uricemic agent, allopurinol. Although allopurinol is generally a well-tolerated drug, there is a small risk of developing potentially fatal complications, such as allopurinol hypersensitivity syndrome. Recent advances in pharmacogenomics have made possible the identification of genes which confer susceptibility to specific drugs. A recent multi-national case-control study has reported allopurinol as the most common drug associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Several studies have established a strong association between the human leukocyte antigen (HLA)-B*5801 gene and development of Stevens-Johnson syndrome and toxic epidermal necrolysis. The allele frequency of HLA-B*5801 is highest in the South East Asian population.Since other hypo-uricemic agents are available, patients may wish to have HLA-B*5801 testing before being started on allopurinol. As the test for HLA-B*5801 is expensive, time-consuming and only available in selected laboratories, there is a need to evaluate the utility and cost-effectiveness of this test in our region., (© 2013 The Author International Journal of Rheumatic Diseases © 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

It is known that rare but severe cutaneous adverse drug reactions (cADRs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS), are induced by carbamazepine (CBZ). Recent studies have shown an association between HLA-A*31:01 and CBZ-induced severe cADRs in Japanese and Caucasian populations. In this study, we developed a simple method to detect the HLA-A*31:01 allele by nested allele-specific primer-polymerase chain reaction combined with restriction fragment length polymorphism analysis. Accuracy of the developed method was evaluated by direct sequencing analysis of PCR products amplified from DNA samples with known HLA-A genotypes and by consigning diagnosis of DNA samples with unknown HLA-A genotypes to a company providing clinical laboratory testing. The method developed in this study is simple, rapid, and of low cost compared to outsourcing tests and may be useful for in-house testing of the HLA-A*31:01 allele.

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologically mediated, severe cutaneous adverse reactions involving cytotoxic T cells, natural killer cells and various mediators. In large studies, up to 15% of SJS/TEN occurred in patients with chronic corticosteroid use. It is unclear if this prior exposure to corticosteroids modified the disease course., Objectives: To evaluate whether systemic corticosteroid usage prior to the onset of SJS/TEN modified the clinical course and outcome. If a disease-modifying effect is present, information from such an analysis may have implications on the therapeutic use of corticosteroids in SJS/TEN., Methods: This is a case-control study based on data collected in the EuroSCAR and RegiSCAR studies. Ninety-two cases of SJS/TEN with exposure to corticosteroids prior to the onset of disease, and 321 randomly selected SJS/TEN patients without prior exposure were included. Primary outcomes included progression of disease, disease severity and mortality. A secondary analysis of latency between the beginning of drug use and the onset of disease, based on exposure to a single high-risk drug, was also performed., Results: On multivariate analysis, cases with prior exposure to corticosteroids had a longer progression of disease by 2·2 days [95% confidence interval (CI) 1·1-3·2]. The disease severity and mortality outcome were unaffected. In addition, there is evidence that corticosteroids delayed the onset of SJS/TEN in patients with exposure to high-risk drugs by 7·1 days (CI -0·2 to 14·5)., Conclusions: The prior use of corticosteroids prolonged the period of disease progression without influencing the disease severity or mortality. In addition, when SJS/TEN is preceded by use of a single high-risk drug, the latency between the drug intake and the onset of SJS/TEN may also be increased. These findings suggest that corticosteroids have a mild impact on the course of SJS/TEN, and further studies are required to clarify any potential therapeutic effects., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

The mortality rate of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) is high; approximately 5% for SJS and 25% for TEN. It is therefore vital for the treating physician to recognise SJS and TEN promptly through the identification of these diseases' characteristic clinical features so that the offending drug is promptly withdrawn, supportive therapy is administered and adjunctive therapies are considered. Supportive therapy addressing the manifestations and complications of acute skin failure include monitoring the fluid - electrolyte balance and providing enteral or parenteral nutrition, wound care and treatment of sepsis. In addition, supportive care of the affected mucosal surfaces is required through the use of aggressive ocular lubrication, topical corticosteroids, hygienic mouthwashes and oral anaesthetics, together with monitoring for urinary retention. There is sufficient evidence for the use of intravenous immune globulin in the acute management of SJS/TEN provided an adequate dose of 2-3 g/kg is administered. Cyclosporine appears to also be an effective agent although randomised control studies are required to demonstrate its benefit and establish the dose, duration of therapy and safety profile. The role of corticosteroids is currently under revision. Some earlier studies have shown a lack of efficacy or increased mortality in their use but the use of high doses early in the course of disease may actually reduce morbidity and mortality. The role of plasmapheresis, anti-tumour necrosis factor (TNF) biologics and N-acetylcysteine is promising but further studies are required to elucidate their benefit. Preventative strategies such as pharmacogenetic screening needs to be strongly considered, with the provision of cost-effective assays with a rapid turn-around time., (© 2012 The Author. Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists.)

In some adverse drug reactions (ADRs), genetic predisposition plays a significant role in pathogenesis, and the skin is the most frequently reported target. These severe cutaneous ADRs include bullous fixed drug eruptions (FDE), acute generalized exanthematous pustulosis (AGEP), drug-induced hypersensitivity syndrome (HSS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). The putative contribution of individual effector cells in drug hypersensitivity is briefly mentioned. To trigger these drug hypersensitivities, certain class I HLA alleles (e.g., HLA-A and HLA-B alleles) and certain class II HLA alleles (e.g., HLA-DR alleles) have been recently found to be the genetic determinants. One of the best characterized examples mentioned in this article is HLA-B*1502 to determine the incidence of carbamazepine-induced SJS. How drugs are processed and presented by these HLA alleles to activate immune responses has been explained by several hypotheses. Further implication of pharmagenomic findings to prevent drug-induced severe skin reactions can be achieved by pre-screening putative risk HLA alleles before using drugs.

Background: Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees., Case Report: We present the case of a 58-year-old woman with history of Sharp's syndrome and adenocarcinoma of the lung, who developed toxic epidermal necrolysis after the first cycle of pemetrexed, including erythema, bullae, extensive skin denudation, subsequent systemic inflammation and severe deterioration in general condition. The generalized skin lesions occurred primarily in the previous radiation field and responded to immunosuppressive treatment with prednisone., Conclusion: Although skin toxicity is a well-known side effect of pemetrexed, severe skin reactions after pemetrexed administration are rare. Caution should be applied in cases in which pemetrexed is given subsequent to radiation therapy, especially in patients with pre-existing skin diseases.

Background: Toxic epidermal necrolysis (TEN) is an uncommon but life-threatening adverse drug reaction. Pemetrexed is a multitargeted antifolate. It was first used in combination with cisplatin as a front-line treatment for malignant pleural mesothelioma. The same combination is nowadays approved in the first-line setting for locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC)., Patient and Methods: We report the case of a 50-year-old man treated for metastatic NSCLC. Within 5 days after administration of the second cycle of cisplatin and pemetrexed, he developed large blisters, which secondarily became hemorrhagic, and mucosal lesions. The characteristic clinical appearance, the histopathological findings, and the clinical course were decisive for the diagnosis of TEN. Treatment with systemic steroids and intravenous antibiotics as well as topical wound treatment led to resolution and improvement of his general condition., Conclusions: To the best of our knowledge, this is the third case of TEN due to pemetrexed in a patient with NSCLC. Clinicians should be aware of TEN as a rare but potentially fatal disorder requiring hospitalization and multidisciplinary management., (Copyright © 2012 S. Karger AG, Basel.)

Background: Carbamazepine, an anticonvulsant and a mood-stabilizing drug, is the main cause of the Stevens-Johnson syndrome (SJS) and its related disease, toxic epidermal necrolysis (TEN), in Southeast Asian countries. Carbamazepine-induced SJS-TEN is strongly associated with the HLA-B*1502 allele. We sought to prevent carbamazepine-induced SJS-TEN by using HLA-B*1502 screening to prospectively identify subjects at genetic risk for the condition., Methods: From 23 hospitals in Taiwan, we recruited 4877 candidate subjects who had not taken carbamazepine. We genotyped DNA purified from the subjects' peripheral blood to determine whether they carried the HLA-B*1502 allele. Those testing positive for HLA-B*1502 (7.7% of the total) were advised not to take carbamazepine and were given an alternative medication or advised to continue taking their prestudy medication; those testing negative (92.3%) were advised to take carbamazepine. We interviewed the subjects by telephone once a week for 2 months to monitor them for symptoms. We used the estimated historical incidence of SJS-TEN as a control., Results: Mild, transient rash developed in 4.3% of subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized. SJS-TEN did not develop in any of the HLA-B*1502-negative subjects receiving carbamazepine. In contrast, the estimated historical incidence of carbamazepine-induced SJS-TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001)., Conclusions: The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects was strongly associated with a decrease in the incidence of carbamazepine-induced SJS-TEN. (Funded by the National Science Council of Taiwan and the Taiwan Drug Relief Foundation.).

Objective: To evaluate the efficacy of lamotrigine for treatment of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) syndrome., Data Sources: Literature was accessed through MEDLINE (1950-June 2010) using the terms lamotrigine, triazines, SUNCT, and trigeminal autonomic cephalgia., Study Selection and Data Extraction: All articles in English and studies conducted in humans were identified and evaluated., Data Synthesis: SUNCT syndrome can be an extremely challenging headache type to manage and has been considered refractory to pharmacotherapy. Many anticonvulsants have been evaluated as promising SUNCT treatments, with lamotrigine specifically reported as an effective first-line treatment option. There is a lack of randomized placebo-controlled clinical trials evaluating lamotrigine in SUNCT syndrome therapy; however, 2 observational studies, 3 case series, and 5 case reports were reviewed. Lamotrigine appears to decrease the frequency and severity of SUNCT attacks, leading to complete resolution in some patients. A decrease in symptoms was achieved with doses ranging from 25 to 600 mg/day. In some cases, there was initial response to low doses, but dosage titrations were often necessary when symptoms returned several days after being managed at the same dose. Lamotrigine should be initiated at 25 mg/day and gradually titrated, guided by response and adverse effects. The risk of Stevens-Johnson syndrome, a dose-related adverse effect, can be minimized with gradual titration., Conclusions: According to case reports and observational studies, lamotrigine therapy has resulted in decreased frequency or resolution of SUNCT syndrome attacks. Randomized, controlled trials are necessary to confirm the efficacy of lamotrigine for this indication.

Background: Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events., Case Report: A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell's syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition., Conclusion: To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination., (Copyright 2009 S. Karger AG, Basel.)

Clinical risk management concedes that risk is inherent to all health-care processes. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but potentially life-threatening reactions to medications. Risk management should be considered prior to starting, during, and after therapy. Prior to starting therapy, risks that need to be assessed include any specific patient groups that may be at greater risk for the development of SJS/TEN. Gene testing is in place for Chinese and Thai patients who are going to be exposed to carbamazepine. During therapy, it is important to recognize SJS/TEN as a possible adverse drug reaction. Diagnostic criteria have changed, and more data exist on drugs with an increased risk. Although there is no standardized treatment for all patients with SJS/TEN, options that have been used include cyclosporine, corticosteroids, and intravenous immunoglobulin. Standards of care are usually defined locally, but new treatments, such as amniotic membrane support for ocular damage, may need to be considered. Good communication skills are needed to allow practitioners to show empathy and to provide disclosure. Risk management after a reaction includes skills in acknowledging bad outcomes or error; freedom to say "sorry" as defined by "apology laws," and knowing the rights provided by "Quality Assurance Conferences," where the information discussed is protected. In other words, the patient is best supported after an event like SJS/TEN if the practitioner is knowledgeable about optimal care standards and their legal rights and obligations.

Introduction: Toxic epidermal necrolysis is a rare disease with high mortality due to generalised infection, sepsis or lung involvement, and requires discontinuation of all potentially triggering medications and intensive care in a specialised burn centre. Apart from wound care with antiseptics, wound coverage may be achieved with a skin substitute; treatments are compared with regard to infection, protein loss, re-epithelialisation and mortality., Patients and Methods: Of 14 people with toxic epidermal necrolysis affecting >30% body surface area, eight received daily dressing changes using Lavasept nd six received wound coverage with Biobrane. Demographic data, SCORTEN score, mortality, visual-analog pain scale, mobilisation, time to re-epithelialisation, serum protein, albumin, C-reactive protein and leukocytes, and body temperature were evaluated in all cases., Results: Mean age of patients was 68.0+/-14.8 years, mean body surface area affected was 66.4%, median SCORTEN score was three and overall mortality was 36%. In the Biobrane ompared with the Lavasept control) group, mean pain was significantly reduced (2.9 versus 5.5 on the scale, p<0.05), mobilisation was significantly earlier (walking at 3 days versus 7 days, p=0.003), re-epithelialisation was complete in 12.5 days versus 16 days, and at 9 days there was reduced decrease of serum proteins and significantly lower levels of C-reactive protein and white cells (p<0.05)., Conclusion: Early wound coverage with synthetic skin substitute such as Biobrane s beneficial compared with conservative antiseptic wound treatment, but mortality rate is not significantly different.

Background: Although a severe form of fixed drug eruption (FDE) clinically and histologically mimics toxic epidermal necrolysis (TEN), subsequent evolution of the two conditions is quite different. It remains unknown, however, which factors determine whether these lesions resolve spontaneously or subsequently progress to TEN., Objectives: Because epidermal injury in TEN can be locally reproduced in the evolving FDE lesions, we sought to investigate how epidermal damage can be induced in the evolving FDE lesions and how disease progression to TEN can be prevented, by analysing the FDE lesions induced by clinical challenge with the causative drug., Methods: We immunohistochemically investigated in vivo dynamics of T-cell trafficking and activation that occur in the evolving FDE lesions using sequential biopsy specimens obtained at multiple time points from the FDE lesions., Results: Intraepidermal CD8+ T cells, which are resident in the lesional epidermis as a stable homogeneous population of memory T cells, transiently acquire a natural killer-like phenotype and express cytotoxic granules upon activation. The influx into the epidermis of CD4+ T cells including Foxp3+ regulatory T cells (Tregs) during the evolution serves to ameliorate epidermal damage induced by activation of the intraepidermal CD8+ T cells. Interleukin-15 derived from the lesional epidermis could maintain the survival of the intraepidermal CD8+ T cells even in the absence of antigenic stimulus over a prolonged period of time (> 4 years)., Conclusions: Whether Tregs could migrate to the lesions upon activation of intraepidermal CD8+ T cells would determine whether the inflammation becomes resolved spontaneously or progresses to TEN.

To analyze immunoregulation of autoreactive T cells specific for epidermal skin antigens, we crossed transgenic mice expressing ovalbumin selectively in keratinocytes under the keratin 5 promoter (K5-mOVA) with mice expressing a K(b)-restricted OVA-specific T cell receptor transgene (OT-I). In athymic double-transgenic mice, OT-I cells developed extrathymically and, at 8-12 weeks of age, initiated severe epidermal damage mimicking toxic epidermal necrolysis (TEN). In contrast, euthymic double-transgenic mice showed thymic deletion of OT-I cells, had few of these cells in the periphery, and never developed skin changes mimicking TEN. Adoptive transfer of OT-I cells isolated from euthymic double-transgenic mice induced TEN in athymic K5-mOVA single-transgenic mice. This spontaneous disease in athymic double-transgenic mice was prevented by transferring lymph node cells from euthymic mice, but was not prevented when CD4(+) or CD25(+) cells were depleted from this population. Although purified CD4(+)CD25(+) cells scarcely prevented the skin disease induced by adoptive transfer of OT-I cells, they efficiently prevented the disease when co-transferred with CD11c(+) dendritic cells. These results suggested that thymus-derived regulatory T cells cooperate with CD11c(+) dendritic cells to prevent life-threatening skin damage such as TEN.

Human intravenous immunoglobulin has been described as a treatment for patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. We describe the prophylactic use of intravenous immunoglobulin to prevent Stevens-Johnson syndrome in a woman undergoing cardiac catheterization with a previous history of four episodes of Stevens-Johnson after receiving intravenous contrast dye.

CIRCUMSTANCES AND CHARACTERISTICS: The risk of toxiderma is greater in patients infected by the human immunodeficiency virus (HIV). The most common toxidermas are maculopapular exanthema and drug hypersensitivity reactions. These toxidermas are predominantly observed with non-nucleoside reverse transcriptase analogs (nevirapine, efavirenz) and abacavir. Toxiderma has also been observed with other nucleoside reverse transcriptase analogs (zalcitabine) and protease inhibitors. REGARDING SEVERITY: The toxidermas observed are usually benign (maculopapular exanthema) and do not always require suspension of the treatment. However, certain toxidermas (Stevens-Johnson syndrome, Lyell syndrome and drug hypersensitivity syndrome) may be life-threatening and therefore contraindicate the continuation of treatment and also its sudden reintroduction. PREVENTION AND PRACTICAL APPROACH: Several studies have assessed the risk factors for toxiderma induced by nevirapine and hypersensitivity reactions to abacavir. The practical approach varies depending on the drug responsible, the clinical form of the toxiderma and the possible alternatives.

Death receptors are a growing family of transmembrane proteins which can detect the presence of specific extracellular death signals and rapidly trigger cellular destruction by apoptosis. The best studied to date is Fas (CD95). Expression and signalling by Fas and its ligand (FasL, CD95L) is a tightly regulated process essential for key physiological functions in a variety of organs, including the maintenance of immune homoeostasis. Recently, strong evidence has shown that dysregulation of Fas expression and/or signalling contributes to the pathogenesis of toxic epidermal necrolysis and acute graft-versus-host disease. With these new developments, strategies for modulating the function of Fas signalling have emerged and opened up novel therapeutic possibilities. Specific blockade of Fas, for example with intravenous immunoglobulin preparations containing specific anti-Fas antibodies, has shown great promise in the treatment of toxic epidermal necrolysis and may also be useful in the treatment of acute graft-versus-host disease. Further developments in this field may have important clinical implications for the treatment of such diseases.