Pharmacogenetics to prevent hypersensitivity reactions to antiepileptic drugs: is testing performed when indicated?

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.

Allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: Signal detection and preventability from Vietnam National pharmacovigilance database.

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.

Genetic testing for prevention of severe drug-induced skin rash.

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.

Recommendations for Prevention of Drug Re-Exposure in Toxic Epidermal Necrolysis

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.

HLA-B*58:01 Genotyping to Prevent Cases of DRESS and SJS/TEN in East Asians Treated with Allopurinol-A Canadian Missed Opportunity [Formula: see text].

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.

Long-term complications of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN): the spectrum of chronic problems in patients who survive an episode of SJS/TEN necessitates multidisciplinary follow-up.

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.

Is universal HLA-B*15:02 screening a cost-effective option in an ethnically diverse population? A case study of Malaysia.

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.

Report from the National Institute of Allergy and Infectious Diseases workshop on drug allergy.

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.

Personalized medicine approaches in epilepsy.

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.

Epidermal necrolysis: 60 years of errors and advances.

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.

Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan.

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.).

[Adverse effects of antiepileptic drugs].

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.

Toxic epidermal necrolysis: Part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.

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.

The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies.

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.

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome.

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.

Toxic epidermal necrolysis related to Cisplatin and pemetrexed for metastatic non-small cell lung cancer.

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.

The management of toxic epidermal necrolysis.

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.