Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered a delayed-type hypersensitivity reaction to drugs. They represent true medical emergencies and an early recognition and appropriate management is decisive for the survival. SJS/TEN manifest with an “influenza-like” prodromal phase (malaise, fever), followed by painful cutaneous and mucous membrane (ocular, oral, and genital) lesions, and other systemic symptoms. The difference between SJS, SJS/TEN overlap, and TEN is defined by the degree of skin detachment: SJS is defined as skin involvement of  30%, and SJS/TEN overlap as 10–30% skin involvement. The diagnosis of different degrees of epidermal necrolysis is based on the clinical assessment in conjunction with the corresponding histopathology. The mortality rates for SJS and TEN have decreased in the last decades. Today, the severity-of-illness score for toxic epidermal necrolysis (SCORTEN) is available for SJS/TEN severity assessment. Drugs with a high risk of causing SJS/TEN are anti-infective sulfonamides, anti-epileptic drugs, non-steroidal anti-inflammatory drugs of the oxicam type, allopurinol, nevirapine, and chlormezanone. Besides conventional drugs, herbal remedies and new biologicals should be considered as causative agents. The increased risk of hypersensitivity reactions to certain drugs may be linked to specific HLA antigens. Our understanding of the pathogenesis of SJS/TEN has improved: drug-specific T cell-mediated cytotoxicity, genetic linkage with HLA- and non-HLA-genes, TCR restriction, and cytotoxicity mechanisms were clarified. However, many factors contributing to epidermal necrolysis still have to be identified, especially in virus-induced and autoimmune forms of epidermal necrolysis not related to drugs. In SJS/TEN, the most common complications are ocular, cutaneous, or renal. Nasopharyngeal, esophageal, and genital mucosal involvement with blisters, erosions as well as secondary development of strictures also play a role. However, in the acute phase, septicemia is a leading cause of morbidity and fatality. Pulmonary and hepatic involvement is frequent. The acute management of SJS/TEN requires a multidisciplinary approach. Immediate withdrawal of potentially causative drugs is mandatory. Prompt referral to an appropriate medical center for specific supportive treatment is of utmost importance. The most frequently used treatments for SJS/TEN are systemic corticosteroids, immunoglobulins, and cyclosporine A.

Current Perspectives on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for HLA‐B*58:01 Genotype and Allopurinol Dosing was originally published in February 2013. We reviewed the recent literature and concluded that none of the evidence would change the therapeutic recommendations in the original guideline; therefore, the original publication remains clinically current. However, we have updated the Supplemental Material and included additional resources for applying CPIC guidelines into the electronic health record. Up‐to‐date information can be found at PharmGKB (http://www.pharmgkb.org).

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update

Background Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children. Objective The aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence. Methods From 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases. Results Incidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred. Conclusions In this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.

Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: a 9‐year experience in a tertiary‐care paediatric hospital setting

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.

Lamotrigine and Stevens-Johnson Syndrome Prevention.

Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are T-cell-mediated skin eruptions that are part of a broader category known as severe cutaneous adverse drug reactions (SCAR). SJS involves less than 10%of the body surface area, whereas skin detachment in TEN is more severe and involves 30% of the body surface area. Skin detachment that falls between 10% and 30% is described as SJS-TEN overlap.1 SJS and TEN are rare syndromes, with an estimated incidence at 1 to 2 cases per 1 million inhabitants per year in European countries.2 However, these conditions may lead to mortality or severe disability of previously healthy people and have prompted the withdrawal of newly released drugs3. Drugs highly suspected to cause SJS/TEN include allopurinol, aromatic anticonvulsants (carbamazepine, phenobarbital, phenytoin, and lamotrigine), nevirapine, sulfonamides, and oxicam-NSAIDs. Weaker associations have been additionally found for paracetamol, aminopenicillins, cephalosporins, and quinolones.2,4 Although hypersensitivity reactions have been considered as “type B” or dose-independent reactions, accumulating evidence suggests that the risk may be greater with high doses and rapid dose escalation, at least for allopurinol and lamotrigine.5–7 The propensity to develop SJS and TEN varies across populations of different ethnicities. The most prominent example is the strong association between carbamazepine-induced SJS/TEN and the presence of the human leukocyte antigen (HLA) allele B*15:02 in individuals of Han Chinese and other Southeast Asian origin8 but not in Northern Europeans.9 In the latter population10 and in patients of Japanese origin,11 carbamazepine-induced cutaneous adverse reactions have been linked to another HLA allele, A*31:01. This information has been translated into an FDA boxed warning that requires screening for HLA-B*15:02 in patients of high-risk ethnic origin and a warning for HLA-A*31:01.12 Likewise, the association between HLA-B*58:01 and allopurinol-induced SCAR is strong in patients of Asian origin13 but is weaker in white populations in Europe, in which HLA-B*58:01 is also much less prevalent than in Han Chinese.14–16 The variability among ethnic groups may also apply to Israeli populations. For instance, we have recently shown that

Causative Drugs of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Israel.

OBJECTIVES
In October 2020 and March 2021, the Federal Drug Agency classified lamotrigine as class IB antiarrhythmic, announcing an increased risk of heart rhythm problems. We sought to investigate the nature of the arrhythmia signal with lamotrigine use compared to anticonvulsants with sodium and non-sodium blocking mechanisms.


METHODS
This retrospective pharmacovigilance case-non-case study used disproportionality analysis to detect signals of adverse reaction of interest reported with lamotrigine to the FDA adverse event reporting system between 1998 and 2022. Our regression model adjusted for interacting concomitant medications. Sensitivity analyses included stratifying by indication and publication date.


RESULTS
Overall, 2917 cases of heart rhythm problems with anticonvulsants were analyzed (1557 female [58.4%] and 1109 male [41.6%]). The mean age was 43±19, the groups did not differ significantly by age. Forty cases [7.91%] in the epileptic indication included more than one concomitant medications that influence cardiac conduction. The disproportionality signal for cardiac arrest did not differ for lamotrigine compared with other anti-convulsants, [adj.ROR, 0.88; 95%CI, 0.59-1.29] in the epileptic indication. A significantly lower reporting risk for bradyarrhythmia was identified with lamotrigine users in the epileptic population, [adj.ROR, 0.45; 95%CI, 0.29-0.68]. The psychiatric indication demonstrated a six-fold reporting risk for cardiac arrest compared to the epileptic indication. Concomitant medications that affect cardiac conduction, as well as reports on overdose and suicide attempts were significant variables in psychiatric patients, [ROR, 2.45; 95%CI, 2.21-2.71], and [ROR, 1.44; 95%CI, 1.34-1.55] respectively.


SIGNIFICANCE
Our results do not support a significant difference in the reporting risk for cardiac arrest, syncope, tachy- and bradyarrhythmia with lamotrigine in the epileptic indication. Signals of cardiac arrest in lamotrigine could be explained by confounding factors in the psychiatric indication, such as greater concomitant use of medications with cardiac adverse events, and greater reports on overdose and suicide attempts. We recommend that patients with polypharmacy undergo clinical and electrocardiographic monitoring. We illustrate the importance of examining signals for seperate indications.

Investigation of Cardiac Arrhythmia Events in Patients Treated with Lamotrigine: FAERS Analysis.

Genetic variation can affect drug pharmacokinetics and pharmacodynamics and contribute to variability between individuals in response to medications. Specifically, differences in allele frequencies among individuals and ethnic groups have been associated with variation in their propensity to develop drug hypersensitivity reactions (HSRs). This article reviews the current knowledge on the genetic background of HSRs and its relevance to Jewish and Arab populations. The focus is on human leukocyte antigen (HLA) alleles and haplotypes as predictive markers of HSRs ("immunopharmacogenetics"), but other genes and alleles are described as well. Also discussed is the translation of the pharmacogenetic information to practice recommendations.

Genetic Basis of Delayed Hypersensitivity Reactions to Drugs in Jewish and Arab Populations

Aim: The multidrug resistance protein 1 (MDR1; P-glycoprotein) has been associated with efflux of chemotherapeutic agents from tumor cells and poor patient prognosis. This study evaluated the feasibility of non-invasive, non-radioactive near infrared (NIR( imaging methodology for detection of MDR1 functional activity in tumors. Methods: Initial accumulation assays were conducted in MDR1-overexpressing MDCK cells (MDCK-MDR1) and control MDCK cells (MDCK-CT) using the NIR dyes indocyanine green (ICG), IR-783, IR-775, rhodamine 800, XenoLight DiR and Genhance 750, at 0.4 µM to 100 µM. ICG and IR-783 were also evaluated in HT-29 cells in which MDR1 overexpression was induced by colchicine (HT-29-MDR1) and their controls (HT-29-CT). In vivo optical imaging studies were conducted using immunodeficient mice bearing HT-29-CT and HT-29-MDR1 xenografts. Results: ICG’s emission intensity was 2.0- and 2.2-fold higher in control versus MDR1-overexpressing cells, in MDCK and HT-29 cell lines, respectively. The respective IR-783 control:MDR1 ratio was 1.4 in both MDCK and HT-29 cells. Optical imaging of mice bearing HT-29-CT and HT-29-MDR1 xenografts revealed a statistically non-significant, 1.7-fold difference (p>0.05) in ICG emission intensity between control and MDR1 tumors. No such differences were observed with IR-783. Conclusion: ICG and IR-783 appear to be weak MDR1 substrates. In vivo, low sensitivity and high between-subject variability impair the ability to use the currently studied probes as markers of tumor MDR1 activity. The results suggest that, for future use of this technology, additional NIR probes should be screened as MDR1 substrates.

/pdf/evaluation-of-near-infrared-dyes-as-markers-of-p-1f71idn9m8.pdf

Evaluation of Near Infrared Dyes as Markers of P-Glycoprotein Activity in Tumors.

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Papers

Causative Drugs of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Israel.

Investigation of Cardiac Arrhythmia Events in Patients Treated with Lamotrigine: FAERS Analysis.

Genetic Basis of Delayed Hypersensitivity Reactions to Drugs in Jewish and Arab Populations

Evaluation of Near Infrared Dyes as Markers of P-Glycoprotein Activity in Tumors.