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.

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.

The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/epi.13498

Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

To the Editors: We have recently reported on antiepileptic drug (AED-) and non–AED-related cases of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in Israel. A subanalysis of the cases in which SJS/TEN was associated with AEDs (mostly phenytoin, lamotrigine, and carbamazepine) now reveals a relatively high percentage of Arabs and Jews of North African and Middle Eastern origin (combined) in this cohort. Of the 16 Israeli patients, 4 were Arab. The other 12 were Jews, among whom the country of origin was recorded for 7, including 2 patients from Morocco and one from each of the following countries: Iraq, Lebanon, former USSR, and Ethiopia (total 8 Middle Eastern Jews, North African Jews and Arabs vs 2 others). A patient from France was not included in the group analysis due to uncertainty regarding her ethnic origin, although the majority of French Jews originate from Algeria, Tunisia, and Morocco. An additional patient, an Arab from the Gaza strip, was also excluded to allow comparisons to Israeli population databases. By the end 2016, Arabs (excluding Druze) and Jews of Moroccan, Iraqi, and Lebanese origin comprised 19.1%, 5.6%, 2.6%, and 0.4% of the Israeli population, respectively (total 27.8%). If these populations were similarly represented in the SJS/TEN cohort of 10 AED-exposed patients, this would have translated to 3 AED-associated SJS/TEN cases (P < .001; Fisher’s exact test). For comparison, among the 9 patients who developed SJS/TEN following consumption of drugs other than AEDs, one was Bedouin, one a Lebanese Jew, 4 Ashkenazi Jews, one Bulgarian Jew, one Ethiopian Jew (P = .054 versus the AED group), and one of mixed Jewish origin. The numbers are small, and bias may be introduced by different prevalence of AED indications and hospitalization rates among subpopulations in the studied hospitals. Yet, our finding may also suggest that genetic variability exists among Jewish and Arab populations in terms of their propensity to develop SJS/TEN following exposure to AEDs. Recently, HLA-A*24:02 was reported to be a common genetic risk factor for cutaneous adverse reactions induced in Han Chinese by carbamazepine, lamotrigine, and phenytoin. The newly published data of the Ezer Mizion Bone Marrow Donor Registry, which includes 275 699 individuals of 19 subethnic Jewish and Arab populations, reveals that the distribution of this allele in Israeli populations is unique: 10.13% in Israeli Arabs and 9%-15% in Jews from the Caucasus (15.0%), Tunisia (12.0%), Morocco (11.4%), Poland (9.0%), and Iraq (8.8%) carry HLA-A*24:02. Among all the other published Israeli subpopulations, including Ashkenazi (other than Polish), Yemen, and Libya Jews, as well as the Druze, the allele frequency is 3% or less (Figure 1). These figures suggest that some Jewish and Arab ethnic groups

https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.14437

Stevens-Johnson syndrome/toxic epidermal necrolysis in Jewish and Arab populations.

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

Genetic risk factors for antiepileptic drug-induced hypersensitivity reactions in Israeli populations.

Stevens-Johnson syndrome/toxic epidermal necrolysis in Jewish and Arab populations.