Drug-induced Reactions Research Articles

Reporting of drug reaction with eosinophilia and systemic symptoms from 2002 to 2019 in the US Food and Drug Administration Adverse Event Reporting System

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a drug-induced severe cutaneous adverse reaction that is often overlooked owing to its overlap with other infectious and inflammatory illnesses; however, early identification and treatment are important to preventing associated morbidity and mortality.1,2 Historically, anticonvulsant use in association with DRESS syndrome was cited as early as the 1930s, with initial descriptions involving drug-associated hypersensitivity.2 In the 1950s, the term “drug-induced pseudolymphoma” described syndromes of cutaneous symptoms with organ involvement and other systemic features.

A prospective study of clinical spectrum of cutaneous adverse drug reactions and their incidence in Indian population

Making the diagnosis of a drug-induced reaction requires familiarity with the clinical patterns as the current understanding of the disease processes is not enough to explain about apparently similar pathological mechanisms generating different clinical patterns. Therefore, it remains useful and relevant to overlay a pathological understanding with a clinical classification. This study concentrated on observing and documenting the clinical presentation of cutaneous adverse drug reactions (CADR) encountered in patients. The purpose of the study was to evaluate causality, severity and preventability of Dermatological ADRs.: To study morphological types of CADR and their incidence in Indian population Method: A prospective, observational study was carried out over a period of one year at Out Patient Department of Dermatology, Government Medical College, Amritsar with diagnosed CADRs. The suspected ADRs were evaluated for causality by Naranjo’s Probability scale and severity by Hartwig and Siegel scale.Total 54 patients were enrolled. The incidence of CADR was 0.09%. Most commonly manifested ADR was fixed drug eruption (FDE) i.e. 35.2%. Maximum incidence of dermatological ADRs were observed with antimicrobial agents (39%) followed by non-steroidal anti-inflammatory drugs (NSAIDS) (24%). Naranjo’s Probabilty scale showed most cases of probable (68.5%) ADRs were of moderate severity (90.7%).Awareness about CADR is essential for early detection, management of patients and drug safety. The healthcare system can promote the spontaneous reporting of dermatological ADR to Pharmacovigilance centers for ensuring safe drug usage and patient care.

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy.

Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

A ten-day-old newborn with acute generalized exanthematous pustulosis

Acute generalized exanthematous pustulosis (AGEP) is a rare reaction related to various causes; in most cases, it is a drug-induced reaction. AGEP can occur at any age but is seldom described in children. In this article, we describe an AGEP case in a ten-day-old patient suspected to be caused by erythromycin, cefotaxime and ampicillin. Until now, according to our knowledge, this is the first pulished case of AGEP in a newborn.

COMPARATIVE EFFECTS OF IV INJECTION OF KETOPROFEN AND PARACETAMOL IN THE TREATMENT OF TENSION-TYPE HEADACHE

Background: Headaches are one of the commonly reported issues throughout the world population. Globally, Tension-type headache is a more common problem. Individuals facing long occurring and more severe headaches may go for care from the medical facility. However, most of the individuals do not do so which usually consequences in inappropriate and inadequate management of this problem.
 Objective: The aim of the present study is to compare the effectiveness of ketoprofen IV injection and paracetamol IV injection in the treatment of tension-type headache.
 Methodology: A validated questionnaire was designed to conduct this study. Certain inclusion and exclusion criteria were established to select the participants. Patients having the age between 20 to 40 years were treated with paracetamol and ketoprofen and their responses were recorded and evaluated.
 Results: Our results suggest that paracetamol has more vital signs stability when compared with ketoprofen and is safer in terms of drug-induced allergic reaction and injection site reaction. However, ketoprofen has a faster onset of action when compared with paracetamol.
 Conclusion: Management of tension-type headache is neglected most of the time which affects the quality of life and productivity in the affected population. Development and update of existing guidelines for tension-type headache are essential in managing this issue. Both ketoprofen and paracetamol are effective in treating this issue but both have some side effects. Future studies are still desired to further evaluate their effects.
 Keywords: Tension-type headache, Headache, analgesics, Ketoprofen, Paracetamol

The Translational Relevance of Human Circulating Memory Cutaneous Lymphocyte-Associated Antigen Positive T Cells in Inflammatory Skin Disorders.

Circulating memory T cells are heterogeneous in their tissue tropism. The skin-seeking T cell subset expresses the cutaneous lymphocyte-associated antigen (CLA) on their surface. CLA+ memory T cells not only migrate from blood to skin but also recirculate between blood and skin. Studying CLA+ memory T cells in cutaneous diseases has allowed a better understanding of immune-inflammatory mechanisms that take place. The analysis of the phenotypical features of these cells, their antigen specificity, cytokine production profile, and changes in relationship to clinical status and therapies among other characteristics have led to the concept that they constitute peripheral cellular biomarkers in T cell-mediated cutaneous conditions. CLA+ memory T cells are of relevance in the pathogenesis of several cutaneous diseases, such as psoriasis (PSO), atopic dermatitis, vitiligo, and drug-induced allergic reactions, to name a few. The interaction of circulating CLA+ T cells with skin-resident cells has been investigated in different ex vivo coculture models made out of clinical samples. Interestingly, microbes that are present in the skin or related with human skin diseases are preferentially recognized by CLA+ T cells. Thus, the interaction of Streptococcus pyogenes with CLA+ T cells in PSO is providing novel concepts that help to understand disease immunopathogenesis. The goal of this review is to present latest results in the field of CLA+ T cells in T cell-mediated inflammatory skin diseases and their translational relevance for human immunodermatology.

Viral Infections and Cutaneous Drug-Related Eruptions.

In the general population, up to 10% of children treated by antibiotics have cutaneous adverse drug reaction, but allergy is confirmed in less than 20% of patients. Most of the non-allergic reactions are probably due to virus, such as enterovirus acute infection or Ebstein-Barr Virus (EBV) acute infection or reactivation. Especially in children, viruses have the propensity to induce skin lesions (maculopapular rash, urticaria) due to their skin infiltration or immunologic response. In drug-related skin eruptions, a virus can participate by activating an immune predisposition. The culprit antibiotic is then the trigger for reacting. Even in severe drug-induced reactions, such as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, viruses take part in immune phenomena, especially herpes viruses. Understanding the mechanisms of both virus- and drug-induced skin reaction is important to develop our clinical reflection and give an adaptive care to the patient. Our aim is to review current knowledge on the different aspects and potential roles of viruses in the different type of drug hypersensitivity reactions (DHR). Although major advances have been made those past year, further studies are needed for a better understanding of the link between viruses and DHR, to improve management of those patients.

Sweet Presentation of a Bitter Disease: Acute Febrile Neutrophilic Dermatosis Associated with Coccidioidomycoses

Acute Febrile Neutrophilic Dermatosis, also known as Sweet Syndrome, is an uncommon inflammatory disorder. Though the exact etiology is unclear, it has been presented in association with various entities. The majority of cases present following upper respiratory infections or viral gastroenteritis. Other causes include drug-induced reactions, pregnancy-related manifestations, or in association with specific hematologic or solid tumors. Rarely, it has been associated with Coccidioidomycosis, a prevalent fungus endemic to the Southwestern regions of the United States with a literature review revealing only three previous cases of Coccidioidomycosis-associated Sweet Syndrome. Here we report two new cases in individuals residing in Arizona.

Covalent Histone Modification by an Electrophilic Derivative of the Anti-HIV Drug Nevirapine.

Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodeficiency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g., H2BK47, H4K32), histidine (e.g., H2BH110, H4H76), and serine (e.g., H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83, and H4H76 were found to be potential hot spots for NVP incorporation. Notably, a remarkable selectivity to the imidazole ring of histidine was observed, with modification by NVP detected in three out of the 11 histidine residues of histones. This suggests that NVP-modified histidine residues of histones are prospective markers of the drug’s bioactivation and/or toxicity. Importantly, NVP-derived modifications were identified at sites known to determine chromatin structure (e.g., H4H76) or that can undergo multiple types of post-translational modifications (e.g., H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.

Ceftolozane/Tazobactam-Induced Leukocytosis and Clinical Failure in a Patient Being Treated for Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Pseudomonas aeruginosa: a Case Report.

Ceftolozane/tazobactam is an intravenous beta-lactam/beta-lactamase inhibitor that utilizes a novel oxyimino-cephalosporin with a traditional beta-lactamase inhibitor. It is approved by the Food and Drug Administration to treat complicated intra-abdominal infections in combination with metronidazole, complicated urinary tract infections, and, most recently, hospital-acquired bacterial and ventilator-associated bacterial pneumonias. It is commonly utilized to treat infections caused by multidrug-resistant Pseudomonas aeruginosa. This case report delineates the first published case of ceftolozane/tazobactam-induced leukocytosis (up to 36.9 × 109 cells/L) and clinical failure when utilized in a high-dose regimen for a patient being treated for ventilator-associated pneumonia secondary to carbapenem-resistant P. aeruginosa. The reaction occurred during initial challenge, resolved after discontinuation, and recurred during re-challenge. In patients who are appropriately being treated with ceftolozane/tazobactam for susceptible infections, consider a drug-induced reaction as a potential cause of rising leukocytosis; this should be differentiated from clinical failure if the patient is clinically stable.

Dermatological Manifestations in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) may be associated with extra-intestinal manifestations. Among these, mucocutaneous manifestations are relatively frequent, often difficult to diagnose and treat, and may complicate the course of the underlying disease. In the present review, a summary of the most relevant literature on the dermatologic manifestations occurring in patients with inflammatory bowel diseases has been reviewed. The following dermatological manifestations associated with IBDs have been identified: (i) specific manifestations with the same histological features of the underlying IBD (occurring only in Crohn’s disease); (ii) cutaneous disorders associated with IBDs (such as aphthous stomatitis, erythema nodosum, psoriasis, epidermolysis bullosa acquisita); (iii) reactive mucocutaneous manifestations of IBDs (such as pyoderma gangrenosum, Sweet’s syndrome, bowel-associated dermatosis-arthritis syndrome, aseptic abscess ulcers, pyodermatitis–pyostomatitis vegetans, etc.); (iv) mucocutaneous conditions secondary to treatment (including injection site reactions, infusion reactions, paradoxical reactions, eczematous and psoriasis-like reactions, cutaneous infections, and cutaneous malignancies); (v) manifestations due to nutritional malabsorption (such as stomatitis, glossitis, angular cheilitis, pellagra, scurvy, purpura, acrodermatitis enteropathica, phrynoderma, seborrheic-type dermatitis, hair and nail abnormalities). An accurate dermatological examination is essential in all IBD patients, especially in candidates to biologic therapies, in whom drug-induced cutaneous reactions may assume marked clinical relevance.

Comorbidities and Cofactors of Anaphylaxis in Patients with Moderate to Severe Anaphylaxis. Analysis of Data from the Anaphylaxis Registry for West Pomerania Province, Poland.

Anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction that is still rarely diagnosed. For safety reasons, patients should visit an allergologist to identify potential causes and cofactors of this reaction. This paper presents the analysis of data from the Anaphylaxis Registry gathered over ten years at the Allergy Clinic, Pomeranian Medical University (PMU). A questionnaire-based survey was used for patients visiting the Allergy Clinic to identify potential augmentation factors/comorbidities and/or cofactors of anaphylaxis in patients with a history of moderate to severe anaphylaxis. The registry comprised patients with grade II or higher anaphylaxis. The gathered data concerned chronic comorbidities (cardiovascular diseases, respiratory diseases, and others), recurrence of anaphylaxis, and potential cofactors in anaphylaxis. In the analyzed group, the incidence rate of anaphylaxis was the highest for women aged 19–60 years. Most common comorbidities in patients with moderate to severe anaphylaxis included: cardiovascular diseases, respiratory tract diseases, features of atopy, and thyroid diseases. More than 30% of drug-induced reactions were anaphylactic reactions due to the re-exposure to the same drug, which points to the need for educational initiatives in this area. The incidence rate of anaphylaxis induced by Hymenoptera stings was comparable in patients who had a previous generalized reaction and those who had good tolerance to the previous sting. It is important to take these cofactors into consideration when evaluating patients with anaphylaxis as they may play a role in future anaphylactic reactions.

A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients.

Most of drugs could have certain mucocutaneous reactions and COVID‐19 drugs are not an exception that we focused. We systematically reviewed databases until August 15, 2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts, and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis, and so on. The treatments have been used before side effects occur, included: antimalarial, anti‐viral, antibiotics, tocilizumab, enoxaparin and and so on. In pandemic, we found 0.004% to 4.15% of definite drug‐induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin, and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions, which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. Lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life‐threatening reactions may occur. Better management strategies could achieve by knowing more about drug‐induced mucocutaneous presentations of COVID‐19.

Plasma exosomal miR-375-3p regulates mitochondria-dependent keratinocyte apoptosis by targeting XIAP in severe drug-induced skin reactions.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced cutaneous reactions characterized by keratinocyte apoptosis. Exosomes are nanometer-sized membranous vesicles in body fluids. They contain functional proteins, mRNAs, and miRNAs, which induce immune dysfunction and influence disease progression. However, their roles and mechanisms in SJS/TEN remain unknown. Our results demonstrate that exosomes isolated from the plasma of patients with SJS/TEN were 30 to 200 nm in diameter and expressed CD9, CD63, CD81, and TSG101 exosome marker proteins. miR-375-3p was markedly up-regulated in 35 patients with SJS/TEN and correlated with clinical severity. Plasma exosomes were internalized by human primary keratinocytes and promoted keratinocyte apoptosis in vitro. Furthermore, miR-375-3p overexpression promoted intrinsic (mitochondria-dependent) apoptosis of human primary keratinocytes via down-regulation of the X-linked inhibitor of apoptosis protein (XIAP), a key apoptosis regulator in primary human keratinocytes. In sum, our study indicates that the circulating exosomal miR-375-3p enters keratinocytes, down-regulates XIAP, and induces keratinocyte apoptosis in patients with SJS/TEN.

A novel ELISA method to determine human MrgX2 in chronic urticaria

BackgroundMas-related G-protein coupled receptor member X2 (MrgX2) directly mediates drug-induced pseudo allergic reactions. Skin mast cell MrgX2 is upregulated in severe chronic urticaria (CU). Mast cells and leukocytes are key effector cells in allergic reactions and undergo degranulation upon stimulation. It is unknown whether circulating MrgX2 expression can be detected occurs in the whole blood of CU patients and reflects pseudo-allergic reaction. There is no effective method for its detection. Therefore, an enzyme-linked immuno-sorbent assay (ELISA) for MrgX2 was developed.MethodsMonoclonal and polyclonal MrgX2 specific antibodies were obtained from rabbits and mice immunized by MrgX2 peptides prepared. Indirect ELISA and Dot blot were used to determine antibody titers before a sandwich ELISA for MrgX2 was established. The whole blood from healthy subjects and CU patients was used to detect MrgX2 concentrations. The use of feasibility of this MrgX2-ELISA as a clinical detection tool was explored and diagnostic purposes was assessed.ResultsThe sandwich antibody ELISA method for MrgX2 was established with good linearity regression (R2 = 0.9910). The lowest detection limit was 3.125 ng/mL. The quantification limit was 6.25 ng/mL. The sandwich ELISA for MrgX2 have good stability and high specificity. The initial truncation value of MrgX2 was 60.91 ng/mL (95% confidence interval). The whole blood MrgX2 concentrations in CU patients (median 98.01 ± 4.317 ng/mL, n = 75) was significantly increased compared to healthy subjects (58.09 ± 1.418 ng/mL, n = 75), with significant difference (p < 0.0001) and higher accuracy of (AUC = 0.8795). Comprehensive the frequency analysis of MrgX2 expression in 75 CU patients reference frequency distribution and ROC curve analysis, determined the threshold for CU patients as 71.23 ng/mL, with 81.33% sensitivity and 90.67% specificity.ConclusionMrgX2-ELISA provides a useful and convenient method for detecting MrgX2 in whole blood samples. The MrgX2-ELISA will help improve the understanding of the role of MrgX2 in regulating chronic urticaria.

Cell Membrane Transporters Facilitate the Accumulation of Hepatocellular Flucloxacillin Protein Adducts: Implication in Flucloxacillin-Induced Liver Injury.

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of HLA-B*57:01 increases susceptibility, little is known about the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the presentation of flucloxacillin-modified peptides by the risk allele. In this study, the binding of flucloxacillin to proteins of liver-like cells was characterized. Flucloxacillin was shown to bind to proteins localized in bile canaliculi regions, coinciding with the site of clinical disease. The localization of flucloxacillin was mediated primarily by the membrane transporter multidrug resistance-associated protein 2. Modification of multiple proteins by flucloxacillin in bile canaliculi regions may provide a potential local source of neo-antigens for HLA presentation in the liver.

DRESS syndrome induced by antibiotic-loaded bone cements and a diagnostic algorithm for related delayed-type hypersensitivity reactions

Drug rash with eosinophilia and systemic symptoms, known as DRESS syndrome, is a delayed type IVb hypersensitivity reaction hypothesized to be mediated by antiviral T cells.1 DRESS syndrome is one of the drug-induced severe cutaneous adverse reactions (SCAR) with a mortality rate of up to 10%.2 Antibiotics are among the most common culprits of DRESS syndrome, and 2 reports of suspected cases due to antibiotic-loaded bone cements (ALBC) have been previously published.3,4 However, previous reports only suspected ALBC-induced DRESS syndrome based on clinical history alone, and no allergy investigations were performed to confirm the exact drug culprits.

Identification of the dog orthologue of human MAS-related G protein coupled receptor X2 (MRGPRX2) essential for drug-induced pseudo-allergic reactions

MAS-related G protein coupled receptor-X2 (MRGPRX2), expressed in human mast cells, is associated with drug-induced pseudo-allergic reactions. Dogs are highly susceptible to drug-induced anaphylactoid reactions caused by various drugs; however, the distribution and physiological function of canine MRGPR family genes, including MRGPRX2, remain largely unknown. In the present study, we clarified the distribution of dog MRGPR family genes by real-time quantitative PCR and in situ hybridisation. We also investigated the stimulatory effects of various histamine-releasing agents, including fluoroquinolones, on HEK293 cells transiently transfected with dog MRGPR family genes to identify their physiological function. Dog MRGPRX2 and MRGPRG were distributed in a limited number of tissues, including the skin (from the eyelid, abdomen, and cheek), whereas MRGPRD and MRGPRF were extensively expressed in almost all tissues examined. Histochemical and in situ hybridisation analyses revealed that MRGPRX2 was expressed in dog connective tissue-type mast cells in the skin. Intracellular Ca2+ mobilisation assay revealed that HEK293 cells, expressing dog MRGPRX2 or human MRGPRX2, but not dog MRGPRD, MRGPRF, and MRGPRG, responded to histamine-releasing agents. Our results suggest that dog MRGPRX2 is the functional orthologue of human MRGPRX2 and plays an essential role in drug-induced anaphylactoid reactions in dogs.

Seizure Mimics: Oculogyric Crisis Following Metoclopramide-Video

A 9-year-old girl who experienced a seizure disorder was referred to our hospital by a medical practitioner. She presented with recurrent episodes of upward deviation of eyes with neck pain. She had taken tab metoclopramide 10 mg every 8 hours one day before for gastroenteritis. She was aware but unable to voluntarily control the attacks. On examination, she had sustained conjugate upward and lateral deviation of the eyes (oculogyric crisis), without loss of consciousness ([Fig. 1] [Video 1]). Symptoms disappeared rapidly following administration of IV promethazine 0.5 mg/kg slowly, and she remained well during follow-up 1 week later. Oculogyric crisis (OGC) is characterized by a prolonged involuntary upward deviation of the eyes. These episodes generally last for minutes, but can range from seconds to hours. Etiology includes drug-induced reactions, hereditary and sporadic movement disorders, and focal brain zdlesions. The majority of OGC cases occurred as adverse effects of neuroleptics and antiemetics. OGC usually disappears within 24 to 48 hours of drug withdrawal. Administration of anticholinergics (benztropine) or antihistamines (diphenhydramine) can alleviate OGC within minutes. The incidence of metoclopramide-induced acute dystonias is 0.2% with female preponderance.[1] A systematic review and meta-analysis revealed that the most common adverse effects following metoclopramide in children were extrapyramidal symptoms (9%), diarrhea (6%), and sedation (6%).[2] Ozel et al reported acute dystonic reaction due to metoclopramide in a 20-year-old female, which was misinterpreted as conversion disorder and seizure.[3] Acute dystonic reactions due to metoclopramide can be confused with conversion disorders, seizures and encephalitis.[1] [3] Our patient was also referred to our center by a medical practitioner on account of a presumed diagnosis of seizure disorder.

Responsiveness to i.v. immunoglobulin therapy in patients with toxic epidermal necrolysis: A novel pharmaco-immunogenetic concept.

Toxic epidermal necrolysis (TEN) represents a rare drug-induced autoimmune reaction with delayed-type hypersensitivity that initiates the process of developing massive keratinocyte apoptosis, dominantly in the dermoepidermal junction. Although the etiopathophysiology has not yet been fully elucidated, the binding of Fas ligand (FasL, CD95L) to the Fas receptor (CD95) was shown to play a key role in the induction of apoptosis in this syndrome. The knowledge of the role of immunoglobulin G (IgG) in inhibition of Fas-mediated apoptosis contributed to the introduction of i.v. Ig (IVIg) in the therapy of TEN patients. Despite great enthusiasm for this therapy at the end of the 1990s, subsequent studies in various populations and meta-analyses could not unequivocally confirm the efficacy of the IVIg-based treatment concept. Today, therefore, we are faced with the dilemmas of how to adjust therapy of TEN patients most effectively, which patients could benefit from IVIg therapy and what dose of the preparation should be administrated. The ground-breaking question is: do the host genetic profiles influence the responsiveness and side-effects of IVIg therapy in TEN patients? Based on recent pharmacological, immunological and genetic findings, we suggest that the variability of IVIg therapy outcomes in TEN patients may be related to functional variants in Fas, FasL and Fc-γ receptor genes. This novel concept could lead to improved quality of care for patients with TEN, facilitating personalized therapy to reduce mortality.