Drug-induced Toxic Epidermal Necrolysis Research Articles

Association between infection and severe drug adverse reactions: an analysis using data from the Japanese Adverse Drug Event Report database.

It has been reported recently that immune reactions are involved in the pathogenesis of certain types of adverse drug reactions (ADRs). We aimed to determine the associations between infections and drug-induced interstitial lung disease (DILD), rhabdomyolysis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or drug-induced liver injury (DILI) using a spontaneous adverse drug event reporting database in Japan. The reported cases were classified into three categories (anti-infectious drug group, concomitant infection group, and non-infection group) based on the presence of anti-infectious drugs (either as primary suspected drug or concomitant drug) and infectious disease. We assessed the association between four severe ADRs and the presence and seriousness of infection using logistic regression analysis. We identified 177,649 cases reported in the study period (2009-2013). Logistic regression analysis showed significant positive associations between infection status and onset of SJS/TEN or DILI (SJS/TEN: anti-infectious drug group: odds ratio (OR) 2.04, 95% CI [1.85-2.24], concomitant infection group: OR 2.44, 95% CI [2.21-2.69], DILI: anti-infectious drug group: OR 1.27, 95% CI [1.09-1.49], concomitant infection group: OR 1.25, 95% CI [1.04-1.49]), compared to the non-infection group. By contrast, there were negative or no associations between infection and DILD or rhabdomyolysis. A significantly positive association between infection and SJS/TEN seriousness (OR 1.48, 95% CI [1.10-1.98]) was observed. This study suggested that infection plays an important role in the development of SJS/TEN and DILI. For the patients with infection and/ or anti-infectious drugs, careful monitoring for severe ADRs, especially SJS/TEN, might be needed.

Incidence, causative drugs, and economic consequences of drug-induced SJS, TEN, and SJS-TEN overlap and potential drug-drug interactions during treatment: a retrospective analysis at an Indonesian referral hospital.

BackgroundStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acute life-threatening adverse drug reactions (ADRs) that are commonly caused by medications. Apart from their contribution to morbidity and mortality, these diseases may also present substantial consequences on health care resources. In this study, we aimed to identify the incidence, causative drugs, and economic consequences of these serious ADRs and potential drug–drug interactions (DDIs) during treatment.MethodsA retrospective study that included 150 patients diagnosed with drug-induced SJS, SJS–TEN overlap, and TEN, from 2009 to 2013 in a referral hospital in West Java Province, Indonesia, was conducted to analyze the causative drugs, cost of illness (COI) as a representation of economic consequences, and potential DDIs during treatment.ResultsThe results showed that analgesic–antipyretic drugs were the most frequently implicated drugs. The COIs for SJS, SJS–TEN overlap, and TEN patients were 119.49, 139.21, and 162.08 US dollars per day, respectively. Furthermore, potential DDIs with several therapeutic medications and corticosteroids used to treat SJS, SJS–TEN overlap, and TEN were also identified.ConclusionThis study showed that analgesic–antipyretic was the major causative drug which contributed to SJS, SJS–TEN overlap, and TEN. Furthermore, our results also showed that SJS, SJS–TEN overlap, and TEN may cause considerable financial consequences to patients.

Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in children: 20 years study in a tertiary care hospital.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe lifethreatening skin conditions. The most common cause of these manifestations is medications. Beside discontinued of the culprit drug, systemic corticosteroids were used as a primary treatment option among pediatric population. This study aimed to explore causative drugs (drug group/ latent period), treaments, complications, and treatment outcome (morbidity, mortality, length of hospital stay) of SJS and TEN in children. A retrospective chart was reviewed during the period of 1992 to 2012 at Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Thailand. SJS and TEN were clinically diagnosed and confirmed by pediatric dermatologists. Other possible causes other than druginduced SJS and TEN were excluded. A total of 30 patients was recorded, including 24 (80%) SJS patients and 6 (20%) TEN patients. The mean age was 6.9 years (SD 4.4). Male to female ratio was 1.5:1. Antiepileptic drug group was the most common causative drug (n=18, 60%), followed by antibiotic drug group (n=8, 26.6%), and others (n=4, 13.3%) which included nonsteroidal antiinflammtory drugs (NSAIDs) and chemotherapy drugs. Systemic corticosteroids were used in 29 patients (96.6%). Intravenous immunoglobulin was used in one TEN patient (3.3%). There was a medium correlation between time to treatment (systemic corticosteroids) and the length of hospital stay (Spearman correlation coefficient=0.63, P=0.005). Two TEN patients (6.6%) died. Carbamazepine was the most common causative drug of SJS and TEN in our study. The severity of skin detachment is not correlated to severity of ocular findings. However, the persistent of ocular complications up to one year is suggested for promptly appropriate ocular treatment in all SJS and TEN patients. Our data suggested that early administration of systemic corticosteroid may reduce the length of hospital stay and should be considered for the treatment of pediatric druginduced SJS and TEN.

Phenytoin-induced toxic epidermal necrolysis: Review and recommendations.

Toxic epidermal necrolysis (TEN) is a serious, life-threatening skin reaction characterized by severe exfoliation and destruction of the epidermis of the skin. In most TEN cases, drugs are believed to be the causative agent; antipsychotics, antiepileptics, and other medications such as sulfonamides are among the most common causes of drug-induced TEN. Phenytoin, a commonly prescribed medication for seizure, was found to cause TEN. Evidence-based treatment guidelines are lacking, so the best strategy is to identify and avoid potential risk factors and to provide intensive supportive care. The aim of this literature review is to focus on phenytoin-induced TEN, to explore the risk factors, and to highlight the possible treatment options once phenytoin-induced TEN is confirmed.

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

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.

Abstract 4304: Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort

Abstract SJS and TEN are extremely rare (approximately 2-7 cases per million per year) hypersensitivity reactions most commonly attributed to medications. The life-threatening nature of SJS/TEN necessitates early diagnosis and immediate identification and withdrawal of causative agents. Some of the most commonly associated culprits include sulfonamide antibiotics, aromatic anticonvulsants (phenytoin, carbamazepine, lamotrigine), -oxicam NSAIDs (e.g., meloxicam), allopurinol, and nevirapine. Individual case reports of SJS/TEN have been associated with anti-cancer agents, but a comprehensive assessment has not been performed. A large-scale retrospective analysis of the prevalence of SJS/TEN in cancer patients treated at Moffitt Cancer Center (MCC) between Jan 1, 2002 - Dec 31, 2014 was conducted. A total of 104,917 cancer patients were screened for SJS/TEN-related ICD-9 codes in the MCC health research informatics database. SJS/TEN diagnoses were identified in 121 patients. Manual chart review of physician, dermatology, and pathology notes confirmed SJS/TEN in 47 patients (in-patient + historical) and possible SJS/TEN in an additional 17 patients, corresponding to an overall prevalence of 0.06%. Confirmed in-patient cases of SJS/TEN were more common in hematologic malignancies compared to solid tumors (n = 12 vs. n = 7, respectively). Notably, 5 of the 19 (26.3%) confirmed cases were observed in patients with acute myeloid leukemia. Physician-reported culprits for SJS/TEN diagnoses included antibiotics, immunomodulators, anticonvulsants, and anti-cancer agents. The observed prevalence of SJS/TEN was higher in cancer patients than previous reports from the general USA population. There were 19 confirmed in-patient diagnoses of SJS/TEN and an additional 45 historical and possible cases of SJS/TEN in 104,917 cancer patients, corresponding to an overall prevalence of 0.018% to 0.06%, an approximately 90-fold increase when compared to the general population. Possible explanations for increased risk in cancer patients include increased exposure to culprit medications, cancer disease process, immunocompromised state, or synergy between risk factors. A thorough understanding of the factors that increase risk to SJS/TEN in cancer patients is critical to facilitate culprit withdrawal and maximize patient outcomes and survival. Citation Format: Nancy K. Gillis, Gillian C. Bell, Howard L. McLeod, Amy J. Brandt. Prevalence and triggers of drug-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in a cancer patient cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4304.

Toxic Epidermal Necrolysis-Like Cutaneous Lupus in Pediatric Patients: A Case Series and Review.

Bullous eruptions in patients with underlying systemic lupus erythematosus (LE) can mimic toxic-epidermal necrolysis (TEN), a rapidly progressive mucocutaneous reaction usually associated with medication use. Differentiating between classic drug-induced TEN and TEN-like cutaneous LE is important but difficult. We report a series of 3 patients with pediatric systemic LE who were admitted with severe worsening of skin disease resembling TEN. However, the initial photo-distribution of the eruption, subacute progression, limited mucosal involvement, mild systemic symptoms, supportive biopsy and laboratory results, and lack of culprit drugs was more suggestive of a TEN-like cutaneous LE. These patients recovered with various systemic immunosuppressive medications including methylprednisolone, intravenous immunoglobulin, and plasmapheresis. Our cases are rare and demonstrate key clinical and histologic features of TEN-like cutaneous LE in young patients and the importance of differentiating this entity from drug-induced TEN.

Genetic screening for human leukocyte antigen alleles prior to carbamazepine treatment

We describe a 28-year-old Malaysian Australian man of Han Chinese descent with toxic epidermal necrolysis (TEN), occurring 2weeks after commencing carbamazepine. He was subsequently found to be positive for human leukocyte antigen (HLA)-B*1502. Carbamazepine-induced Stevens–Johnson syndrome/TEN is strongly associated with the HLA-B*1502 allele, which is highly prevalent in Han Chinese, Malay, Thai and Indian populations. Prospective screening for the allele may prevent this cutaneous adverse drug reaction from occurring, but many neurologists and other medical practitioners are still unaware of the medico-legal risks of prescribing carbamazepine in susceptible populations and the availability of HLA-B*1502 testing. Performing HLA-B*1502 genotyping and avoiding carbamazepine in at-risk individuals has been proven to decrease incidences of drug-induced TEN. This test is widely available at most large pathology services in Australia, with results available within 2weeks. The recommendation by regulatory bodies should be strengthened to ensure that the broad medical community is made more aware of this pertinent issue.

Toxic epidermal necrolysis secondary to Mycoplasma pneumoniae and herpes simplex virus infection

Summary Toxic epidermal necrolysis (TEN) is a life-threatening skin reaction associated with a high mortality rate. Most TEN is induced by drugs, but some cases are caused by other insults. Mycoplasma pneumoniae and herpes simplex virus are the most common infectious pathogens associated with TEN. In identifying the etiology of TEN, it is crucial to include not only a detailed drug history but also potential infection sources. Any suspicious infections should be treated in a timely and efficient manner to improve survival rates. In this article, we report on five patients who developed TEN related to M. pneumoniae and herpes simplex virus infections. We also reviewed the relevant literature. We performed a retrospective medical chart review of five patients with TEN, which was considered secondary to M. pneumoniae and herpes simplex virus infections. We compared patients with infection-induced and drug-induced TEN. We found that patients with infection-induced TEN were younger in age and had lower SCORTEN scores, less renal dysfunction, shorter hospitalization periods, and higher survival rates compared with patients with drug-induced TEN. Identifying the etiology of TEN requires the inclusion of not only a detailed drug history but also infection sources, such as M. pneumoniae and herpes simplex virus. Our findings corroborate previously reported clinical and etiologic association with TEN. TEN induced by M. pneumoniae and herpes simplex virus manifested less severe clinical courses than its drug-induced counterpart.

Clinical features of and genetic predisposition to drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a single Korean tertiary institution patients-investigating the relation between the HLA -B*4403 allele and lamotrigine.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but fatal adverse mucocutaneous reactions to certain drugs. Recent studies suggest that ethnicity and genetic predisposition may play a crucial role in the manifestation of the reaction. In this study, we described the role of human leukocyte antigen (HLA)-B alleles in the development of clinical characteristics and treatment outcomes of SJS/TEN in a single Korean tertiary hospital. We retrospectively reviewed the medical records (from March 1, 2010 to February 28, 2014) of 30 patients diagnosed with SJS and/or TEN. The main causative drugs were anticonvulsants (26.7 %) and allopurinol (26.7 %), followed by antibiotics (16.7 %), acetazolamide (10.0 %), acetaminophen (10.0 %), and herbal medication (6.7 %). The mean latencies of these drugs were variable. Liver damage was the most common symptom (observed in 63.3 % of the patients). Of the five patients with lamotrigine-induced SJS/TEN, three expressed the HLA-B*4403 allele (60.0 %). Of the seven patients with allopurinol-induced SJS/TEN, five expressed the HLA-B*5801 allele (71.4 %). The major SJS/TEN-inducing drugs were found to be allopurinol and anticonvulsants (such as lamotrigine). We speculated that Korean individuals expressing the HLA-B*4403 allele may be highly susceptible to lamotrigine-induced SJS/TEN.

Fever, Rash, and Systemic Symptoms: Understanding the Role of Virus and HLA in Severe Cutaneous Drug Allergy

Drug hypersensitivity syndromes such as abacavir hypersensitivity and the severe cutaneous adverse drug reactions have been associated with significant short- and long-term morbidity and mortality. More recently, these immunologically mediated and previously unpredictable diseases have been shown to be associated with primarily class I but also class II HLA alleles. The case of the association of HLA-B*57:01 and abacavir hypersensitivity has created a translational roadmap for how this knowledge can be used in the clinic to prevent severe reactions. Although many hurdles exist to the widespread translation of such HLA screening approaches, our understanding of how drugs interact with the major histocompatibility complex has contributed to the discovery of new models that have provided considerable insights into the immunopathogenesis of severe cutaneous adverse drug reactions and other T-cell-mediated drug hypersensitivity syndromes. Future translation of this knowledge will facilitate the development of preclinical toxicity screening to significantly improve efficacy and safety of drug development and design.

A case report of hydralazine-induced skin reaction: Probable toxic epidermal necrolysis (TEN)

Patient: Female, 75Final Diagnosis: Hypertensive crisis with multi organ failureSymptoms: Anemia • general weakness • hypokalemia • nausea • tachycardiaMedication: —Clinical Procedure: —Specialty: CardiologyObjective:Unexpected drug reactionBackground:Skin reactions are common adverse drug reactions and may include angioedema, erythroderma, Stevens-Johnson syndrome, and toxic epidermal necrolysis (TEN). TEN is a rare but serious reaction characterized by widespread erythema, necrosis, and bullous detachment of the epidermis and mucous membranes.Case Report:An elderly woman presented with generalized weakness and nausea, associated with a hypertensive crisis. Following the initiation of hydralazine, well-demarcated erythematous maculopapular rashes appeared on her right forearm and left leg, which transformed into a bullous rash. Subsequently, a similar patch appeared on her left forearm, with a similar progression and associated with generalized edema of the extremities.A clinical diagnosis of drug-induced toxic epidermal necrolysis was made and hydralazine was discontinued. Following this, the skin lesions improved, with complete subsequent resolution. Skin biopsy was not performed due to the rapid resolution of the lesions. A negative screen for autoantibodies ruled out systemic lupus erythematosus, scleroderma, and other undifferentiated connective tissue disorders.After re-administration of hydralazine, the same lesions appeared again, which again resolved after its discontinuation, thus confirming our initial clinical suspicion.Treatment is immediate discontinuation of the offending drug and supportive care.Conclusions:Clinical awareness with close monitoring is important for the identification of a rare adverse drug reaction, which can be fatal if not diagnosed and treated promptly.

Toxic Epidermal Necrolysis and Graft-versus-Host Reaction: Revisiting a Puzzling Similarity

Drug-induced toxic epidermal necrolysis (TEN) and acute cutaneous graft-versus-host reaction (GVHR) under immunopreventive therapy share some histopathological resemblance. So far, there are no serum biomarkers and no immunohistochemical criteria distinguishing with confidence and specificity the skin lesions of TEN and GVHR. Both diseases present as an inflammatory cell-poor necrotic reaction of the epidermis. This report compares three sets of 15 immunostaining patterns found in TEN, GVHR, and partial thickness thermal burns (PTTB), respectively. Three series of 17 skin biopsies were scrutinized. Irrespective of the distinct causal pathobiology of TEN and GVHR, similar secondary effector cells were recruited in lesional skin. Burns were less enriched in cells of the monocyte-macrophage disease. These cells likely exert deleterious effects in TEN and GVHR and cannot be simply regarded as passive bystanders. These life-threatening conditions are probably nursed, at least in part, by macrophages.

Proteomic Kinetic Analysis of Blister Fluid and Serum in a Patient with Drug-Induced Toxic Epidermal Necrolysis. A Comparison with Skin Immunohistochemistry

Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN pathobiology using a combination of immunohistochemistry and proteomics. Skin blister fluid (BF) and serum were collected in a patient in the early TEN stage at day (D) +4 of evolution and three days later (D +7). Intravenous cyclosporine A (CsA) treatment was initiated since D +4. Immunohistochemistry was performed on skin blister biopsies. In addition, proteomic analyses compared the BF protein content before and at the issue of the 3-day CsA treatment. Proteins were selected according to their prominent differential abundance in BF between D+4 and D+7, when influenced by lesional skin cells, but not in serum. Among 300 proteins, four were considered. Glutathione transferase π was related to oxidative stress in TEN epidermis. The monocyte differentiation antigen CD14 and myeloperoxidase indicated macrophage activation. The proinflammatory S100-A8 protein probably originated from activated keratinocytes and/or macrophages. These proteomic findings were in line with immunohistochemistry and supported the prominent involvement of keratinocytes and macrophages in TEN pathomechanism. As opposed to CD14, other proteins were mainly present in BF at D+7, confirming that CsA expressed little effect, if any, on the activity of keratinocytes and macrophages in the present TEN patient. Of note, the present exploratory study using proteomic analyses in a single TEN case supports a pathogenic hypothesis without establishing any firm conclusion.

Drug Interactions with Normal and TEN Epidermal Keratinocytes

Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug metabolization, and more specifically drug processing are reviewed in normal EKs. The overall drug metabolism involves different phases corresponding to the uptake, biotransformation and anti-transport steps. In EKs, both the enzymes and transportassociated proteins are different from those involved in the hepatocyte metabolism. Some cytochrome P450 enzymes and the flavin-containing mono-oxygenases are particularly involved in EKs. Basically, EKs represent key cells likely involved during the initial stage of drug-induced toxic epidermal necrolysis (TEN). Only limited advances have been made so far in this field. Nevertheless, mitigating EKs metabolic disturbances in TEN probably represent a promising specific treatment of the disease. Keywords: Drug metabolism, toxic epidermal necrolysis, drug disposition, biotransformation, anti-transport mechanism, cytochrome P450, keratinocyte, aromatic anti-epileptics, lamotrigine, pantoprazole

A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous drug reactions. No large scale epidemiological data are available for this disorder in India. To carry out a systematic review of the published evidence of the drug-induced SJS and TEN in Indian population. Publications from 1995 to 2011 describing SJS and TEN in Indian population were searched in PubMed, MEDLINE, EMBASE and UK PUBMED Central electronic databases. Data were collected for the causative drugs and other clinical characteristics of SJS and TEN from the selected studies. From 225 references, 10 references were included as per selection criteria. The major causative drugs were antimicrobials (37.27%), anti-epileptics (35.73%) and non-steroidal anti-inflammatory drugs (15.93%). Carbamazepine (18.25%), phenytoin (13.37%), fluoroquinolones (8.48%) and paracetamol (6.17%) were most commonly implicated drugs. Regional differences were observed for fluoroquinolones, sulfa drugs and carbamazepine. Total 62.96% of patients showed systemic complications. Most common complications were ocular (40.29%) and septicemia (17.65%). Higher mortality was observed for TEN as compared to SJS (odd ratio-7.19; 95% confidence interval (CI) 1.62-31.92; p = 0.0023). Observed mortality is higher than expected as per SCORTEN score 3. Duration of hospital stay was significantly higher in TEN (20.6 days; 95% CI 14.4-26.8) as compared to SJS (9.7 days; 95% CI 5.8-13.6; p = 0.020). Cost of management was significantly higher in TEN (Rs. 7910; 95% CI 5672-10147; p < 0.0001) as compared to SJS (Rs 2460; 95% CI 1762-3158). No statistical data were described for steroid use in the studies included. Carbamazepine, phenytoin, fluoroquinolones and paracetamol were the major causative drugs. TEN is showing higher mortality, morbidity and economic burden than SJS.

Rapidly Developing Toxic Epidermal Necrolysis

Severe cutaneous reactions with potentially fatal outcomes can have many different causes. The Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare. They are characterized by a low incidence but high mortality, and drugs are most commonly implicated. Urgent active therapy is required. Prompt recognition and withdrawal of suspect drug and rapid intervention can result in favourable outcome. No further international guidelines for treatment exist, and much of the treatment relies on old or experimental concepts with no scientific evidence. We report on a 54-year-old man experiencing rapidly developing drug-induced severe TEN and presented multiorgan failure involving the respiratory and circulatory system, coagulopathy, and renal insufficiency. Detachment counted 30% of total body surface area (TBSA). SCORTEN = 5, indicating a mortality rate >90%. The patient was sedated and mechanically ventilated, supported with fluids and inotropes to maintain a stable circulation. Component therapy was guided by thromboelastography (TEG). The patient received plasmapheresis, and shock reversal treatment was initiated. He was transferred to a specialized intensive care burn unit within 24 hours from admittance. The initial care was continued, and hemodialysis was started. Pulmonary, circulatory, and renal sequelae resolved with intensive care, and re-epithelialization progressed slowly. The patient was discharged home on hospital day 19.

Proteomic Kinetic Analysis of Blister Fluid and Serum in a Patient with Drug-Induced Toxic Epidermal Necrolysis. A Comparison with Skin Immunohistochemistry

Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN pathobiology using a combination of immunohistochemistry and proteomics. Skin blister fluid (BF) and serum were collected in a patient in the early TEN stage at day (D) +4 of evolution and three days later (D +7). Intravenous cyclosporine A (CsA) treatment was initiated since D +4. Immunohistochemistry was performed on skin blister biopsies. In addition, proteomic analyses compared the BF protein content before and at the issue of the 3-day CsA treatment. Proteins were selected according to their prominent differential abundance in BF between D+4 and D+7, when influenced by lesional skin cells, but not in serum. Among 300 proteins, four were considered. Glutathione transferase π was related to oxidative stress in TEN epidermis. The monocyte differentiation antigen CD14 and myeloperoxidase indicated macrophage activation. The proinflammatory S100-A8 protein probably originated from activated keratinocytes and/or macrophages. These proteomic findings were in line with immunohistochemistry and supported the prominent involvement of keratinocytes and macrophages in TEN pathomechanism. As opposed to CD14, other proteins were mainly present in BF at D+7, confirming that CsA expressed little effect, if any, on the activity of keratinocytes and macrophages in the present TEN patient. Of note, the present exploratory study using proteomic analyses in a single TEN case supports a pathogenic hypothesis without establishing any firm conclusion.

Drug Interactions with Normal and TEN Epidermal Keratinocytes

Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug metabolization, and more specifically drug processing are reviewed in normal EKs. The overall drug metabolism involves different phases corresponding to the uptake, biotransformation and anti-transport steps. In EKs, both the enzymes and transportassociated proteins are different from those involved in the hepatocyte metabolism. Some cytochrome P450 enzymes and the flavin-containing mono-oxygenases are particularly involved in EKs. Basically, EKs represent key cells likely involved during the initial stage of drug-induced toxic epidermal necrolysis (TEN). Only limited advances have been made so far in this field. Nevertheless, mitigating EKs metabolic disturbances in TEN probably represent a promising specific treatment of the disease.

Esophageal Stricture Secondary to Drug-induced Toxic Epidermal Necrolysis Presenting in an Adult: An Unusual Complication of a Rare Disease

Purpose: Toxic epidermal necrolysis (TEN) is an idiosyncratic, potentially life-threatening skin disease characterized by widespread inflammation and necrosis of the epidermis and mucous membranes. It may result in narrowing of the esophageal lumen through fibrosis and esophageal stricture in very rare situations, mostly encountered in children. To the best of our knowledge, we report the first case of esophageal stricture secondary to allopurinol-induced TEN in an adult patient. A 70-year-old male presented to our clinic with severe dysphagia secondary to allopurinol-induced TEN involving his mouth and esophagus. At the time of presentation the patient had a percutaneous endoscopic gastrostomy feeding tube and was unable to handle his oral secretions. Endoscopy revealed near complete proximal esophageal stricture (Figure 1). A bidirectional esophageal dilatation procedure via the mouth and percutaneous endoscopic gastrostomy site was successfully performed over a guide wire for treatment of this patient. The patient tolerated the procedure well. Esophagogastroduodenoscopy (EGD) with dilation was performed in a regular anterograde fashion 5 times over the next 3 months. Triamcinolone acetonide was injected using carr-locke injection needle from Ultrasound Endoscopy during the last 3 sessions. During his last EGD, his esophagus was serially dilated to 17 mm (Figure 2). He currently tolerates a regular diet without difficulty.Figure: [617] Figure 1. Endoscopic appearance of the proximal esophagus showing a severe stricture with near complete obstruction before dilatation.Figure: [617] Figure 2. Endoscopic appearance of the proximal esophagus showing significant opening of the proximal esophagus after dilatation.