allopurinol and Stevens-Johnson-Syndrome

Drug hypersensitivity reactions (DHR) are heterogeneous in their pathomechanisms, clinical presentation, severity, and outcomes. Novel DHR mechanisms, phenotypes, and endotypes have been described. The key to prevention from further exposure to the culprit drugs involves correct identification of the putative drug through a combination of in vitro and/or in vivo tests, accurate drug allergy labeling and reporting, and electronic decision support systems within electronic medical records to prevent future accidental prescribing. Prescreening and premedication, the focus of this review, may be a useful adjunct to preventive measures in certain situations. After an index immediate drug hypersensitivity reaction, prescreening may be useful in perioperative anaphylaxis, and iodinated (ICM) and gadolinium-based contrast media (GCM) where the culprit and potential alternative agents are skin tested. In certain nonimmediate DHR, pharmacogenomic prescreening may be used before prescribing high-risk drugs (eg, carbamazepine and allopurinol) where specific human-leukocyte antigen genotypes are associated with severe cutaneous adverse reactions. Premedication with antihistamine and systemic corticosteroids is another therapeutic strategy to prevent infusion reactions for certain biologicals and chemotherapeutic agents, in cases of perioperative anaphylaxis, ICM and GCM DHR, and clonal mast cell disorders. Rapid drug desensitization may also be used to induce temporary tolerance in situations where there are limited alternative drugs.

Topics: Allopurinol; Contrast Media; Drug Hypersensitivity; Humans; Premedication; Skin Tests; Stevens-Johnson Syndrome

Severe cutaneous adverse reactions (SCARs) are important in postmarketing drug safety because SCAR patients were highest in the adverse drug reaction relief system of Japan. The SCAR symptoms of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) include high fever, severe mucosal impairment, and epidermal necrosis-induced erosions and blisters. Approximately 600 cases of SJS and 300 cases of TEN are reported annually in Japan. Many suspected drugs such as acetaminophen, lamotrigine, allopurinol, and carbamazepine have been reported. Over the last 15 years, an association between human leukocyte antigen and SJS/TEN onset has been reported with several drugs. Pathophysiological examinations in those reports revealed marked CD8-positive T cell infiltration into epidermal lesions, and the presence of cytotoxic granulysin, soluble Fas ligand, and tumor necrosis factor (TNF)-α in blister fluid. Therefore, SJS and TEN are immunological disorders that lead to epidermal necrosis and are consequently treated with the systemic administration of corticosteroids and with high-dose intravenous immunoglobulin therapy and plasma exchange in severe cases. Additionally, because the epidermal necrosis has characteristics similar to those of organ rejection after transplantation, the administration of cyclosporine, an immunosuppressant that inhibits helper T cell activation, has been attempted. Further, the administration of the TNF-α inhibitor etanercept has also been reported. This review summarizes current knowledge on the mechanisms of onset of SJS/TEN and their treatments.

Topics: Acetaminophen; Adrenal Cortex Hormones; Allopurinol; Antigens, Differentiation, T-Lymphocyte; Carbamazepine; CD8-Positive T-Lymphocytes; Cyclosporine; Epidermis; Etanercept; Fas Ligand Protein; HLA Antigens; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Japan; Lamotrigine; Plasma Exchange; Stevens-Johnson Syndrome; Tumor Necrosis Factor-alpha

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are mucocutaneous hypersensitivity reactions, usually to drugs or their metabolites. TEN is the most severe involving greater than 30% of the total body surface area (TBSA). Management of these patients usually benefits from a large multidisciplinary team for both wound and medical management. Treatment of these patients varies between centers and physicians and there is lack of a standardized treatment protocol in the medical literature.. To review the literature and complete a retrospective review of patients treated at Vancouver General Hospital over a 11-year period.. A retrospective chart review of all patients diagnosed with SJS/TEN and treated at Vancouver General Hospital from 2001 to 2011 was completed. Data collected include patient demographics, time to transfer to a burn center, SCORTEN calculation, suspected cause of TEN, %TBSA involved, length of stay in hospital and ICU, medications, dressings, infections/cultures, fluids, mucosal involvement, teams involved, associated complications, morbidity and mortality. Data is reported quantitatively.. A total of 67 patients were identified (28 SJS, 21 SJS/TEN overlap, 18 TEN). In SJS/TEN overlap and TEN patients, oral mucosa and trunk were the primary sites involved. SCORTEN calculations were highest in the TEN group. Plastic surgery was consulted in 53% of TEN cases, 52% of SJS/TEN cases and 25% of SJS cases. Patients were admitted to a burn unit in 74% of TEN cases, 57% of TEN/SJS cases and 21% of SJS cases. Time from symptoms to diagnosis and transfer to a burn unit was highest for TEN patients. Time from presentation to diagnosis was highest in SJS/TEN overlap. Triggers were identified in 67-82% of cases. Treatment varied widely. Patients were treated conservatively, with steroids, IVIg, and cyclosporine alone or in combination. Observed mortality was higher than predicted by SCORTEN for patients treated with IVIg and lower for those treated with Cyclosporin. Dressings varied greatly and were often changed throughout a patients stay. Total mortality was 20.9% being the highest in the TEN group (35%).. SJS and TEN are a spectrum of severe mucocutaneous reactions that have unclear treatment recommendations within the literature and within our Level 1 hospital. Information gleaned from this research will help educate physicians involved in the treatment and management of patients with these diagnoses and has resulted in development of treatment guidelines in our hospital.

Topics: Adrenal Cortex Hormones; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Bandages; British Columbia; Comorbidity; Cyclosporine; Dermatologic Agents; Dermatology; Diabetes Mellitus; Dietetics; Disease Management; Female; Gout; Gout Suppressants; Humans; Immunocompromised Host; Immunoglobulins, Intravenous; Immunologic Factors; Intensive Care Units; Length of Stay; Male; Middle Aged; Mouth Mucosa; Neoplasms; Patient Care Team; Retrospective Studies; Seizures; Stevens-Johnson Syndrome; Surgery, Plastic; Torso

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acutely occurring, unpredictable, often life-threatening reactions that are a huge challenge in clinical practice. They are characterized by extensive blistering of skin and mucosa and are considered as one disease entity of different severity. Thus, they are summarized as SJS/TEN or EN (for epidermal or epithelial necrolysis). The diagnosis can be confirmed through synopsis of clinical pattern and histopathological findings. To identify the inducing factors, it is crucial to obtain a detailed and thorough medication and infection history. Based on the results of large epidemiological studies, potentially inducing drugs can be narrowed down even in cases of multimedication and underlying diseases. Agents with a high risk for SJS/TEN are allopurinol, antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam-type, various antiepileptics and nevirapine. They alone explain more than half of the cases of SJS/TEN. Typically, the reaction occurs during the first continuous use of the medication, while the beginning of use most often is one to four weeks prior to reaction onset. However, a drug is not always the cause of the reaction, but in approximately 70-75% of the cases very likely. In other cases infections may be potential causes. If certain medications are thought to be the inducing factors, they should be withdrawn without delay. In addition, symptomatic treatment should be initiated. In case of progression, an additional immunomodulating therapy should be considered. In this respect, systematic reviews have shown best results for cyclosporine A and systemic steroids.

Topics: Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Drug-Related Side Effects and Adverse Reactions; Exanthema; Humans; Nevirapine; Skin; Stevens-Johnson Syndrome; Sulfonamides

The association between human leukocyte antigen (HLA) variants and allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) was evaluated through a pooled analysis of published studies.. A comprehensive search was performed in multiple databases, including PubMed, MEDLINE, ISI Web of Knowledge, EMBASE, Cochrane Register of Controlled Trials, and Science Direct. Studies investigating the association between. A total of 4 studies with 81 allopurinol-induced SJS or TEN cases and matched controls (allopurinol-tolerant patients) or population controls (general population) were identified. SJS and TEN were found to be significantly associated with HLA-A*33:03 and HLA-C*03:02 alleles in both groups of studies with matched controls and population controls. All of the pooled ORs were not significantly affected by the remaining studies and different modeling methods, indicating robust results.. A strong association was found between HLA-A*33:03 and HLA-C*03:02 alleles and allopurinol-induced SJS or TEN, especially in an Asian population.

Topics: Allopurinol; Asian People; Genetic Predisposition to Disease; Gout; Gout Suppressants; HLA Antigens; Humans; Hyperuricemia; Stevens-Johnson Syndrome

Despite many studies suggesting an association between human leukocyte antigen (HLA)-B*5801 and allopurinol-induced toxic epidermal necrolysis (TEN) and Stevens-Johnsons syndrome (SJS), the evidence of association in different populations and the degree of association remain uncertain.. The primary analysis was based on population-control studies. Data were pooled by means of a random-effects model, and sensitivity, specificity, positive likelihood ratios (LR+), negative likelihood ratios (LR-), diagnostic odds ratios (DOR), and areas under summary receiver operating characteristic (SROC) curves (AUC) were calculated.. In nine population-control studies, HLA-B*5801 was measured in 162 patients with allopurinol-induced TEN/SJS and 7372 patients without allopurinol-induced TEN/SJS. The pooled sensitivity, specificity, LR+, LR-, DOR and AUC were 0.78 (95% CI = 0.71-0.85), 0.96 (95% CI = 0.96-0.97), 14.23 (95% CI = 7.89-25.63), 0.29 (95% CI = 0.16-0.54), 83.5 (95% CI = 50.7-137.4), and 0.97 (95% CI = 0.95-0.99), respectively. Subgroup analyses of the DORs for Chinese, Japanese, and Caucasian populations yielded similar findings for Chinese (196.1; 95% CI = 57.3-672.0), Japanese (78.8; 95% CI = 30.4-203.9), and Caucasian (58.4; 95% CI = 16.9-201.5) populations. Overall, HLA-B*5801 was associated with allopurinol-induced TEN/SJS in European and Japanese populations, but only had a 50-60% sensitivity (pooled sensitivity 56%), compared to the 80-100% sensitivity (pooled sensitivity 97%) observed in Korean, Thai, Sardinia Italian and Han Chinese populations.. The present study reveals that allopurinol is the leading cause of TEN/SJS in many countries. In contrast to carbamazepine, which is ethnic/population specific, the HLA-B*5801 for detecting allopurinol-induced TEN/SJS is universal. Screening of HLA-B*5801 may help patients to prevent the occurrence of allopurinol-induced TEN/SJS, especially in populations with a higher (≥ 5%) risk allele frequency.

Topics: Allopurinol; Area Under Curve; Chi-Square Distribution; Enzyme Inhibitors; Gene Frequency; Genetic Predisposition to Disease; Genetic Testing; Gout Suppressants; HLA-B Antigens; Humans; Odds Ratio; Phenotype; Predictive Value of Tests; Racial Groups; Risk Factors; ROC Curve; Severity of Illness Index; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction characterized by necrosis of the epidermis. Its incidence is approximately 1 per million a year and average mortality rate is high at 25-50%. TEN has a flu-like prodrome, followed by atypical, targetoid erythematous or purpuric macules on the skin. These macules coalesce to form flaccid blisters that slough off as areas of epidermal necrosis. Drugs such as allopurinol, sulfonamides, and carbamazepine are the most common causes. The human leukocyte antigen (HLA)-B*15:02 in Asians being administered carbamazepine and the HLA-B*58:01 antigen in patients of all ethnicities being administered allopurinol are known to be high-risk factors. Rapid diagnosis, discontinuation of the causative drug, and supportive treatment are essential for better prognosis and improvement of sequelae. Till now, systemic corticosteroids and intravenous immunoglobulins have been used as the most common active interventions; however, no gold standard has been established. In Japan, physicians follow a unique diagnostic criteria and treatment guideline to improve the diagnosis rate and streamline treatments. This may be a contributing factor for the lower mortality rate (14.3%). The efficacy of systemic corticosteroids, immunoglobulins, and plasmapheresis may have been beneficial as well. In Japan, TEN is defined as an epidermal detachment of over 10% of the body surface area (BSA), while the globally accepted definition established by Bastuji-Garin describes it as an epidermal detachment of over 30% of the BSA. In Japanese individuals, HLA-A*02:06, HLA-A*02:07, HLA-A*31:01 and HLA-B*51:01 may be linked to higher risks of TEN.

Topics: Allopurinol; Carbamazepine; Female; HLA-B Antigens; HLA-B15 Antigen; Humans; Japan; Male; Stevens-Johnson Syndrome; Sulfonamides

Severe cutaneous adverse reactions (SCARs), previously thought to be idiosyncratic or unpredictable, are a deadly form of adverse drug reactions with skin manifestations. Current pharmacogenomic studies of SCARs have made important strides, as the prevention of SCARs, to some extent, appears attainable with the identification of genetic variants for genes encoding drug-metabolizing enzymes and human leukocyte antigens (HLAs). Despite the improvement of incidence, a treatment guideline for this devastating condition is still unavailable, highlighting the inadequacy of contemporary accepted therapeutic interventions. As such, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we discuss recent cutting-edge findings concerning the discovery of biomarkers for SCARs and their clinical utilities in the better prediction and early diagnosis of this disease. The knowledge compiled herein provides clues for future investigations on deciphering additional genetic markers for SCARs and the design of clinical trials for the prospective identification of subjects at genetic risk for this condition, ultimately personalizing the medicine.

Topics: Allopurinol; Anti-HIV Agents; Anticonvulsants; Biomarkers; Carbamazepine; Dideoxynucleosides; Genetic Markers; Gout Suppressants; HLA-B Antigens; Humans; Inactivation, Metabolic; Pharmacogenetics; Precision Medicine; Prognosis; Safety-Based Drug Withdrawals; Stevens-Johnson Syndrome

Immune-mediated (IM) adverse drug reactions (ADRs) are an underrecognized source of preventable morbidity, mortality, and cost. Increasingly, genetic variation in the HLA loci is associated with risk of severe reactions, highlighting the importance of T-cell immune responses in the mechanisms of both B cell-mediated and primary T cell-mediated IM-ADRs. In this review we summarize the role of host genetics, microbes, and drugs in IM-ADR development; expand on the existing models of IM-ADR pathogenesis to address multiple unexplained observations; discuss the implications of this work in clinical practice today; and describe future applications for preclinical drug toxicity screening, drug design, and development.

Topics: Allopurinol; B-Lymphocytes; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Expression Regulation; Genetic Loci; HLA Antigens; Humans; Models, Immunological; Pharmacogenetics; Stevens-Johnson Syndrome; T-Lymphocytes; Virus Diseases

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe, life-threatening drug reactions involving skin and membranes mucous, which are associated with significant morbidity and mortality and triggered, especially by drug exposure. Different studies have demonstrated that drug response is a multifactorial character and that the interindividual variability in this response depends on both environmental and genetic factors. The last ones have a relevant significance. In fact, the identification of new specific genetic markers involved in the response to drugs, will be of great utility to establish a more personalized therapeutic approach and to prevent the appearance of these adverse reactions. In this review, we summarize recent progresses in the Pharmacogenetics studies related to Stevens-Johnson syndrome/toxic epidermal necrolysis reporting the major genetic factors identified in the last years as associated with the disease and highlighting the use of some of these genomic variants in the clinical practice.

Topics: Allopurinol; Animals; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; Humans; Pharmacogenetics; Severity of Illness Index; Stevens-Johnson Syndrome

Over the past decade, there have been significant advances in our understanding of the immunopathogenesis and pharmacogenomics of severe immunologically-mediated adverse drug reactions. Such T-cell-mediated adverse drug reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug-induced liver disease (DILI) and other drug hypersensitivity syndromes have more recently been shown to be mediated through interactions with various class I and II HLA alleles. Key examples have included the associations of HLA-B*15:02 and carbamazepine induced SJS/TEN in Southeast Asian populations and HLA-B*57:01 and abacavir hypersensitivity. HLA-B*57:01 screening to prevent abacavir hypersensitivity exemplifies a successful translational roadmap from pharmacogenomic discovery through to widespread clinical implementation. Ultimately, our increased understanding of the interaction between drugs and the MHC could be used to inform drug design and drive pre-clinical toxicity programs to improve drug safety.

Topics: Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Genotype; HLA-B Antigens; Humans; Nevirapine; Pharmacogenetics; Protein Conformation; Stevens-Johnson Syndrome

Different responses, in terms both of efficacy and toxicity, are commonly observed for any drug administered to apparently homogeneous groups of patients. It is estimated that adverse drug reactions (ADRs) cause 3-6% of all hospitalizations, accounting for 5% to 9% of hospital admission costs. The skin is often involved in ADRs and although most cutaneous ADRs have a favorable course, they may present as severe adverse cutaneous drug reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also referred to as drug-induced hypersensitivity syndrome), and acute generalized exanthematous pustulosis. SCARs are associated with significant mortality and require prompt diagnosis and adequate treatment. Pharmacogenetics studies individual variants in the DNA sequence associated with drug efficacy and toxicity, allowing prescription of a drug to patients expected to benefit from it, and excluding from treatment those who are at risk of developing ADRs. Pharmacogenetics already achieved several important results in the prevention of SCARs, and pharmacogenetic testing is now recommended by regulatory agencies before administration of abacavir and carbamazepine, leading to reduced incidence of SCARs. In this review, the pharmacogenetic associations of SCARs that have been validated in independent, case-control association studies will be presented. By familiarizing with principles of pharmacogenetics, dermatologists should be able to correlate specific cutaneous ADR phenotypes to the underlying genotype, thus contributing to better drug safety and facilitating drug discovery, development and approval.

Topics: Allopurinol; Anti-HIV Agents; Anticonvulsants; Biomarkers; Carbamazepine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity Syndrome; Enzyme Inhibitors; Genes, MHC Class I; Genome-Wide Association Study; Genotype; HLA Antigens; Humans; Nevirapine; Pharmacogenetics; Polymorphism, Single Nucleotide; Stevens-Johnson Syndrome

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

Topics: Alleles; Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity Syndrome; Gene Expression; Genetic Predisposition to Disease; HLA Antigens; Humans; Stevens-Johnson Syndrome; T-Lymphocytes

Pharmacogenomics is gradually becoming more and more indispensable in modern medicine. In several cases, a pharmacogenomics test may alleviate serious drug-induced adverse reactions, if it precedes drug prescription. In this article, we provide an overview of the well-established HLA-based carbamazepine- and allopurinol-induced adverse reactions, as one of the most characteristic examples of the clinical application of pharmacogenomics, highlighting its regional impact in Southeast Asian populations in preventing adverse reactions of certain drug/allele pairs. This example provides useful insights towards evidence generation for policy implementation, including economic evaluation analysis, the implementation of pharmacogenomics testing procedures and monitoring of policy effectiveness, hence serving, per se or in the context of international collaborative efforts, as a model for similar cases in several national healthcare systems worldwide.

Topics: Acute Generalized Exanthematous Pustulosis; Alleles; Allopurinol; Anticonvulsants; Antimetabolites; Asian People; Carbamazepine; Drug Hypersensitivity Syndrome; Histocompatibility Antigens Class I; Histocompatibility Antigens Class II; Humans; Pharmacogenetics; Polymorphism, Genetic; Stevens-Johnson Syndrome

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings.

Topics: Alleles; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Azetidines; Benzylamines; Carbamazepine; Chemical and Drug Induced Liver Injury; Diclofenac; Dideoxynucleosides; Drug Hypersensitivity; Floxacillin; Genetic Markers; HLA Antigens; HLA-A Antigens; HLA-B Antigens; HLA-DQ alpha-Chains; Humans; Lapatinib; Pharmacogenetics; Quinazolines; Skin; Stevens-Johnson Syndrome; Ticlopidine

Gout is a common condition which is mainly treated with the hypo-uricemic agent, allopurinol. Although allopurinol is generally a well-tolerated drug, there is a small risk of developing potentially fatal complications, such as allopurinol hypersensitivity syndrome. Recent advances in pharmacogenomics have made possible the identification of genes which confer susceptibility to specific drugs. A recent multi-national case-control study has reported allopurinol as the most common drug associated with Stevens-Johnson syndrome and toxic epidermal necrolysis. Several studies have established a strong association between the human leukocyte antigen (HLA)-B*5801 gene and development of Stevens-Johnson syndrome and toxic epidermal necrolysis. The allele frequency of HLA-B*5801 is highest in the South East Asian population.Since other hypo-uricemic agents are available, patients may wish to have HLA-B*5801 testing before being started on allopurinol. As the test for HLA-B*5801 is expensive, time-consuming and only available in selected laboratories, there is a need to evaluate the utility and cost-effectiveness of this test in our region.

Topics: Allopurinol; Asia; Australasia; Cost-Benefit Analysis; Drug Hypersensitivity Syndrome; Genetic Predisposition to Disease; Genetic Testing; Gout; Gout Suppressants; Health Care Costs; HLA-B Antigens; Humans; Patient Selection; Pharmacogenetics; Phenotype; Predictive Value of Tests; Risk Factors; Stevens-Johnson Syndrome

With the advent of Twenty-First century, more and more genome-wide association studies (GWAS) showed that idiosyncratic adverse drug reactions (ADRs) were closely related with human leukocyte antigen (HLA) alleles, such as the associations of abacavir-HLA-B*5701, allopurinol-HLA-B*5801, and carbamazepine-HLA-B*1502, etc. To explore the mechanisms of these idiosyncratic drug reactions, hapten hypothesis, danger signal hypothesis, pharmacological interaction (P-I) concept and autoimmune mechanism are proposed. In this paper, recent GWAS studies on the HLA-mediated adverse drug reactions and underlying mechanism are reviewed in detail.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Anticonvulsants; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity Syndrome; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Genome-Wide Association Study; HLA Antigens; HLA-B Antigens; HLA-B15 Antigen; Humans; Stevens-Johnson Syndrome

The human leucocyte antigen (HLA) system is well known for its association with certain diseases such as ankylosing spondylitis, celiac disease and many others. More recently, severe and even fatal drug hypersensitivity reactions linked to particular HLA alleles have been discovered. The significance of these discoveries has led the European Medicines Agency (EMA) and its member state agencies to recommend HLA gene testing before initiation of drug treatment. To date, the following drugs have been identified as causing significant drug hypersensitivity reactions in patients who have the following HLA alleles: abacavir and HLA-B*57:01, carbamazepine and HLA-B*15:02/A*31:01 and finally allopurinol and HLA-B*58:01. This review will outline and discuss these three drugs and their associated HLA alleles as well as examine the pathogenesis of the drug hypersensitivity reactions.

Topics: Alleles; Allopurinol; Anti-HIV Agents; Carbamazepine; Dideoxynucleosides; Drug Hypersensitivity; Gene Frequency; Genetic Testing; HLA-B Antigens; HLA-B15 Antigen; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

Most of adverse drug reactions (ADRs) occur as an extension of pharmacological effects. They occur dependently on their blood concentrations and can be potentially reduced by controlling their dose. On the other hand, ADRs categorized as Type B usually occur irrelevantly to their pharmacological effects at different organs from their target, and are often life-threatening and unpredictable. The incidences of Type B ADRs are very low. Severe cutaneous adverse reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are delayed allergic reactions in which T-cells are involved and categorized as Type B ADRs. Recent progress of pharmacogenomic studies has revealed that particular types of human leukocyte antigen (HLA) class I antigens have strong associations with severe cutaneous adverse reactions and that the associations are specific to causative drugs, phenotypes of adverse reactions and ethnic groups. We established a research group in 2006 with professionals of pharmacogenomics, dermatologists, ophthalmologists and psychiatrists to explore genetic biomarkers associated with Japanese SJS/TEN patients. To date, we have collected more than 100 Japanese SJS/TEN patients through participating institutes and a case-collecting system covering all over Japan constructed by us. No carriers of HLA-B*1502 which was reported to have extremely strong association with carbamazepine-induced SJS/TEN in Han Chinese and south Asians, although a moderate association between allopurinol-induced SJS/TEN and HLA-B*5801 detected in Han Chinese was observed.

Topics: Allopurinol; Carbamazepine; HLA-B Antigens; Humans; Pharmacogenetics; Racial Groups; Stevens-Johnson Syndrome; T-Lymphocytes

Drug-induced hypersensitivity reactions are of major medical concern because they are associated with high morbidity and high mortality. In addition, individual patients' reactions are impossible to predict in each patient. In the field of severe cutaneous adverse drug reactions (cutaneous ADR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug-induced hypersensitivity syndrome (DHIS) or drug rash with eosinophilia and systemic symptoms (DRESS), major advances have recently been gained through studies of an association between HLA alleles and drug hypersensitivity induced by specific drugs. The results of these pharmacogenomic studies allow prediction of the risk of adverse reactions in patients treated with certain drugs, including carbamazepine and other aromatic antiepileptic drugs, allopurinol and abacavir. However, different ethnic populations show variations in the genetic associations. A strong association between carbamazepine-induced SJS/TEN and HLA-B*1502 has been found in Southeast Asian patients but not in Caucasian and Japanese patients. Moderate associations between aromatic amine anticonvulsants and other HLA alleles have been proposed in Japanese patients. In contrast, HLA-B*5801 was found to be associated with allopurinol-induced cutaneous ADR, including SJS/TEN and DIHS/DRESS, in Caucasian and Asian patients, including the Japanese. These differences may, at least in part, be due to the differences in allele frequency in different ethnic populations. This article reviews the progress in pharmacogenomics, associated mainly with carbamazepine and allopurinol in different ethnic populations. Pharmacogenetic screening based on associations between adverse reactions and specific HLA alleles helps to avoid serious conditions associated with drug hypersensitivity.

Topics: Allopurinol; Anti-Retroviral Agents; Anticonvulsants; Asian People; Carbamazepine; Drug Eruptions; Enzyme Inhibitors; HLA-B Antigens; Humans; Pharmacogenetics; Stevens-Johnson Syndrome; White People

Despite some studies suggesting a possible association between human leukocyte antigen, HLA-B*5801 and allopurinol induced Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), the evidence of association and its magnitude remain inconclusive. This study aims to systematically review and meta-analyze the association between HLA-B*5801 allele and allopurinol-induced SJS/TEN.. A comprehensive search was performed in databases including MEDLINE, Pre-MEDLINE, Cochrane Library, EMBASE, International Pharmaceutical Abstracts (IPA), CINAHL, PsychInfo, the WHO International, Clinical Trial Registry, and ClinicalTrial.gov from their inceptions to June 2011. Only studies investigating association between HLA-B*5801 with allopurinol-induced SJS/TEN were included. All studies were extracted by two independent authors. The primary analysis was the carrier frequency of HLA-B*5801 comparison between allopurinol-induced SJS/TEN cases and each comparative group. The pooled odds ratios were calculated using a random effect model.. A total of 4 studies with 55 SJS/TEN cases and 678 matched-controls (allopurinol-tolerant control) was identified, while 5 studies with 69 SJS/TEN cases and 3378 population-controls (general population) were found. SJS/TEN cases were found to be significantly associated with HLA-B*5801 allele in both groups of studies with matched-control (OR 96.60, 95%CI 24.49-381.00, p < 0.001) and population-control (OR 79.28, 95%CI 41.51-151.35, p < 0.001). Subgroup analysis for Asian and Non-Asian population yielded similar findings.. We found a strong and significant association between HLA-B*5801 and allopurinol-induced SJS/TEN. Therefore, HLA-B*5801 allele screening may be considered in patients who will be treated with allopurinol.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Allopurinol; Case-Control Studies; Female; Genotype; Heterozygote; HLA-B Antigens; Humans; Male; Middle Aged; Odds Ratio; Stevens-Johnson Syndrome

Off-label use is common in dermatology, and is inevitable for rare cutaneous diseases such as perforating dermatosis. Allopurinol is traditionally considered to be a drug for hyperuricemia only, but the recent demonstration of its efficacy in congestive heart failure has spurred renewed interest in its application in other clinical specialties. In dermatology, allopurinol is best known for its severe cutaneous adverse reactions. Recent genomic studies conducted in Taiwan have discovered useful HLA markers for determining the susceptibility of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with allopurinol. Allopurinol has also been used in a number of dermatologic disorders including acquired reactive perforating collagenosis, sarcoidosis, psoriasis and granulomas caused by methacrylate microspheres, silicon and tattoos. Allopurinol may express its therapeutic effects via its antioxidation or anti-inflammatory properties, or its ability to improve vascular function.

Topics: Allopurinol; Animals; Dermatologic Agents; Drug Eruptions; Drug Interactions; Gout Suppressants; Humans; Off-Label Use; Skin Diseases; Stevens-Johnson Syndrome

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions, usually induced by drugs. The reactions, which are characterized by extensive necrosis and detachment of the epidermis, followed by erosions of the skin and mucous membranes, are associated with high rates of mortality. There is growing evidence that SJS and TEN are a single disease with common causes and mechanisms. The present article summarizes recent updates and innovations related to the etiology, pathogenesis, genetic background, prognosis and treatment of these reactions. Among high-risk drugs associated with SJS/TEN, allopurinol is the most common cause of SJS/TEN in Europe and Israel. The prognosis of SJS/TEN can be predicted by a scoring system based on seven clinical and laboratory parameters. Founded on the genetic background of SJS/TEN, predictive tests can be used prior to starting high-risk medications. Treatment is still controversial, and further controlled studies are necessary.

Topics: Allopurinol; Drug Hypersensitivity; Humans; Israel; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse reactions, which could be induced by a variety of drugs. It was proposed that human leukocyte antigen (HLA)-restricted presentation of antigens (drugs or their metabolites) to T lymphocytes initiates the immune reactions of SJS/TEN. However, the genetic susceptibility and the exact pathogenesis were not clear until the recent studies. We first identified that HLA-B*1502 is strongly associated with carbamazepine (CBZ)-induced SJS/TEN and HLA-B*5801 with allopurinol-SJS/TEN in Han Chinese. The same associations had been validated across different human populations. For the downstream danger signals, Fas-Fas ligand (FasL) and perforin/granzyme B had been advocated as cytotoxic mediators for keratinocyte death in SJS/TEN. However, expression levels of these cytotoxic proteins from the skin lesions were too low to explain the distinct and extensive epidermal necrosis. Our recent study identified that the granulysin, a cytotoxic protein released from cytotoxic T cells or natural killer (NK) cells, is a key mediator for disseminated keratinocyte death in SJS/TEN. This article aims to provide an overview of both of the genomic and immunologic perspectives of SJS/TEN. These studies give us a better understanding of the immune mechanisms, biomarkers for disease prevention and early diagnosis, as well as providing the therapeutic targets for the treatments of SJS/TEN.

Topics: Allopurinol; Apoptosis; Biomarkers; Carbamazepine; Cytotoxicity, Immunologic; Genetic Predisposition to Disease; Granzymes; HLA-B Antigens; HLA-B15 Antigen; Humans; Keratinocytes; Killer Cells, Natural; Polymorphism, Genetic; Stevens-Johnson Syndrome; T-Lymphocytes, Cytotoxic

The present article reviews the recent literature on the identification of human leukocyte antigen (HLA) alleles as major susceptible genes for drug hypersensitivity and discusses the clinical implications.. Several recent studies have reported strong genetic associations between HLA alleles and susceptibility to drug hypersensitivity. The genetic associations can be drug specific, such as HLA-B*1502 being associated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), HLA-B*5701 with abacavir hypersensitivity and HLA-B*5801 with allopurinol-induced severe cutaneous adverse reactions. A genetic association can also be phenotype-specific, as B*1502 is associated solely with carbamazepine-SJS/TEN, and not with either maculopapular eruption or hypersensitivity syndrome. Furthermore, a genetic association can also be ethnicity specific; carbamazepine-SJS/TEN associated with B*1502 is seen in south-east Asians but not in whites, which may be explained by the different allele frequencies.. The strong genetic association suggests a direct involvement of HLA in the pathogenesis of drug hypersensitivity when the HLA molecule presents an antigenic drug for T cell activation. The high sensitivity/specificity of some markers provides a plausible basis for developing tests to identify individuals at risk for drug hypersensitivity. Application of HLA-B*1502 genotyping as a screening tool before prescribing carbamazepine could be a valuable tool in preventing carbamazepine-induced SJS/TEN in south-east Asian countries.

Topics: Allopurinol; Carbamazepine; Dideoxynucleosides; Drug Eruptions; Drug Hypersensitivity; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Pharmacogenetics; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRβ repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRβ sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.

Topics: Allopurinol; Carbamazepine; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Methazolamide; Receptors, Antigen, T-Cell, alpha-beta; Stevens-Johnson Syndrome

Topics: Allopurinol; Asian People; Drug Hypersensitivity Syndrome; Female; Gout Suppressants; HLA-B Antigens; Humans; Male; Middle Aged; Retrospective Studies; Stevens-Johnson Syndrome

HLA-B*58:01 allele was strongly associated with allopurinol induced severe cutaneous adverse drug reaction (SCAR). However, HLA-B genotype is not sufficient to predict the occurrence of allopurinol-induced SCAR.. To discover DNA methylation markers for allopurinol-induced SCAR which may improve the prediction accuracy of genetic testing.. The study was designed as a retrospective case-control clinical study in multicenter hospitals across Taiwan, Mainland China, Malaysia and Canada. 125 cases of allopurinol-induced SCAR patients and 139 cases of allopurinol tolerant controls were enrolled in this study during 2005 to 2021.. The results of genome-wide DNA methylation assay of 62 patients revealed that ITGB2 showed strong discriminative ability of allopurinol-induced SCAR in both HLA-B*58:01 positive and negative patients with AUC value of 0.9364 (95% CI 0.8682-1.000). In validation study, significant hypermethylation of ITGB2 were further validated in allopurinol-induced SCAR patients compared to tolerant controls, especially in those without HLA-B*58:01(AUC value of 0.8814 (95% CI 0.7121-1.000)). Additionally, the methylation levels of 2 sites on ITGB2 were associated with SCAR phenotypes. Combination of HLA-B*58:01 genotyping and ITGB2 methylation status could improve the prediction accuracy of allopurinol-induced SCAR with the AUC value up to 0.9387 (95% CI 0.9089-0.9684), while the AUC value of HLA-B*58:01 genotyping alone was 0.8557 (95% CI 0.8030-0.9083).. Our study uncovers differentially methylated genes between allopurinol-induced SCAR patients and tolerant controls with positive or negative HLA-B*58:01 allele and provides the novel epigenetic marker that improves the prediction accuracy of genetic testing for prevention of allopurinol-induced SCAR.

Topics: Allopurinol; DNA Methylation; Drug Hypersensitivity; HLA-B Antigens; Humans; Retrospective Studies; Stevens-Johnson Syndrome

Topics: Adult; Allopurinol; Gout Suppressants; HLA-B Antigens; Humans; Male; Stevens-Johnson Syndrome

Allopurinol, widely used in gout treatment, is the most common cause of severe cutaneous adverse drug reactions. The risk of developing such life-threatening reactions is increased particularly for HLA-B*58:01 positive individuals. However the mechanism of action between allopurinol and HLA remains unknown. We demonstrate here that a Lamin A/C peptide KAGQVVTI which is unable to bind HLA-B*58:01 on its own, is enabled to form a stable peptide-HLA complex only in the presence of allopurinol. Crystal structure analysis reveal that allopurinol non-covalently facilitated KAGQVVTI to adopt an unusual binding conformation, whereby the C-terminal isoleucine does not engage as a PΩ that typically fit deeply in the binding F-pocket. A similar observation, though to a lesser degree was seen with oxypurinol. Presentation of unconventional peptides by HLA-B*58:01 aided by allopurinol contributes to our fundamental understanding of drug-HLA interactions. The binding of peptides from endogenously available proteins such as self-protein lamin A/C and viral protein EBNA3B suggest that aberrant loading of unconventional peptides in the presence of allopurinol or oxypurinol may be able to trigger anti-self reactions that can lead to Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

Topics: Allopurinol; Genotype; HLA-B Antigens; Humans; Lamin Type A; Oxypurinol; Peptides; Stevens-Johnson Syndrome

Topics: Allopurinol; CD8-Positive T-Lymphocytes; HLA-B Antigens; Humans; Oxypurinol; Stevens-Johnson Syndrome

Taiwan Drug-Injury Relief System (TDRS) has been implemented since 1999. More than 60% of the approved applications were associated with severe cutaneous adverse reactions (SCARs). Studies assessing SCARs using real-world evidence are very limited. TDRS offers abundant case information as a source of real-world evidence to investigate the characteristics of SCARs in Taiwan. The purpose of this study is to understand the trends and characteristics of SCARs in Taiwan.. Applications from Drug-Injury Relief Database (TDRD) from 1999 to 2016 were retrospectively analyzed.. A declining trend in SCARs application was noticed after 2012, and 952 applications of SCARs were identified. The most common subtypes of SCARs were SJS/TEN (n = 455/206), DRESS (n = 228), GBFDE (n = 34) and AGEP (n = 18). The most common culprit drugs were allopurinol, carbamazepine, phenytoin, diclofenac and lamotrigine for SJS/TEN; allopurinol, phenytoin, co-trimoxazole, carbamazepine and phenobarbital for DRESS; mefenamic acid for GBFDE; non-steroidal anti-inflammatory drugs (NSAIDs) and beta-lactam antibacterials for AGEP. The proportions of mortality cases were 28.9% for SJS/TEN; 36% for DRESS; 11.8% for GBFDE and 5.6% for AGEP. The mean latent period of SJS/TEN, DRESS, GBFDE and AGEP were 21.8 days, 29.2 days, 3.3 days and 6.7 days, respectively.. The approved drug-injury relief applications associated with SCARs were mainly SJS, TEN and DRESS. The most common culprit drugs were antiepileptics, antibacterials, antigout agents, and NSAIDs. The latent periods showed some distinct features for different types of SCARs. In light of the high mortality rate, public awareness and vigilance of SCARs are crucial for the patient safety.

Topics: Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Carbamazepine; Cicatrix; Humans; Phenytoin; Retrospective Studies; Stevens-Johnson Syndrome; Taiwan

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis Syndrome (TENS) are severe and potentially lethal adverse drug reactions characterized by acute inflammation of the skin, mucous membranes, and ocular surface that typically occurs within weeks of a culprit drug ingestion. The purpose of this study is to report a retrospective trend analysis of SJS spectrum diagnoses and associated culprit drugs in patients admitted to the Loyola University Medical Center (LUMC) Burn Unit, the major referral center in the Chicagoland region for patients with SJS disease spectrum.. The electronic medical records (EMR) of 163 patients with a diagnosis of SJS/TENS admitted to the LUMC Burn Unit from 2000 to 2019 were reviewed. Clinical data in addition to the well-established algorithm of drug causality for epidermal necrolysis (ALDEN) allowed us to identify the single most probable culprit drug in 131 cases.. From 2000 to 2019, the most common spectrum classification was TENS (48.1%), followed by SJS (33.6%) and SJS-TEN Overlap Syndrome (18.3%). Anticonvulsants were found to be the most probable culprit class in 30% of cases followed by Trimethoprim-Sulfamethoxazole in 19% of cases. Beta-lactams were the most probable culprit class in 11% of cases while NSAIDs and allopurinol were each the most probable culprit class/drug in 8.4% of cases.. This is one of the largest single center series of SJS/TENS cases in the United States. Further study into culprit drug distribution by region as well as continuous monitoring of trends is crucial in order to advise prescribing practices.

Topics: Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; beta-Lactams; Burn Units; Burns; Humans; Retrospective Studies; Stevens-Johnson Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

Stevens-Johnson syndrome is a rare but serious skin condition, which can lead to death. Stevens-Johnson syndrome is usually attributed to drug-induced reactions, thus making it vital for clinicians to prevent its occurrence by knowing the trigger drugs. The objective of this study was to comprehensively and systematically excavate the drugs that cause SJS to provide references for clinician.. This is an observational, retrospective study, conducting a disproportionality analysis. Where the Information Component (IC) method and Reporting odds ratio (ROR) are used to mine the drugs that cause SJS.. A total of 17,787,905 reports were extracted from VigiBase database, of which 25,051 reports were related to SJS. The 18-44 age group had the largest number of cases (N=7,973, 31.83%). A total of 295 drugs was detected as signals. Allopurinol (IC025/ROR025=5.86/69.84), phenytoin (IC025/ROR025=5.60/57.65) and carbamazepine (IC025/ROR025=5.25/43.88) were the top 3 strongest signals. Our study only considered the possibility of SJS caused by a single drug.. Allopurinol, phenytoin and carbamazepine were three strongest signals. Garenoxaci, carbocisteine and dimetindene were strong signals, but there are no relevant cases reported on PubMed or specific SJS in labels, which need further study to verify.

Topics: Allopurinol; Carbamazepine; Humans; Pharmacovigilance; Phenytoin; Retrospective Studies; Stevens-Johnson Syndrome; World Health Organization

Allopurinol is known to cause severe cutaneous adverse drug reactions (SCAR) in Malaysia. However, the incidence of allopurinol-induced SCAR is unknown. Therefore, we aimed to determine the incidence of allopurinol-induced SCAR in Malaysia over 5 years from 2015 to 2019.. This retrospective analysis was done in collaboration with the National Pharmaceutical Regulatory Agency (NPRA). All allopurinol-induced adverse drug reaction cases reported to NPRA from 2015 to 2019 were extracted. Allopurinol-induced SCAR cases were identified and the incidence over the 5 years was calculated.. Incidence of allopurinol-induced SCAR averaged at 2.5 cases per 1000 new users over the 5-year period, with a reducing trend from 3.2 per 1000 new users in 2015 to 2.25 per 1000 in 2019; despite the increasing number of adverse drug reaction cases being reported over the years. Stevens-Johnson syndrome was the commonest form of allopurinol-induced SCAR reported, at 143 cases (46.8% of total SCAR reported). Among Malaysia's 3 main ethnicities, the Chinese had the highest percentages of allopurinol-induced SCAR when compared to the Bumiputera and Indians (3.18 × 10. The estimated incidence of allopurinol-induced SCAR in Malaysia from 2015 to 2019 was 2.5 cases per 1000 new users. This figure is consistent with the incidence reported in other Asian countries, namely Taiwan and Thailand.

Topics: Allopurinol; Humans; Incidence; Malaysia; Retrospective Studies; Stevens-Johnson Syndrome; Thailand

Allopurinol, widely used in the treatment of hyperuricemia and gout, has been shown to cause severe cutaneous reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as systemic reactions such as DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). The HLA-B*5801 allele is known to be a risk factor for severe cutaneous manifestations of hypersensitivity to allopurinol, mostly in Asian populations.. We report the observation of a 47-year-old Chinese patient, with no previous medical history, carrying the HLA-B*5801 allele, who developed an isolated allopurinol hypersensitivity necrotizing renal vasculitis without cutaneous manifestations.. . The identification of this allele should be proposed before prescribing allopurinol in patients originating from certain regions of Asia, and the imputability of allopurinol should be evoked in case of necrotizing renal vasculitis, even without associated cutaneous involvement.

Topics: Allopurinol; China; Drug Hypersensitivity; Drug Hypersensitivity Syndrome; Gout Suppressants; HLA-B Antigens; Humans; Kidney Diseases; Middle Aged; Stevens-Johnson Syndrome; Vasculitis

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.. Signal generation was assessed using the case/non-case method. Reporting odds ratios (RORs) and 95% confidence intervals (95% CI) were calculated.. 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.. 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.

Topics: Allopurinol; Humans; Hyperuricemia; Pharmacovigilance; Stevens-Johnson Syndrome; Vietnam

Severe cutaneous adverse reactions (SCARs) are potentially lethal adverse drug reactions that involve the skin, mucous membranes, and internal organs, resulting in disability. SCARs include drug-induced epidermal necrolysis, which is Steven Johnson syndrome (SJS)/ Steven Johnson syndrome and toxic epidermal necrolysis overlap (SJS-TEN overlap)/ toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP), generalised bullous fixed drug eruption (GBFDE), and acute erythroderma. Awareness of local epidemiology of SCARs plays an important role in prescribing practices by healthcare provider. Recognition of SCARs enables the offending drug to be withdrawn immediately, which is the definitive treatment of SCARs.. This is a retrospective study reviewing SCAR cases reported to the Malaysian Adverse Drug Reactions Advisory Committee (MADRAC) registry at the Department of Dermatology, Hospital Melaka, for 5 years and 3 months from December 2014 to February 2020.. A total of 41 SCARs cases were identified over the study duration. The incidence rate was 0.18%. All 41 cases require hospitalisations, with four cases (9.8%) managed in ICU and one mortality (2.4%) due to SJS-related complication. One patient had two episodes of SCARs. There were 22 male patients and 18 female patients. The majority were Malays (33, 80.5%), followed by Chinese (7, 17.1%) and Indonesian (1, 2.4%). There was no Indian patient with SCARs in this study. The mean age of patients was 47.2±17 years. Drug-induced epidermal necrolysis was the commonest type of SCARs (63.4%), and out of this, SJS accounted for the majority of cases (48.8%). Antibiotic was the main group of offending medication in this SCAR study (29.3%). The top five individual causative drugs of SCARs in sequence include allopurinol, phenytoin, carbamazepine, co-amoxiclav, and cephalexin. Allopurinol was the commonest culprit drug for drug-induced epidermal necrolysis and DRESS, phenytoin for acute erythroderma, and co-amoxiclav for AGEP.. SJS was the most common manifestation and Allopurinol was the commonest culprit drug for SCAR cases in our cohort.

Topics: Acute Generalized Exanthematous Pustulosis; Adult; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Cicatrix; Dermatitis, Exfoliative; Eosinophilia; Female; Hospitals; Humans; Malaysia; Male; Middle Aged; Phenytoin; Retrospective Studies; Stevens-Johnson Syndrome

Severe, blistering, adverse drug reactions involving the skin include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Allopurinol, anticonvulsants, sulphonamide antibiotics and non-steroidal anti-inflammatory drugs in the oxicam class have been repeatedly described as triggers. Increasingly, immunotherapies are also coming into focus as triggers of severe skin reactions. Two patients with bullous skin symptoms after administration of the checkpoint inhibitor pembrolizumab are presented. As the clinical picture does not always allow an unequivocal classification, a histological assessment is often indispensable.. Zu den schweren, blasenbildenden Arzneimittelreaktionen an der Haut gehören das Stevens-Johnson-Syndrom (SJS) und die toxisch epidermale Nekrolyse (TEN). Allopurinol, Antikonvulsiva, Sulfonamidantibiotika und nichtsteroidale Antirheumatika vom Oxicam-Typ sind wiederholt als Auslöser beschrieben. Zunehmend rücken auch Immuntherapien als Auslöser schwerer Hautreaktionen in den Fokus. Vorgestellt werden 2 Patienten mit bullösen Hauterscheinungen nach Gabe des Checkpointinhibitors Pembrolizumab. Da das klinische Bild nicht immer eine zweifelsfreie Einordnung zulässt, ist eine histologische Mitbeurteilung vielfach unverzichtbar.

Topics: Allopurinol; Antibodies, Monoclonal, Humanized; Humans; Skin; Stevens-Johnson Syndrome

Human leukocyte antigen (HLA)-B*58:01 allele is a significant risk factor for allopurinol-induced severe cutaneous adverse reactions (SCARs) which is potentially fatal. In some studies, chronic kidney disease (CKD) was also implicated to compound the risk of SCARs. We aim to investigate if pre-treatment HLA-B*58:01 screening can prevent allopurinol-induced SCARs in Chinese patients with CKD and its cost-effectiveness. We prospectively recruited Chinese CKD patients who required allopurinol during 2011-2015 and performed pre-treatment HLA testing (HLA screening group). Patients tested positive for HLA-B*58:01 were refrained from allopurinol while those tested negative were prescribed allopurinol. The incidence of SCARs in the HLA screening group was compared with the historical control in previous 5 years and the cost-effectiveness of HLA testing was analyzed. In the historical control (2006-2010), 3605 patients on allopurinol were screened, 22 out of 1027 (2.14%) CKD Chinese patients newly started on allopurinol developed SCARs, including 6 SJS/TEN. In the HLA screening group, 28 out of 192 patients (14.6%) tested HLA-B*58:01 positive were advised to avoid allopurinol; 156 out of 164 HLA-B*58:01-negative patients received allopurinol and none developed SCARs. The incidence rate of SCARs was significantly lower in the HLA screening group compared with controls (0% vs 2.14% respectively, p = 0.037*). The targeted HLA screening approach was associated with lower healthcare costs compared with no HLA screening (US$ 92,430 vs US$ 281,226). Pre-treatment HLA-B*58:01 screening is cost-effective to target on patients with CKD in Chinese to prevent allopurinol-induced SCARs.

Topics: Allopurinol; China; Drug-Related Side Effects and Adverse Reactions; HLA-B Antigens; Humans; Renal Insufficiency, Chronic; Stevens-Johnson Syndrome

BACKGROUND Allopurinol is the first-line therapy for the treatment of symptomatic hyperuricemia (gout). In clinical practice, there is a tendency to overmedicate asymptomatic patients who have elevated serum urate. Because of this practice, serious and life-threatening reactions such as Stevens-Johnson syndrome (SJS) or the more dramatic toxic epidermal necrolysis (TEN), both frequently caused by uricostatics, may occur. To increase awareness of these complications, we present a case with fulminant TEN caused by allopurinol. CASE REPORT A 75-year-old woman noticed a mildly itching skin rash accompanied by fever, shivering, and weakness approximately 3 weeks after taking newly prescribed allopurinol. The initial clinical examination revealed a generalized maculopapular exanthema. An adverse drug reaction was recognized, and allopurinol was discontinued. Ambulatory supportive therapy using prednisolone and cetirizine was started but failed. The patient developed a progressive exanthema with painful widespread blistering, skin peeling, and mucosal and conjunctival lesions. After recurrent presentations to the Emergency Department, the patient was transferred to our Intensive Care Unit (ICU). The clinical picture confirmed the suspected diagnosis of TEN. Massive fluid replacement, prednisolone, and cyclosporine were used as anti-inflammatory therapy. Polyhexanide and octenidine were applied for local treatment. All treatment measures were guided daily by a multidisciplinary team. After 7 days in the ICU, the patient was transferred to the Dermatology Department and was discharged from the hospital 42 days later. CONCLUSIONS With the prescription of allopurinol, there should be awareness of potentially life-threatening complications such as SJS or TEN. Patients with SJS or TEN should be immediately transferred to an ICU with dermatological expertise and multidisciplinary therapy.

Topics: Aged; Allopurinol; Blister; Cyclosporine; Exanthema; Female; Humans; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening immune-mediated hypersensitivity reactions. Various drugs, such as Non Steroidal Anti-inflammatory drugs (NSAIDS), allopurinol, anticonvulsants and antibiotics, have been implicated as triggering agent of SJS/TEN. Levamisole is frequently used as an antihelminthic and as an immunomodulator in cases of nephrotic syndrome. However, levamisole has not been reported as a trigger for SJS/TEN. The current case describes levamisole-induced TEN in a 15-year-old male who presented to emergency with erythematous lesions, blistering and denudation of skin involving up to 30% of body surface area. Algorithm of drug causality for epidermal necrolysis scoring was applied for causality assessment and a relationship was found to be "possible". Immediate withdrawal of levamisole along with a short course of corticosteroids and cyclosporine led to improvement in signs and symptoms. Clinicians should be aware of the possible association of levamisole and SJS/TEN.

Topics: Adolescent; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Humans; Levamisole; Male; Stevens-Johnson Syndrome

Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking.. To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry.. SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record.. A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms.. Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months.

Topics: Allopurinol; Carbamazepine; Humans; Registries; Republic of Korea; Stevens-Johnson Syndrome

Topics: Allopurinol; Asian; Black or African American; Cost-Benefit Analysis; Drug Hypersensitivity Syndrome; Ethnicity; Gout Suppressants; Hispanic or Latino; HLA-B Antigens; Humans; Mexican Americans; Pharmacogenomic Testing; Pharmacogenomic Variants; Practice Guidelines as Topic; Precision Medicine; Puerto Rico; Stevens-Johnson Syndrome; United States

Allopurinol-induced severe cutaneous adverse drug reactions (SCARs) are potentially debilitating and life-threatening reactions, which can cause a financial burden to the healthcare system.. We aimed to identify risk factors for allopurinol-induced SCARs and to assess their impact on fatality.. Adverse drug reaction (ADR) reports with allopurinol as suspected drug were extracted from the Malaysian pharmacovigilance database from year 2000 to 2018. Multiple logistic regression analysis was used to identify significant predictors of allopurinol-induced SCARs. We further analysed the association between covariates and SCARs-related fatality in a separate model. Level of significance was set at p value < 0.05.. Out of 1747 allopurinol ADR reports, 612 involved SCARs (35%). The strongest predictors significantly associated with SCARs were underlying renal disease (odds ratio [OR] 2.02; 95% confidence interval [CI] 1.36, 3.00; p = 0.001), allopurinol-prescribed dose of 300 mg/day or higher (OR 1.72; 95% CI 1.38, 2.15; p < 0.001), females (OR 1.54; 95% CI 1.24, 1.93; p < 0.001), age 65 years and above (OR 1.31; 95% CI 1.04, 1.64; p = 0.020), and allopurinol-prescribed indication. SCARs cases were higher in patients who received allopurinol for unspecified hyperuricaemia (OR 1.87; 95% CI 1.29, 2.70; p = 0.001) and off-label indications (OR 3.45; 95% CI 2.20, 5.42; p < 0.001) compared to registered indications. Fatality was associated with older age and a diagnosis of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap or TEN.. Malaysian pharmacovigilance data show that predictors of allopurinol-induced SCARs were elderly females, patients with underlying renal disease and high allopurinol doses. These patients need close monitoring and must be educated to stop allopurinol at the first signs of rash.

Topics: Aged; Allopurinol; Female; Humans; Malaysia; Pharmaceutical Preparations; Skin; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe adverse drug reactions with high mortality. The use of corticosteroids and the management of complications (e.g. infection) in SJS/TEN remains controversial.. A retrospective study was performed among 213 patients with SJS/TEN who were hospitalized in our department between 2008 and 2018, to investigate the causative agents, clinical characteristics, complications, and prognoses of SJS/TEN mainly treated by systemic corticosteroids combined with intravenous immunoglobulin (IVIG).. The causative drugs of SJS/TEN in these patients mainly consisted of antibiotics (61/213, 28.6%), anticonvulsants (52/213, 24.4%), and nonsteroidal anti-inflammation drugs (24/213, 11.3%), among which carbamazepine was the most frequently administered drug (39/213, 18.3%). There were significant differences in the maximum dosage, time to corticosteroid tapering, and the total dosage of corticosteroid between the SJS group and the TEN group, as well as among the three groups (P = 0.000), whereas in the initial dose of corticosteroid was not statistically significant among the three groups (P = 0.277). In a series of 213 cases, 18.4 cases (8.6%) were expected to die based on the score for the toxic epidermal necrolysis (SCORTEN) system, whereas eight deaths (3.8%) were observed; the difference was not statistically significant (P = 0.067; SMR = 0.43, 95% CI: 0.06, 0.48). The most common complications were electrolyte disturbance (174/213, 81.7%), drug-induced liver injury (64/213, 30.0%), infection (53/213, 24.9%), and fasting blood sugar above 10 mmol/L (33/213, 15.5%). Respiratory system (22/213, 10.3%) and wound (11/213, 5.2%) were the most common sites of infection. Multivariate logistic regression analysis indicated that the maximum blood sugar (≥10 mmol/L), the time to corticosteroid tapering (≥12 d), the maximum dosage of corticosteroid (≥1.5 mg/kg/d), and the total body surface area (TBSA) (≥10%) were defined as the most relevant factors of the infection.. The mortality of patients in this study was lower than that predicted by SCORTEN, although there was no significant difference between them. Hyperglycemia, high-dose corticosteroid, and the TBSA were closely related to the infections of patients with SJS/TEN.

Topics: Acute Kidney Injury; Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Blood Glucose; Body Surface Area; Chemical and Drug Induced Liver Injury; China; Cohort Studies; Drugs, Chinese Herbal; Female; Gastrointestinal Hemorrhage; Glucocorticoids; Gout Suppressants; Humans; Hyperglycemia; Hypertension; Immunoglobulins, Intravenous; Immunologic Factors; Klebsiella Infections; Male; Middle Aged; Pneumonia; Pulmonary Aspergillosis; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Stevens-Johnson Syndrome; Survival Rate; Water-Electrolyte Imbalance; Wound Infection

Steven Johnson syndrome and toxic epidermal necrolysis are severe and rare adverse drug reactions usually caused by drugs like antiepileptics, penicillin and allopurinol and sometimes also due to infections, malignancy or idiopathic in some cases. Here we are reporting a case of a 50 years female who came with complaint of a burning sensation on the upper half of the body with atypical flat target lesion that later coalesced involving her face, chest and bilateral upper limbs. On examination, positive nikolsky sign and tenderness with <10% body surface area involvement was noticed. The diagnosis of cotrimoxazole induced Steven Johnson syndrome was made. Patient was shifted to ICU and given supportive care along with prophylactic teicoplanin, itraconazole and dexamethasone. The mechanism of eruptions in our patient was due to cotrimoxazole. Cotrimoxazole induced Steven Johnson syndrome is rare and the supportive management with broad spectrum antibiotic and the corticosteroid was enough to beat this life-threatening condition. Keywords: cotrimoxazole; pneumonia; Steven Johnson syndrome.

Topics: Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Female; Humans; Middle Aged; Stevens-Johnson Syndrome; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Allopurinol; Gout Suppressants; Humans; Male; Middle Aged; Piroxicam; Recurrence; Stevens-Johnson Syndrome

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is an autoimmune condition with significant morbidity and mortality.. A retrospective review was performed at a single institution. All patients admitted to the LAC+USC burn unit from May 1st 2015-January 1st 2018 with a histologic diagnosis of SJS/TEN were reviewed. Patient characteristics and outcomes were recorded. These outcomes were compared to our previously published cohort.. Thirteen total consecutive SJS/TEN patients were treated with etanercept. Compared to non-etanercept treated patients, etanercept-treated patients did not experience a significant difference in mortality (15.4% vs. 10%, P=0.58), ICU days (6.9 vs. 15.1, P=0.08), length-of-stay (9.8 vs 16.4, P=0.11), or infections (38.5% vs. 57.5%, P=0.58). The standardized mortality ratio in etanercept-treated patients was 0.44 (95% CI, 0.21, 0.65). In general, etanercept-treated patients had higher SCORTENs (3 vs. 2, P=0.03) and longer delays to presentation (5.2 vs. 2.7 days, P<0.01).. Etanercept can be considered in the treatment of SJS/TEN patients in addition to IVIg, and supportive care in a burn unit.

Topics: Adult; Aged; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Combined Modality Therapy; Etanercept; Female; Gout Suppressants; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Male; Middle Aged; Retrospective Studies; Stevens-Johnson Syndrome; Treatment Outcome; Young Adult

Specific ethnic genetic backgrounds are associated with the risk of Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) especially in Asians. However, there have been no large cohort, multiple-country epidemiological studies of medication risk related to SJS/TEN in Asian populations. Thus, we analyzed the registration databases from multiple Asian countries who were treated during 1998-2017. A total 1,028 SJS/TEN cases were identified with the algorithm of drug causality for epidermal necrolysis. Furthermore, those medications labeled by the US Food and Drug Administration (FDA) as carrying a risk of SJS/TEN were also compared with the common causes of SJS/TEN in Asian countries. Oxcarbazepine, sulfasalazine, COX-II inhibitors, and strontium ranelate were identified as new potential causes. In addition to sulfa drugs and beta-lactam antibiotics, quinolones were also a common cause. Only one acetaminophen-induced SJS was identified, while several medications (e.g., oseltamivir, terbinafine, isotretinoin, and sorafenib) labeled as carrying a risk of SJS/TEN by the FDA were not found to have caused any of the cases in the Asian countries investigated in this study.

Topics: Allopurinol; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antipsychotic Agents; Asian People; Cohort Studies; Drug Labeling; Free Radical Scavengers; Humans; Registries; Risk Factors; Stevens-Johnson Syndrome; United States; United States Food and Drug Administration

Previous studies have reported that the indication and starting dose of allopurinol may be associated with the incidence of hypersensitive reactions. As allopurinol-related severe cutaneous adverse reactions (SCARs) constitute a significant proportion of drug injury relief applications in Taiwan, this study sought to examine allopurinol use and related adverse reactions through an analysis of recent drug injury relief applications.. Allopurinol-related drug injury relief applications from 1999 to 2016 were collected, and descriptive statistical methods were used to analyze recent applications dating from 2011 to 2016.. Old age and renal dysfunction are key risk factors for allopurinol hypersensitivity. When considering allopurinol for elderly patients with impaired kidney function, a full risk-benefit assessment, dosage adjustments, and careful monitoring may be warranted.

Topics: Adult; Age Factors; Aged; Allopurinol; Comorbidity; Diabetes Mellitus; Female; Glomerular Filtration Rate; Gout Suppressants; Humans; Hypertension; Incidence; Male; Middle Aged; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Stevens-Johnson Syndrome; Taiwan

Allopurinol is a first line agent in treating gout, but it also carries the risk of severe side effects. Stevens-Johnson syndrome (SJS) is one of the life threatening severe cutaneous adverse reactions caused by allopurinol. The severity of the severe cutaneous adverse reactions can be categorized based upon the area of skin involvement: (1) erythema multiforme major limited to 1-2 % of the body surface area (BSA); (2) SJS involving <10% of the BSA, (3) SJS and toxic epidermal necrolysis overlap involving 10-30% of the BSA and (4) toxic epidermal necrolysis syndrome involving >30% of the BSA. SJS can be caused by drugs and viruses, the former being more frequent. We report a case of an 85-year-old Han-Chinese female who developed SJS after ingestion of allopurinol 8 days prior to the hospitalization. The patient also had concomitant acute viral illness, which complicated the clinical scenario causing acute renal failure and hemodynamic compromise.

Topics: Acute Kidney Injury; Aged, 80 and over; Allopurinol; China; Female; Gout Suppressants; Humans; Stevens-Johnson Syndrome; Treatment Outcome; Virus Diseases

Despite morbidities and fatalities, nationwide epidemiologic data for severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), are not widely available. We aimed to investigate SCAR epidemiology over the last two decades in Korea.. We analyzed individual case safety reports (ICSRs) of SCARs in the Korea Adverse Event Reporting System from 1988 to 2013. Administered drugs, demographic profiles, and causality assessment according to the World Health Organization-Uppsala Monitoring Center system were analyzed.. A total of 755 SCAR cases (508 SJS/TEN, 247 DRESS) were reported. The number of SCAR ICSRs has been increasing with increasing ICSRs for overall adverse drug events. Since 2010, the number of SCAR ICSRs has increased up to 100 cases/year. Allopurinol was the most common causative drug (SJS/TEN: 10.2%; DRESS: 11.3%; SCAR ICSRs: 10.6%), followed by carbamazepine (SJS/TEN: 8.7%; DRESS: 9.7%; SCAR ICSRs: 8.6%). Regarding drug groups, antiepileptics (19.5%) and antibiotics for systemic use (12.7%) were common causative drug groups. Twenty SCAR-related deaths were recorded. Antibacterials were the most common causes of deaths (8 cases), followed by antiepileptics (5 cases). The potential risk of SCARs was not specified in the drug information leaflet for 40.2% of drugs causing SJS/TEN and 82.5% causing DRESS syndrome in Korea.. The number of SCAR ICSRs has increased rapidly with recent active pharmacovigilance programs in Korea. Allopurinol and antiepileptics are the most common individual and categorical causative agents, respectively.

Topics: Adverse Drug Reaction Reporting Systems; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Carbamazepine; Drug Labeling; Female; Humans; Male; Middle Aged; Republic of Korea; Skin Diseases; Stevens-Johnson Syndrome

Topics: Academies and Institutes; Allopurinol; Attitude of Health Personnel; Canada; Carbamazepine; Drug Eruptions; Genetic Testing; Health Knowledge, Attitudes, Practice; Humans; Severity of Illness Index; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease. Rarely, clinical pharmacists participating in finding the etiology have been reported.. A 33-year-old male presented to the emergency department with a 1-day history of fever and rash. The patient, being newly diagnosed with gout 10 days ago, received allopurinol at a dose of 250 mg by mouth daily. After 10 days' exposure to allopurinol, the patient manifested with an "influenza-like" prodromal phase (fever of 38°C, throat pains), which was treated with amoxicillin and nonsteroidal anti-inflammatory drugs of the oxicam type. The next day, he developed a worsening fever of 39.5°C, accompanied by a pruriginous rash all over his body.. On physical examination, we observed coalescing dusky red macules over >60% of his body surface area, with blisters and detachment of large sheets of necrolytic epidermis all over his chest and face. The diagnosis of TEN was confirmed.. The patient recovered following treatment with short-term high-dose methylprednisolone sodium succinate, immunoglobulin therapy, topical medication, and supportive therapy.. He showed a slow but progressive improvement both in symptoms and cutaneous manifestations. Reepithelization of the skin was achieved after 3 weeks.. Drug-induced-TEN is potentially fatal. This case underlines the necessity of asking medication history in detail and detecting related drug gene to correctly identify the cause of TEN.

Topics: Adult; Allopurinol; Emergency Service, Hospital; Gout Suppressants; Humans; Male; Stevens-Johnson Syndrome

Recent studies have shown that sparse distribution of regulatory T cells (Tregs) in the skin might be involved in the onset of severe cutaneous adverse drug reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Treg migration toward epithelial cells is regulated by certain chemokines, including TARC/CCL17 and MDC/CCL22. In this study, we analyzed the effect of allopurinol (APN), a drug known to cause severe adverse reactions, on the expression of factors affecting Treg migration and the mechanisms involved. APN inhibited the tumor necrosis factor (TNF)-α- and interferon (IFN)-γ-associated expression of TARC/CCL17 and MDC/CCL22 mRNA in HaCaT cells in a dose-dependent manner. Consistent with this, APN also suppressed TNF-α- and IFN-γ-induced production of TARC/CCL17 and MDC/CCL22 proteins and the migration of C-C chemokine receptor type 4-positive cells. Activity of the transcription factors NF-κB and STAT1, which are involved in TARC/CCL17 and MDC/CCL22 expression, was also investigated. APN inhibited activation of NF-κB, but not that of STAT1. Furthermore, it restricted p38 MAPK phosphorylation. These results suggest that APN inhibits TNF-α- and IFN-γ-induced TARC/CCL17 and MDC/CCL22 production through downregulation of p38 MAPK and NF-κB signaling, resulting in the sparse distribution of Tregs in the skin of patients with APN-associated Stevens-Johnson syndrome/toxic epidermal necrolysis.

Topics: Allopurinol; Cell Movement; Chemokine CCL17; Chemokine CCL22; HEK293 Cells; Humans; K562 Cells; Keratinocytes; NF-kappa B; Oxypurinol; Stevens-Johnson Syndrome; T-Lymphocytes, Regulatory

Studies found a strong association between allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and the HLA-B*58:01 allele. HLA-B*58:01 screening-guided therapy may mitigate the risk of allopurinol-induced SJS/TEN. This study aimed to evaluate the cost-effectiveness of HLA-B*58:01 screening before allopurinol therapy initiation compared with the current practice of no screening for Malaysian patients with chronic gout in whom a hypouricemic agent is indicated.. This cost-effectiveness analysis adopted a societal perspective with a lifetime horizon. A decision tree model coupled with Markov models were developed to estimate the costs and outcomes, represented by quality-adjusted life years (QALYs) gained, of three treatment strategies: (a) current practice (allopurinol initiation without HLA-B*58:01 screening); (b) HLA-B*58:01 screening before allopurinol initiation; and (c) alternative treatment (probenecid) without HLA-B*58:01 screening. The model was populated with data from literature review, meta-analysis, and published government documents. Cost values were adjusted for the year 2016, with costs and health outcomes discounted at 3% per annum. A series of sensitivity analysis including probabilistic sensitivity analysis were carried out to determine the robustness of the findings.. Both HLA-B*58:01 screening and probenecid prescribing were dominated by current practice. Compared with current practice, HLA-B*58:01 screening resulted in 0.252 QALYs loss per patient at an additional cost of USD 322, whereas probenecid prescribing resulted in 1.928 QALYs loss per patient at an additional cost of USD 2203. One SJS/TEN case would be avoided for every 556 patients screened. At the cost-effectiveness threshold of USD 8695 per QALY, the probability of current practice being the best choice is 99.9%, in contrast with 0.1 and 0% in HLA-B*58:01 screening and probenecid prescribing, respectively. This is because of the low incidence of allopurinol-induced SJS/TEN in Malaysia and the lower efficacy of probenecid compared with allopurinol in gout control.. This analysis showed that HLA-B*58:01 genetic testing before allopurinol initiation is unlikely to be a cost-effective intervention in Malaysia.

Topics: Alleles; Allopurinol; Cost-Benefit Analysis; Female; Genetic Testing; Genotype; Heterozygote; HLA-B Antigens; Humans; Malaysia; Male; Middle Aged; Probenecid; Quality-Adjusted Life Years; Risk Factors; Stevens-Johnson Syndrome

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Female; Gout Suppressants; Humans; Male; Middle Aged; Retrospective Studies; Severity of Illness Index; Stevens-Johnson Syndrome; Survival Rate

The goal of our study was to investigate the incidence of Stevens-Johnson syndrome (SJS), the frequency of SJS diagnosis, and the association between SJS and prior use of allopurinol, carbamazepine or phenytoin. This case-control study utilized data from the National Health Insurance Research Database (NHIRD) of Taiwan. Controls visited the emergency department of the same hospital for trauma or fractures (excluding burns) and used allopurinol, carbamazepine or phenytoin during the past 3 months. We determined whether patients were prescribed a combination of drugs in addition to allopurinol, carbamazepine or phenytoin within the last 3 months. We identified 1 853 985 controls and 7327 SJS-diagnosed patients using the Taiwan NHIRD records for 2000-2008. Higher use of allopurinol (49.8%), carbamazepine (39.1%) or phenytoin (21.3%) was observed among patients (n = 3131) than among controls (n = 2858). The overall SJS incidence rate was 3.6/1 000 000. Drug combinations were uncommon (<10%) in patients or controls taking allopurinol. However, combination drug use exceeded 10% in patients taking carbamazepine or phenytoin. Logistic regression analysis of recent combination drug use revealed that phenobarbital, valproate, non-steroidal anti-inflammatory drugs (NSAIDs) including piroxicam and tenoxicam, and antibiotics including amoxicillin and cephalexin were strongly associated with SJS. Patients with gout or epilepsy taking allopurinol, carbamazepine or phenytoin should be evaluated carefully by physicians. Concurrent use of piroxicam, tenoxicam, phenobarbital, valproate, amoxicillin or cephalexin, in addition to carbamazepine or phenytoin, may increase the incidence of SJS.

Topics: Adult; Aged; Allopurinol; Anticonvulsants; Carbamazepine; Case-Control Studies; Drug Combinations; Epilepsy; Female; Gout; Gout Suppressants; Humans; Incidence; Male; Middle Aged; Phenytoin; Stevens-Johnson Syndrome; Taiwan

Topics: Allopurinol; China; HLA-B Antigens; Humans; Hyperuricemia; Retrospective Studies; Stevens-Johnson Syndrome

To explore the clinical characteristics of various types of severe drug eruption and common sensitized drugs, and to provide clinical references for reducing the incidence of severe drug eruption.
 Methods: The clinical data regarding 126 cases of severe drug eruption were analyzed retrospectively from June 2009 to May 2017 in Xiangya Hospital, Central South University.
 Results: In the 126 cases of severe drug eruption, the distribution of men and women ratio was 1:1.38. The length of stay was (12.7±9.8) d. The most common type was Steven-Johnson syndrome; the most dangerous type was drug-induced bullosa epidermolysis. The most common sensitized drug category in these patients was antibiotics; the most common single sensitizing drug was carbamazepine, following by allopurinol.
 Conclusion: Severe drug eruption occurs mostly in young and middle-aged people. Steven-Johnson syndrome is the most common type; drug hypersensitive syndrome has the longest length of hospital course. Mortality rate of drug-induced bullosa epidermolysis is the highest. Timely stop using of allergens, early using glucocorticoids, and timely combination of non-glucocorticoids treatment (such as intravenous immunogloblin, plasma exchange and hemodialysis), can improve the efficacy and reduce the complications and mortality. 
.. 目的：探讨各型重症药疹的临床特点、常见致敏药物及治疗，为重症药疹的合理防治、减少其并发症、提高治愈率提供参考。方法：对中南大学湘雅医院2009年6月至2017年5月收治的126例重症药疹的临床资料进行回顾性分析。结果：126例重症药疹中，男女比例为1:1.38；住院时间为(12.7±9.8) d。最常见类型为重症多形红斑型药疹，最凶险的类型为大疱性表皮松解型药疹，死亡2例。抗生素为本组患者最常见的致敏药物类别；最常见的单一致敏药物为卡马西平，其次为别嘌呤醇。结论：本地区重症药疹多见于中青年人群，重症多形红斑型药疹为最常见类型，大疱性表皮松解型药疹病死率最高，药物超敏反应综合征的住院时间最长。及时停用致敏药物，早期足量应用糖皮质激素，适时联合使用非激素治疗手段如静脉注射免疫球蛋白(intravenous immunogloblin，IVIG)、血浆置换、血液透析，有助于提高疗效，降低并发症和病死率。.

Topics: Allopurinol; Drug Eruptions; Female; Humans; Male; Prognosis; Retrospective Studies; Stevens-Johnson Syndrome

Severe cutaneous adverse drug reactions (SCARs) are life-threatening reactions. The strong association between the

Topics: Adult; Aged; Aged, 80 and over; Alleles; Allopurinol; Chromosomes, Human, Pair 6; Drug Hypersensitivity Syndrome; Female; Genetic Testing; HLA-B Antigens; Humans; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Stevens-Johnson Syndrome; Thailand

The diffuse epidermal exfoliation seen in Steven Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) is similar to skin loss in second degree burns, and many of these patients are referred for treatment at burn centers. Treatment can differ markedly from center to center, and mortality can range from 25% to 70%, including a considerable morbidity. However, our experience over a 15-year period from 2000 to 2015 with 40 patients found a mortality rate of only 10% (4/40). The purpose of this paper is to discuss our treatment algorithm as a model for other centers treating SJS/TENs patients.. Records were reviewed for all patients admitted to the LAC+USC burn unit between 2000 and 2015 and 40 patients were identified with biopsy-proven SJS or TENS. These cases were reviewed for age, gender, initial and greatest TBSA, causative drug, pre-existing medical conditions, and morbidity and mortality. All data were entered into the SPSS statistical software package and all statistical analyses were performed using this program.. Our treatment algorithm focused on early referral to a specialty burn unit, immediate discontinuation of the offending drug, fluid resuscitation, nutritional supplementation, and meticulous wound care. Average time to transfer to a burn unit was 3.36 days. Silver-releasing antimicrobial dressings were applied to the affected skin surface and changed every 3 days. Mupirocin coated petroleum gauze was used for facial involvement. Steroids were tapered and discontinued if initiated at an outside facility (58% of patients), and starting after 2001, all patients received a course of IVIG. All patients received fluid resuscitation and the majority received supplemental tube feedings (69%). Average length of total stay was 17.1 days and length of ICU stay 15.9 days. While 44% were transferred to another facility for further rehabilitative care, 37% of patients discharge to home. In patients discharged home with complete resolution of skin lesions, time to healing was an average of 14 days.. With our 10% mortality rate in 40 patients, our study represents a relatively large study population while maintaining a relatively low mortality rate. The demographic data from our study largely aligns with the existing literature, and we therefore feel that our low mortality rate is due to our treatment algorithm, rather than to a less severe pathology in our patient population. This claim is supported by a standard mortality ratio of 1.68. This ratio proves a significantly improved mortality than would be expected based on disease severity on admission.

Topics: Administration, Cutaneous; Algorithms; Allopurinol; Anti-Bacterial Agents; Anti-Infective Agents, Local; Anticonvulsants; Bandages; Body Surface Area; Burn Units; Clinical Protocols; Enteral Nutrition; Female; Fluid Therapy; Gout Suppressants; Hospitalization; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Intensive Care Units; Length of Stay; Male; Middle Aged; Mupirocin; Patient Transfer; Polyesters; Polyethylenes; Rehabilitation Centers; Retrospective Studies; Severity of Illness Index; Stevens-Johnson Syndrome

Positive HLA-B*5801 carriers are at greater risk of experiencing rare but severe allopurinol hypersensitivity syndrome (AHS) [i.e., Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)]; however, HLA-B*5801 prevalence and AHS risk vary by race/ethnicity. We evaluated the cost-effectiveness of HLA-B*5801 testing according to race/ethnicity in the United States.. We determined the cost-effectiveness of universal testing for HLA-B*5801 compared to no testing prior to the initiation of allopurinol per US major race/ethnicity groups. Using US-specific data, SJS/TEN risks and HLA-B*5801 prevalences were modeled per race/ethnicity (i.e., 1/3846 and 0.7% among Caucasians and Hispanics, 1/735 and 3.8% among African Americans, and 1/336 and 7.4% among Asians, respectively). Those who tested positive for HLA-B*5801 received febuxostat. Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were estimated over a lifetime.. Compared to no testing, universal testing for HLA-B*5801 costs more and was more effective for all races/ethnicities. The ICERs varied substantially across racial/ethnic groups, following their HLA-B*5801 prevalences. HLA-B*5801 testing was cost-effective for African Americans (ICER $83,450) and Asians (ICER $64,190), but not for Caucasians or Hispanics (ICER $183,720), using accepted US willingness-to-pay threshold ($109,000/QALY). Results were robust in sensitivity analyses, except that reducing the risk of SJS/TEN by a half made testing not cost-effective for all races/ethnicities.. Testing for HLA-B*5801 prior to allopurinol initiation is cost-effective for Asians and African Americans, but not for Caucasians or Hispanics in the United States. Reducing AHS risk by other predictive measures could make HLA-B*5801 testing not cost-effective even among Asians and Blacks.

Topics: Allopurinol; Asian; Black or African American; Cost-Benefit Analysis; Female; Genetic Markers; Genetic Testing; Gout; Gout Suppressants; HLA-B51 Antigen; Humans; Male; Risk Factors; Sensitivity and Specificity; Stevens-Johnson Syndrome; United States; Uric Acid

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are very serious forms of drug-induced cutaneous adverse reaction. SJS/TEN induced by certain drug is well known to be associated with some human leukocyte antigen (HLA) gene type. We aimed to explore HLA allele frequencies and their association with SJS/TEN according to culprit drugs in Korea.. We enrolled 5802 subjects who had results of HLA typing test from August 2005 to July 2014. Total 28 SJS/TEN patients were categorized based on culprit drugs (allopurinol, lamotrigine, carbamazepine) and identified the presence of HLA-B*58:01, HLA-B*44:03, HLA-B*15:02, and HLA-A*31:01.. HLA-A*24:02 (20.5%), HLA-B*44:03 (10.0%), and HLA-Cw*01:02 (17.1%) were the most frequent type in HLA-A, -B, and -C genes, respectively. Allele frequencies of HLA-B*58:01, HLA-B*44:03, HLA-A*31:01, and HLA-B*15:02 were 7.0%, 10.0%, 5.0%, and 0.3%, respectively. In 958 allopurinol users, 9 subjects (0.9%) were diagnosed with SJS/TEN. Among them, 8 subjects possessed HLA-B*58:01 allele. SJS/TEN induced by allopurinol was more frequently developed in subjects with HLA-B*58:01 than in subjects without it [odds ratio: 57.4; confidence interval (CI) 7.12-463.50; p<0.001]. Allopurinol treatment, based on screening by HLA-B*58:01 genotyping, could be more cost-effective than that not based on screening. HLA-B*44:03 may be associated with lamotrigine-induced SJS/TEN (odds ratio: 12.75; CI 1.03-157.14; p=0.053). Among carbamazepine users, only two patients experienced SJS/TEN and possessed neither HLA-B*15:02 nor HLA-A*31:03.. HLA gene frequencies varied in Korea. Screening of HLA-B*58:01 before the use of allopurinol might be needed to anticipate probability of SJS/TEN.

Topics: Adult; Aged; Alleles; Allopurinol; Anticonvulsants; Asian People; Carbamazepine; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; HLA-B Antigens; Humans; Lamotrigine; Male; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Republic of Korea; Retrospective Studies; Risk Factors; Stevens-Johnson Syndrome; Triazines

To describe the clinical characteristics and genetic background of allopurinol-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in South Korea.. This is a prospective, noncomparative case series. Visual acuity, detailed medical history, ocular findings, and systemic manifestations of 5 patients (10 eyes) with allopurinol-induced SJS/TEN were recorded. The acute ocular involvement score and the chronic ocular manifestation score were graded on scales of 0-3 and 0-39, respectively, based on severity. Human leukocyte antigen (HLA) genotyping was also performed during the hospitalization.. Three patients were diagnosed with SJS, and 2 with TEN. Mild ocular involvement with only conjunctival hyperemia (acute ocular involvement score ≤ 1) was present in all 10 eyes during the acute stage. Patients were treated with systemic steroids and topical antibiotics, steroids, and preservative-free artificial tears, with rinsing of the ocular surface, in the acute stages of SJS/TEN. In the final follow-up, none of the patients had developed severe chronic ocular complications (chronic ocular manifestation score ≤ 8), including keratinization, corneal conjunctivalization, mucocutaneous junction involvement, or symblepharon. One patient developed bilateral persistent epithelial defects 3 months after the disease onset, which healed after conservative treatment, leaving a bilateral central corneal haze. HLA genotyping showed that 4 of the 5 patients (80%) were positive for HLA-B*58:01.. Allopurinol-induced SJS/TEN might not cause serious acute or chronic complications of the ocular surface. In addition, our HLA genotyping results are consistent with previous studies reporting a strong association between HLA-B*58:01 and allopurinol-induced SJS/TEN among Koreans.

Topics: Aged; Allopurinol; Asian People; Conjunctival Diseases; Drug Eruptions; Female; Genotype; Genotyping Techniques; Glucocorticoids; Gout Suppressants; HLA Antigens; Humans; Male; Middle Aged; Polymerase Chain Reaction; Prednisolone; Prospective Studies; Republic of Korea; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse drug reactions. We assessed incidence, drug exposure and mortality, analysing data obtained from the Lombardy Registry of Severe Cutaneous Reactions (REACT).. Data were collected from hospitals in the Italian Lombardy region (9,502,272 people). A trained monitor was sent to the reporting hospital to collect data on drug exposure and clinical features. The algorithm for drug causality for epidermal necrolysis algorithm was applied to assess drug causality. Defined Daily Dose (DDD) was used to express drug consumption.. From April 2009 to November 2014, 17 cases of TEN and 59 cases of SJS were collected. The overall incidence rate was 1.40 cases (95%CI, 1.12-1.76) per million people per year. A total of 15 cases died during hospitalization with a mortality rate of 16.9% for SJS and 29.4% for TEN. Overall, 55.4% of cases had a probable or very probable relation with drug exposure. In a total of five patients (6.6%), no causative drug for the reaction was identifiable. Allopurinol contributed to the highest number of cases (23 cases), while the highest incidence based on more than one case reported was observed for cotrimoxazole and lamotrigine, with 5.37 cases (95%CI, 2.09-13.80) and 3.54 (95%CI, 1.21-10.42) per 10 million DDD/year, respectively.. We confirmed that SJS and TEN are rare adverse cutaneous reactions. As expected, mortality was influenced by the degree of skin detachment. The profile of drugs associated with the reactions was in agreement with data from other surveillance systems.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aged, 80 and over; Allopurinol; Child; Child, Preschool; Female; Humans; Incidence; Italy; Lamotrigine; Male; Middle Aged; Mortality; Registries; Stevens-Johnson Syndrome; Triazines; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

The purpose of this study is to describe a novel technique using amniotic membrane suture-fixated onto custom-designed symblepharon rings in a patient with acute toxic epidermal necrolysis (TEN).. A 61-year-old man developed bilateral symblephara and severe ocular surface inflammation from Stevens-Johnson syndrome/TEN secondary to allopurinol. Eight days after admission, he was treated with placement of custom-designed symblepharon rings, designed by one of the authors (A.A.), covered with amniotic membrane. This method was used to allow for efficient placement of the membrane and to minimize operative time and perioperative risks due to his worsening systemic condition.. On postoperative day 49, his visual acuity was 20/20 in the right eye and 20/25 in the left eye. Both eyes were quiet with only small symblephara noted temporally.. The use of amniotic membrane suture-fixated to custom-designed symblepharon rings provides sufficient coverage of the ocular surface, leading to excellent visual and clinical outcomes by reducing inflammation and protecting the ocular surface from the cicatrizing sequelae associated with ocular-involving TEN. This novel technique is less invasive, more time efficient, and likely safe for even the most critically ill patients with significant risk for mortality, thus allowing any treating ophthalmologist to comfortably perform this important sight-saving procedure.

Topics: Acute Disease; Allopurinol; Amnion; Conjunctival Diseases; Eyelid Diseases; Gout; Gout Suppressants; Humans; Male; Middle Aged; Prostheses and Implants; Prosthesis Implantation; Stevens-Johnson Syndrome; Suture Techniques; Visual Acuity; Wound Healing

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Allopurinol; Child; China; Drug Eruptions; Eosinophilia; Exanthema; Female; Genotype; Glomerular Filtration Rate; HLA-B Antigens; Homozygote; Humans; Hyperuricemia; Kidney; Male; Middle Aged; Odds Ratio; Risk; ROC Curve; Sensitivity and Specificity; Skin; Stevens-Johnson Syndrome; Young Adult

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe mucocutaneous adverse drug reactions characterized by extensive epidermal detachment. The mortality rates have been reported to vary between 1% and 5% for Stevens-Johnson syndrome and 25% and 35% for patients with toxic epidermal necrolysis. Studies have shown that early recognition and prompt withdrawal of the causative agent leads to increased patient survival.. A retrospective chart review was conducted on 64 patients admitted to Vancouver General Hospital with a diagnosis of Stevens-Johnson syndrome or toxic epidermal necrolysis from 2001 to 2011. The aim of this study was to identify the medications most often implicated in triggering Stevens-Johnson syndrome and toxic epidermal necrolysis, as well as to delineate the timeline of identification and removal of these triggers.. A trigger was identified in 75% of cases. Allopurinol was the single most common offending agent (20% of cases). Anticonvulsants and antibiotics were common triggers. The offending agent was often removed at time of hospital admission/diagnosis but not at onset of symptoms. A history of prior culprit drug exposure with previous mucocutaneous adverse reaction was noted in 19% of cases with identified triggers. Asians and Native North Americans had a higher mortality than whites, and Asians more frequently had allopurinol as a trigger.. The onset and high mortality rate of Stevens-Johnson syndrome/toxic epidermal necrolysis may be related to unawareness of the early signs and symptoms of Stevens-Johnson syndrome and toxic epidermal necrolysis, the common drug triggers that cause it, and what investigations (human leukocyte antigen typing in Asians) can be done to prevent it.

Topics: Adult; Aged; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Asian People; British Columbia; Female; Gout Suppressants; HLA Antigens; Humans; Indians, North American; Male; Middle Aged; Retrospective Studies; Stevens-Johnson Syndrome; White People

Allopurinol is a frequent cause of severe cutaneous adverse reactions (SCARs), such as drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). The reactions can potentially be fatal. As drug rechallenge in patients with a history of drug-induced SCARs is contraindicated, in vitro testing may have a diagnostic role as a confirmation test.. To study the diagnostic value of interferon (IFN)-γ enzyme-linked immunospot (ELISpot) assay as a confirmatory test in patients with a history of allopurinol-induced SCARs.. Peripheral blood mononuclear cells (PBMCs) from 24 patients with a history of allopurinol-induced SCAR (13 DRESS, 11 SJS/TEN) and 21 control subjects were incubated with allopurinol or oxypurinol in the presence or absence of antiprogrammed death ligand 1 antibody (anti-PD-L1). The numbers of IFN-γ-releasing cells after stimulation in each group were subsequently measured with ELISpot.. The measurement of oxypurinol/anti-PD-L1-inducing IFN-γ-releasing cells yields a high diagnostic value in distinguishing between allopurinol-allergic and control subjects. This technique is beneficial in confirming diagnosis of allopurinol-induced SCARs in patients whose reaction develops while taking multiple drugs.

Topics: Allopurinol; Antibodies; Area Under Curve; B7-H1 Antigen; Case-Control Studies; Enzyme Inhibitors; Enzyme-Linked Immunospot Assay; Female; Humans; Interferon-gamma; Leukocytes, Mononuclear; Male; Middle Aged; Oxypurinol; Stevens-Johnson Syndrome

HLA-B*5801 allele carriage (a strong determinant of allopurinol hypersensitivity syndrome) varies substantially among races, which may lead to racial disparities in the risk of Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) in the context of urate-lowering drug adverse events (ULDAEs). We examined this hypothesis in a large, racially diverse, and generalizable setting.. Using a database representative of US hospitalizations (2009-2013), we investigated the racial distribution of hospitalized SJS/TEN (principal discharge diagnosis) as ULDAEs (ICD-9-CM Classification of External Causes). Our reference groups included the US Census population, US allopurinol users, and ULDAE hospitalizations without SJS/TEN.. We identified 606 cases hospitalized for SJS/TEN as ULDAEs (mean age = 68 years; 44% male), among which there was an overrepresentation of Asians (27%) and Blacks (26%), and an underrepresentation of Whites (29%) and Hispanics (% too-low-to-report), compared with the US Census population (5%, 12%, 67%, and 15%, respectively). The hospitalization rate ratios for SJS/TEN among Asians, Blacks, and Whites were 11.9, 5.0, and 1.0 (referent), respectively. These associations persisted using other national referents. According to the NHANES 2009-2012, allopurinol constituted 96.8% of urate-lowering drug use, followed by probenecid (2.1%).. These national data indicate that Asians and Blacks have a substantially higher risk of SJS/TEN as ULDAEs than Whites (or Hispanics), correlating well with corresponding frequencies of HLA-B*5801 in the US population (i.e., 7.4%, 4%, 1%, and 1%, respectively). Given its market dominance and established association with SJS/TEN, our findings support the use of vigilance in these minorities when considering allopurinol.

Topics: Aged; Allopurinol; Databases, Factual; Female; Gout Suppressants; Hospitalization; Humans; Male; Racial Groups; Risk Assessment; Stevens-Johnson Syndrome; United States

Stevens-Johnson syndrome/toxic epidermal necrolysis overlap is an acute hypersensitivity reaction that compromises the integrity of mucous membranes and cutaneous tissue. While the pathophysiology of this syndrome has not been fully elucidated, it is commonly associated with the medication use and carries a significant mortality risk of approximately 30%. No commonalities among causative medications have been identified, and determining the offending agent can be challenging. This case report describes fatal Stevens-Johnson syndrome/toxic epidermal necrolysis overlap in a patient after receiving his first cycle of allopurinol, rituximab, and bendamustine treatment for non-Hodgkin's B-cell lymphoma. An analysis of FDA Medwatch adverse reaction case reports involving allopurinol, rituximab, and bendamustine is also presented.

Topics: Aged; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Fatal Outcome; Humans; Lymphoma, B-Cell; Male; Rituximab; Stevens-Johnson Syndrome

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.

Topics: Acetaminophen; Acetazolamide; Adult; Aged; Aged, 80 and over; Alleles; Allopurinol; Anti-Bacterial Agents; Anticonvulsants; Asian People; Female; Genetic Predisposition to Disease; HLA-B Antigens; Humans; Lamotrigine; Male; Middle Aged; Plants, Medicinal; Republic of Korea; Stevens-Johnson Syndrome; Tertiary Care Centers; Triazines; Young Adult

Topics: Administration, Ophthalmic; Allopurinol; Anti-Bacterial Agents; Biopsy; Corneal Ulcer; Critical Care; Diagnosis, Differential; Disease Management; Female; Fluid Therapy; Gout Suppressants; Humans; Middle Aged; Rehydration Solutions; Skin; Stevens-Johnson Syndrome; Treatment Outcome; Visual Acuity; Water-Electrolyte Imbalance

Topics: Aged; Aged, 80 and over; Alleles; Allopurinol; Fatal Outcome; Gout Suppressants; HLA-B Antigens; Humans; Hyperuricemia; Male; Stevens-Johnson Syndrome

Allopurinol, a first-line drug for treating gout and hyperuricemia, is one of the leading causes of severe cutaneous adverse reactions (SCARs). To investigate the molecular mechanism of allopurinol-induced SCAR, we enrolled 21 patients (13 Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and 8 drug reaction with eosinophilia and systemic symptoms (DRESS)), 11 tolerant controls, and 23 healthy donors. We performed in vitro T-cell activation assays by culturing peripheral blood mononuclear cells (PBMCs) with allopurinol, oxypurinol, or febuxostat and measuring the expression of granulysin and IFN-γ in the supernatants of cultures. TCR repertoire was investigated by next-generation sequencing. Oxypurinol stimulation resulted in a significant increase in granulysin in the cultures of blood samples from SCAR patients (n=14) but not tolerant controls (n=11) or healthy donors (n=23). Oxypurinol induced T-cell response in a concentration- and time-dependent manner, whereas allopurinol or febuxostat did not. T cells from patients with allopurinol-SCAR showed no crossreactivity with febuxostat. Preferential TCR-V-β usage and clonal expansion of specific CDR3 (third complementarity-determining region) were found in the blister cells from skin lesions (n=8) and oxypurinol-activated T-cell cultures (n=4) from patients with allopurinol-SCAR. These data suggest that, in addition to HLA-B*58:01, clonotype-specific T cells expressing granulysin upon oxypurinol induction participate in the pathogenesis of allopurinol-induced SCAR.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Antigens, Differentiation, T-Lymphocyte; Case-Control Studies; Cells, Cultured; Cross Reactions; Drug Eruptions; Enzyme-Linked Immunosorbent Assay; Febuxostat; Female; Humans; Interferon-gamma; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Oxypurinol; Reference Values; Stevens-Johnson Syndrome; Thiazoles

The aim of this study was to examine risk factors and mortality among patients with erythema multiforme (EM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN).. This was a retrospective evaluation of the med-ical records of 250 patients from two Danish tertiary dermatological departments during a ten-year period.. In a total of 192 cases (77.4%), the primary diagnosis of EM (66.5%), SJS (62.2%) and TEN (100%) was confirmed, whereas the remaining cases (22.6%) were diagnosed differently. Antibiotics and allopurinol were predominantly associated with TEN, whereas SJS was associated with a broad spectrum of drugs. EM was related mainly to viral infections, predominantly herpes (30.6%); 38.2% of the causes of EM remained unknown. Patients with TEN had the highest mortality; i.e. 60% in the course of the ten-year study period: adjusted hazard ratio (HR) = 11.2 (95% confidence interval (CI): 3.65-34.35); p < 0.001 compared with EM patients. The risk of death was also increased among patients with SJS relative to patients with EM: HR = 2.60 (95% CI: 1.10-6.16); p = 0.030; however, this did not remain statistically significant after adjustment for age, co-morbidity, infection, cancer and polypharmacy, HR = 0.99 (95% CI: 0.38-2.57); p = 0.976.. We validated diagnoses in 250 patients with EM, SJS and TEN diagnosed during a ten-year period. The survival of patients with TEN was expectedly low compared with patients with EM. We extend previous findings by showing that after adjustment for confounders, the survival rates of SJS and EM are comparable.. none.. not relevant.

Topics: Adult; Allopurinol; Anti-Bacterial Agents; Antimetabolites; Denmark; Erythema Multiforme; Female; Herpes Simplex; Humans; Male; Middle Aged; Pneumonia, Mycoplasma; Proportional Hazards Models; Retrospective Studies; Risk Factors; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), caused by allopurinol therapy, are strongly associated with the human leukocyte antigen (HLA), HLA-B*5801. Identification of HLA-B*5801 genotype before prescribing allopurinol offers the possibility of avoiding allopurinol-induced SJS/TEN. As there is a paucity of evidence about economic value of such testing, this study aims to determine the cost-effectiveness of HLA-B*5801 testing compared with usual care (no genetic testing) before allopurinol administration in Thailand.. A decision analytical and Markov model was used to estimate life time costs and outcomes represented as quality adjusted life years (QALYs) gained. The model was populated with relevant information of the association between gene and allopurinol-induced SJS/TEN, test characteristics, costs, and epidemiologic data for Thailand from a societal perspective. Input data were obtained from the literature and a retrospective database analysis. The results were expressed as incremental cost per QALY gained. A base-case analysis was performed for patients at age 30. A series of sensitivity analyses including scenario, one-way, and probabilistic sensitivity analyses were constructed to explore the robustness of the findings. Based on a hypothetical cohort of 1,000 patients, the incremental total cost was 923,919 THB (USD 29,804) and incremental QALY was 5.89 with an ICER of 156,937.04 THB (USD 5,062) per QALY gained. The cost of gout management, incidence of SJS/TEN, case fatality rate of SJS/TEN, and cost of genetic testing are considered very influential parameters on the cost-effectiveness value of HLA-B*5801 testing.. The genetic testing for HLA-B*5801 before allopurinol administration is considered a highly potential cost-effective intervention in Thailand. The findings are sensitive to a number of factors. In addition to cost-effectiveness findings, consideration of other factors including ethical, legal, and social implications is needed for an informed policy decision making.

Topics: Allopurinol; Cost-Benefit Analysis; Decision Support Techniques; Genetic Testing; HLA-B Antigens; Humans; Stevens-Johnson Syndrome; Thailand; Treatment Outcome

The objective of this study was to demonstrate the clinical profiles of Stevens-Johnson syndrome (SJS) in Thai patients, and to compare those clinical features between younger and older patients. Medical records of all patients with SJS who were admitted to Srinagarind Hospital Medical School, Khon Kaen, Thailand, from January 2002 to December 2014 were reviewed. Epidemiological features, etiologies, treatment and clinical outcomes were collected. There were 45 patients with SJS during the 10-year period. Females were the majority (57.8%) and the median age was 49 years. Hepatitis was the most frequent complication (67.5%). Phenytoin (15.6%), sulfonamide drugs (15.6%) and allopurinol (13.3%) were implicated as leading causes of SJS. Steroids were prescribed in 37 cases (82.2%). The mortality rate was 4.4%. Comparing older patients to younger patients, allopurinol appeared to be the main instigating drug to develop SJS with an odds ratio of 5.6 (95% confidence interval, 2.8-10.6). In conclusion, clinical features of Thai patients with SJS were similar to other reports. Allopurinol had the strongest association with SJS in older patients as compared to the younger ones.

Topics: Adolescent; Adult; Age Factors; Aged; Allopurinol; Female; Hepatitis; Humans; Male; Middle Aged; Phenytoin; Retrospective Studies; Stevens-Johnson Syndrome; Sulfonamides; Thailand; Young Adult

Severe cutaneous adverse reactions (SCAR) are rare but important causes of morbidity and mortality. Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous drug reactions that can be potentially life threatening. Our study aims to look at the epidemiology of SCAR in the local setting in Singapore and the underlying characteristics of our patients that may influence the drug reaction seen.. Data was collected retrospectively from in-patient records in the period of January 2007 to December 2011. We looked at several factors: (i) patient demographics including age, gender, ethnicity, comorbidities, (ii) culprit drug(s), (iii) latent period, (iv) drug reaction observed, (v) systemic complications, (vi) length of hospital stay, (vii) treatment given, and (viii) outcomes (mortality, morbidity).. We collected data from 42 patients. The mean age of our patients was 51.8 years. Twenty-nine (69%) of the patients had underlying comorbidities. The most common culprit drug group was antibiotics. SJS was the most common SCAR observed (54.8%), followed by acute generalized exanthematous pustolosis (AGEP; 24%), TEN (11.9%), and DRESS (2%). Sixteen patients (38.1%) had complications, and there was one reported death. There was a weak correlation (correlation coefficient 0.29, P value = 0.15, 95% CI = 2.07) between early steroid therapy and the length of stay.. Antibiotics are the most common culprit drugs. The most common SCAR observed in our study was SJS. Early initiation of steroids may lead to a more favorable outcome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Child; Comorbidity; Drug Hypersensitivity Syndrome; Female; Gout Suppressants; Hospitals, Community; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Length of Stay; Male; Middle Aged; Retrospective Studies; Risk Factors; Singapore; Steroids; Stevens-Johnson Syndrome; Young Adult

A 41 year old patient started treatment with 300 mg/d allopurinol for asymptomatic hyperuricaemia (9,2 mg/dl).. 4 weeks later he developed exfoliative skin lesions with haemorrhage, fever, eosinophilia and acute liver and renal failure, typical for an allopurinol hypersensitivity syndrome (AHS).An orthotopic liver-transplantation was performed.. The AHS is a serious iatrogenic disease. 2 % of the treated patients develop a skin rash. 0,4 % of these patients experience suddenly and unforeseen a severe hypersensitivity with a mortality of 14-30 %. An early diagnosis is often very difficult. In the pathogenesis different causes are discussed. A hereditary component is involved. Of essential importance is the amount of the starting dose, the kidney function and concomitant drugs. In an asymptomatic hyperuricaemia the application of allopurinol is not indicated. If strong indications are present, the allopurinol therapy has to start with the lowest dose (100 mg/d). If required this dose should be increased under consequent supervision only.

Topics: Adult; Allopurinol; Amoxicillin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Hypersensitivity; Drug Interactions; Drug Therapy, Combination; Follow-Up Studies; Humans; Hyperuricemia; Kidney Failure, Chronic; Liver Transplantation; Male; Risk Factors; Scarlet Fever; Stevens-Johnson Syndrome

HLA-B*58:01 is associated with allopurinol-induced severe cutaneous adverse drug reactions (sCADR) particularly in Han Chinese, but the risk in European populations has seldom been studied.. To study the association of HLA-B*58:01 with allopurinol-induced sCADR in a Portuguese population.. We studied 25 patients (11 male/14 female, mean age 67·4 years) with sCARD from allopurinol: 19 DRESS (drug reaction eosinophilia and systemic symptoms) and six Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). HLA was genotyped by reverse sequence-specific oligonucleotide-polymerase chain reaction and results compared statistically with a control group of 23 allopurinol-tolerant individuals and the control population.. HLA-B*58:01 was present in 16 patients with sCADR (64%) [12 DRESS (63%), four SJS/TEN (67%)], one allopurinol-tolerant individual (4%) and 63 normal controls (1·96%), with a statistically significant difference between sCADR and the two control groups. When compared with the normal population, HLA-B*58:01 was associated with a higher risk of sCADR, both DRESS [odds ratio (OR) 85·36, 95% confidence interval (CI) 32·52-224·04] and SJS/TEN (OR 99·59, 95% CI 17·91-553·72). There was no statistically different risk between these two types of CADR.. Portuguese patients with sCADR from allopurinol, both DRESS and SJS/TEN, have a high frequency of HLA-B*58:01, with an OR similar to European patients with SJS/TEN. This study also extends this association to DRESS in Europeans. The recommendation to genotype systematically before therapy is controversial, particularly when HLA-B*58:01 prevalence in the normal population is low, as in Europe. However it could be an option for patients with other risks factors.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Female; Genotype; Gout Suppressants; HLA-B Antigens; Homozygote; Humans; Male; Middle Aged; Portugal; Prospective Studies; Retrospective Studies; Risk Factors; Stevens-Johnson Syndrome; Young Adult

Topics: Aged; Allopurinol; Biopsy; Combined Modality Therapy; Fatal Outcome; Female; Glucocorticoids; Gout Suppressants; Herpesvirus 6, Human; Humans; Immunoglobulins, Intravenous; Methylprednisolone; Plasmapheresis; Pulse Therapy, Drug; Roseolovirus Infections; Sepsis; Skin; Stevens-Johnson Syndrome; Time Factors; Treatment Outcome; Virus Activation

The liver is the most commonly involved internal organ in drug-induced systemic hypersensitivity. However, data obtained from these patients have yet to be analyzed in depth with respect to liver injury.. The medical records of 136 patients who developed delayed-type drug hypersensitivity were reviewed at a tertiary referral hospital. Culprit drugs, the pattern and degree of liver injury, and the effect of systemic corticosteroids were evaluated in the group of patients with drug-induced systemic hypersensitivity and liver dysfunction (aspartate aminotransferase or alanine aminotransferase ≥80 IU/L). Clinical characteristics of patients with drug-induced systemic hypersensitivity and liver injury were analyzed.. Among the 61 patients with drug-induced systemic hypersensitivity and liver dysfunction, the clinical phenotypes were drug reaction with eosinophilia and systemic symptoms (n = 29, 48%), Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 11, 18%), and maculopapular rash (n = 17, 28%). Antibiotics (n = 27, 44%) were the most common cause of drug-induced systemic hypersensitivity with liver dysfunction. Whereas patients with Stevens-Johnson syndrome/toxic epidermal necrolysis had mild hepatocellular-type liver injury of relatively brief duration, those with drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome had more severe and prolonged hepatocellular injury in addition to moderate to severe cholestatic-type liver injury. The use of systemic corticosteroids did not significantly affect either recovery from liver injury or mortality.. This study was retrospective and the number of subjects was small.. The results suggest that the severity, pattern, and duration of liver injury differ according to the drug-hypersensitivity phenotype. Further studies are needed to evaluate the role of systemic corticosteroids in drug-induced systemic hypersensitivity and liver injury.

Topics: Adrenal Cortex Hormones; Adult; Aged; Alanine Transaminase; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Enzyme Inhibitors; Eosinophilia; Female; Humans; Male; Middle Aged; Retrospective Studies; Stevens-Johnson Syndrome

Topics: Aged; Aged, 80 and over; Allopurinol; Asian People; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions; Erythema; Female; Gout Suppressants; HLA-B Antigens; Humans; Japan; Male; Odds Ratio; Pharmacogenetics; Stevens-Johnson Syndrome

The objective of this study was to estimate the association between adverse drug reactions (ADRs) and exposure to allopurinol maintenance doses higher than those in the 1984 suggested limits of Hande et al. adjusted for level of renal function.. We conducted a retrospective review of electronic health records of patients prescribed allopurinol from January 1, 2004, to June 30, 2011, to identify those who had a definite or possible ADR to allopurinol. The associations of ADRs with maintenance doses of allopurinol 1 to 1.5 times and more than 1.5 times the suggested limits of Hande et al. compared with doses within the suggested limits of Hande et al. were estimated using logistic regression models.. Of 4755 patients prescribed allopurinol, 2946 had a serum creatinine measured within 6 months of starting allopurinol, and of these, 1268 patients' records were reviewed. Forty-eight patients had a definite ADR to allopurinol, 2 of which were allopurinol hypersensitivity syndrome. The odds ratios of definite ADRs with maintenance doses of allopurinol 1.0 to 1.5 times and more than 1.5 times suggested compared with doses within suggested limits were, respectively, 1.42 (95% confidence interval [CI], 0.66-3.04) and 2.04 (95% CI, 0.87-4.77). Among those with an allopurinol maintenance dose more than 1.5 times suggested limits, the proportion of patients with a definite ADR was 2.6% (95% CI, 1.0%-5.2%).. There is no significant association of high maintenance doses of allopurinol with ADRs, and the absolute risk of ADRs at doses higher than 1.5 times the 1984 suggested limits of Hande et al. is low. Cautious, gradual increases in allopurinol maintenance doses above the suggested limits of Hande et al. are warranted if necessary to achieve a serum uric acid level less than 6 mg/dL.

Topics: Aged; Allopurinol; Creatinine; Diarrhea; Dose-Response Relationship, Drug; Drug Hypersensitivity; Eosinophilia; Female; Fever; Gout Suppressants; Humans; Logistic Models; Male; Middle Aged; Nausea; Retrospective Studies; Sex Factors; Stevens-Johnson Syndrome; Thrombocytopenia; Transaminases; Vomiting

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 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. A bidirectional esophageal dilatation procedure via the mouth and percutaneous endoscopic gastrostomy site was successfully performed over a guidewire for treatment of this patient. The patient tolerated the procedure well. Esophagogastroduodenoscopy with dilation was performed in a regular anterograde fashion five times over the next three months. Triamcinolone acetonide was injected using Carr-Locke injection needle from ultrasound endoscopy during the last three sessions. He currently tolerates a regular diet without difficulty.

Topics: Aged; Allopurinol; Diagnosis, Differential; Endoscopy, Digestive System; Esophageal Stenosis; Gout Suppressants; Humans; Male; Stevens-Johnson Syndrome

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are severe, cutaneous adverse drug reactions that are rare but life threatening. Genetic biomarkers for allopurinol-related SJS/TEN in Japanese were examined in a genome-wide association study in which Japanese patients (n=14) were compared with ethnically matched healthy controls (n=991). Associations between 890 321 single nucleotide polymorphisms and allopurinol-related SJS/TEN were analyzed by the Fisher's exact test (dominant genotype mode). A total of 21 polymorphisms on chromosome 6 were significantly associated with allopurinol-related SJS/TEN. The strongest association was found at rs2734583 in BAT1, rs3094011 in HCP5 and GA005234 in MICC (P=2.44 × 10(-8); odds ratio=66.8; 95% confidence interval, 19.8-225.0). rs9263726 in PSORS1C1, also significantly associated with allopurinol-related SJS/TEN, is in absolute linkage disequilibrium with human leukocyte antigen-B*5801, which is in strong association with allopurinol-induced SJS/TEN. The ease of typing rs9263726 makes it a useful biomarker for allopurinol-related SJS/TEN in Japanese.

Topics: Aged; Aged, 80 and over; Allopurinol; Asian People; Biomarkers; Chromosomes, Human, Pair 6; Drug-Related Side Effects and Adverse Reactions; Female; Genome-Wide Association Study; HLA Antigens; Humans; Linkage Disequilibrium; Male; Middle Aged; Polymorphism, Single Nucleotide; Skin; Stevens-Johnson Syndrome

Allopurinol is the most commonly used drug for the treatment of hyperuricemia and gout. However, allopurinol is also one of the most common causes of severe cutaneous adverse reactions (SCARs), which include drug hypersensitivity syndrome, Stevens–Johnson syndrome, and toxic epidermal necrolysis. A variant allele of the human leukocyte antigen (HLA)-B, HLA-B*58:01, associates strongly with allopurinolinduced SCAR. We have summarized the evidence from the published literature and developed peer-reviewed guidelines for allopurinol use based on HLA-B genotype.

Topics: Alleles; Allopurinol; Dose-Response Relationship, Drug; Genotype; Gout; Gout Suppressants; HLA-B Antigens; Humans; Hyperuricemia; Pharmacogenetics; Stevens-Johnson Syndrome

Topics: Allopurinol; Arthritis, Gouty; Asian People; Genetic Testing; HLA-B Antigens; Humans; Risk; Stevens-Johnson Syndrome

Topics: Adrenal Cortex Hormones; Aged; Allopurinol; Antimetabolites; Azathioprine; Drug Therapy, Combination; Female; Heart; Humans; Immunosuppressive Agents; Magnetic Resonance Imaging; Myocarditis; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, but potentially life-threatening, reactions to medications. Both conditions have significant morbidity and mortality. The aim of this study was to document the epidemiological features, aetiologies, treatment and clinical outcomes of retrospectively reviewed data of all patients with SJS or TEN treated from January 2004 to November 2010 in a general hospital. There were 18 cases of SJS, seven cases of SJS/TEN overlap and three cases of TEN. Mean age was 50.6 years, with a range of 13-85 years. The male/female ratio was 1. Drugs accounted for 26 cases; one case was caused by Neisseria gonorrhoea infection. Anti-convulsants (35.7%) were the most common implicated drugs followed by antibiotics (28.5%), non-steroidal anti-inflammatory drugs (NSAIDS) (14.3%), allopurinol (7.1%) and traditional Chinese medication (7.1%). In seven cases, multiple drugs were implicated. Most SJS cases (88%) were treated with corticosteroids, of which 61% were given high-dose systemic corticosteroids. No infective complications were observed. Six out of the seven SJS/TEN overlap syndrome and all three TEN cases were given intravenous immunoglobulins. One patient with TEN died. In conclusion, anti-convulsants, especially carbamazepine, were the most frequently implicated drugs, followed by antibiotics and NSAIDS. High-dose corticosteroids were effective in SJS, whereas intra-venous immunoglobulin were useful in TEN and SJS/TEN overlap syndrome.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antimetabolites; Female; Gonorrhea; Humans; Hydrocortisone; Immunoglobulins, Intravenous; Immunologic Factors; Male; Medicine, Chinese Traditional; Middle Aged; Neisseria gonorrhoeae; Prednisolone; Retrospective Studies; Severity of Illness Index; Singapore; Stevens-Johnson Syndrome; Treatment Outcome; Young Adult

Allopurinol hypersensitivity (AH) can rarely be manifest as Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) that have high mortality rates. Less serious, but still significant, skin and systemic hypersensitivity reactions form part of the AH spectrum. One hundred per cent of Han Chinese with SJS/TEN due to allopurinol have been found to be at least heterozygous for HLA-B*5801, the carriage rate for this allele in the Han Chinese population being about 15%. The association has been found to be weaker in Caucasians whose HLA-B*5801 carriage rate is less than 6%. We examined the relationship between the different skin hypersensitivity reactions to allopurinol and the HLA-B locus in Australian patients.. We examined 23 patients referred with AH.. Five of six Australian SJS/TEN patients were heterozygous for HLA-B*5801 and four were of South-East Asian origin. Five AH patients without SJS/TEN were all Caucasian and only one of these was positive for HLA-B*5801. Twelve patients with allopurinol-induced maculopapular exanthema were negative for HLA-B*5801, including one South-East Asian.. Cases of AH manifesting as SJS/TENS in Australians are more likely to be in those of Asian heritage. The place of routine testing for HLA-B*5801 prior to commencing allopurinol therapy requires further investigation. However, Han Chinese origin patients commencing allopurinol might be informed of the test and may elect to have it performed as there are alternative hypouricaemic medicines, such as probenecid thereby reducing the risk of a catastrophic reaction to allopurinol.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Asian People; Australia; Drug Hypersensitivity; Female; Genetic Predisposition to Disease; HLA Antigens; HLA-B Antigens; Humans; Male; Middle Aged; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Antimetabolites, Antineoplastic; Brain Neoplasms; Drug Eruptions; Female; Humans; Lymphoma, B-Cell; Methotrexate; Photosensitivity Disorders; Stevens-Johnson Syndrome; Ultraviolet Rays

Allopurinol-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is strongly associated with HLA-B*58:01 in various populations including Japanese. We demonstrated that several single nucleotide polymorphisms (SNPs) around the HLA region on chromosome 6 were strongly linked with HLA-B*58:01 in a previous study using Japanese allopurinol-related SJS/TEN patients. Their very strong linkage suggests that these SNPs could be used as surrogate biomarkers to find carriers of HLA-B*58:01 to avoid these serious adverse effects. In the present study, to expedite the application of this pharmacogenomic information to the proper usage of allopurinol in a clinical situation, we developed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay for the genotyping of rs9263726 in the psoriasis susceptibility 1 candidate 1 (PSORS1C1) gene, which is in absolute linkage disequilibrium (r(2) = 1, D' = 1) with HLA-B*58:01. The developed PCR-RFLP assay using FokI restriction enzyme was able to detect three different genotypes, GG, GA, and AA of rs9263726 robustly, and thus to find HLA-B*58:01 carriers. This robust and inexpensive assay would be useful for pre-screening the subjects with HLA-B*58:01, a genetically high risk factor for allopurinol-induced SJS/TEN.

Topics: Allopurinol; Amplified Fragment Length Polymorphism Analysis; Asian People; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; HLA-B Antigens; Humans; Japan; Linkage Disequilibrium; Phenotype; Polymorphism, Single Nucleotide; Predictive Value of Tests; Proteins; Risk Assessment; Risk Factors; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) is a serious drug eruption that results in death in approximately 25% to 50% of patients. There is controversy over whether SCORTEN accurately predicts mortality or if treatment interventions such as intravenous immunoglobulin (IVIg) can alter mortality.. We sought to determine whether SCORTEN accurately predicts mortality in this cohort, whether IVIg improved survival, and which drugs and medical comorbidities impacted mortality.. We summarize our experience prospectively over 5 years and 82 patients. Patients either received supportive care, intravenous immunoglobulin, or cyclosporine as treatment. All patients had a SCORTEN on admission, an offending drug on record, and a list of medical comorbidities.. Of the 82 patients, 29% died from TEN. SCORTEN accurately predicted mortality in this cohort with an area under the curve (AUC) of 0.83 in a receiver operator curve (ROC) analysis. A Kaplan-Meier curve did not show improved mortality if patients received IVIg versus supportive care (P = .9). Medications most often responsible for TEN were trimethoprim/sulfamethoxazole, followed by anticonvulsants, nonsteroidal anti-inflammatories, and allopurinol.. This prospective cohort study design is not as ideal as patients presenting for a randomized controlled trial.. SCORTEN was an accurate predictor of mortality in this cohort. Age older than 40 years, the presence of metabolic syndrome and/or gout, higher body surface area involvement, higher SCORTEN, and higher number of medical comorbidities statistically significantly increased risk of death. IVIg did not significantly alter mortality. Although the highest number of cases was due to trimethoprim/sulfamethoxazole, the greatest proportion of deaths was due to allopurinol.

Topics: Adult; Aged; Allopurinol; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Antimetabolites; Area Under Curve; Burn Units; Burns; Comorbidity; Drug Combinations; Female; Humans; Immunoglobulins, Intravenous; Kaplan-Meier Estimate; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; ROC Curve; Stevens-Johnson Syndrome; Sulfadoxine; Trimethoprim; Young Adult

Drug hypersensitivity reactions are an immune-mediated reaction to otherwise innocuous antigens derived from drugs. These reactions can affect many different organs, with the skin being the commonest. Skin involvement can range in severity with hypersensitivity syndrome (or DRESS) and the blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), also termed serious cutaneous adverse drug reactions, being the most severe and most feared. There is increasing evidence for the role of the immune system in the pathogenesis of these reactions, with drug-specific T cells having been identified in many patients. Until recently, very little was known about the predisposition to these reactions. However, the availability of more accurate molecular typing methods, and the ability to analyse the whole genome in an unbiased fashion, has led to some remarkable findings of the role of the HLA genes as genomic biomarkers of predisposition. The 'revolution' started with abacavir where the predisposition to hypersensitivity was linked to HLA-B*57:01, which was confirmed in a clinical trial, and where its implementation has shown to reduce the incidence of hypersensitivity in a cost-effective manner. Since then, associations have also been shown for allopurinol (HLA-B*58:01)- and carbamazepine (HLA-B*1502 and HLA-A*3101)-induced serious cutaneous adverse drug reactions. The latter is interesting since the association with HLA-B*1502 is present in certain South-Eastern Asian populations, and the predisposition is phenotype specific (only for SJS/TEN). The utility of this biomarker has been shown in a prospective cohort study performed in Taiwan. By contrast, the association with HLA-A*3101 is seen in more diverse ethnic groups, and predisposes to mild as well more severe cutaneous reactions associated with carbamazepine. It is important to note that strong HLA associations have also been shown with a number of drugs that cause liver injury including flucloxacillin, lumiracoxib, lapatinib and ximelagatran, indicating that the immune system is also important in the pathogenesis of other forms of drug-induced organ toxicity. The crucial question as to whether these HLA alleles are truly causative or acting as surrogate markers of predisposition, however, is still unclear, and will require further investigations in larger patient cohorts, through the use of bioinformatic techniques, fine mapping using next generation sequencing technologies and functional stud

Topics: Allopurinol; Anti-Bacterial Agents; Anti-HIV Agents; Anticonvulsants; Antimetabolites; Biomarkers; Carbamazepine; Chemical and Drug Induced Liver Injury; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; HLA Antigens; HLA-A Antigens; HLA-B Antigens; Humans; Immune System; Predictive Value of Tests; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are rare but severe adverse cutaneous drug reactions that are to be considered medical emergencies. The average reported mortality rate for SJS is 1-5%, and up to 25-35% for TEN. TEN and SJS are characterized by more or less extensive painful erythematous and erosive lesions of the skin, conjunctiva and mucous membranes resulting from massive apoptosis of epithelial cells, and are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs including allopurinol, antibiotics, anticonvulsants and NSAIDs of the oxicam type are the main cause of SJS/TEN in most cases. Recent evidence supports a genetic susceptibility to SJS and TEN as exemplified by the strong association observed in Han Chinese between the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnoses include autoimmune bullous dermatoses, acute generalized exanthematous pustulosis, disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome. Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, rapid identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and the consideration of immunomodulatory agents such as high-dose intravenous immunoglobulin.

Topics: Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Apoptosis; Diagnosis, Differential; Epithelial Cells; Genetic Predisposition to Disease; HLA-B15 Antigen; Humans; Immunoglobulins; Injections, Intravenous; Prognosis; Skin; Stevens-Johnson Syndrome

Allopurinol is widely used as an effective urate-lowering drug and is one of the most frequent causes of cutaneous adverse drug reactions (cADRs). Recently, a strong association of HLA-B*58:01 with allopurinol-induced severe cADRs was identified. This study investigated the predisposition to different types of allopurinol-cADRs conferred by HLA-B*5801 in a Han population from mainland China.. HLA-B genotyping was performed on 38 Chinese patients with different types of allopurinol-cADRs from 2008 to 2011.. All the allopurinol-cADR patients carried HLA-B*58:01, in contrast with only 11.11% (7/63) in the allopurinol-tolerant patients (odds ratio [OR] = 580.07; p < 0.0001) and 13.99% (80/572) in a Han Chinese population from the human MHC database (dbMHC; OR: 471.09; p < 0.0001) carried the genotype. Each type of allopurinol cADRs revealed a statistically significant association with HLA-B*58:01. In particular, the risk of allopurinol-induced maculopapular eruption was significantly higher in patients with HLA-B*58:01 (OR: 339.00; p < 0.0001).. The strong association of both the mild and severe types of allopurinol cADRs with the HLA-B*58:01 allele were observed. The results indicated that the prospective use of a genetic test of HLA-B*58:01 might reduce the prevalence of allopurinol-induced cADRs. Original submitted 7 March 2012; Revision submitted 21 May 2012.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Allopurinol; China; Drug-Related Side Effects and Adverse Reactions; Exanthema; Female; Genetic Predisposition to Disease; Genotype; HLA-B Antigens; Humans; Male; Middle Aged; Risk; Stevens-Johnson Syndrome

Lyell's syndrome or toxic epidermal necrolysis (TEN) is an extremely rare and dangerous severe skin disorder characterized by a high proportion of cutaneous lesions leading to necrosis and subsequent shedding of the epidermis over large areas of skin after an idiosyncratic reaction triggered by a drug. The patients who suffer it pathophysiologically have similar complications to those seen in major burns. TEN traditionally has been treated with immunomodulators such as glucocorticoids, intravenous gammaglobulin, cyclophosphamide, thalidomide or plasmapheresis. A variable, and sometimes contradictory response, has been obtained in some series. Cyclosporin A has been tested as a single immunomodulator in patients with TEN since the end of the 90 s in a limited number series. The results have improved in regards to survival compared with studies with other drugs. We report three consecutive cases of toxic epidermal necrolysis treated with cyclosporin A in this article.

Topics: Adult; Allopurinol; Amoxicillin-Potassium Clavulanate Combination; Cyclosporine; Female; Humans; Immunologic Factors; Male; Middle Aged; Remission Induction; Stevens-Johnson Syndrome

Recent investigations suggest genetic susceptibility of allopurinol-induced severe cutaneous adverse reactions (SCARs). However, the strength of association was variable according to phenotypes and ethnic backgrounds. To explore genetic markers for allopurinol-induced SCARs in Koreans, we genotyped human leukocyte antigen (HLA) class I alleles of 25 cases of allopurinol-induced SCARs (20 cases of drug-induced hypersensitivity syndrome and five cases of Stevens-Johnson syndrome/toxic epidermal necrolysis) and 57 patients tolerant to allopurinol. Frequencies of B*5801 [92.0 vs. 10.5%, P(c)=2.45×10(-11), odds ratio (OR)=97.8], Cw*0302 (92.0 vs. 12.3%, P(c)=9.39×10(-11), OR=82.1), and A*3303 (88.0 vs. 26.3%, P(c)=3.31×10(-6), OR=20.5) were significantly higher in SCARs compared with tolerant controls. In contrast, A*0201 was not found in SCARs patients despite relatively high frequency in tolerant controls (29.8%). We found strong positive association of HLA-B*5801 and negative association of HLA-A*0201 with the development of allopurinol-induced SCARs in the Korean population.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Asian People; Female; Genes, MHC Class I; Genome-Wide Association Study; Gout Suppressants; Humans; Male; Middle Aged; Stevens-Johnson Syndrome

Although allopurinol is a very effective urate-lowering drug for complicated hyperuricemia, in some patients, it can induce severe cutaneous adverse reactions (SCARs). Recent investigations suggest that HLA-B*5801 is a very strong marker for allopurinol-induced SCARs, especially in the population with a high frequency of HLA-B*5801. Korea is one of the countries with a high frequency of HLA-B*5801 which is the only subtype of HLA-B58 in the Korean population. Objective. This study was conducted to find out the incidence of allopurinol-induced hypersensitivity on patients with chronic renal insufficiency (CRI) according to HLA-B58 and the clinical implications of HLA-B58 as a risk marker for the development of allopurinol-induced hypersensitivity.. We retrospectively reviewed the medical records of patients with CRI who took allopurinol and carried out serologic human leukocyte antigen (HLA) typing for kidney transplantation between January 2003 and May 2010.. Among a total of 448 patients with CRI, 16 (3.6%) patients experienced allopurinol hypersensitivity. Nine of these patients (2.0%) were diagnosed with SCARs (two Stevens-Johnson syndrome and seven allopurinol hypersensitivity syndrome) and seven patients (1.6%) had simple maculopapular rashes. The HLA-B58 allele was present in all patients with allopurinol-induced SCARs, while the frequency of HLA-B58 was only 9.5% in allopurinol-tolerant patients (P < 0.05). The incidence of allopurinol-induced SCARs in CRI shows a wide disparity according to HLA-B58 [18% in HLA-B58 (+) versus 0% in HLA-B58 (-)]. Among patients without HLA-B58, most (98.2%) of the CRI patients were tolerant to allopurinol and only 1.8% experienced simple rashes after taking allopurinol.. In this study, the incidence of allopurinol-induced SCARs was considerably high in CRI patients with HLA-B58. This finding indicates that the presence of HLA-B58 may increase the risk of allopurinol-induced SCARs. Screening tests for HLA-B58 in CRI patients will be clinically helpful in preventing severe allopurinol hypersensitivity reactions.

Topics: Adolescent; Adult; Allopurinol; Biomarkers; Drug Hypersensitivity; Female; Follow-Up Studies; Gout Suppressants; HLA-B Antigens; Humans; Male; Middle Aged; Prognosis; Renal Insufficiency, Chronic; Republic of Korea; Retrospective Studies; Stevens-Johnson Syndrome; Young Adult

Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare but extremely severe cutaneous adverse drug reactions in which drug-specific associations with HLA-B alleles were described.. To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients.. We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel.. Six SNPs located in the HLA region showed significant evidence for association (OR range: 1.53-1.74). The haplotype formed by their risk allele was more associated with the disease than any of the single SNPs and was even much stronger in patients exposed to allopurinol (OR(allopurinol) = 7.77, 95%CI = [4.66; 12.98]). The associated haplotype is in linkage disequilibrium with the HLA-B*5801 allele known to be associated with allopurinol induced SJS/TEN in Asian populations.. The involvement of genetic variants located in the HLA region in SJS/TEN is confirmed in European samples, but no other locus reaches genome-wide statistical significance in this sample that is also the largest one collected so far. If some loci outside HLA play a role in SJS/TEN, their effect is thus likely to be very small.

Topics: Allopurinol; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions; Europe; Female; Gene Frequency; Genome-Wide Association Study; HLA-B Antigens; Humans; Male; Odds Ratio; Stevens-Johnson Syndrome; White People

Use of pharmacogenetics to inform treatment decisions remains a priority for clinicians, patients and public health agencies. We previously developed a framework for systematically assessing whether pharmacogenetic test information would likely bring value to clinical decision-making and enjoy practical uptake. We applied this tool to allopurinol to determine potential usefulness of HLA genetic information in assessing risk for allopurinol-induced severe cutaneous adverse reactions. We quantified allopurinol use data and the magnitude of adverse event signals using US FDA databases, reviewed reported cases of allopurinol-associated severe cutaneous adverse reactions to assess whether clinical subtypes of patients could be identified, performed pooled analyses of associations between HLA variation and allopurinol-induced severe cutaneous adverse reactions and described considerations in clinical implementation of allopurinol pharmacogenetics.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Child; Erythema Multiforme; Female; Genetic Association Studies; Genetic Testing; Genetic Variation; Gout; Gout Suppressants; HLA Antigens; Humans; Hyperuricemia; Male; Middle Aged; Pharmacogenetics; Risk Assessment; Skin Diseases; Stevens-Johnson Syndrome

With an incidence of 1.5-1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug-induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis.. This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case.. After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died. conclusions: Immediate beginning of therapy is essential for a successful treatment of toxic epidermal necrolysis. Besides systemic therapy with corticosteroids, certain basic measures such as isolation of patients at adequate room temperature to prevent hypothermia, strict control of circulation, temperature and laboratory parameters, daily smears of skin and mucous membranes and a diet rich in calories due to the catabolic metabolic status are very important for successful outcome.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anticonvulsants; Bacterial Infections; Ciprofloxacin; Drug Combinations; Female; Folic Acid; Gout Suppressants; Humans; Hydroxocobalamin; Lidocaine; Male; Middle Aged; Phenytoin; Prednisone; Pyridoxine; Stevens-Johnson Syndrome; Superinfection; Survival Rate; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Alleles; Allopurinol; Anticonvulsants; Asian People; Carbamazepine; China; Cyclosporine; Drug Hypersensitivity; Genetic Predisposition to Disease; Genetic Testing; Gout Suppressants; HLA-B Antigens; Humans; Immunization, Passive; Immunosuppressive Agents; Keratoconjunctivitis; Male; Stevens-Johnson Syndrome; Urethritis

Toxic epidermal necrolysis (TEN) is characterized by fever, scalded appearance of the skin, and epidermolysis associated to blister formation and exfoliation, and it is caused by hypersensitivity reaction to a drug. The authors report two cases of death as a result of TEN; both referred to old aged women treated with a polytherapy including allopurinol. Both patients displayed erythematous skin lesions similar to scald burns and epidermolysis at the face, chest, and abdomen and died shortly after hospitalization. Autopsy findings and histological examinations revealed epidermal necrolysis and confirmed the clinical diagnosis. A strict time-correlation between allopurinol administration and symptoms was evidenced. Because of its iatrogenic origin, TEN often arises suspicions of medical liability; however, because of its unpredictable nature, the occurrence of this syndrome cannot be ascribed to the medical staff whose main task is the rapid diagnosis and the correct management.

Topics: Aged; Allopurinol; Fatal Outcome; Female; Gout Suppressants; Humans; Multiple Organ Failure; Stevens-Johnson Syndrome

The present report describes the case of a 67-year-old patient who developed an allopurinol-induced hypersensitivity syndrome (AHS) with toxic epidermal necrolysis and subsequently died of septic multiorgan failure. Considering the increasing prescription rate of allopurinol, the present case report intends to demonstrate the underestimated threat of AHS.

Topics: Aged; Allopurinol; Diagnosis, Differential; Drug Hypersensitivity; Fatal Outcome; Gout; Humans; Kidney Failure, Chronic; Male; Multiple Organ Failure; Recurrence; Stevens-Johnson Syndrome

Topics: Allopurinol; Angina Pectoris; Humans; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe adverse cutaneous reactions to drugs. We report here the first case of severe pneumonia caused by an unusual combined infection with Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus fumigatus in a 63-year-old female patient with allopurinol-induced SJS/TEN overlap syndrome. Following treatment with high-dose systemic corticosteroids and intravenous immunoglobulin for SJS/TEN, her mucocutaneous lesions improved and she was due to be discharged. However, 15 days after cessation of corticosteroids, she developed pneumonia. Broncho-alveolar lavage revealed that the cause of infection was Pneumocystis carinii (jiroveci), parainfluenza virus type 3, cytomegalovirus and Aspergillus. These findings indicate that patients with SJS/TEN, particularly those treated with systemic corticosteroids, may be susceptible to infection with combinations of pathological agents resulting from damage to the bronchial epithelia.

Topics: Adrenal Cortex Hormones; Allopurinol; Anti-Infective Agents; Aspergillus fumigatus; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Humans; Immunoglobulins, Intravenous; Lung Diseases, Interstitial; Middle Aged; Parainfluenza Virus 3, Human; Pneumocystis carinii; Pneumonia, Pneumocystis; Pulmonary Aspergillosis; Radiography; Respiration, Artificial; Respirovirus Infections; Severity of Illness Index; Stevens-Johnson Syndrome; Treatment Outcome

Topics: Adolescent; Allopurinol; Drug Eruptions; Enzyme Inhibitors; Humans; Hypertension; Stevens-Johnson Syndrome; Uric Acid; Xanthine Oxidase

1) Lyell syndrome is characterised by toxic epidermal necrolysis in which epidermal detachment affects more than 30% of the body surface area. Stevens-Johnson syndrome is a minor form affecting less than 10% of the body surface area; 2) Patients who present with these cutaneous symptoms, along with throat pain, red eyes and a damaged or detached oral mucosa must be hospitalised immediately; 3) Lyell syndrome is exclusively caused by drugs while Stevens-Johnson syndrome can also be caused by bacteria and viruses. Rapid withdrawal of the drug improves prognosis.

Topics: Allopurinol; Anti-Infective Agents; Anti-Inflammatory Agents; Anticonvulsants; Erythema Multiforme; Humans; Stevens-Johnson Syndrome; Sulfonamides; Trimethoprim, Sulfamethoxazole Drug Combination

We report a case of Stevens-Johnson syndrome (SJS) caused by imatinib combined with allopurinol. An 82-year-old female patient who had a diagnosis of chronic myeloid leukemia was initially treated with imatinib 200 mg/day and allopurinol 100 mg for 42 days, and had a satisfactory hematological response. The dose of imatinib was adjusted to 400 mg/day for 14 days. After two weeks, she developed SJS and was transferred to the intensive care unit for further treatment because her general condition had deteriorated. The aggravated cutaneous adverse reaction improved approximately 7 days after withdrawal of imatinib. Oral steroids with antihistamines were prescribed for the treatment of severe cutaneous reaction. The symptoms of SJS completely improved 1 month after discontinuation of imatinib and allopurinol. We concluded that imatinib alone may cause serious cutaneous reaction, but the combination of 2 high-risk drugs may increase the likelihood of exposed patients developing SJS. Physicians should be aware of the possibility of SJS caused by imatinib and allopurinol prescribed simultaneously.

Topics: Aged, 80 and over; Allopurinol; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Chronic Disease; Female; Humans; Imatinib Mesylate; Kidney Failure, Chronic; Leukemia, Myeloid; Piperazines; Pyrimidines; Stevens-Johnson Syndrome

Topics: Allopurinol; Antitubercular Agents; Child; Female; Gout Suppressants; HLA Antigens; Humans; Risk Factors; Stevens-Johnson Syndrome; Tuberculosis

Allopurinol, a uric acid lowering drug commonly used for hyperuricemia and gouty arthritis, has been reported as a common cause of severe cutaneous adverse drug reactions (SCAR) including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). A strong association between allopurinol-induced SCAR and HLA-B*5801 was observed in a Han Chinese population with high frequency of this allele, whereas only a moderate association was observed in populations with low frequency (i.e. European and Japanese). This study investigated the relationship between SJS/TEN and HLA-B*5801 in a Thai population that has a high allelic frequency of this allele.. Twenty-seven allopurinol-induced SJS/TEN and 54 allopurinol-tolerant patients were enrolled in the study. The presence of HLA-B*5801 and HLA-B genotypes in these patients were analyzed using a PG5801 DNA detection kit and sequence-based typing, respectively.. All of the 27 (100%) allopurinol-induced SJS/TEN patients who were examined carried HLA-B*5801 whereas only seven (12.96%) of the control patients had this allele. The risk of allopurinol-induced SJS/TEN was significantly greater in patients with HLA-B*5801 when compared with those who did not carry this allele, with an odds ratio of 348.3 (95% confidence interval=19.2-6336.9, P = 1.6 x10). The sensitivity and specificity of the HLA-B*5801 allele for prediction of allopurinol-induced SJS/TEN were 100 and 87%, respectively. By assuming a 0.2% prevalence rate, the positive predictive value and the negative predictive value of the HLA-B*5801 allele was 1.52 and 100%, respectively.. A strong association of allopurinol-induced SJS/TEN with the HLA-B*5801 allele was observed in a Thai population. The results suggest that HLA-B*5801 is a valid genetic marker for screening Thai individuals who may be at risk for allopurinol-induced life-threatening SJS and TEN.

Topics: Adult; Aged; Aged, 80 and over; Allopurinol; Case-Control Studies; Cross-Sectional Studies; Female; Gene Frequency; Genetic Markers; Genotype; Gout Suppressants; HLA-B Antigens; Humans; Male; Middle Aged; Stevens-Johnson Syndrome; Thailand

Topics: Adverse Drug Reaction Reporting Systems; Allopurinol; Gout Suppressants; Humans; Stevens-Johnson Syndrome

Topics: Alleles; Allopurinol; Anticonvulsants; Asian People; Carbamazepine; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gout Suppressants; HLA-B Antigens; Humans; Japan; Stevens-Johnson Syndrome; Syndrome; Virus Activation

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 and HLA-B*5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B*1502 and HLA-B*5801 in Japanese SJS/TEN patients.. HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan.. There were no HLA-B*1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B*5801 carriers, which included four allopurinol-related SJS/TEN patients.. While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Allopurinol; Anticonvulsants; Asian People; Child; Female; Genotype; HLA-B Antigens; Humans; Japan; Male; Middle Aged; Severity of Illness Index; Stevens-Johnson Syndrome; Young Adult

Hyperuricemia is present in about 5% of the population, and allopurinol is frequently used to treat it. The use of this drug can be associated with a number of side effects, indicating allergic reactions, such as skin rash, reversible after its withdrawal. In some cases more severe hypersensitivity reactions may be seen, such as erythema multiforme exudativum, or Steven-Johnson Syndrome (SJS). Reversible clinical hepatotoxicity, as well as acute renal failure, may also develop after allopurinol therapy. We describe here the case of a 74-year-old woman with chronic renal failure who was admitted to hospital after 1 week of sore throat and fever, presenting mucous membrane lesions, widespread blistering of the skin, evolving to flaccid vesicles and bullae, and extensive epidermal detachment associated with acute renal failure and cholestatic jaundice. A diagnosis of allopurinol-induced toxic epidermal necrolysis (TEN) was established. Allopurinol was discontinued, and intensive care management was required: the patient was successfully treated by using intravenous immunoglobulin (IVIg), standard hemodialysis, and albumin dialysis (Molecular Adsorbents Recirculating System - MARS, Teraklin AG, Rostock, Germany). Allopurinol-induced TEN is extremely rare, however, the survival rate is extremely low. Clinicians should be aware of this potentially severe adverse effect. This report emphasizes the importance of an aggressive pharmacological and dialysis treatment in the case of TEN.

Topics: Acute Kidney Injury; Aged; Allopurinol; Biopsy; Female; Follow-Up Studies; Gout Suppressants; Humans; Hyperuricemia; Liver Failure, Acute; Risk Factors; Skin; Stevens-Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions.. We sought to update knowledge on the causes of SJS or TEN with a focus on the rate of allopurinol-associated cases and to identify risk factors for allopurinol-associated SJS or TEN.. We conducted a multinational case-control study.. In all, 379 patients with severe cutaneous adverse reactions validated as SJS or TEN and 1505 matched hospitalized control subjects were enrolled. Allopurinol was the drug most frequently associated with SJS or TEN, with 66 exposed patients (17.4%) and 28 exposed control subjects (1.9%) (adjusted odds ratio = 18, 95% confidence interval: 11-32). Allopurinol use was greater than in a previous case-control European study. Daily doses equal to or greater than 200 mg were associated with a higher risk (adjusted odds ratio = 36, 95% confidence interval: 17-76) than lower doses (adjusted odds ratio = 3.0, 95% confidence interval: 1.1-8.4). The risk was restricted to short-term use (

Topics: Adult; Aged; Allopurinol; Case-Control Studies; Demography; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Europe; Female; Gout Suppressants; Humans; Incidence; Israel; Male; Middle Aged; Population Surveillance; Stevens-Johnson Syndrome

A 51-year-old Caucasian woman developed severe drug-induced toxic epidermal necrolysis (TEN) due to allopurinol. The withdrawal of the culprit drug was unfortunately delayed, and dramatic retardation of reepithelialization was observed. At that stage of disease evolution, an inflammatory cell infiltrate was present in the dermis. Coverage of eroded lesions by frozen cultured keratinocyte allografts failed to hasten reepithelialization compared to ungrafted sites. This unusual protracted TEN evolution was followed by the development of extensive hypertrophic and keloid scars. Several biopsies were taken over 6 months. The histologic presentation of the grafted and ungrafted eroded scar tissues looked similar. Both the number and size of the Factor XIIIa-positive dermal dendrocytes, as well as the number of alpha-actin-positive myofibroblasts showed a marked increase between weeks 2 and 12 after grafting. They were reduced after 6 months when the scarring process was stabilized. alpha1 [IV] collagen was never expressed over the eroded scars. Similar to burn patients, delayed reepithelialization might be a risk factor for abnormal scarring in TEN. Cultured keratinocyte allograft apparently offered no improvement in reepithelialization and did not prevent abnormal scarring in this TEN patient.

Topics: Allopurinol; Antimetabolites; Cicatrix, Hypertrophic; Female; Humans; Keratinocytes; Lupus Erythematosus, Systemic; Middle Aged; Skin Transplantation; Stevens-Johnson Syndrome; Transplantation, Homologous

Topics: Aged; Aged, 80 and over; Alleles; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Follow-Up Studies; Gout; HLA-B Antigens; Humans; Male; Middle Aged; Risk Assessment; Sampling Studies; Stevens-Johnson Syndrome; Syndrome

The purpose of this case-control study is to estimate the risks of Stevens-Johnson syndrome or toxic epidermal necrolysis associated with the use of specific drugs. The suspected cases were identified from the computerized hospital discharge file. We calculated crude relative risks and adjusted them for confounding by multivariate analysis. The analysis was based on 35 cases and 105 controls. This study showed that the use of carbamazepine, phenytoin and allopurinol is most associated with the risks in the oriental population.

Topics: Adult; Allopurinol; Analgesics, Non-Narcotic; Anticonvulsants; Antimetabolites; Carbamazepine; Case-Control Studies; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Phenytoin; Risk Assessment; Stevens-Johnson Syndrome; Taiwan

Topics: Aged; Allopurinol; Epidermis; Fatal Outcome; Gout Suppressants; Humans; Kidney Failure, Chronic; Male; Necrosis; Stevens-Johnson Syndrome; Uric Acid

To report a case of acute myocardial infarction (MI) experienced by a patient receiving intravenous immune globulin (IVIG) and review other published cases of MI associated with IVIG.. An 81-year-old Vietnamese man was prescribed IVIG for treatment of toxic epidermal necrolysis secondary to allopurinol. Thirty minutes following the start of the IVIG infusion, the patient developed crushing retrosternal chest pain and shortness of breath. The pain improved upon discontinuation of IVIG infusion but recurred when IVIG was restarted. The troponin level reached 140 microg/L, and a persantine sestamibi stress test (MIBI) indicated anterolateral ischemia. The patient was diagnos ed with non-ST-elevation MI. An objective causality assessment using the Naranjo probability scale revealed a probable association between this adverse reaction and IVIG treatment.. Although an association between IVIG administration and MI has not been demonstrated in clinical trials, accumulating clinical experience suggests that a relationship between IVIG and myocardial ischemia exists. Twenty published case reports were identified. Risk of acute MI seems to be increased with use of high-dose IVIG and in older individuals, especially those with at least one cardiovascular risk factor, such as ischemic heart disease or hypertension.. Case reports suggest a causal relationship between the use of IVIG and MI and other thrombotic events. While cardiovascular disease is not considered an absolute contraindication to therapy, expanding indications and subsequent use of IVIG merit that clinicians be aware of patient characteristics that may increase the risk for adverse reactions and recognize early signs of infarction.

Topics: Aged; Aged, 80 and over; Allopurinol; Chest Pain; Gout Suppressants; Humans; Immunoglobulins, Intravenous; Male; Myocardial Infarction; Radionuclide Imaging; Risk Factors; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) is a rare life-threatening disease characterized by blister formation and erosion over the entire body surface resulting from extensive keratinocyte death. We reported a case of TEN that developed in a 68-year-old man with hepatitis C virus liver cirrhosis three weeks after treatment with allopurinol. Exanthema developed as multiple target-like lesions, and erythroderma within five days without forming visible erosive lesions or obvious mucous membrane involvement. Reactivation of human herpes virus-6 or other herpes virus was not detected by polymerase chain reaction or serologic studies, and drug-induced hypersensitivity syndrome was ruled out. The finding of panepidermal necrosis on histopathological examination led to a diagnosis of TEN. Exanthema, fever and renal dysfunction responded to oral prednisolone, but the patient died of liver failure. Cases of TEN with histopathologically proven panepidermal necrosis without apparent blisters or erosions have rarely been reported because they do not fulfill the previously proposed diagnostic criteria for TEN. This finding, the discrepancy between the clinical and the histopathological manifestations, should not be overlooked in a case suspicious of TEN, and the importance of the histopathological examination should be emphasized in the differential diagnosis of TEN.

Topics: Aged; Allopurinol; Diagnosis, Differential; Gout Suppressants; Humans; Immunohistochemistry; Male; Severity of Illness Index; Stevens-Johnson Syndrome

Minor hypersensitivity reactions to allopurinol presenting as skin rash occur in approximately 2% of patients. A more severe, albeit rare, hypersensitivity reaction with fever, eosinophilia, dermatitis, renal failure, vasculitis and hepatic dysfunction carries a mortality of up to 20%. The incidence of this severe reaction can probably be reduced by adjusting the dose of allopurinol in patients with impaired renal function. Azathioprine and mercaptopurine are metabolised by xanthine oxidase, the enzyme that is inhibited by allopurinol. Concomitant administration can result in life-threatening neutropenia unless the dose of allopurinol is reduced by approximately 75%. The uricosuric agent benzbromarone has recently been withdrawn from the market because of several cases of fulminant hepatic failure with subsequent death of the patient or liver transplantation.

Topics: Allopurinol; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Drug Eruptions; Drug Hypersensitivity; Drug Interactions; Gout; Humans; Stevens-Johnson Syndrome; Uricosuric Agents; Vasculitis, Leukocytoclastic, Cutaneous

Stevens-Johnson syndrome (SJS) is an extreme, systemic allergic reaction with potentially morbid ocular complications. The main ocular complications include severe dry eyes, corneal scarring, symblepharon, and keratopathy.. Stevens-Johnson syndrome developed in a 69-year old man as a result of a hypersensitivity reaction to the drug allopurinol three years before his referral to our clinic. He had been treated, but was left with corneal scarring, hyperemia, and sore, chronic dry eyes, which necessitated continuous lubrication. The patient was fit with RGP sealed scleral contact lenses of high oxygen permeability, which produced a remarkable improvement of his signs and symptoms and allowed him to completely cease the use of artificial tears.. Stevens-Johnson syndrome is a serious systemic condition in which the foremost ocular complication is severe dry eyes. This report shows that it can be managed successfully with RGP sealed scleral lenses of high permeability.

Topics: Aged; Allopurinol; Contact Lenses; Drug Hypersensitivity; Dry Eye Syndromes; Enzyme Inhibitors; Gout Suppressants; Humans; Male; Prosthesis Fitting; Stevens-Johnson Syndrome

A 86-year-old woman with chronic renal failure was treated with allopurinol for asymptomatic hyperuricemia. After one week she developed quickly progressive exanthema, bullous eruptions, epidermolysis, fever of 39.1; C and dyspnoea at rest.. The diagnosis of an allopurinol-induced hypersensitivity syndrome with toxic epidermal necrolysis was made from the history, the typical clinical picture and a skin biopsy. Initial therapy starts with steroids. Because of a lack of clinical improvement therapy was changed to immunoglobulins. In addition, systemic analgesia and cardiocirculatory supportive therapy were given. Because of increasing somnolence and severe pain intubation and controlled artificial ventilation were initiated. Despite intensive therapy progressive multi- organ failure developed and the patient died 3 weeks after start of symptoms.. The life threatening hypersensitivity syndrome with fever, eosinophilia, hepatitis, renal failure and skin eruptions as severe as epidermal necrolysis is the most dangerous complication of therapy with allopurinol. The trigger seems to be oxipurinol, the main metabolite of allopurinol, which particularly accumulates in patients with renal failure and concomitant therapy with thiazides. There is no specific treatment of the disease. The use of allopurinol in patients with asymptomatic hyperuricaemia is not indicated in most cases. Dose adjustment according to the clearance of creatinine is mandatory.

Topics: Aged; Aged, 80 and over; Allopurinol; Antimetabolites; Drug Hypersensitivity; Fatal Outcome; Female; Humans; Stevens-Johnson Syndrome; Uric Acid

Topics: Aged; Allopurinol; Emergencies; Enzyme Inhibitors; Female; Humans; Stevens-Johnson Syndrome

Drug-related T-cell activity in cutaneous drug reactions may be assessed by in vitro cytokine release tests. The diagnostic role of in vitro drug-induced interferon-gamma (IFN-gamma) release was evaluated in a patient with Stevens-Johnson syndrome.. Stevens-Johnson syndrome was diagnosed in a 58-year-old man, treated with colchicine (1 mg daily for 39 days) and allopurinol (300 mg daily for 13 days). Based on a clinical-epidemiologic score, allopurinol was more likely to be the causative agent. In vitro drug-induced IFN-gamma release test was conducted on this patient and on two controls, using an enzyme-linked immunoabsorbent assay (ELISA) technique. Increased IFN-gamma release was observed following an in vitro challenge of the patient's lymphocytes with allopurinol, but not following in vitro challenge with colchicine. An in vitro challenge with allopurinol in two control patients, treated with allopurinol without adverse drug reactions, did not induce a significant increase in IFN-gamma release.. The role of allopurinol as the drug responsible for the induction of Stevens-Johnson syndrome in our patient was confirmed by in vitro allopurinol-induced IFN-gamma release, which may indicate a drug-specific immune response.

Topics: Allopurinol; Colchicine; Gout; Gout Suppressants; Humans; Interferon-gamma; Lymphocytes; Male; Middle Aged; Stevens-Johnson Syndrome

A 76 year-old otherwise healthy man was treated with allopurinol after a single episode of gout. He developed allopurinol hypersensitivity syndrome with epidermal necrolysis, dermal vasculitis, impaired renal function, fever, gastrointestinal bleeding, and possibly pulmonary vasculitis. The outcome was lethal. Controlling allopurinol therapy according to renal function is emphasized.

Topics: Aged; Allopurinol; Drug Hypersensitivity; Fatal Outcome; Gout; Gout Suppressants; Humans; Kidney; Male; Stevens-Johnson Syndrome; Vasculitis, Leukocytoclastic, Cutaneous

Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare, life-threatening, drug-induced cutaneous reactions. We conducted a case-control study to quantify the risks associated with the use of specific drugs.. Data were obtained through surveillance networks in France, Germany, Italy, and Portugal. Drug use before the onset of disease was compared in 245 people who were hospitalized because of toxic epidermal necrolysis or Stevens-Johnson syndrome and 1147 patients hospitalized for other reasons (controls). Crude relative risks were calculated and adjusted for confounding by multivariate methods when numbers were large enough.. Among drugs usually used for short periods, the risks were increased for trimethoprim-sulfamethoxazole and other sulfonamide antibiotics (crude relative risk, 172; 95 percent confidence interval, 75 to 396), chlormezanone (crude relative risk, 62; 21 to 188), aminopenicillins (multivariate relative risk, 6.7; 2.5 to 18), quinolones (multivariate relative risk, 10; 2.6 to 38), and cephalosporins (multivariate relative risk, 14; 3.2 to 59). For acetaminophen, the multivariate relative risk was 0.6 (95 percent confidence interval, 0.2 to 1.3) in France but 9.3 (3.9 to 22) in the other countries. Among drugs usually used for months or years, the increased risk was confined largely to the first two months of treatment, when crude relative risks were as follows: carbamazepine, 90 (95 percent confidence interval, 19 to infinity); phenobarbital, 45 (19 to 108); phenytoin, 53 (11 to infinity); valproic acid, 25 (4.3 to infinity); oxicam nonsteroidal antiinflammatory drugs (NSAIDs), 72 (25 to 209); allopurinol, 52 (16 to 167); and corticosteroids, 54 (23 to 124). For many drugs, including thiazide diuretics and oral hypoglycemic agents, there was no significant increase in risk.. The use of antibacterial sulfonamides, anticonvulsant agents, oxicam NSAIDs, allopurinol, chlormezanone, and corticosteroids is associated with large increases in the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. But for none of the drugs does the excess risk exceed five cases per million users per week.

Topics: Adrenal Cortex Hormones; Allopurinol; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Case-Control Studies; Chlormezanone; Humans; Multivariate Analysis; Risk; Stevens-Johnson Syndrome; Sulfonamides

A woman with severe cicatricial conjunctival changes secondary to allopurinol-induced Stevens-Johnson syndrome developed bilateral palpebral conjunctival cysts. Pathologic examination of these lesions revealed respiratory-like pseudostratified ciliated epithelium in the walls of several cysts of one eye. To our knowledge, this is the first report of this phenomenon.

Topics: Aged; Allopurinol; Cilia; Conjunctival Diseases; Cysts; Epithelium; Female; Humans; Stevens-Johnson Syndrome

Toxic epidermal necrolysis (TEN) or Lyell's syndrome is a rare fulminating skin disease notorious for its rapidly progressive course and high mortality rate. TEN is characterized by the sudden onset of epithelial necrosis of skin with frequently associated involvement of the gastrointestinal, genitourinary tract and bronchopulmonary linings. We describe the clinical course of five patients with severe drug-induced TEN, treated with PE. The suspected drugs were carbamazepine in one patient, paracetamol in one, a combination of paracetamol and mefenamic acid in one, allopurinol in one and ciprofloxacin in one. Three had a skin involvement affecting almost the entire surface of the body. In addition to the skin lesions, mouth, esophagus and lungs were also involved. Steroids proved ineffective. PE was carried out because of the rapid deterioration of the clinical picture. The mean number of PE sessions was 3.22 (range 1-5). Complete remission of the syndrome was achieved in four patients. One patient died due to septic shock. As so far there is no treatment of proven value for this condition, controlled trials should be set up in order to assess the value of PE in TEN.

Topics: Aged; Allopurinol; Amoxicillin; Carbamazepine; Child; Ciprofloxacin; Humans; Male; Mefenamic Acid; Middle Aged; Plasma Exchange; Skin; Stevens-Johnson Syndrome; Tetanus Toxoid

In this article we describe the immunocytochemical and electron microscopic findings in five patients with toxic epidermal necrolysis. They indicate the occurrence of necrotic keratinocytes with nuclear disintegration associated with apposed dendritic cells with the nuclear chromatin configuration of T lymphocytes. These findings, including the presence of blebbing of the keratinocytes and membrane defects associated with cytoplasmic processes from these apposed lymphoid cells, fit known electron microscopic criteria that suggest the involvement of T lymphocyte-mediated cytolysis of drug-altered target keratinocytes in toxic epidermal necrolysis. The effector cell appears to be a dendritic subset, with the phenotypic characteristics (CD3+, CD4-, CD8+, CD2+, DR+) of a T cell subset. There is some evidence that tumor necrosis factor alpha, secreted by activated macrophages, may play a role in necrolysis of the epidermis. The dramatic response of our patients to cyclophosphamide, which is known to inhibit cell-mediated cytotoxicity by inhibiting both the recognition and lethal hit stages, together with the rapid regrowth of the epidermis within 4 days to a week in patients who received adequate dosage of the drug, supports the preceding concepts.

Topics: Adult; Aged; Allopurinol; Ampicillin; Basement Membrane; Cell Membrane; Chlorpropamide; Cyclophosphamide; Drug Therapy, Combination; Epidermis; Humans; Immunohistochemistry; Infusions, Intravenous; Keratinocytes; Male; Microscopy, Electron; Middle Aged; Phenytoin; Stevens-Johnson Syndrome; T-Lymphocyte Subsets

To evaluate the usefulness of the case report literature concerning toxic epidermal necrolysis, we surveyed English-language reports published from January 1966 to April 1987, using epidermal necrolysis as a key word in the MEDLINE database. Of the 345 articles identified, 80 definitely or possibly contained individual case reports of at least 100 words; 59 of these 82 (72%) were available and reviewed. These 59 reports included a total of 73 separate cases of toxic epidermal necrolysis possibly related to drugs, which represents less than 5% of the case of toxic epidermal necrolysis that occurred in this period. In 62% of these 73 cases the apparent purpose of the report was to show an association between a given drug and the development of toxic epidermal necrolysis. The drugs most frequently associated with toxic epidermal necrolysis are allopurinol, the nonsteroidal anti-inflammatory agents, phenytoin, and the sulfonamide antibiotics. Given that only a small proportion of cases of toxic epidermal necrolysis appear in the case report literature, except to present association with drugs not previously reported, the contribution of case reports in providing an estimate of the relative risk of drug-associated toxic epidermal necrolysis is limited. Furthermore, our analysis suggests that the adoption of specific diagnostic criteria for and more uniform reporting of signs, symptoms, and therapy could greatly increase the usefulness of the case report literature. We propose a minimum set of informational and specific diagnostic criteria.

Topics: Adolescent; Adult; Aged; Allopurinol; Child; Child, Preschool; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medical Records; MEDLARS; Middle Aged; Publishing; Stevens-Johnson Syndrome; United States

Topics: Aged; Allopurinol; Female; Humans; Stevens-Johnson Syndrome

Toxic epidermal necrolysis, a serious allergically triggered skin reaction, has a mortality of about 30% largely due to internal diseases. The management involves several specialties. Clinical picture and therapy are described in a case probably induced by allopurinol, with 70% involvement of body surface.

Topics: Aged; Allopurinol; Combined Modality Therapy; Gout; Humans; Male; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Drug Eruptions; Humans; Male; Stevens-Johnson Syndrome; Uremia; Uric Acid

Topics: Adult; Aged; Allopurinol; Female; Humans; Male; Middle Aged; Stevens-Johnson Syndrome; Uric Acid

Topics: Aged; Allopurinol; Female; Humans; Hydrocortisone; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Captopril; Drug Synergism; Humans; Kidney Failure, Chronic; Male; Proline; Stevens-Johnson Syndrome

Topics: Adult; Allopurinol; Burns; Critical Care; Drug Combinations; Emergencies; Female; Humans; Middle Aged; Phenylbutazone; Stevens-Johnson Syndrome; Sulfamethoxazole; Trauma Centers; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acute Kidney Injury; Adult; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Hypersensitivity; Gout; Humans; Male; Respiratory Distress Syndrome; Stevens-Johnson Syndrome

An erythematous eruption with itching developed in an 84-year-old man 4 days after therapy with allopurinol was initiated. The diagnosis of toxic epidermal necrolysis, suspected when separation of the epidermis was noted, was confirmed by skin biopsy. This is the third reported case that can be attributed exclusively to allopurinol and the first patient who did not die.

Topics: Aged; Allopurinol; Humans; Male; Stevens-Johnson Syndrome

Topics: Allopurinol; Diagnosis, Differential; Female; Humans; Middle Aged; Mouth Diseases; Stevens-Johnson Syndrome; Ulcer

The frequency of severe reactions to allopurinol has probably been underestimated. A retrospective study encompassing a five-year period has yielded 20 patients with severe hypersensitivity reactions to allopurinol. Patients with preexisting renal impairment or who were receiving concomitant thiazide diuretics appeared to be especially predisposed. Cutaneous reaction patterns included maculopapular eruptions, exfoliative dermatitis, and toxic epidermal necrolysis. eosinophilia was uncommon. Forty percent of the patients developed hepatic involvement and 45% had renal involvement. Hepatic and renal changes usually were reversible and were not unique to any one cutaneous reaction pattern. Three patients with renal involvement required prolonged administration of systemic steroids. Complications included sepsis, decubitus ulcers, and thromboembolism. Two patients required hyperalimentation. Sequelae included dry eyes, pigmentary disturbances, and keloids. Three patients died as a result of their reaction. It is concluded that allopurinol should be used only in select patients, and the dosage should be modified if renal disease exists.

Topics: Adult; Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Dermatitis, Exfoliative; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kidney Diseases; Male; Middle Aged; Prednisone; Retrospective Studies; Stevens-Johnson Syndrome

Topics: Aged; Allopurinol; Chemical and Drug Induced Liver Injury; Drug Eruptions; Drug Hypersensitivity; Humans; Kidney Diseases; Male; Middle Aged; Prednisone; Stevens-Johnson Syndrome

Five patients developed fever, "toxaemia", severe skin reactions and eosinophilia, three to six weeks after commencing allopurinol therapy. The presenting feature in these patients was an extensive erythema, progressing to an exfoliative dermatitis, sometimes with oral mucous membrane involvement. One patient developed toxic epidermal necrolysis. The clinical course in two patients was complicated by acute renal failure which necessitated dialysis. The clinical and laboratory features support an acute hypersensitivity mechanism in these allopurinol associated reactions, in agreement with previous studies. Patients with chronic renal failure appear particularly prone to severe, potentially fatal reactions. If these patients need allopurinol, a lower dose than would be normally required should be given.

Topics: Acute Kidney Injury; Adult; Allopurinol; Drug Eruptions; Drug Hypersensitivity; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Stevens-Johnson Syndrome

A 54-year-old man was receiving allopurinol therapy to treat hyperuricemia that followed an inferior wall, myocardial infarction. After three weeks of allopurinol therapy, the patient developed signs and symptoms of toxic epidermal necrolysis that included pseudomembranous conjunctivitis with ulcerative lesions on the lids and conjunctiva, and punctate corneal staining with subsequent corneal abrasions. Treatment with topical antibiotics and artificial tears relieved the symptoms somewhat, but punctate staining and dry eyes persisted after 14 months of follow-up. Bilateral corneal ulcers developed and necessitated conjunctival flaps in each eye. Visual acuity in each eye was 20/40.

Topics: Allopurinol; Cellulose; Conjunctiva; Conjunctivitis; Corneal Ulcer; Humans; Lubrication; Male; Middle Aged; Stevens-Johnson Syndrome; Visual Acuity

Topics: Allopurinol; Drug Interactions; Humans; Stevens-Johnson Syndrome

Topics: Allopurinol; Humans; Male; Middle Aged; Staphylococcal Infections; Stevens-Johnson Syndrome

Allopurinol, now established as a standard form of therapy in hyperuricemia and gout, may be associated with life-threatening skin reactions. This study reports the occurrence of toxic epidermal necrolysis TEN) in three patients receiving Allopurinol. The patients receiving allopurinol. The patients had complicated medical illnesses and were receiving various other medications, but the most apparent common denominator was allopurinol ingestion. Two other cases of TEN and five cases of severe hypersensitivity reactions with vasculitis and extensive skin manifestations, secondary to this drug, have been described in the recent literature. Allopurinol has several unique biochemical and metabolic properties that may increase its ability to cause hypersensitivity or toxic skin reactions.

Topics: Aged; Allopurinol; Female; Humans; Male; Middle Aged; Stevens-Johnson Syndrome

Topics: Adult; Aged; Allopurinol; Biopsy; Female; Humans; Male; Middle Aged; Prednisone; Prognosis; Pyrazoles; Silver Nitrate; Skin; Stevens-Johnson Syndrome

Topics: Allopurinol; Analgesics; Chlorothiazide; Colchicine; Drug Eruptions; Humans; Lichen Planus; Photosensitivity Disorders; Probenecid; Quinolines; Stevens-Johnson Syndrome; Sulfinpyrazone

Topics: Aged; Allopurinol; Gout; Humans; Male; Mortality; Stevens-Johnson Syndrome; Urea