Cutaneous adverse drug reactions seen in a tertiary hospital in Johor,Malaysia

Background Adverse drug reactions are most commonly cutaneous in nature. Patterns of cutaneous adverse drug reactions (ADRs) and their causative drugs vary among the different populations previously studied. Objective Our aim is to determine the clinical pattern of drug eruptions and the common drugs implicated, particularly in severe cutaneous ADRs in our population. Materials and Methods This study was done by analyzing the database established for all adverse cutaneous drug reactions seen from January 2001 until December 2008. Results A total of 281 cutaneous ADRs were seen in 280 patients. The most common reaction pattern was maculopapular eruption (111 cases, 39.5%) followed by Stevens‐Johnson Syndrome (SJS: 79 cases, 28.1%), drug reaction with eosinophilia and systemic symptoms (DRESS: 19 cases, 6.8%), toxic epidermal necrolysis (TEN: 16 cases, 5.7 %), urticaria/angioedema (15 cases, 5.3%) and fixed drug eruptions (15 cases, 5.3%). Antibiotics (38.8%) and anticonvulsants (23.8%) accounted for 62.6% of the 281 cutaneous ADRs seen. Allopurinol was implicated in 39 (13.9%), carbamazepine in 29 (10.3%), phenytoin in 27 (9.6%) and cotrimoxazole in 26 (9.3%) cases. Carbamazepine, allopurinol and cotrimoxazole were the three main causative drugs of SJS/TEN accounting for 24.0%, 18.8% and 12.5% respectively of the 96 cases seen whereas DRESS was mainly caused by allopurinol (10 cases, 52.6%) and phenytoin (3 cases, 15.8%). Discussion The reaction patterns and drugs causing cutaneous ADRs in our population are similar to those seen in other countries although we have a much higher proportion of severe cutaneous ADRs probably due to referral bias, different prescribing habit and a higher prevalence of HLA‐B*1502 and HLA‐B*5801 which are genetic markers for carbamazepine‐induced SJS/TEN and allopurinol‐induced SJS/TEN/DRESS respectively. Conclusion The most common reaction pattern seen in our study population was maculopapular eruptions. Antibiotics, anticonvulsants and NSAIDs were the most frequently implicated drug groups. Carbamazepine and allopurinol were the two main causative drugs of severe ADRs in our population.     

HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population

Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A*3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ-induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ-induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P < 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA-B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ-induced lymphocyte proliferation.     

Recent advances in the genetics and immunology of Stevens-Johnson syndrome and toxic epidermal necrosis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are majorly (65-75%) induced by a variety of drugs. SJS/TEN could be recognized as SCARs or drug immune reactions, if the reactions are elicited by drugs. The recent studies suggested that SJS/TEN is a specific immune reaction initiated by the cytotoxic T lymphocytes (CTLs) via human leukocyte antigens (HLAs)-restricted pathway. The patho-mechanism involving HLA-restricted presentation of a drug or its metabolites for T-cell activation is supported by the findings of strong genetic associations with HLA alleles (e.g. HLA-B*15:02 and carbamazepine-SJS/TEN, and HLA-B*58:01 and allopurinol-SJS/TEN). However, the genetic associations of SJS/TEN or drug induced cutaneous immune reactions are complex, which are drug specific and ethnicity specific. The genetic polymorphisms and diversity of HLA alleles may provide different binding affinities for drug antigens to launch the activation of specific CTLs responses, further leading to the unique clinical manifestations in SJS/TEN. Fas-FasL and perforin/granzyme B have been advocated mediating the epidermal necrosis in SJS/TEN. Our recent study showed that granulysin, a cytotoxic protein produced by CTLs or natural killer (NK) cells, is the key mediator for disseminated keratinocyte death in SJS/TEN. From the point of view of a physician, the profounder understanding of the genetic predisposition and patho-mechanism we discover, the better strategies for prevention, clinical management, and therapeutic methods of SJS/TEN we can develop in the near future.     

A multicentre study to determine the value and safety of drug patch tests for the three main classes of severe cutaneous adverse drug reactions

Background Drug patch tests (PTs) can reproduce delayed hypersensitivity to drugs and entail a moderate re‐exposure of patients to offending drugs. Objectives To determine the value of PTs for identifying the responsible drug in severe cutaneous adverse drug reactions (SCARs) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Methods In a multicentre study, PTs were conducted on patients referred for DRESS, AGEP or SJS/TEN within 1 year of their SCAR. All drugs administered in the 2 months prior to and the week following the onset of the SCAR were tested. Results Among the 134 patients included (48 male, 86 female; mean age 51·7 years), positive drug PTs were obtained for 24 different drugs. These included positive tests for 64% (46/72) of patients with DRESS, 58% (26/45) of those with AGEP and 24% (4/17) of those with SJS/TEN, with only one relapse of AGEP. The value of PTs depended on the type of drug and the type of SCAR (e.g. carbamazepine was positive in 11/13 DRESS cases but none of the five SJS/TEN cases). PTs were frequently positive for beta lactams (22 cases), pristinamycin (11 cases) and in DRESS with pump proton inhibitors (five cases), but were usually negative for allopurinol and salazopyrin. Of 18 patients with DRESS, eight had virus reactivation and positive PTs. In DRESS, multiple drug reactivity was frequent (18% of cases), with patients remaining sensitized many years later. Conclusions PTs are useful and safe for identifying agents inducing SCAR.     

A patch testing and cross‐sensitivity study of carbamazepine‐induced severe cutaneous adverse drug reactions

Background The usefulness of the drug patch testing for Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is still controversial. Recent studies have shown that HLA‐B*1502 is strongly associated with CBZ‐SJS/TEN in Chinese and Southeast Asian populations. Objective To evaluate the usefulness of patch tests for patients with carbamazepine (CBZ)‐induced SJS, TEN and drug reaction with eosinophilia and systemic symptoms (DRESS) and the cross‐reactivity in patch tests among the aromatic antiepileptic drugs. Methods We measure the frequency of positive patch test reactions and cross‐sensitivity to structure‐related aromatic anti‐epileptic drugs (AEDs) for patients after SJS/TEN or DRESS episodes caused by CBZ. CBZ and other structure‐related AEDs used for patch testing were prepared in 10% and 30% petrolatum. Secondary measures included the association of HLA‐B*1502 genotype and frequency of possible side effects from the patch tests. Results Positive patch test reactions to 30% CBZ in the CBZ‐SJS/TEN were 62.5% (10/16), and 70% (7/10) in the CBZ‐DRESS. None of the 10 healthy controls displayed a positive reaction to tested agents. Cross‐sensitivity to other aromatic AEDs was observed in both the CBZ‐SJS/TEN and the CBZ‐DRESS. Only the HLA‐B*1502 genotype was present and strongly associated with the CBZ‐SJS/TEN, but not with the CBZ‐DRESS. Conclusion Drug patch testing is a safe and useful method for the identification of CBZ as the culprit drug of SJS/TEN as well as DRESS. Testing of chemically or pharmacologically related AEDs may provide information on cross‐reactivity for these patients.     

Long-term outcome of patients with severe cutaneous adverse reactions

Visceral involvement associated with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is well documented. However, little is known about the long-term outcomes of severe drug eruptions due to a lack of long-term follow-up. Long-term sequelae may arise in patients who survive the acute complications of severe drug reactions. In SJS/TEN, extensive scarring that result from the healing of mucocutaneous ulcerative lesions may interfere with organ function. Severe sequelae include visual impairment and pulmonary obliterative disease that impair patients' quality of life. In DIHS/DRESS, recent observations suggest that fulminant type 1 diabetes mellitus (FT1D) and autoimmune diseases such as autoimmune thyroiditis and lupus erythematosus can occur after a disease-free period of several months to years. Thus, DIHS/DRESS may lead to the development of autoimmune diseases, which may be overlooked. Dermatologists need to be aware of the sequelae that may arise following resolution of severe cutaneous adverse reactions and should be vigilant for manifestations of autoimmune disease during follow-up.     

Differential diagnosis of severe cutaneous drug eruptions

Adverse cutaneous reactions to drugs are frequent, mostly secondary to antibacterials, however, serious adverse cutaneous reactions are infrequent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a spectrum of the same disease. They are the more severe drug eruptions, with a mortality around 30% for TEN. The confusion between erythema multiforme major and SJS means that erythema multiforme major is the main differential diagnosis. Skin disorders involving desquamation, in particular after pustulosis, are also common differential diagnoses. Mechanical or autoimmune blistering are also potential misdiagnoses of TEN/SJS. Hypersensitivity Syndrome (HSS) or Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) is a severe cutaneous drug reaction with often a long duration of eruption and serious other organ involvement. Exfoliative dermatitis, whether caused by psoriasis, dermatitis or lymphoma, can be thought of as a differential diagnosis of DRESS/HSS. Angio-immunoblastic lymphadenopathy, viral eruption and vasculitis are other differential diagnoses of DRESS/HSS. Prompt recognition of a severe drug reaction and withdrawal of the culprit drug is often the most important therapeutic action. Alternatively, a delay in starting a specific treatment for a disease misdiagnosed as a drug eruption could be deleterious.     

Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population

Background Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life‐threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA‐B*1502 and CBZ‐induced TEN/SJS in the Taiwan Han Chinese population. Objectives This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ‐induced TEN/SJS in the multi‐ethnic Malaysian population. Methods A sample of 21 unrelated patients with CBZ‐induced TEN/SJS and 300 race‐matched, healthy controls were genotyped for HLA‐A, ‐B and ‐DR using polymerase chain reaction (PCR). Allele frequencies were compared. Results HLA‐B*1502 was present in 75.0% (12/16) of Malay patients with CBZ‐induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57–62.4; corrected P‐value = 7.87 × 10^?6), which suggests a strong association between HLA and CBZ‐induced TEN/SJS. Additionally, HLA‐B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA‐B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries. Conclusions HLA‐B*1502 is strongly associated with CBZ‐induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ‐induced TEN/SJS is linked with the presence of HLA‐B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.     

Update on pathobiology in Stevens-Johnson syndrome and toxic epidermal necrolysis

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions (SCARs), which are mainly induced by a variety of drugs. Once considered to be unpredictable, significant progress has been achieved in understanding the pathological mechanisms underlying such reactions. Recent studies suggested that SJS/TEN is a specific immune reaction where human leukocyte antigen (HLA) alleles specific for certain drugs in defined populations are involved in the activation of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Upon the activation, various cytotoxic and immunological signals, including but not limited to Fas/Fas ligand, perforin/granzyme B, and granulysin are launched to mediate the disseminated keratinocyte death in SJS/TEN. This review provides an update on the pathobiology of SJS/TEN in both the genomic and immunologic perspectives. The knowledge gained from these cutting-edge studies will form the basis for better prevention and management of SJS/TEN.     

Severe Cutaneous Adverse Reactions: A Single-Center Retrospective Study of 173 Patients in China

BackgroundSevere cutaneous adverse reactions (SCAR) to drugs are a crucial public health issue and the use of systemic corticosteroids in SCAR has been controversial.ObjectiveTo analyze clinical features, causative drugs, treatment, outcomes, and prognostic factors of SCAR in the case-series of 173 patients, and add more information to the debate of using systemic corticosteroids in SCAR management.MethodsA retrospective study of 173 SCAR patients diagnosed with drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) or acute generalized exanthematous pustulosis (AGEP) at a tertiary care institution in China between January 2014 and December 2017 was conducted.ResultsOf 173 patients, allopurinol, carbamazepine, and antibiotics are the most frequently implicated drugs for DRESS (40.4%), SJS/TEN (26.0%), and AGEP (40.0%) respectively. Moreover, there is a strongly negative correlation between early corticosteroids use and the progression (p=0.000) and severity (p=0.01) of skin lesions. However, there is no association between early corticosteroids use and the mortality of SCAR (odds ratio: 1.01, 95% confidence interval: 0.95~1.08). In addition, lymphadenopathy, eosinophilia, and interval from onset to corticosteroids treatment were correlated with SCAR prognosis.ConclusionPrompt short-course systemic corticosteroids use is associated with early-stage skin lesions remission without influencing the disease mortality. Lymphadenopathy and eosinophilia were the independent poor prognostic factors of SCAR.     

内蒙古汉族Stevens-Johnson综合征/中毒性表皮坏死松解症患者致敏药物及HLA基因筛查

【摘要】 目的 总结内蒙古汉族Stevens-Johnson综合征/中毒性表皮坏死松解症（SJS/TEN）患者致敏药物及筛查易感基因。方法 内蒙古医科大学附属医院皮肤科2015—2019年确诊的68例汉族SJS/TEN患者,抽取外周血提取DNA,采用PCR筛查HLA-B*5801、HLA-B*1502、HLA-A*3101等位基因。收集患者的临床资料,参照基因分型,分析致敏药物。结果 68例SJS/TEN患者,男36例,女32例,年龄46.06 ± 19.97（3 ~ 84）岁。检出HLA-B*5801阳性5例,4例为别嘌醇致敏;HLA-B*1502阳性14例,5例为卡马西平、4例为拉莫三嗪致敏,5例致敏/可疑致敏药物为抗菌药物、解热镇痛药等;HLA-A*3101阳性1例,可疑致敏药物为中药活血针剂,成分不清。结论 HLA-B*5801对别嘌醇、HLA-B*1502对卡马西平和拉莫三嗪的预测性良好,建议用药前筛查,而HLA-A*3101在本地区人群阳性率不高。     

Genotype–phenotype association between HLA and carbamazepine-induced hypersensitivity reactions: Strength and clinical correlations

BackgroundIncreasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN).ObjectiveTo carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions.MethodsWe analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects.ResultsCBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc = 5.8 × 10⁻⁴³; odds ratio (OR) (95% CI) = 97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc = 8.3 × 10⁻⁵; OR (95% CI) = 0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc = 2.7 × 10⁻³; OR (95% CI) = 6.86(2.4–19.9), and HLA-B*51:01 (Pc = 0.01; OR (95% CI) = 4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed.ConclusionThis study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions.     

Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: the dilemma of classification

According to contemporary vernacular, when the cutaneous manifestations of drug rash with eosinophilia and systemic signs (DRESS) syndrome are those of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the condition is defined as "DRESS syndrome with severe cutaneous reactions". In this article, we have presented arguments for and against including patients with skin lesions of the SJS/TEN syndromes who also have fever (practically all of the patients) and internal organ involvement (most of the patients) under the definition of DRESS syndrome. After weighing the arguments for and against this alteration of definition, we conclude that it makes more sense for patients with SJS/TEN to be classified as such and not be lumped together under the misleading label of DRESS syndrome.     

Severe cutaneous adverse drug reactions

The clinical manifestations of drug eruptions can range from mild maculopapular exanthema to severe cutaneous adverse drug reactions (SCAR), including drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which are rare but occasionally fatal. Some pathogens may induce skin reactions mimicking SCAR. There are several models to explain the interaction of human leukocyte antigen (HLA), drug and T‐cell receptor (TCR): (i) the “hapten/prohapten” theory; (ii) the “p‐i concept”; (iii) the “altered peptide repertoire”; and (iv) the “altered TCR repertoire”. The checkpoints of molecular mechanisms of SCAR include specific drug antigens interacting with the specific HLA loci (e.g. HLA‐B*15:02 for carbamazepine‐induced SJS/TEN and HLA‐B*58:01 for allopurinol‐induced SCAR), involvement of specific TCR, induction of T‐cell‐mediated responses (e.g. granulysin, Fas ligand, perforin/granzyme B and T‐helper 1/2‐associated cytokines) and cell death mechanism (e.g. miR‐18a‐5p‐induced apoptosis; annexin A1 and formyl peptide receptor 1‐induced necroptosis in keratinocytes). In addition to immune mechanism, metabolism has been found to play a role in the pathogenesis of SCAR, such as recent findings of strong association of CYP2C9*3 with phenytoin‐induced SCAR and impaired renal function with allopurinol SCAR. With a better understanding of the mechanisms, effective therapeutics and prevention for SCAR can be improved.     

The association of HLA B*15:02 allele and Stevens–Johnson syndrome/toxic epidermal necrolysis induced by aromatic anticonvulsant drugs in a South Indian population

Background

The presence of HLA‐B*15:02 allele is considered a risk factor for development of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in patients taking aromatic anticonvulsant drugs like carbamazepine and phenytoin. The genetic association is ethnicity specific. Testing for HLA‐B*15:02 allele is suggested as a prerequisite before starting carbamazepine in certain ethnic groups. There are only a few/no studies from south India on HLA association of SJS/TEN.

Aims

To identify any association between HLA‐B*15:02 allele and SJS/TEN induced by carbamazepine/phenytoin among native population.

Methods (including settings, design, and statistical analysis used)

A case–control study done in a tertiary care center at Kottayam in Kerala state of south India. Cases were 12 native patients who developed SJS/TEN owing to aromatic anticonvulsant drugs (phenytoin – 8; carbamazepine – 4), and controls were 11 persons tolerant to these drugs from unrelated families of the same ethnic group. HLA‐B typing was done by PCR SSP method.

Results

There was only one HLA‐B*15:02 carrier among cases and controls. He/she had SJS/TEN induced by carbamazepine.

Conclusions

Association of HLA‐B*15:02 with phenytoin‐induced SJS/TEN is rare in the population studied. The one limitation of the study was the small sample size.     

Epicutaneous patch testing in drug hypersensitivity syndrome (DRESS)

Background: In some patterns of cutaneous adverse drug reactions, and depending on the culprit drug, patch testing has been helpful in confirming its cause. Its value in Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) has not been established in a large cohort of patients.
Objective: The aim of the present study is to evaluate the safety and usefulness of patch testing in DRESS.
Patients/Methods: Between January 1998 and December 2008, we studied 56 patients with DRESS induced by antiepileptic agents in 33 patients (59%), allopurinol in 19 (34%) and sulfasalazine, cotrimoxazole, tenoxicam, and amoxicillin in 1 patient each (7%).
Results: A positive patch test reaction was observed in 18 patients (32.1%), of which 17 were with antiepileptics and 1 with tenoxicam. In the antiepileptic group, carbamazepine alone was responsible for 13 of 17 positive reactions (76.5%). Patch tests with allopurinol and its metabolite were negative in all cases attributed to this drug.
Conclusions: In this study, patch testing was a safe and useful method in confirming the culprit drug in DRESS induced by antiepileptic drugs, whereas it had no value in DRESS induced by allopurinol. The pathogenesis of DRESS is not yet entirely clarified, but positive patch tests suggest a drug-dependent delayed hypersensitivity mechanism.     

3 Severe cutaneous adverse reactions time latency between beginning of drug use and onset of reaction

Background Toxic epidermal necrolysis (TEN) and Stevens–Johnson syndrome (SJS) are acute life‐threatening severe cutaneous adverse reactions (SCAR) with an unclear pathogenesis mainly caused by drugs. Allopurinol and trimethoprim/sulphamethoxazole (TMS) are both well known to be associated with these conditions. In addition, TMS is known to induce generalized bullous fixed drug eruption (GBFDE), a less severe condition with a very short induction period that is clinically often confused with SJS or TEN. Aim We want to further investigate the risk profile of allopurinol and TMS for inducing SCAR, as the hazard functions of these substances are different. Furthermore, the re‐review of cases using more specific criteria to differentiate between SCAR and GBFDE should allow us to detect misclassification of cases. Methods 984 cases of SJS, SJS/TEN overlap and TEN were ascertained by a population‐based registry between 1990 and 1999. The following analysis is based on a random sample of 115 cases earlier accepted as SJS or TEN, which were exposed to either allopurinol or TMS, and 38 cases excluded in the previous review. An independent expert committee blinded for possible causes re‐reviewed these cases in clinical terms, as the original review process took place over a period of 10 years. In this analysis special emphasis is given to the time latency between beginning of drug use and onset of SCAR. Results Before re‐review 162/984 patients with SCAR reported the use of allopurinol and 131/984 the use of TMS within 2 weeks prior to the onset of the adverse reaction. After the re‐review the percentage of doubtful cases was higher for TMS (28/57) than for allopurinol (30/83). For definite cases of SJS or TEN the range between the lower and upper quartile of the time latency between beginning of drug use and onset of SCAR was 14–34 days for allopurinol, in contrast to 5–15 days for TMS. The time latency for doubtful and excluded cases after the use of TMS was much shorter (2.5 and 2 days, respectively). Conclusions The high numberof doubtful cases after the re‐review reveals the difficulty of applying approved detailed definitions to the variety of clinical patterns of cutaneous adverse reactions. We could confirm a high correlation of time latency between beginning of drug use and onset of SCAR and GBFDE for allopurinol and TMS, which may have an important impact on the risk profile of these and other suspected drugs, as well as on pathogenetic and therapeutic considerations of severe adverse events. When drug exposure occurs outside the relevant interval of time latency for SJS and TEN, other risk factors and/or differential diagnoses such as GBFDE should be considered.     

Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking

Summary Drug reaction with eosinophilia and systemic symptoms (DRESS) describes a severe medication-induced adverse reaction, which has cutaneous, haematological and solid-organ features. It is one of the triad of life-threatening drug hypersensitivity dermatoses, along with acute generalized exanthematous pustulosis (AGEP) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). In this article, we discuss several controversies that surround DRESS, including problems with nomenclature and the lack of consensus in diagnostic criteria.