Maja Mockenhaupt

Risk factors for acute generalized exanthematous pustulosis (AGEP)—results of a multinational case–control study (EuroSCAR)

Backgroundu2002 Acute generalized exanthematous pustulosis (AGEP) is a disease characterized by the rapid occurrence of many sterile, nonfollicular pustules usually arising on an oedematous erythema often accompanied by leucocytosis and fever. It is usually attributed to drugs.

Epidemiology of erythema exsudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990–1992): Structure and results of a population-based registry

The severe skin reactions erythema exsudativum multiforme majus (EEM with mucosal involvement, EEMM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) are difficult to study as they are very rare diseases with an incidence of about two cases per 1 million inhabitants per year. We report on the structure of a registry with the aim of ascertaining all hospitalized cases of EEMM, SJS, and TEN in western Germany and Berlin. The registry is structured as an intensive reporting system, regularly contacting more than 1500 departments including 100% of the burn units (n = 34), departments of pediatrics (n = 241), departments of dermatology (n = 106), and 100% of all internal medicine departments in hospitals with intensive care facilities or with more than 200 beds (n = 1161). With a coverage rate up to 95% based on the number of responding departments between April 1, 1990 and December 31, 1992, from a total of 767 reported cases 353 patients with EEMM, SJS, and TEN were finally included in the registry. Most of these patients were directly reported to the registry; only 2.54% (9 of 353) were primarily registered by the German spontaneous reporting systems. Assuming an average population of 64.5 million for western Germany and Berlin an incidence up to 1.89 per 1 million inhabitants per year could be calculated for SJS and TEN.

The current understanding of Stevens–Johnson syndrome and toxic epidermal necrolysis

Stevens–Johnson syndrome has long been considered to resemble erythema multiforme with mucosal involvement, but is now thought to form a single disease entity with toxic epidermal necrolysis. Although Stevens–Johnson syndrome is less severe, etiology, genetic susceptibility and pathomechanism are the same for Stevens–Johnson syndrome/toxic epidermal necrolysis. The condition is mainly caused by drugs, but also by infections and probably other risk factors not yet identified. Identification of the cause is important for the individual patient and in cases of drug-induced disease withdrawal of the inducing drug(s) has an impact on the patient’s prognosis. If an infectious cause is suspected, adequate anti-infective treatment is needed. Besides this, supportive management is crucial to improve the patient’s state, probably more than specific immunomodulating treatments. Despite all of the therapeutic efforts, mortality is high and increases with disease severity, patients’ age and underlying medical conditions. Survivors may suffer from long-term sequelae such as strictures of mucous membranes including severe eye problems.

Histopathological and epidemiological characteristics of patients with erythema exudativum multiforme major, Stevens-Johnson syndrome and toxic epidermal necrolysis

Summary The clinical and histopathological classification of erythema exudativum multiforme major (EEMM), Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are difficult, due to the lack of clear‐cut criteria. Based on a new clinical classification, 149 of 219 (68%) histopathological specimens, from a total of 534 patients with EEMM. SJS and TEN, have been reviewed. A comparison was made with the clinical picture, and any past history of infection or drug intake. All patients had been included in the German Registry of Severe Skin Reactions between April 1990 and December 1993. No differences could be found between the biopsies examined and the total number of histopathological specimens, concerning clinical diagnosis, gender and age. Sections from 28 of 149 specimens were not diagnostic or were too old to be properly evaluated. In nine cases, other diagnoses were proposed. One hundred and eleven of the histological slides with the diagnosis of EEMM (n= 16), SJS (n=34) and TEN (n=61), were classified as epidermal type of erythema multiforme. In these 111 slides, necrotic keratinocytes could be found, ranging from individual cells to confluent epidermal necrosis. The epidermo‐dermal junction showed changes ranging from vacuolar alteration up to subepidermal blisters. The dermal infiltrate was superficial and mostly perivascular. It was sparse in SJS and TEN, and more pronounced in EEMM. Oedema in the papillary dermis was evident occasionally in all clinical groups. In 59 of 111 cases (53%), at least one eosinophil was present in the dermis. In 11 of 111 (10%), more than 10 eosinophils per field could be seen. Eosinophils were less common in the patients with the most severe forms of TEN, in whom there was detachment of more than 30% of the skin surface area. No differences in the history for drug intake, or for infection with Mycoplasma pneumoniae, herpes simplex and other organisms, could be detected between patients with or without eosinophils in their skin sections. This dermatopathological study of patients with EEMM. SJS and TEN indicates that the epidermal type of erythema multiforme is the pathological correlate for these diseases.

HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis

HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0–340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2–125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6–192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4–20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4–11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.

The Influence of Lysophosphatidic Acid on the Functions of Human Dendritic Cells

Lysophosphatidic acid (LPA) is a bioactive lipid mediator which is generated by secretory phospholipase A2. In this study, we studied the biological activity of LPA on human dendritic cells (DCs), which are specialized APCs characterized by their ability to migrate into target sites and secondary lymphoid organs to process Ags and activate naive T cells. We show that immature and mature DCs express the mRNA for different LPA receptors such as endothelial differentiation gene (EDG)-2, EDG-4, and EDG-7. In immature DCs, LPA stimulated pertussis toxin-sensitive Ca2+ increase, actin polymerization, and chemotaxis. During the maturation process, DCs lost their ability to respond toward LPA with Ca2+ transients, actin polymerization, and chemotaxis. However, LPA inhibited in a pertussis toxin-insensitive manner the secretion of IL-12 and TNFα as well as enhanced secretion of IL-10 from mature DCs. Moreover, LPA did not affect the endocytic or phagocytic capacities and the surface phenotype of DCs, although it increased the allostimulatory function of mature DC and inhibited their capacity to induce Th1 differentiation. In summary, our study implicates that LPA might regulate the trafficking, cytokine production, and T cell-activating functions of DCs.

Lysophosphatidic Acid Induces Chemotaxis, Oxygen Radical Production, CD11b Up-Regulation, Ca2+ Mobilization, and Actin Reorganization in Human Eosinophils via Pertussis Toxin-Sensitive G Proteins

Lysophosphatidic acid (LPA) is a bioactive lipid mediator, which is generated by secretory type II phospholipase A2 and is thought to play a major role in the pathogenesis of atopic diseases. In this study, the biological activity of LPA on human eosinophils was characterized. We showed by reverse transcription and PCR that human eosinophils express the mRNA of the LPA receptors endothelial differentiation gene (EDG)-2 and EDG-7. Experiments revealed that LPA has chemotactic activity toward eosinophils, stimulates the production of reactive oxygen metabolites, and induces up-regulation of the integrin CD11b. Signal pathway measurements indicated Ca2+-mobilization from intracellular stores and transient actin polymerization upon stimulation with LPA. Cell responses elicited by LPA were inhibited by pertussis toxin indicating that in eosinophils the LPA receptor(s), presumably EDG-2 and/or EDG-7, are coupled to Gi/o proteins. Moreover, LPA-induced activation of eosinophils could be completely blocked by the EDG-2/EDG-7 antagonist diacylglycerol pyrophosphate. In addition, at optimal doses the changes induced by LPA were comparable to those obtained by the other well-characterized chemotaxins. These results indicate that LPA is a strong chemotaxin and activator of eosinophils. These findings point to a novel role of LPA in the pathogenesis of diseases with eosinophilic inflammation such as atopic diseases as chemotaxin as well as activator of proinflammatory effector functions.

Low N‐acetylating capacity in patients with Stevens‐Johnson syndrome and toxic epidermal necrolysis*

Abstract Low constitutive N‐acetylating capacity has been implicated as a predisposing factor for the development of adverse reactions to certain drugs. This prompted us to investigate whether the N‐acetylating capacity of patients with serious cutaneous adverse reactions, i.e., Stevens‐Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) differed from that of healthy control subjects. N‐acctylating activity was measured in hair root cells by preparing a homogenate from freshly extracted hair roots and assessing acetyl‐CoA‐dependent N‐acetylation by RP‐HPLC using 2‐aminofluorene as a substrate. Samples were obtained from hospitalized patients suffering from acute SJS and TEN or from healthy controls. All patients with SJS and TEN were found to have a low N‐acetylating capacity (0.85 nmol/mg/min compared to 2.21 nmol/mg/min in controls, p<0.05). Based on these findings, a low constitutive N‐acetylating capacity may be one of the predisposing factors for the development of serious cutaneous adverse reactions to drugs that require N‐acetylation in these patients.

Evaluation of SCORTEN on a Cohort of Patients With Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Included in the RegiSCAR Study

The purpose of this study was to evaluate the severity-of-illness score called SCORTEN with respect to its predictive ability and by using data obtained in the RegiSCAR study, the most comprehensive European registry of patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). For advanced comparisons, an auxiliary score (AS) was defined using data obtained in a previous study. Three hundred sixty-nine patients with SJS/TEN were included in RegiSCAR between 2003 and 2005. The data needed for calculation of SCORTEN were available for 45% of patients. The score revealed a moderate predictive ability with a slight underestimation of the total number of in-hospital deaths by 11%, an area under the receiver operating characteristic curve of 0.75, and a Brier score of 0.14. Problems could be seen by analyzing subgroups such as patients with TEN. The AS was better calibrated but discriminated worse (area under the receiver operating characteristic curve: 0.72; Brier score: 0.14). With the help of a refined score derived from SCORTEN and AS, potential for a possible improvement could be demonstrated. The authors were able to show that the predictive ability of SCORTEN is acceptable. Although improvement might be possible, SCORTEN remains the tool of choice, whereas AS might be an alternative in retrospective settings with missing laboratory data.

Systemic Immunomodulating Therapies for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A Systematic Review and Meta-analysis

Importance Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse reactions with high mortality. There is no evidence-based treatment, but various systemic immunomodulating therapies are used. Objectives To provide an overview on possible immunomodulating treatments for SJS/TEN and estimate their effects on mortality compared with supportive care. Data Sources A literature search was performed in December 2012 for articles published in MEDLINE, MEDLINE Daily, MEDLINE Inprocess, Web of Science, EMBASE, Scopus, and the Cochrane Library (Central) from January 1990 through December 2012, and updated in December 2015, in the English, French, Spanish, and German languages looking for treatment proposals for SJS/TEN. Other sources were screened manually. Study Selection Initially, 157 randomized and nonrandomized studies on therapies (systemic immunomodulating therapies or supportive care) for SJS/TEN were selected. Data Extraction and Synthesis Relevant data were extracted from articles. Authors were contacted for further information. Finally, 96 studies with sufficient information regarding eligibility and adequate quality scores were considered in the data synthesis. All steps were performed independently by 2 investigators. Meta-analyses on aggregated study data (random-effects model) and individual patient data (IPD) (logistic regression adjusted for confounders) were performed to assess therapeutic efficacy. In the analysis of IPD, 2 regression models, stratified and unstratified by study, were fitted. Main Outcomes and Measures Therapy effects on mortality were expressed in terms of odds ratios (ORs) with 95% CIs. Results Overall, 96 studies (3248 patients) were included. Applied therapies were supportive care or systemic immunomodulating therapies, including glucocorticosteroids, intravenous immunoglobulins, cyclosporine, plasmapheresis, thalidomide, cyclophosphamide, hemoperfusion, tumor necrosis factor inhibitors, and granulocyte colony-stimulating factors. Glucocorticosteroids were associated with a survival benefit for patients in all 3 analyses but were statistically significant in only one (aggregated data: OR, 0.5; 95%% CI, 0.3-1.01; IPD, unstratified: OR, 0.7; 95% CI, 0.5-0.97; IPD, stratified: OR, 0.8; 95% CI, 0.4-1.3). Despite the low patient size, cyclosporine was associated with a promising significant result in the only feasible analysis of IPD (unstratified model) (OR, 0.1; 95% CI, 0.0-0.4). No beneficial findings were observed for other therapies, including intravenous immunoglobulins. Conclusions and Relevance Although all analyses, including the unstratified model, had limitations, glucocorticosteroids and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN. Further evaluation in prospective studies is required. However, this work provides a comprehensive overview on proposed systemic immunomodulating treatments for SJS/TEN, which is of great relevance for treating physicians.