Epidermal necrolysis: 60 years of errors and advances.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare conditions characterized by extensive epidermal detachment and mucositis. Both are associated with a high mortality rate and significant long-term morbidity. Since the initial report introducing the term TEN in 1956, diagnosis of the condition has been fraught with difficulties that continue to exist today. The terms 'erythema multiforme major' (EMM) and SJS, and their relationship to TEN have also been confusing to clinicians. It is now recognized that EMM is a different entity from SJS and TEN in terms of demographics, causality and severity. SJS and TEN represent a continuum of disease, and differ only by the extent of epidermal detachment and therefore severity. The term 'epidermal necrolysis' (EN) is used in this article to describe the spectrum of disease that includes SJS and TEN. Important advances in understanding the pathomechanism and treatment of EN have been made over the years. These include the recognition of human leucocyte antigen (HLA) associations (e.g. HLA-B*1502 with carbamazepine-induced TEN) and understanding of the pathogenic roles of drug-specific cytotoxic T cells and granulysin. It was previously believed that widespread keratinocyte death in EN is predominantly mediated by soluble Fas-ligand and that intravenous immunoglobulin therapy is useful in blocking this mechanism with resultant survival benefits. Further studies have since proven these theories to be incorrect. This short review describes the key advances in the terminology, classification, causality and treatment of EN, and identifies future priorities and challenges in the understanding and management of this condition.

Histopathology of drug rash with eosinophilia and systemic symptoms syndrome: a morphological and phenotypical study.

BACKGROUND: The histopathological features of drug rash with eosinophilia and systemic symptoms (DRESS) syndrome remain poorly characterized. OBJECTIVES: To better characterize the histopathological features of DRESS syndrome, and define the phenotype of the effector cells in the skin and compare it with maculopapular rash (MPR). METHODS: We conducted a retrospective study on 50 skin biopsies from patients with DRESS syndrome (n = 36). Histopathological and immunophenotypical features were studied and compared with a series of MPRs (n = 20). RESULTS: Foci of interface dermatitis, involving cutaneous adnexae, were frequently seen in cases of DRESS. Eosinophils were seen in only 20% of cases and neutrophils in 42%. Eczematous (40%), interface dermatitis (74%), acute generalized exanthematic pustulosis-like (20%) and erythema multiforme-like (24%) patterns were observed. The association of two or three of these patterns in a single biopsy was significantly more frequent in cases of DRESS than in a series of nondrug-induced dermatoses (P < 0.01), and appeared to be more marked in DRESS syndrome with severe cutaneous lesions (P = 0.01) than in less severe cases of DRESS and MPR. A higher proportion of CD8(+) and granzyme B(+) lymphocytes was observed in cases of DRESS with severe cutaneous eruptions (erythroderma and/or bullae). Atypical lymphocytes were found in 28% of biopsies, and expressed CD8 in most cases; a cutaneous T-cell clone was rarely found (6%). CONCLUSIONS: The histopathology of DRESS syndrome highlights various associated inflammatory patterns in a single biopsy. Cutaneous effector lymphocytes comprise a high proportion of polyclonal CD8(+) granzyme B(+) T lymphocytes.

Stevens-Johnson syndrome and toxic epidermal necrolysis: follow-up of pulmonary function after remission.

BACKGROUND: Acute-stage specific bronchial epithelial detachment has been described in 27% of patients with Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To assess the pulmonary function of patients with SJS/TEN after remission. METHODS: Analysis of pulmonary function tests (PFTs) performed during the usual follow-up of patients with SJS/TEN managed in a referral centre from April 2007 to January 2010. RESULTS: Of 58 patients admitted, 32 underwent PFTs (17 male, 15 female). The median time from the acute stage to PFTs was 3 months (interquartile range 1-18). Three patients had grade 2 dyspnoea. Eighteen patients (56%) had abnormal PFTs, including 13 patients (41%) with moderately altered diffusion capacity for carbon monoxide (DLCO ) normalized by the alveolar volume (VA) (giving the ratio KCO , which equals DLCO /VA) and five patients with decreased total lung capacity. No airway obstruction was observed. Patients with decreased KCO had higher initial detached body surface area than others (30% vs. 10%, P = 0·006), as did those with decreased DLCO (25% vs. 10%; P = 0·054). There were correlations between detached body surface area and both KCO (r = -0·41, P = 0·026) and DLCO (r = -0·47, P = 0·011). Among 10 patients with decreased KCO on the first PFT, eight patients had a sustained decrease in KCO on a second PFT. CONCLUSIONS: More than half of patients with SJS/TEN displayed abnormalities on PFTs, mainly diffusion impairment, which was associated with higher initial skin surface detachment. These abnormalities were mostly asymptomatic and remained stable over time.

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.

Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study.

BACKGROUND: Cases of severe drug hypersensitivity, demonstrating a variable spectrum of cutaneous and systemic involvement, are reported under various names, especially drug reaction with eosinophilia and systemic symptoms (DRESS). Case definition and overlap with other severe cutaneous adverse reactions (SCAR) are debated. OBJECTIVES: To analyse the spectrum of signs and symptoms of DRESS and distribution of causative drugs in a large multicentre series. PATIENTS AND METHODS: RegiSCAR, a multinational registry of SCAR, prospectively enrolled 201 potential cases from 2003 to mid-2009. Using a standardized scoring system, 117 cases were validated as showing probable or definite DRESS. RESULTS: The male/female ratio was 0.80; females were borderline significantly younger than males. Next to the ubiquitous exanthema, the main features were eosinophilia (95%), visceral involvement (91%), high fever (90%), atypical lymphocytes (67%), mild mucosal involvement (56%) and lymphadenopathy (54%). The reaction was protracted in all but two patients; two patients died during the acute phase. Drug causality was plausible in 88% of cases. Antiepileptic drugs were involved in 35%, allopurinol in 18%, antimicrobial sulfonamides and dapsone in 12% and other antibiotics in 11%. The median time interval after drug intake was 22 days (interquartile range 17-31) for all drugs with (very) probable causality, with differences between drugs. CONCLUSION: This prospective observational study supports the hypothesis that DRESS is an original phenotype among SCAR in terms of clinical and biological characteristics, causative drugs, and time relation. The diversity of causative drugs was rather limited, and mortality was lower than that suggested by prior publications.

Prognosis of generalized bullous fixed drug eruption: comparison with Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND: Generalized bullous fixed drug eruption (GBFDE) is a rare cutaneous adverse reaction to drugs, and may resemble Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), but is usually considered less severe. OBJECTIVES: To compare the severity and mortality rate in cases of GBFDE and control cases of SJS or TEN of similar extent of skin detachment. METHODS: This was a case-control analysis of 58 patients with GBFDE matched by age and extent of skin detachment to 170 control patients with a validated diagnosis of SJS or SJS/TEN overlap. Data for cases and controls were extracted from the EuroSCAR and RegiSCAR databases resulting from two population-based studies of severe cutaneous adverse reactions conducted in Europe. Preselected outcome criteria were death (primary), and fever, duration of hospitalization and transfer to an intensive care or burn unit (secondary). RESULTS: GBFDE affected mainly older patients (median age 78 years, interquartile range 68-84 years); 13 of 58 cases died (22%). The mortality rate was slightly but not significantly lower for patients with GBFDE than controls [28%, multivariate odds ratio 0·6 (95% confidence interval 0·30-1·4)]. Patients with GBFDE and controls did not differ in other preselected criteria for severity. CONCLUSIONS: Although our study featured limited statistical power, we were not able to confirm that GBFDE had better prognosis than SJS or SJS/TEN of similar disease extent in older patients. Severe cases of GBFDE deserve the attention and active management given to patients with SJS or TEN.

Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a severe cutaneous adverse reaction characterized by rash with sterile pustules, high fever and elevated circulating neutrophil counts. OBJECTIVES: To investigate the frequency and clinical features of AGEP systemic involvement. METHODS: This retrospective study included all patients hospitalized in our department between 2000 and 2010 with a discharge diagnosis of AGEP. Patients had to fulfil the following criteria: (i) a specific EuroSCAR score > 4 and (ii) biological and radiological work-up available. RESULTS: Among the 58 patients enrolled, 10 had at least one systemic involvement: hepatic function test results were abnormal for seven; six had renal insufficiency; two developed acute respiratory distress, with one patient's bronchoalveolar lavage fluid containing many neutrophils but no microorganisms; one was agranulocytotic. Mean peripheral neutrophil counts and mean C-reactive protein levels were elevated significantly in patients with systemic involvement. Amoxicillin rechallenge and hospitalization duration were associated with systemic involvement. AGEP systemic involvement was observed in 17% of cases studied, including liver, kidney, bone-marrow and lung involvement. Outcomes were favourable after drug withdrawal, and symptomatic and topical steroid treatments. CONCLUSIONS: The neutrophil count-systemic involvement association may suggest a role for neutrophils in AGEP systemic involvement. Physicians should be aware of the possibility of systemic involvement in AGEP and should actively look for signs of extracutaneous reactions.

Linear IgA bullous dermatosis: comparison between the drug-induced and spontaneous forms.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering skin disorder characterized by linear deposits of IgA along the dermoepidermal junction, visualized by direct immunofluorescence (DIF). It is usually spontaneous and drug induced. OBJECTIVES: To compare the clinical and histological forms of LABD. METHODS: This retrospective single-centre cohort study concerned 28 patients diagnosed with LABD between 1 January 1995 and 31 December 2010. Imputability, determined according to the French imputability method (modified Bégaud score) and Naranjo score, enabled classification into drug-induced and spontaneous LABD groups. Clinical and histological features were compared by blinded analysis of images and histological patterns. RESULTS: Sixteen patients had spontaneous LABD and 12 had drug-induced LABD. Nikolsky sign and large erosions were significantly more frequent in drug-induced than spontaneous LABD (P = 0.003 and P = 0.03, respectively), with no between-group differences for erythematous plaques, target or target-like lesions, string of pearls, location, mucosal involvement or histological features. CONCLUSIONS: Drug-induced LABD was more severe than the spontaneous form, with lesions mimicking toxic epidermal necrolysis. Because LABD may be polymorphic and sometimes life threatening, DIF assay is recommended for all patients with Nikolsky sign and large erosions.

Poor relevance of a lymphocyte proliferation assay in lamotrigine-induced Stevens-Johnson syndrome or toxic epidermal necrolysis.

BACKGROUND: Prior use of 'lymphocyte transformation test' (LTT) in Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) provided conflicting results, possibly dependent on sampling dates (acute vs. late). OBJECTIVE: Evaluation of LTT in patients with SJS or TEN who reacted to lamotrigine (LTG). In a small subgroup we explored the possible role of regulatory T cells (T-reg). METHODS: Acute phase samples (9) and post-recovery samples (14) from cases of SJS or TEN to LTG were provided by the RegiSCAR-study group. Controls were persons never exposed to LTG (12), patients exposed without reaction (6), and patients who developed a mild eruption to LTG (6). LTT was performed by measuring (3) H-thymidine incorporation after 3 days of incubation with phytohemmaglutinin, LTG (10 µg/mL) or medium. Stimulation index ≥ 2 was considered positive. In 16 cases LTT was redone after depletion of T-reg by fluorescence activated cell sorting. RESULTS: Positive LTT was observed in 3/6 cases of mild eruptions, 1/9 SJS/TEN-cases tested during the acute phase and 3/14 SJS/TEN-cases tested after recovery. We noted a very mild and nonsignificant trend for an increased response after depletion of T-reg in late samples from SJS or TEN patients. CONCLUSIONS AND CLINICAL RELEVANCE: With the largest number of LTT performed in patients with SJS or TEN to a single drug, we confirmed that reactive cells are rarely detected in these reactions. Poor reactivity did not seem related to T-reg. Other in vitro assays than those testing proliferation should be evaluated, before raising the hypothesis that specific cells disappeared by undergoing apoptosis during the reaction.

The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immunologically mediated, severe cutaneous adverse reactions involving cytotoxic T cells, natural killer cells and various mediators. In large studies, up to 15% of SJS/TEN occurred in patients with chronic corticosteroid use. It is unclear if this prior exposure to corticosteroids modified the disease course. OBJECTIVES: To evaluate whether systemic corticosteroid usage prior to the onset of SJS/TEN modified the clinical course and outcome. If a disease-modifying effect is present, information from such an analysis may have implications on the therapeutic use of corticosteroids in SJS/TEN. METHODS: This is a case-control study based on data collected in the EuroSCAR and RegiSCAR studies. Ninety-two cases of SJS/TEN with exposure to corticosteroids prior to the onset of disease, and 321 randomly selected SJS/TEN patients without prior exposure were included. Primary outcomes included progression of disease, disease severity and mortality. A secondary analysis of latency between the beginning of drug use and the onset of disease, based on exposure to a single high-risk drug, was also performed. RESULTS: On multivariate analysis, cases with prior exposure to corticosteroids had a longer progression of disease by 2·2 days [95% confidence interval (CI) 1·1-3·2]. The disease severity and mortality outcome were unaffected. In addition, there is evidence that corticosteroids delayed the onset of SJS/TEN in patients with exposure to high-risk drugs by 7·1 days (CI -0·2 to 14·5). CONCLUSIONS: The prior use of corticosteroids prolonged the period of disease progression without influencing the disease severity or mortality. In addition, when SJS/TEN is preceded by use of a single high-risk drug, the latency between the drug intake and the onset of SJS/TEN may also be increased. These findings suggest that corticosteroids have a mild impact on the course of SJS/TEN, and further studies are required to clarify any potential therapeutic effects.

The value of BP230 enzyme-linked immunosorbent assay in the diagnosis and immunological follow-up of bullous pemphigoid.

BACKGROUND: The value of 230-kDa bullous pemphigoid antibody (BP230) enzyme-linked immunosorbent assay (ELISA) for the diagnosis of bullous pemphigoid (BP) was investigated, but in the immunological follow-up of the disease remains unknown. OBJECTIVE: Evaluation of BP230 ELISA for diagnosis, follow-up and prediction of relapse in BP. METHODS: Monocenter retrospective and prospective study. Patients with typical BP. Detection of autoantibodies by indirect immunofluorescence (IIF), BP180 and BP230 ELISA tests at diagnosis, during the treatment (disease control or failure) and at treatment stop (relapse or not 3 months after). RESULTS: 74 patients were included. At diagnosis, BP230 ELISA sensitivity was lower than IIF and BP180 ELISA. Combining both ELISA added a weak gain of sensitivity. Both tests paralleled the clinical evolution, especially in case of disease control. At the end of the treatment, BP230 ELISA was not different in patients with or without relapse. CONCLUSION: In routine practice, BP230 ELISA does not seem to be a useful additional test in typical BP.

Management of bullous pemphigoid with topical steroids in the clinical practice of a single center: outcome at 6 and 12 months.

BACKGROUND: The efficacy of topical steroids in bullous pemphigoid (BP) was assessed by prospective therapeutic trials. Systemic corticosteroids and immunosuppressant agents are indicated in situations of failure or relapses. OBJECTIVES: To report our experience in the management of BP outside therapeutic trials focusing on the outcome of the patients at 6 and 12 months, compliance and follow-up difficulties. METHODS: Monocenter retrospective study with collection of clinical, therapeutic and follow-up data after 6 and 12 months. RESULTS: Ninety-six patients, mean age 84 years, 65 females, 54% had neurological impairment. The initial dose of clobetasol propionate was 30 g/day, followed by a progressive decrease. In the first 6 months, 14% were lost to follow-up and 17.7% died; 62% were controlled with topical steroids alone, and 25% had adjunctive systemic treatment. Difficulties of compliance were mentioned in 34.4%, without significant difference between controlled and noncontrolled patients. After 12 months, 23% were lost to follow-up and 27.1% died. The mean duration of the treatment was 11.7 ± 8.4 months. After the stop, 18.9% of patients relapsed within 3 months. CONCLUSION: We emphasize the frequent recourse to systemic treatments in the first few months, the difficulties of compliance and of follow-up in our day-to-day experience.

[Auto-immune thyroiditis and drug reaction with eosinophilia and systemic symptoms (DRESS) associated with HHV-6 viral reactivation]. / Thyroïdite auto-immune et syndrome d'hypersensibilité médicamenteuse (DRESS) associés à une réactivation virale HHV6.

INTRODUCTION: DRESS syndrome is a severe adverse drug reaction with visceral involvement. Its physiopathology includes immunological disorders associated with human herpes virus (HHV) reactivation. We report two cases of auto-immune thyroiditis occurring in the context of DRESS syndrome associated with HHV-6 reactivation. OBSERVATIONS: Case 1 : A 39-year-old woman presented DRESS syndrome with HHV-6 reactivation, cutaneous, lymph node, hepatic and renal disorders treated with systemic corticosteroids for 10 months. Following discontinuation of the corticosteroids, she developed Graves's disease, which was stabilized with carbimazole and a beta-blocker. CASE 2: A 31-year-old woman was hospitalized for DRESS syndrome with delayed HHV-6 reactivation and severe hepatic involvement. She was successfully treated by topical steroids. Six weeks later, she presented De Quervain thyroiditis associated with moderate relapsing DRESS, which were treated by sodium levothyroxine and topical steroids. DISCUSSION: There is currently debate about the implication of viral reactivation, in particular HHV-6, in chronic DRESS, relapse and development of auto-immune diseases. These observations highlight the potential risk of patients developing auto-immune diseases and underline the need for prolonged clinical and laboratory follow-up of patients with DRESS.

Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis.

Background Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)are acute mucocutaneous reactions associated with poor prognosis. The treatment is mainly symptomatic, based on supportive care. Until now, several curative treatments have been proposed without evidence of effectiveness.Objectives To evaluate the effect of ciclosporin on SJS and TEN after a short series had suggested a benefit.Methods We conducted an open, phase II trial to determine the safety and possible benefit of ciclosporin. Among the 45 consecutive patients admitted for SJS /TEN from March 2005 to September 2007, 29 fulfilled inclusion criteria. Ciclosporin was administered orally (3 mg kg)1 daily for 10 days) and tapered over a month. Clinical and biological evaluations were performed sequentially. Predicted death rate was estimated with a validated prognostic score (SCORTEN).Results Twenty-nine patients were included at a mean +/- SD of 2.8 +/- 1.8 days after onset. The final diagnosis was SJS (n = 10), SJS /TEN overlap (n = 12) and TEN(n = 7). One month of treatment was completed in 26. Ciclosporin was stopped after more than 10 days in three cases for side-effects including posterior leucoencephalopathy (n = 1), neutropenia (n = 1) and nosocomial pneumopathy(n = 1). Ciclosporin dosage was tapered earlier than scheduled in two cases for alteration in renal function. The prognostic score predicted 2.75 deaths; none occurred (P = 0.1). Mean epidermal detachment remained stable in 18 of 29 cases (62%). The mean ± SD hospital stay was 16.2 +/- 9.1 days.Conclusions Both the death rate and the progression of detachment seemed lower than expected, suggesting a possible usefulness of ciclosporin in SJS and TEN that needs to be confirmed.

An application of propensity score methods to estimate the treatment effect of corticosteroids in patients with severe cutaneous adverse reactions.

PURPOSE: To investigate whether propensity score (ps) methods could reasonably be applied to estimate the treatment effect on mortality, based on a comparatively small sample of patients with severe cutaneous adverse reactions (SCAR) and who come from different countries where physicians prefer different treatment schemes. METHODS: Ps methods were applied to cope with confounding due to non-randomized treatment assignment for the analysis of the treatment data obtained in the case-control study EuroSCAR. For the study's purpose, the analysis focused on the comparison of the treatments: corticosteroids (STER) and supportive care only (SUPP). RESULTS: 206 French and German patients were treated either with SUPP or STER. Imbalances between treatment groups as well as between the countries were recognized. Concerning the balance between the treatment groups no ps model for the full cohort was satisfying. In addition, the inclusion of a variable for patient's country led to a separation of the patients by country. Thus, we developed ps models for each country separately and estimated the treatment effects (France: odds ratio (OR) 0.52, 95% confidence interval (CI) 0.09-3.10, Germany: OR 0.23, CI 0.06-0.92, Overall: OR 0.33 CI 0.11-1.04). CONCLUSIONS: The application of the ps methods was successful and provided valuable information. We could confirm the findings of the original analysis which was based on standard logistic regression, especially concerning the necessity of a country-specific analysis. The observed country differences in the estimated treatment effects were less pronounced and thus seemed to be more reasonable than those of the past analysis.