Summary
Background 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.
Objectives To evaluate the risk for different drugs of causing AGEP.
Patients and methods A multinational case–control study (EuroSCAR) conducted to evaluate the risk for different drugs of causing severe cutaneous adverse reactions; the study included 97 validated community cases of AGEP and 1009 controls.
Results Strongly associated drugs, i.e. drugs with a lower bound of the 95% confidence interval (CI) of the odds ratio (OR) > 5 were pristinamycin (CI 26–∞), ampicillin/amoxicillin (CI 10–∞), quinolones (CI 8·5–∞), (hydroxy)chloroquine (CI 8–∞), anti‐infective sulphonamides (CI 7·1–∞), terbinafine (CI 7·1–∞) and diltiazem (CI 5·0–∞). No significant risk was found for infections and a personal or family history of psoriasis (CI 0·7–2·2).
Conclusions Medications associated with AGEP differ from those associated with Stevens–Johnson syndrome or toxic epidermal necrolysis. Different timing patterns from drug intake to reaction onset were observed for different drugs. Infections, although possible triggers, played no prominent role in causing AGEP and there was no evidence that AGEP is a variant of pustular psoriasis.
Summary
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.
What's already known about this topic?
Linear IgA bullous dermatosis (LABD) is a rare autoimmune dermatosis usually considered spontaneous or drug induced.
Clinical features are polymorphic, and pseudotoxic epidermal necrolysis forms have been described.
To date, spontaneous and drug‐induced LABD have not been compared.
What does this study add?
Drug‐induced LABD, often with Nikolsky sign and large erosions, is more severe than the spontaneous form.
Summary
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.
What's already known about this topic?
DRESS is a hypersensitivity reaction, characterized by a variable combination of symptomatic and asymptomatic features.
What does this study add?
DRESS is an original phenotype among severe cutaneous adverse reactions in terms of clinical and biological characteristics, drugs, time relation, and course.
Besides eosinophilia, other haematological abnormalities are frequent.
The diversity of causative drugs is rather limited.
The prodromal period is quite variable, introducing risk of protopathic bias, especially for antibiotics and NSAIDs.
Summary
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.
What’s already known about this topic?
•
Generalized bullous fixed drug eruption (GBFDE) is a rare variant of FDE.
•
It is often confused with toxic epidermal necrolysis (TEN) and is considered less severe than TEN.
What does this study add?
•
Comparison of GBFDE cases with Stevens–Johnson syndrome (SJS) or SJS/TEN cases matched for age and extent of skin detachment was carried out.
•
The mortality rate was slightly but not significantly lower for GBFDE than for cases of SJS or SJS/TEN.
•
The reputation of the benign nature of GBFDE should be reconsidered.
Summary
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.
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.
Summary
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.
Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually ...tailored, unexpected effect mediated by a drug specific activation of the immune response.
The clinical presentation of “drug eruptions” is highly variable, from the most common transient and benign erythema that occurs 6–9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users.
Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for “hypersensitivity syndrome”/DRESS and 25% for SJS or TEN. In addition if some medications are “usual suspects” for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis).
The “phenotypic” diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.
Summary
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.
What's already known about this topic?
The histological features of drug rash with eosinophilia and systemic symptoms (DRESS) vary from spongiotic dermatitis to an erythema multiforme‐like aspect.
In DRESS, skin biopsies often show eosinophils and apoptotic bodies.
Atypical lymphocytes may be found in skin infiltrates.
What does this study add?
The association of several inflammatory patterns in a single biopsy is suggestive for diagnosis.
Cutaneous infiltrates can compromise atypical lymphocytes resembling Sézary cells.
DRESS shows a higher density of inflammatory infiltrates, more apoptosis, associated inflammatory patterns and granzyme B+ cells than maculapapular rash.
Effector T cells are mainly polyclonal granzyme B+ CD8+ T cells.
