Interleukin-15 Is Associated with Severity and Mortality in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Early diagnosis and prognosis monitoring for Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN) still remain a challenge. This study aims to explore any cytokine/chemokine with prognostic potential in Stevens-Johnson syndrome/TEN. Through screening a panel of 28 serological factors, IL-6, IL-8, IL-15, tumor necrosis factor-α, and granulysin were upregulated in patients with Stevens-Johnson syndrome/TEN and selected for the further validation in total 155 patients with Stevens-Johnson syndrome/TEN, including 77 from Taiwan and 78 from the Registry of Severe Cutaneous Adverse Reactions. Among these factors evaluated, the levels of IL-15 (r = 0.401; P < 0.001) and granulysin (r = 0.223; P = 0.026) were significantly correlated with the disease severity in 112 samples after excluding patients with insufficient data to calculate the score of TEN. In addition, IL-15 was also associated with mortality (P = 0.002; odds ratio, 1.09; 95% confidence interval, 1.03-1.14; P = 0.001; adjusted odds ratio, 1.10; 95% confidence interval, 1.04-1.16). Consistent results were obtained after the exclusion of Taiwanese patients with sepsis to rule out possible confounders. Moreover, IL-15 was shown to enhance cytotoxicity of cultured natural killer cells and blister cells from patients with TEN. Our findings highlight a usefulness of IL-15 in prognosis monitoring and therapeutic intervention of this devastating condition.

Risk of cutaneous adverse events with febuxostat treatment in patients with skin reaction to allopurinol. A retrospective, hospital-based study of 101 patients with consecutive allopurinol and febuxostat treatment.

OBJECTIVE: To investigate the cutaneous tolerance of febuxostat in gouty patients with skin intolerance to allopurinol. METHODS: We identified all gouty patients who had sequentially received allopurinol and febuxostat in the rheumatology departments of 4 university hospitals in France and collected data from hospital files using a predefined protocol. Patients who had not visited the prescribing physician during at least 2 months after febuxostat prescription were excluded. The odds ratio (OR) for skin reaction to febuxostat in patients with a cutaneous reaction to allopurinol versus no reaction was calculated. For estimating the 95% confidence interval (95% CI), we used the usual Wald method and a bootstrap method. RESULTS: In total, 113 gouty patients had sequentially received allopurinol and febuxostat; 12 did not visit the prescribing physician after febuxostat prescription and were excluded. Among 101 patients (86 males, mean age 61±13.9 years), 2/22 (9.1%) with a history of cutaneous reactions to allopurinol showed skin reactions to febuxostat. Two of 79 patients (2.5%) without a skin reaction to allopurinol showed skin intolerance to febuxostat. The ORs were not statistically significant with the usual Wald method (3.85 [95% CI 0.51-29.04]) or bootstrap method (3.86 [95% CI 0.80-18.74]). CONCLUSION: The risk of skin reaction with febuxostat seems moderately increased in patients with a history of cutaneous adverse events with allopurinol. This moderate increase does not support the cross-reactivity of the two drugs.

Telaprevir-related dermatitis.

OBJECTIVE: To evaluate the incidence, type, and severity of telaprevir-associated skin reactions. DESIGN: Three dermatologists assessed available information including photographs, biopsy results, and clinical summaries of all cases with skin eruptions reported as moderate or severe during the telaprevir clinical development program. For cases from placebo-controlled trials, they were masked to exposure. SETTINGS: Phase 1 to 3 studies of telaprevir combination therapy for hepatitis C. PATIENTS: All patients with skin eruptions enrolled in telaprevir clinical trials prior to 2011 MAIN OUTCOME MEASURES: Incidence, diagnosis, morphologic features, extent, and severity of skin eruption. RESULTS: Skin eruptions were more frequent in patients who received telaprevir as part of hepatitis C treatment compared with pegylated interferon (peginterferon) and ribavirin alone (56% vs 34% overall; 3.7% vs 0.4% severe). Occurring at any time during the 12 weeks of telaprevir combination regimen, in more than 90% of cases, this eruption is pruritic eczematous dermatitis. None of the clinical or genetic factors examined were substantial risk factors for dermatitis. Three cases of Stevens-Johnson Syndrome (SJS), and 11 cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) were suspected, with 2 SJS and 3 DRESS cases considered likely. CONCLUSIONS: Telaprevir-related dermatitis occurs in a majority of telaprevir-treated patients. It is an eczematous dermatitis that differs in timing and appearance from the eruptions usually associated with drug reactions. The strong signal for an increased risk of DRESS or SJS requires particular vigilance in telaprevir-treated patients.

Prognostic value of histologic features of toxic epidermal necrolysis.

BACKGROUND: The prognosis of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), and SJS/TEN overlap syndrome has been assessed using a disease-specific severity score (SCORTEN) based on clinical and laboratory data. Histologic data may improve outcome prediction. OBJECTIVE: We sought to evaluate whether dermal mononuclear infiltration and epidermal necrosis predict survival of patients with TEN, SJS, or SJS/TEN. METHODS: We conducted a retrospective review of clinical records and skin biopsy specimens read without knowledge of clinical data. RESULTS: We identified 108 patients (SJS, n = 42; SJS/TEN, n = 36; TEN, n = 30). Overall mortality was 21.3%. Dermal infiltration and epidermal necrosis were not associated with time from disease onset to biopsy. Extensive dermal infiltrates were seen in 19 (18.5%) patients and full-thickness epidermal necrosis in 56 (52%) patients. Dermal infiltrate severity was not associated with day-1 (D1) SCORTEN or hospital death. Epidermal necrosis severity showed trends toward associations with D1 SCORTEN (P = .11) and hospital death (P = .06). In univariate analyses, full-thickness epidermal necrosis was significantly associated with hospital death (32.1% vs 11.4%, P = .017) and worse D1 SCORTEN values (1.98 ± 1.29 vs 1.55 ± 1.21; P = .04). In the bivariate analysis, however, D1 SCORTEN remained significantly associated with hospital death (odds ratio = 3.07, 95% confidence interval 1.83-5.16) but the association with full-thickness epidermal necrosis was no longer significant (odds ratio = 2.02, 95% confidence interval 0.65-7.12). LIMITATIONS: Retrospective study design and indirect assessment of progression are limitations. CONCLUSION: Full-thickness epidermal necrosis was associated with mortality but did not independently predict hospital death after adjustment based on the SCORTEN value. Dermal infiltrate severity was not associated with hospital death.

Toxic epidermal necrolysis, DRESS, AGEP: do overlap cases exist?

BACKGROUND: Severe cutaneous adverse reactions to drugs (SCARs) include acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS) and epidermal necrolysis (Stevens-Johnson syndrome-toxic epidermal necrolysis [SJS-TEN]). Because of the varied initial presentation of such adverse drug reactions, diagnosis may be difficult and suggests overlap among SCARs. Overlapping SCARs are defined as cases fulfilling the criteria for definite or probable diagnosis of at least 2 ADRs according to scoring systems for AGEP, DRESS and SJS-TEN. We aimed to evaluate the prevalence of overlap among SCARs among cases in the referral hospital in France. METHODS: We retrospectively analyzed data for 216 patients hospitalized in the referral centre over 7 years with a discharge diagnosis of AGEP (n = 45), DRESS (n = 47), SJS-TEN (n = 80) or "drug rash" (n = 44). Each case with detailed clinical data and a skin biopsy specimen was scored for AGEP, DRESS and SJS-TEN by use of diagnostic scores elaborated by the RegiSCAR group. RESULTS: In total, 45 of 216 cases (21%) had at least 2 possible diagnoses: 35 had a single predominant diagnosis (definite or probable), 7 had several possible diagnoses and 3 (2.1% of 145 confirmed SCARs) were overlap SCARs. CONCLUSIONS: Despite ambiguities among SCARs, confirmed overlap cases are rare. This study did not avoid pitfalls linked to its retrospective nature and selection bias. In the acute stage of disease, early identification of severe ADRs can be difficult because of clinical or biologic overlapping features and missing data on histology, biology and evolution. Retrospectively analyzing cases by use of diagnostic algorithms can lead to reliable discrimination among AGEP, DRESS and SJS-TEN.

Genome-wide association study of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Europe.

BACKGROUND: 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. OBJECTIVES: To investigate genetic association at a genome-wide level on a large sample of SJS/TEN patients. METHODS: We performed a genome wide association study on a sample of 424 European cases and 1,881 controls selected from a Reference Control Panel. RESULTS: 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. CONCLUSION: 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.

The DRESS syndrome: a literature review.

The Drug Reaction with Eosinophilia and Systemic Symptom (DRESS) is a severe adverse drug-induced reaction. Diagnosing DRESS is challenging due to the diversity of cutaneous eruption and organs involved. We used the RegiSCAR scoring system that grades DRESS cases as "no," "possible," "probable," or "definite" to classify cases reported in the literature. We also analyzed the clinical course and treatments of the cases. A total of 44 drugs were associated with the 172 cases reported between January 1997 and May 2009 in PubMed and MEDLINE. The most frequently reported drug was carbamazepine, and the vast majority of cases were classified as "probable/definite" DRESS cases. Hypereosinophilia, liver involvement, fever, and lymphadenopathy were significantly associated with "probable/definite" DRESS cases, whereas skin rash was described in almost all of the cases, including "possible cases." Culprit drug withdrawal and corticosteroids constituted the mainstay of DRESS treatment. The outcome was death in 9 cases. However, no predictive factors for serious cases were found. This better knowledge of DRESS may contribute to improve the diagnosis and management of this syndrome in clinical practice.

Death ligand TRAIL, secreted by CD1a+ and CD14+ cells in blister fluids, is involved in killing keratinocytes in toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is characterized by an acute detachment and destruction of keratinocytes, affecting large areas of the skin. It is often related to adverse drug reactions. Previous studies have shown that effector CD8+ T cells, which accumulate in the blister fluid, are functionally cytotoxic and act through a classical perforin/granzyme B pathway. It has recently been shown that these cytotoxic T cells also secrete granulysin peptide, which is lethal to keratinocytes. These cytotoxic T cells exert their killer activity against autologous keratinocytes in the presence of the drug. However, they are unlikely to be the only effectors of TEN. We therefore searched for soluble death factors in the blister fluids that might kill keratinocytes. We found that the amounts of interferon-γ, TRAIL and TNF-α proteins were significantly greater in TEN blister fluids than in all controls (normal sera, TEN sera, burns and Eosinophilic pustular folliculitis blister fluids) and TNF-like weak inducer of apoptosis (TWEAK) amounts are also greater in all controls except burns. We showed that these proteins acted in synergy to induce the death of keratinocytes in vitro. We also found that TRAIL and TWEAK were secreted by CD1a+ and CD14+ cells present in the blister fluids. Thus, in addition to MHC class I-restricted cytotoxic T lymphocytes (CTLs), which lyse keratinocytes, ligands secreted by non-lymphoid cells capable of inducing keratinocyte death in an MHC class I-independent manner, also seem to be present in the blister fluids of patients with TEN.

In vivo confocal microscopic evaluation of corneal changes in chronic Stevens-Johnson syndrome and toxic epidermal necrolysis.

PURPOSE: To describe corneal changes visible on in vivo confocal microscopy, in patients with debilitating ocular sequelae because of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS). PATIENTS AND METHODS: Forty-one eyes of 25 consecutive patients suffering from chronic TEN or SJS were studied using in vivo confocal microscopy. RESULTS: Severe dry eye syndrome with no associated limbal stem cell deficiency (25 eyes, 16 patients, 61%) was the most frequent clinical pattern. Limbal stem cell deficiency was noted in 16 eyes (12 patients, 39%). Three patients had asymmetric disease. Confocal microscopy showed a consistent change in the superficial epithelial cells in both clinical presentations. Patients with dry eye syndrome had frequent pathological nerve damages, and the presence of dendritic cells was prevalent (65%). Inflammatory cells were observed in a large number in 4 of the 12 patients presenting neovascularization of the cornea. CONCLUSIONS: The corneas of patients with chronic ocular sequelae linked to SJS and TEN present a number of abnormalities. In vivo confocal microscopy is a potentially useful tool for therapeutic indications and for follow-up of the debilitating chronic ocular problems associated with these diseases.

Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies.

BACKGROUND: Conflicting opinions have been reported regarding the epidemiology of hidradenitis suppurativa. OBJECTIVE: We sought to evaluate the prevalence of hidradenitis suppurativa and to identify associated factors. METHODOLOGY: Prevalence was evaluated using a representative sample of the French population (n=10,000). Associated risk factors were assessed using two case-control studies, one population-based with 67 self-reported patients and 200 control subjects, and the other clinic-based with 302 medically assessed patients and 906 control subjects. RESULTS: The prevalence was 1% of the French population. Multivariate analyses showed a strong association with current smoking in self-reported (odds ratio=4.16, 95% confidence interval [2.99-8.69]) and in medically assessed (odds ratio=12.55 [8.58-18.38]) populations. Association with body mass index was significant in medically assessed patients (odds ratio=1.12 [1.08-1.15]) for each increase of 1 U of BMI. LIMITATIONS: A causal relationship could not be established with such a cross-sectional study. CONCLUSION: Hidradenitis suppurativa is a common disease, frequently associated with smoking and being overweight.

Allopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions. OBJECTIVES: 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. METHODS: We conducted a multinational case-control study. RESULTS: 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 (

Drug-induced skin, nail and hair disorders.

Drug eruptions are among the most common adverse drug reactions, affecting approximately 3% of hospitalised patients. Although the rate of severe cutaneous adverse reactions to medications is low, these reactions can affect anyone who takes medication, and can result in death or disability. Two general patterns can be distinguished, depending on the type of onset of these cutaneous adverse drug reactions: acute or chronic. Acute-onset events are usually rather specific cutaneous 'syndromes' that constitute emergencies and should therefore be promptly recognised and treated, while chronic-onset events often present as dermatological diseases. The challenge is therefore to recognise the drug aetiology in front of a 'classical' dermatosis such as acne, lichen or pemphigus. Therefore, clinicians should carefully evaluate the signs or symptoms of all adverse reactions thought to be drug related, and discontinue the offending agent when feasible. Erythematous drug eruptions are the most frequent and less severe acute immune drug-induced rashes, and are sometimes difficult to differentiate from viral eruptions. On the other hand, acute urticaria and angioedema are sometimes life-threatening eruptions for which a drug aetiology must be investigated. Photosensitivity, vasculitis and skin necrosis belong to the acute onset reactions, which are not always drug-induced, in contrast to fixed drug eruptions. The early recognition of acute generalised exanthematous pustulosis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis are of high importance because of the specific mechanisms involved and the different prognosis of each of these diseases. Chronic onset drug-induced disorders include pigmentary changes, drug-induced autoimmune bullous diseases, lupus, pseudo lymphoma and acneiform eruptions; these are discussed, along with specific data on drug-induced hair and nail disorders. As the disorders are numerous, the mechanisms and the drugs involved in the development of these various reactions are multiple. The list of drugs discussed in relation to the different disorders are as accurate as possible at the time of preparation of this review, but will need updating as new drugs emerge onto the market. We emphasize the clinical recognition, pathophysiology and treatment of skin, hair and nail adverse drug reactions, and the role of each doctor involved in the management of these patients in the notification of the adverse drug reaction to health authorities, using the minimal requirement for notification proposed.

[Toxic epidermal necrolysis and Stevens-Johnson syndrome]. / Syndromes de Lyell et de Stevens-Johnson.

Epidermal necrolysis (Stevens-Johnson syndrome, toxic epidermal necrolysis) is an acute and severe skin disease, induced by "(drug allergy" and characterized by the destruction of the epithelium of the skin and mucous membranes. It is extremely rare: about 2 cases per million per year. It is a life-threatening emergency. Blisters and detachment may involve a high portion of the body surface area and several mucosal sites. Visceral complications are frequent. The clinical diagnosis should be confirmed by a skin biopsy showing full-thickness necrosis of the epidermis. A dozen "high risk" medications account for 50% of cases. Symptomatic management in specialized units is urgent. The mortality rate is high (20-25%) and about one half of survivors will have sequelae, especially on the eyes.

Acute bacterial skin infections and cellulitis.

PURPOSE OF REVIEW: Acute bacterial skin infections are very common, with various presentations and severity. This review focuses on deep skin infections. We separate acute nonnecrotizing infections of the hypodermis (erysipelas), forms with abscesses or exudates and necrotizing fasciitis. These three types actually differ in risk factors, bacteriology, treatment and prognosis. RECENT FINDINGS: Leg erysipelas/cellulitis occurs in more than one person/1000/year. It remains mainly due to streptococci. Foot intertrigo is an important risk factor. Necrotizing fasciitis is much rarer and usually occurs in patients with chronic diseases. Staphylococci, especially community-acquired methicillin-resistant strains in some areas, play a growing role in the intermediate form of cellulitis with abscesses and exudates. For erysipelas or noncomplicated cellulitis, antibiotic treatment at home, when feasible, is much less expensive and as effective as hospital treatment. Intermediate cases with collections and exudates often require surgical drainage. For necrotizing fasciitis early surgery remains essential in order to decrease the mortality rate. SUMMARY: Antibiotic treatment of deep skin infections must be active on streptococci; the choice of a larger spectrum of activity depends on clinical presentation, risk factors and the burden of methicillin-resistant staphylococci in the environment.