Acute generalized exanthematous pustulosis and psoriasis: what can be learned from comorbidities.

BACKGROUND: Acute generalized exanthematous pustulosis (AGEP) is a rare pustular severe cutaneous adverse reaction. Differentiating between AGEP and pustular psoriasis may represent a diagnostic challenge. We sought to evaluate the prevalence of comorbidities in a series of patients with AGEP compared to a series of patients with psoriasis vulgaris and to a series of patients with drug-related psoriasis. METHODS: Medical records of 14 patients with AGEP, 33 patients with psoriasis vulgaris, and 18 patients with drug-related psoriasis were reviewed. The presence of comorbidities was recorded, and a comparative analysis was performed. RESULTS: A personal history of psoriasis was present in 4 (28%) patients with AGEP compared to 12 (66%) patients with drug-related psoriasis (Pv=0.03). The prevalence of psoriasis-related morbidities was significantly lower in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01, 0.05, respectively). Each of the psoriasis-related morbidities had significantly lower prevalence in the AGEP group compared to the psoriasis group and to the drug-related psoriasis group (Pv<0.01). CONCLUSIONS: In conclusion, differences between AGEP, psoriasis vulgaris, and drug-related psoriasis regarding the prevalence of psoriasis-related morbidities may assist differentiation in borderline cases.

Melkersson-Rosenthal Syndrome: the possible role of comorbidities in the etiopathogenesis.

BACKGROUND: Melkersson-Rosenthal Syndrome (MRS) is a rare syndrome. Recently, possible association between MRS and psoriasis was reported. Our objective is to evaluate the presence of comorbidities in MRS with a focus on psoriasis-related morbidities. METHODS: We conducted a case-control study consisting of a series of 12 patients with MRS and two groups of age- and gender-matched controls: 30 patients with psoriasis vulgaris and 28 patients with acute contact dermatitis. A comparative analysis for the prevalence of comorbidities, with a focus on psoriasis-related morbidities, was done. RESULTS: Psoriasis-related morbidities including smoking, obesity, dyslipidemia, hypertension, and diabetes mellitus were recorded in 5 (42%) patients with MRS, compared to 15 (50%) patients with psoriasis and 2 (7%) patients with acute contact dermatitis. The prevalence of psoriasis-related morbidities did not differ significantly between the group of patients with MRS and the group of patients with psoriasis. On the other hand, the difference between the group of patients with MRS and the group of patients with contact dermatitis was statistically significant (P=0.01). CONCLUSIONS: The similar prevalence of psoriasis-related morbidities in MRS and in psoriasis may further support an association between MRS and psoriasis.

Comprehensive survival analysis of a cohort of patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome and toxic epidermal necrolysis are severe cutaneous adverse reactions that are of major concern because of high mortality rates. On the basis of data collected in the RegiSCAR study, the aim was to assess risk factors (including modalities of patient management) for mortality, regardless of the cause, up to 1 year after the reaction. Within this cohort, the mortality rate was 23% (95% confidence interval (CI) 19-27%) at 6 weeks and 34% (95% CI 30-39%) at 1 year. Severity of reaction was a risk factor for mortality only in the first 90 days after onset, whereas serious comorbidities and age influenced mortality beyond 90 days and up to 1 year after onset of reaction. The risk of death for patients with identified drug cause was borderline lower than for patients with a reaction of unknown cause (hazard ratio 0.66, 95% CI 0.45-0.96). The study could not provide conclusive evidence regarding patient management. This large-scale population-based follow-up study of such patients confirmed high in-hospital mortality and revealed a remarkable number of deaths after discharge, which could mainly be attributed to severe comorbidities and older age, whereas the impact of severity of reaction on the risk of death was limited to the first few weeks.

[Cutaneous polyarteritis nodosa--is it really benign?].

Polyarteritis nodosa (PAN) is a multi-system disease, characterized by necrotizing vasculitis of medium-sized arteries that may affect any organ system. Cutaneous PAN is the cutaneous limited form of PAN. It affects 10% of all cases of PAN and usually demonstrates a benign and chronic course. We hereby describe a 47-year-old female with diabetes mellitus who presented with painful ulcers on both legs. The clinical and histological findings were consistent with PAN. A thorough investigation ruled out systemic PAN and cutaneous PAN was determined. Despite intensive therapies including corticosteroids and azathioprine, marked progression of the ulcers was noted and large areas of necrosis appeared. The patient underwent above-knee amputation of both legs and eventually died in less than three years. Although cutaneous PAN is known to have a benign and chronic course, we have presented an unusual progressive and severe course that resulted in the death of the patient.

Pregnancy outcome in women with vitiligo.

BACKGROUND: Vitiligo, characterized by destruction of melanocytes, causes a patchy depigmentation of the skin. It has been hypothesized to have an autoimmune pathogenesis. Autoimmune disorders are more common among women and may be associated with adverse pregnancy outcomes, such as recurrent abortions, intrauterine growth restriction (IUGR), and pre-eclampsia. OBJECTIVE: The purpose of this study was to investigate whether patients with vitiligo have increased rates of gestational complications. METHODS: A retrospective comparative study was undertaken comparing pregnancy complications of patients with and without vitiligo. The population was composed of all singleton deliveries that occurred at the Soroka University Medical Center in Israel during the years 1988-2006. Women lacking prenatal care and multiple gestations were excluded from the study. A multivariable logistic regression model was constructed to control for confounders. RESULTS: Of 186,222 singleton deliveries, 79 (0.04%) were patients with vitiligo. Vitiligo was not found to be associated with adverse pregnancy outcomes, including obstetric risk factors, labor characteristics and complications, and birth outcome. Using multivariable analysis, only grand multiparity (above five deliveries) was independently associated with vitiligo (OR = 2.01; 95% CI 1.2-3.2; P = 0.007). LIMITATIONS: Retrospective analysis was a limitation. CONCLUSION: Vitiligo is not associated with adverse pregnancy outcomes. Accordingly, patients with vitiligo should not be managed differently from the general obstetric population.

[Necrotizing cutaneous vasculitis with massive gastrointestinal bleeding following naproxen treatment].

Cutaneous necrotizing vasculitis is usually induced by an acute infection or exposure to a drug. Cutaneous vasculitis may precede severe systemic involvement, and may end in death. Accordingly, diagnosis of cutaneous vasculitis, identification of etiological factors, follow-up for systemic involvement and treatment are important. The authors present a case study of a 58-year-old male with fever and extensive eruption involving the trunk and extremities which appeared two days after initiation of treatment with oral naproxen. The clinical and histological findings were consistent with cutaneous necrotizing leukocytoclastic vasculitis. Two events of massive upper gastrointestinal bleeding occurred during treatment with systemic corticosteroids. The possible etiological factors and the mechanisms involved in the induction of the vasculitis and the gastrointestinal bleeding are discussed.

[Stevens-Johnson syndrome and toxic epidermal necrolysis--updates and innovations].

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe cutaneous adverse reactions, usually induced by drugs. The reactions, which are characterized by extensive necrosis and detachment of the epidermis, followed by erosions of the skin and mucous membranes, are associated with high rates of mortality. There is growing evidence that SJS and TEN are a single disease with common causes and mechanisms. The present article summarizes recent updates and innovations related to the etiology, pathogenesis, genetic background, prognosis and treatment of these reactions. Among high-risk drugs associated with SJS/TEN, allopurinol is the most common cause of SJS/TEN in Europe and Israel. The prognosis of SJS/TEN can be predicted by a scoring system based on seven clinical and laboratory parameters. Founded on the genetic background of SJS/TEN, predictive tests can be used prior to starting high-risk medications. Treatment is still controversial, and further controlled studies are necessary.

Acute generalized exanthematous pustulosis.

PURPOSE OF REVIEW: The purpose of the present review is to update knowledge on acute generalized exanthematous pustulosis (AGEP) in terms of epidemiology, pathogenesis, cause, clinical features, diagnosis, and treatment. RECENT FINDINGS: AGEP is a rare reaction pattern attributed mainly to drugs. Drug-specific T cells (CD4+ and CD8+) and the production of interleukin-8/CXCL8 play an important role in its pathogenesis. A large-scale case-control study (EuroSCAR study) revealed a broad spectrum of drugs strongly associated with AGEP characterized by different time patterns (latent periods). Recent publications have supported the recognized role of individual drugs in the induction of AGEP and some have reported newly incriminated drugs. Many recent publications on AGEP have used the AGEP validation score (EuroSCAR group criteria) to establish the diagnosis. The value of in-vivo tests (mainly patch tests), in-vitro tests (the lymphocyte transformation test and cytokine release tests), or both for the identification of causative drugs has been demonstrated. Infections do not play a prominent role in the development of AGEP. There is no evidence for the assumption that AGEP is a variant of pustular psoriasis. Unique observations related to AGEP include a marked female predominance, a possible role for seasonality and a causal role for spider bites. SUMMARY: A broad spectrum of drugs is associated with AGEP, a T cell-mediated reaction. Genetic susceptibility and the possible role of other risk factors in AGEP should be further evaluated in larger studies of AGEP patients with a validated diagnosis.

Profile of acute generalized exanthematous pustulosis in Israel during 2002-2005: results of the RegiSCAR Study.

BACKGROUND: Acute generalized exanthematous pustulosis is a rare pustular severe cutaneous adverse reaction characterized by a rapid clinical course and unique histological findings. It is usually attributed to drugs, although other factors have also been implicated. OBJECTIVES: To analyze demographic, clinical and laboratory data of AGEP cases in Israel, based on the RegisCAR study, a multinational European study. METHODS: Patients included in the present study were actively recruited by the Israeli RegiSCAR network, which comprised 10 dermatology departments and units. The cases were validated by a multinational expert committee of dermatologists based on a standardized scoring system. RESULTS: Overall, 11 potential cases of AGEP were collected in Israel: 9 (81.8%) definite and 2 (19.2%) possible. The adjusted annual incidence of AGEP in Israel was 0.35/million/year. The nine definite cases that entered the analyses showed a male/female ratio of 0.28 with an age range of 10-60 years. Most cases were reported during the summer months. The clinical course and laboratory findings in most of our patients were in accordance with previous reports. A drug etiology was suspected in the majority of cases and consisted of analgesics (66.7%), antibiotics (22.2%) and non-steroidal anti-inflammatory drugs (11.1%) as the main culprit drugs. CONCLUSIONS: Whereas the clinical and laboratory findings of AGEP in Israel corresponded to the reported features of AGEP in the literature, some unique findings were noted, namely, marked female predominance, seasonality and a profile of culprit drugs.

A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs.

BACKGROUND: Stevens-Johnson syndrome (SJS) and its severe form, toxic epidermal necrolysis (TEN), are rare but life-threatening cutaneous adverse reactions to drugs, especially to allopurinol, carbamazepine, lamotrigine, phenobarbital, phenytoine, sulfamethoxazole, oxicam and nevirapine. Recently, a strong association between carbamazepine and allopurinol induced SJS or TEN has been described with respectively, HLA-B*1502 and HLA-B*5801 in a Han Chinese population from Taiwan and other Asian countries. OBJECTIVE: The objective is to further investigate the relationship between SJS/TEN and HLA-B in a large number of patients in a European population. METHODS: HLA-B genotyping was performed on 150 patients included in a European study (RegiSCAR) of SJS and TEN. We focused on patients related to 'high-risk' drugs including: 31 cases related to allopurinol, 28 to sulfamethoxazole, 19 to lamotrigine and 14 to oxicam. RESULTS: Sixty-one percent of 31 allopurinol-induced SJS/TEN patients carried the HLA-B*5801 allele and the figure was 55% for 27 patients of European ancestry [odds ratio=80 (34-187)], (P<10(-6)) as previously observed in Han Chinese. For other drugs, two rare alleles showed a weaker association with SJS/TEN in a limited number of patients: B*38 for sulfamethoxazole or lamotrigine-related patients, and B*73 for oxicam. CONCLUSION: At variance with prior results in Asia, this study shows that even when HLA-B alleles behave as strong risk factors, as for allopurinol, they are neither sufficient nor necessary to explain the disease. Further investigations are necessary to delineate the exact role of the HLA region in SJS/TEN, and to look for other associations in other regions of the genome.

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 (

Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe cutaneous adverse reactions (SCAR) related to a variety of medications. They have a significant public health impact because of high mortality and morbidity. A multinational case-control study conducted in Europe between 1997 and 2001 evaluated the risk of medications to induce SCAR. Cases were actively detected through a hospital network covering more than 100 million inhabitants. Three hospitalized patients per case matched on age, gender, and date of interview were enrolled as controls. After validation by an expert committee blinded to exposures, 379 SCAR cases and 1,505 controls were included. Among drugs recently introduced into the market, strong associations were documented for nevirapine (relative risk (RR)>22) and lamotrigine (RR>14), and weaker associations for sertraline (RR=11 [2.7-46]), pantoprazole (RR=18 [3.9-85]), and tramadol (RR=20 [4.4-93]). Strong associations were confirmed for anti-infective sulfonamides, allopurinol, carbamazapine, phenobarbital, phenytoin, and oxicam-NSAIDs , with some changes in relative numbers of exposed cases. Thus, many cases were still related to a few "old" drugs with a known high risk. Risk was restricted to the first few weeks of drug intake. The use of such drugs as first-line therapies should be considered carefully, especially when safer alternative treatments exist. A number of widely used drugs did not show any risk for SJS and TEN.

Multiple drug allergy in patients with cutaneous adverse drug reactions diagnosed by in vitro drug-induced interferon-gamma release.

BACKGROUND: Multiple drug allergy syndrome is a rarely reported clinical condition characterized by an adverse reaction to more than one different class of pharmacologically and structurally unrelated drugs. The pathogenesis may involve immediate-type or delayed-type hypersensitivity. OBJECTIVES: To further characterize patients with MDA in terms of the type of CADR, drug intake and clinical drug suspicion. METHODS: The study group comprised 12 patients (6 males, 6 females) with CADRs showing in vitro drug-induced IFNgamma release for multiple drugs, suggesting the presence of MDA. The diagnostic role of in vitro IFNgamma release in identifying the culprit drugs was evaluated in terms of clinical data and the results of in vivo tests (withdrawal and/or challenge tests) with the offending drugs. RESULTS: Clinical relevance was attributed to in vitro drug-induced IFNgamma release towards multiple drugs in this series of 12 patients with a variety of CADRs, implying MDA. The results of in vivo tests for the offending drugs confirmed the diagnosis. The main causative agents responsible were antibiotics and non-steroidal anti-inflammatory drugs. CONCLUSIONS: The study further supports the role of a T cell-mediated mechanism in the pathogenesis of MDA. The in vitro drug-induced IFNgamma release test may serve as a laboratory tool to identify the culprit drugs associated with this allergy.

Acute generalized exanthematous pustulosis following a spider bite: report of 3 cases.

Acute generalized exanthematous pustulosis (AGEP) is a rare severe cutaneous adverse reaction caused mostly by drugs. Three of 22 AGEP cases (13.6%), recruited by us as part of two prospective multinational studies, occurred 24 to 48 hours after a spider bite. We suggest that a spider bite is a possible trigger for AGEP.

[Acute generalized exanthematous pustulosis (AGEP) following intake of furosemide].

INTRODUCTION: Acute generalized exanthematous pustulosis (AGEP) is an acute pustular eruption with unique clinical features, a rapid clinical course and a typical histopathology. The causative agents are mostly drugs but other triggers have also been described. CASE REPORT: A 52 year-old woman with a history of diabetes mellitus type II, dyslipidemia and osteomyelitis was treated for about a year with metformin (Glucophage) and simvastatin (Simovil) tablets. Due to the osteomyelitis, the patient was started on a regimen of intravenous vancomycin as well as furosemide tablets (Fusid) for pedal edema. About seventeen days after beginning treatment with vancomycin and a week after starting furosemide the patient was hospitalized due to an acute pruritic pustular eruption, involving most of her body surface area. Both vancomycin and furosemide treatment were discontinued, and topical treatment was provided. The clinical course was rapid with spontaneous resolution of the pustules followed by a characteristic pin-point post-pustular desquamation. The morphological, clinical and histological findings suggested a definite case of AGEP based on the EuroSCAR scoring system. The latent period between the initiation of medication intake and the appearance of AGEP, as well as a literature search, suggest that furosemide might be the incriminated drug. CONCLUSION: We have described a rare case of typical AGEP most probably induced by furosemide.