Background We have reported that in patients with chronic idiopathic urticaria (CIU) who reacted adversely to aspirin, the frequency of the −444C allele of the leukotriene C4 synthase gene (LTC4S) was higher than in patients who tolerated aspirin well. Objectives To study the pattern of aspirin‐induced urticaria (AIU) in two families, with special interest on the polymorphisms of LTC4S (AA, AC, CC) and the glutathione S‐transferase M1 and P1 genes (GSTM1 and GSTP1). Methods Of 74 patients with CIU and a history of aspirin hypersensitivity studied by us, two patients (probands) gave a family history of aspirin intolerance. Oral challenge tests with aspirin were carried out in members of these families. Genomic DNA samples were obtained from peripheral blood to study the polymorphisms of LTC4S, GSTM1 and GSTP1. Results In family 1 the aspirin challenge test confirmed AIU in three of five (60%) individuals, but in family 2 only in two of seven (29%). In both families, the variant genotypes of LTC4S (AC or CC) were present in the parents, but only one of them had CIU. In family 1, with both parents healthy, the three children had AIU; in two it was associated with variant LTC4S genotype. In family 2, urticaria following aspirin ingestion was present only with variant LTC4S genotype. In patients of both families with positive aspirin challenge test, deletion of the GSTM1 gene was present. Conclusions AIU aggregates in families inheriting the LTC4S−444C allele. Segregation of aspirin sensitivity in these families does not follow a clear Mendelian pattern. A common deletion of GSTM1, one of several enzymes involved in conjugation of a wide range of electrophilic substances with glutathione, was present in all individuals ascertained to have AIU.
Darier disease (DD) is an uncommon genetic skin disorder, which begins in adolescence or early adult life. This disease is observed more often among men and where the disease course is more severe. Many dermatologists observe in patients with DD neuropsychiatric disorders: psychosis, depression and rare mental retardation. We present familial DD in a mother and her two sons. Men demonstrated a typical onset and course of the disease. The onset of the disease in the 52nd year of age and the skin lesions (more characteristic for the Lyell disease) which occurred suddenly in women, were atypical. Besides skin lesions, mental retardation with a various degree of intensity was observed in all three patients.
Objective: We aimed to investigate systemic production of prostaglandin E2 in chronic idiopathic urticaria patients, stratified by positive or negative clinical reaction during oral aspirin challenge. Materials and Methods: Urinary concentrations of semi-stable prostaglandin E2 metabolite, 13,14- dihydro-15-keto-PGE2, were measured using commercial enzyme immunoassay at baseline and following aspirin challenge. Results: Aspirin precipitated skin reactions in 14 (63.6%) out of 22 patients with chronic idiopathic urticaria. At baseline, mean urinary prostaglandin E2 metabolite values did not differ between patients who reacted to the drug and those who tolerated it. Following aspirin administration, urinary prostaglandin E2 metabolite excretion significantly decreased in all patients. No correlation was found between urinary prostaglandin E2 metabolite excretion and dose of aspirin precipitating hypersensitivity symptoms. Conclusion: Administration of aspirin decreases systemic production of prostaglandin E2 in chronic idiopathic urticaria patients. This effect is independent of the outcome of aspirin challenge and does not discriminate between patients who develop hypersensitivity symptoms and those who tolerate aspirin well.
Background: The high‐affinity receptor for immunoglobulin‐E (IgE) (Fc ɛ RI) plays a major role in the pathogenesis of allergy, but there are only two published studies on its α subunit (Fc ɛ RI α ) genetic variability in allergic diseases. Aims of the study: Mutational screening in the region of the Fc ɛ RIα gene promoter and the first exon with subsequent genetic variability assessment in allergic patients and a random population sample. Methods: Allergic subjects were individuals with asthma or urticaria. Age‐ and sex‐matched controls were randomly selected from a large population sample. Mutational screening was performed using a single‐stranded conformational polymorphism and subsequent sequencing. Detected polymorphisms were genotyped by restriction fragment length polymorphism. Total serum IgE was measured in allergic subjects and controls. Skin prick tests, blood eosinophil count and aspirin challenge test were performed only in the subjects. A subgroup of the subjects was further characterized by autologous serum skin test, histamine release test, Phadiatop and IgE antibodies against staphylococcal enterotoxins. Results: Two linked polymorphisms −344 C>T and −95 T>C were found within the Fc ɛ RI α gene. The allele −344 T frequency was 0.45 vs 0.37 ( P = 0.33), and the allele −95 C frequency was 0.26 in subjects vs 0.30 in controls ( P = 0.62). Serum IgE was significantly higher in subjects homozygous for the −344T allele (TT genotype) than in those carrying the −344 C allele (CT or CC genotype; P = 0.003), but this association was not detectable in controls. Conclusions: Our findings of genotype‐related differences in IgE levels in allergic patients suggest an impact of −344 C>T but not −95 T>C gene polymorphism of Fc ɛ RI α on total levels of IgE. The genetic variability in Fc ɛ RI α at the −344 nucleotide of its regulatory sequence, though not related to atopy, predicts higher levels of the immunoglobulin.
Nonsteroidal anti-inflammatory drugs (NSAIDs) exacerbate various forms of urticaria by a nonallergic mechanism involving inhibition of cyclooxygenases.
Objectives
To assess safety of cyclooxygenase inhibitors in patients with chronic idiopathic urticaria (CIU) and NSAID sensitivity and to evaluate a role of cysteinyl leukotriene metabolism and mast cell activation in sensitivity to NSAIDs in CIU.
Design
Aspirin challenge test followed by randomized, prospective, double-blind, placebo-controlled crossover trial with cyclooxygenase 2 inhibitors.
Setting
Tertiary referral center of a university hospital.
Patients
Thirty-six patients with CIU.
Interventions
Aspirin challenge test (up to 500 mg); randomized trial with rofecoxib (up to 37.5 mg) and celecoxib (up to 300 mg) in aspirin-sensitive patients. After completion of the trial, 7 patients received naproxen sodium (500 mg) as a positive control.
Main Outcome Measures
Standardized skin examination, skin biopsy with mast cell count, urinary levels of leukotriene E4(LTE4), and serum levels of mast cell tryptase.
Results
Aspirin induced skin eruption in 18 patients. Rofecoxib or celecoxib did not elicit skin eruption in any of the aspirin-sensitive patients. Patients with CIU had higher urinary excretion of LTE4than healthy control subjects. Basal urinary levels of LTE4and serum mast cell tryptase were increased in aspirin-sensitive compared with aspirin-tolerant patients. Severity and duration of aspirin-induced urticaria showed a positive correlation with urinary LTE4excretion. Naproxen precipitated urticaria in 5 of 7 aspirin-sensitive patients and caused further increase in urinary LTE4.
Conclusions
Cyclooxygenase 2 inhibitors do not induce urticaria in patients with CIU sensitive to NSAIDs. Sensitivity to NSAIDs in CIU is associated with overproduction of cysteinyl leukotrienes and mast cell activation and most likely depends on inhibition of cyclooxygenase 1.
Pro- and anti-inflammatory metabolites of arachidonic acid - eicosanoids - participate in skin homeostasis, affecting the growth and differentiation of keratinocytes. Alterations of 12-lipoxygenase (LOX) and 15-LOX and their metabolites have been described in the epidermis of patients with psoriasis, but systemic production of 12-LOX and 15-LOX eicosanoids has not been studied in the disease.To ascertain the frequencies of the genetic variants ALOX12 rs1126667 and ALOX15 rs11568070 in cases and controls, and to compare urinary metabolites of 12(S)-hydroxyeicosatetraenoic acid (HETE) between patients with psoriasis and healthy controls.Patients with psoriasis (n = 200) were stratified depending on the severity of their dermal lesions. Genotyping was performed using a 5'-nuclease real-time assay. The concentrations of 12(S)-HETE, its metabolites and 15(S)-HETE were determined in urine samples using high-performance liquid chromatography-tandem mass spectrometry.Tetranor-12(S)-HETE metabolite excretion was significantly higher in urine of patients with psoriasis, while excretion of 12(S)-HETE was decreased. Neither 12(S)-HETE nor tetranor-12(S)-HETE correlated with the type of disease or severity score. No difference in urinary 15(S)-HETE was found between the study groups. Genotype distribution of the ALOX12 rs1126667 or ALOX15 rs11568070 polymorphisms did not discriminate for the disease or its severity.Systemic metabolism of 12(S)-HETE is accelerated in psoriasis because excretion of the tetranor-12(S)-HETE inactivation product is elevated. No correlation with the severity or extent of psoriasis is detectable. We propose that in patients with psoriasis, 12(S)-HETE to tetranor-12(S)-HETE conversion could be at least a marker for this disease, in which inflammation of the skin can induce microsomal beta-oxidation of this eicosanoid.
