Pathogenesis, diagnosis, and treatment of aspirin intolerance.

OBJECTIVES: To provide an overview of aspirin intolerance (AI), to summarize the latest genetic and pathophysiologic findings, and to discuss the current therapeutic recommendations, including aspirin desensitization. DATA SOURCES: Using the PubMed database, a systematic search of articles published between 1968 and 2006 was performed to evaluate the current literature on AI. The bibliographies of selected articles served as a source of additional literature. STUDY SELECTION: Included articles were selected for their relevance to the pathogenesis, diagnosis, and management of AI. RESULTS: The prevalence of AI is approximately 0.3% to 0.9%, but AI is often overlooked. It can display a wide range of clinical pictures, such as acute asthma attacks, urticaria, angioedema, chronic rhinitis, myocardial ischemia, and anaphylactic shock. Regarding the pathogenesis of AI, modifications of eicosanoid metabolism are supposed to underlie AI, including aspirin-induced asthma and aspirin-induced urticaria. However, the pathogenesis of AI has not yet been clearly elucidated. Associations of several HLA alleles with subtypes of AI, such as aspirin-induced urticaria and aspirin-induced asthma, and single nucleotide polymorphisms in genes encoding enzymes involved in arachidonic acid metabolism have been shown. CONCLUSIONS: Because aspirin therapy should be avoided in AI patients, the use of alternative drugs is recommended. Patients intolerant of alternative drugs and those with therapy-resistant asthma or sinusitis benefit from aspirin desensitization.

The safety and efficacy of alefacept in the treatment of chronic plaque psoriasis.

Alefacept is the first biological agent approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe chronic plaque psoriasis. It is a full human fusion protein binding to CD2 on T cells. With its dual mechanism of action, alefacept blocks the interaction between the leukocyte-function-associated antigen (LFA)-3 and CD2 and thereby impedes the activation and proliferation of T cells. In addition, alefacept induces apoptosis of activated memory T cells. This paper presents an overview about the clinical studies on alefacept, its mechanism of action, and the results of the clinical trials focused on efficacy and safety of alefacept in different populations. Further on, data available on the use of alefacept in combination with other therapeutic agents are discussed.

Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease with a strong genetic background. One of the characteristic features of AD and causative factor for the disease is an impaired epidermal skin barrier based on a primary defect of epidermal differentiation. OBJECTIVES: Recently, 2 loss-of-function mutations (R501X and 2282derl4) in the filaggrin gene (FLG) that cause ichthyosis vulgaris, one of the most common inherited skin disorders of keratinization, have been reported to be strong predisposing factors for AD. METHODS: We evaluated the association of the loss-of-function mutations R501X and 2282del4 within the FLG gene in a large collection of 476 well-characterized white German families with AD by using the transmission-disequilibrium test. RESULTS: Our family-based approach revealed prominent associations between the 2 loss-of-function FLG mutations and AD, as previously observed in a traditional Mendelian linkage analysis and case-control cohort analysis approach. In addition, we observed associations of the FLG mutations in particular with the extrinsic subtype of AD, which is characterized by high total serum IgE levels and concomitant allergic sensitizations. Furthermore, FLG mutations are significantly associated with palmar hyperlinearity in patients with AD, which represents a shared feature of AD and ichthyosis vulgaris. CONCLUSION: Together these data implicate that FLG is the first really strong genetic factor identified in a common complex disease. CLINICAL IMPLICATIONS: These findings underline the crucial role of the skin barrier in preventing allergic sensitization.

Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema.

BACKGROUND: Human IL-18 is an inflammatory cytokine that plays a role in atopic diseases, such as atopic eczema (AE), by enhancing IL-4 and IL-13 production and stimulating the synthesis of IgE. OBJECTIVE: To evaluate associations of polymorphisms in the IL18 gene on chromosome 11q22 with AE, we performed genotyping for single nucleotide polymorphisms (SNPs) in the IL18 gene in 225 patients with AE and 175 healthy control volunteers. METHODS: Genotyping was performed by means of restriction fragment length polymorphism analysis. RESULTS: Analyses revealed significant associations of SNPs +113[t/g] and +127[c/t] in exon 1, -137[g/c] in promoter region 1, and -133[c/g] in promoter region 2 with AE. These associations were not directly dependent on a specific subtype of AE or the concomitant manifestation of allergic rhinitis or asthma. On the functional level, the amount of IL-18 in the supernatants of PBMCs of patients with AE stimulated with Staphylococcus aureus enterotoxin B was significantly higher than that in healthy control subjects. In parallel, the amount of active IL-18 in the sera of patients with AE was enhanced at the exacerbation of their disease. CONCLUSION: In conclusion, our data suggest that SNPs in the IL18 gene might be involved in the development of AE by contributing to a functional dysregulation of the IL-18 production in vivo .

Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis.

BACKGROUND: The high-affinity receptor for IgE (FcepsilonRI) on myeloid dendritic cells has been shown to play a major role in atopic dermatitis (AD). Plasmacytoid dendritic cells (pDCs), which are instrumental in the defense of viral infections, are present in reduced amounts in the skin of patients with AD, which is characterized by a high susceptibility to viral infections. OBJECTIVE: We explored phenotypical and functional characteristics of pDC in the peripheral blood of patients with AD and healthy individuals. METHODS: Blood dendritic cell antigen-2+CD123+ pDCs were enriched from the peripheral blood of patients with AD and studied in functional assays. RESULTS: Skin-homing molecules such as cutaneous lymphocyte antigen and L-selectin CD62L were expressed in lower levels on pDCs of patients with AD. pDCs expressed high amounts of IgE-occupied FcepsilonRI. Further, FcepsilonRI aggregation on pDCs impaired the surface expression of MHC I and II, induced the production of IL-10, and enhanced the apoptosis of pDCs. Importantly, FcepsilonRI preactivated pDC produced less IFN-alpha and IFN-beta after stimulation with CpG motifs and enhanced the outcome of immune responses of the TH2 type. CONCLUSION: From these data, we conclude that FcepsilonRI-bearing pDCs from patients with AD (1) are different from pDCs of healthy individuals, (2) might be important in the pathophysiology of AD, and (3) contribute to the enhanced susceptibility of patients with AD to viral infections.