Mast cells and basophils (MCs/Bs) play a crucial role in type I allergy, as well as in innate and adaptive immune responses. These cells mediate their actions through soluble mediators, some of which ...are targeted therapeutically by, for example, H1- and H2-antihistamines or cysteinyl leukotriene receptor antagonists. Recently, considerable progress has been made in developing new drugs that target additional MC/B mediators or receptors, such as serine proteinases, histamine 4-receptor, 5-lipoxygenase–activating protein, 15-lipoxygenase-1, prostaglandin D2 , and proinflammatory cytokines. Mediator production can be abrogated by the use of inhibitors directed against key intracellular enzymes, some of which have been used in clinical trials (eg, inhibitors of spleen tyrosine kinase, phosphatidylinositol 3-kinase, Bruton tyrosine kinase, and the protein tyrosine kinase KIT). Reduced MC/B function can also be achieved by enhancing Src homology 2 domain–containing inositol 5′ phosphatase 1 activity or by blocking sphingosine-1-phosphate. Therapeutic interventions in mast cell–associated diseases potentially include drugs that either block ion channels and adhesion molecules or antagonize antiapoptotic effects on B-cell lymphoma 2 family members. MCs/Bs express high-affinity IgE receptors, and blocking their interactions with IgE has been a prime goal in antiallergic therapy. Surface-activating receptors, such as CD48 and thymic stromal lymphopoietin receptors, as well as inhibitory receptors, such as CD300a, FcγRIIb, and endocannabinoid receptors, hold promising therapeutic possibilities based on preclinical studies. The inhibition of activating receptors might help prevent allergic reactions from developing, although most of the candidate drugs are not sufficiently cell specific. In this review recent advances in the development of novel therapeutics toward different molecules of MCs/Bs are presented.
In patients given a diagnosis of chronic spontaneous urticaria (CSU), there are no obvious external triggers, and the factors that initiate the clinical symptoms of wheal, flare, and itch arise from ...within the patient. Most patients with CSU have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or double-stranded DNA, whereas other patients make IgG autoantibodies against FcεRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcεRI on mast cells without FcεRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcεRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcεRI or other receptors for the degranulation process. Furthermore, IgE-FcεRI engagement potentiates the ability of mast cells to store and synthesize de novo inflammatory mediators and cytokines. Administration of omalizumab, by virtue of its ability to deplete IgE, attenuates the multiple effects of IgE to maintain and enhance mast cell activities and hence reduces the ability of mast cells to manifest inflammatory mechanisms in patients with CSU.
Background Psoriasis vulgaris is characterized by disfiguring and stigmatizing skin lesions. The links among lesions distribution, severity, and stigmatization remain unclear. Objective We sought to ...investigate if the involvement of visible and sensitive areas is linked to stigmatization. Methods In all, 115 patients with psoriasis vulgaris were assessed for disease severity, skin lesions distribution, itch, and stigmatization using the Feelings of Stigmatization Questionnaire. Quality of life was assessed with the Dermatology Life Quality Index and the World Health Organization Quality of Life-BREF. Results The localization of psoriatic lesions on the back of hands was related to higher stigmatization levels ( P = .011, total score of the Feelings of Stigmatization Questionnaire), but not the involvement of nails, the palms, the face, or the genital area nor overall disease severity. All patients reported some level of stigmatization, regardless of the localization of lesions and type of psoriasis. Higher levels of stigmatization characterized patients who claimed not to be able to hide their lesions by clothing ( P = .025), women ( P = .001), and the unemployed ( P = .004). Stigmatization was the strongest predictor of quality of life impairment. Limitations Only hospitalized patients were included. Conclusions Psoriatic lesions on the back of hands are debilitating and warrant effective treatment. Special attention should be paid to female patients, who are more sensitive to stigmatization.
Background Increased dosing of nonsedating antihistamines is recommended by the current European Academy of Allergology and Clinical Immunology/Global Allergy and Asthma European Network/European ...Dermatology Forum guidelines on patients with acquired cold urticaria (ACU) who do not respond satisfactorily to the standard dose. Prospective data supporting this recommendation are scant. Objective We sought to assess the effects of 5 and 20 mg of desloratadine and placebo on cold-induced urticarial reactions in patients with ACU. Methods In this prospective, randomized, double-blind, 3-way crossover trial, patients with ACU (n = 30) received placebo, 5 mg of desloratadine, and 20 mg of desloratadine every day each for 7 days separated by 14-day washout periods. At the end of each treatment, patients underwent cold provocation with the TempTest 2.0/2.1 system, and urticarial reactions were assessed by using digital 3-dimensional time-lapse photography and thermography; the critical temperature threshold (CTT) and critical stimulation time threshold (CSTT) were measured. Adverse events (AEs) reported during the study were assessed. Results Compared with placebo, 7 days of desloratadine at 5 and 20 mg/d significantly reduced the volume of cold-induced wheals and areas of hyperthermic skin and improved CTT and CSTT results. Desloratadine at 20 mg/d significantly reduced cold-induced wheal volume and CTT and CSTT values versus desloratadine at 5 mg/d. Desloratadine was well tolerated, with no increased rate of somnolence or other AEs with 20 mg of desloratadine. Conclusions Desloratadine at standard and high doses significantly improved objective signs of ACU provoked by cold exposure. Desloratadine at 4 times the standard dose significantly reduced ACU lesion severity versus 5 mg of desloratadine without an increase in AEs. This study supports current guidelines that increased desloratadine dosing might benefit patients with urticaria who do not respond to standard doses.
To the Editor: Chronic spontaneous urticaria (CSU) presents as recurrent itchy wheals, angioedema, or both for at least 6 weeks without a specific trigger.1 Roughly half of the patients with CSU ...achieve symptomatic control with H1-antihistamine therapy at approved doses, increased doses, or with additional therapies such as leukotriene receptor antagonists.1 CSU can be unpredictable and debilitating for patients because of a lack of clinical response.2 Recently, omalizumab, a neutralizing anti-IgE mAb, has gained approval for treatment of patients with CSU on the basis of evidence of substantial efficacy.3 However, the treatment benefit with omalizumab is usually lost when treatment is stopped. Specific IgE may target an endogenous antigen, a hypothesis supported by evidence that approximately 50% of patients with CSU have elevated levels of antithyroperoxidase IgE.5 Quilizumab, a humanized, afucosylated, monoclonal IgG1 antibody, binds membrane IgE at the M1-prime segment, which is absent in soluble IgE.6 In animal studies, quilizumab bound membrane IgE on IgE-switched B cells and plasmablasts and depleted them through apoptosis and antibody-dependent cell-mediated cytotoxicity.6 In clinical trials, quilizumab reduced serum total and specific IgE levels in healthy volunteers and in patients with allergic rhinitis or mild asthma.7,8 These reductions were sustained for at least 6 months after the last dose, suggesting that quilizumab affected long-term IgE memory.
Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) causes swelling in the skin and upper airways and pain in the abdomen because of mucosal swelling. C1-INH-HAE is frequently ...misdiagnosed, leading to delays in diagnosis, inadequate treatment, and unnecessary procedures.
To evaluate the history of misdiagnosis in patients participating in the Icatibant Outcome Survey (IOS).
The IOS is an observational study in which safety and effectiveness of icatibant have been evaluated since 2009. As part of the IOS, patients record any misdiagnoses received before being diagnosed as having C1-INH-HAE.
In January 2016, a total of 418 of 633 IOS patients with C1-INH-HAE type I or II had provided misdiagnosis data. Of these, 185 of 418 (44.3%) received 1 or more prior misdiagnoses. The most common misdiagnoses were allergic angioedema (103 of 185) and appendicitis (50 of 185). A variety of other misdiagnoses were reported, including a substantial number of gastrointestinal disorders (excluding appendicitis). Misdiagnosis rates were similar between males (41.1%) and females (46.5%) and between C1-INH-HAE type I (43.7%) and type II (51.6%). Patients with family members diagnosed as having C1-INH-HAE were significantly less likely to be misdiagnosed than patients without a family history (140 of 366 41.7% vs 38 of 58 65.5%, respectively; P = .001). Patients with a prior misdiagnosis had longer median delay to C1-INH-HAE diagnosis (13.3 years) than patients without (1.7 years; P < .001).
From this large database, approximately 50% of patients with C1-INH-HAE type I or II have previously had their conditions misdiagnosed, most commonly as allergic angioedema or appendicitis. Misdiagnosis results in marked delays in receiving the correct diagnosis, during which time patients cannot access effective, lifesaving treatment.
ClinicalTrials.gov: NCT01034969.
Secondary end points included changes in the physician and patient global assessment of disease activity (10-point visual analog scale VAS) and changes in inflammation markers C-reactive protein ...(CRP) and erythrocyte sedimentation rate (ESR) during the 16 weeks following canakinumab treatment as compared to baseline. Methods Eligibility criteria To be included in the study, patients had to fulfill the following diagnostic criteria of UV: (1) urticarial rash with individual lesions persisting for more than 24 hours and (2) UV confirmed by biopsy from lesional skin showing signs of leukocytoclasis (fragmentation of neutrophils with nuclear dust) and/or fibrinoid deposits in perivascular and interstitial locations.E1 Participation in the study required active UV and insufficient response to treatment with antihistamines, nonsteroidal anti-inflammatory drugs, and/or immunomodulating or immunosuppressive drugs.
Extending the bioinformatic analysis to all the 95 amino acid substitutions presented in HAEdb (C1 inhibiTor gene muTATion dATAbAse, available at hae.enzim.hu7), we found that several additional ...alterations previously described by other researchers were estimated to be tolerant for the protein function (Table E5 in this article's Online Repository at www.jacionline.org). ...we suggest that bioinformatic analysis performed in cases of novel (missense) mutations could provide indications for a comprehensive analysis of SERPING1.
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