This update on chronic urticaria (CU) focuses on the prevalence and pathogenesis of chronic spontaneous urticaria (

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Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor FcɛRI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor κB (NF-κB) nor produce tumor necrosis factor α or interleukin 6 upon FcɛRI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of FcɛRI-dependent mast cell activation that selectively uncouple NF-κB–induced proinflammatory cytokine production from degranulation and leukotriene synthesis.

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To cite this article: Ring J, Gutermuth J. 100 years of hyposensitization: history of allergen‐specific immunotherapy (ASIT). Allergy 2011; 66: 713–724. Abstract Hundred years ago, Leonhard Noon and John Freeman published their pioneering works on allergen‐specific immunotherapy (ASIT) using grass pollen extracts. To honor their contribution to the development of ASIT as the only causal treatment of IgE‐mediated allergies, we review the history of ASIT that started with the anecdotal descriptions of ASIT performed by the ancient king Mithridates (132–63 B.C.) and Jenner’s development of a cowpox vaccine. Following Noon’s and Freeman’s first controlled human trials, ASIT was performed by a large number of modalities and with a myriad of pharmacologic preparations. These developments range from early aqueous pollen extracts and whole bee extracts to chemically modified allergens (allergoids) and various recombinant allergens. In addition to allergen‐specific immunotherapy, non‐specific immune response modifiers have been used in the past or are in the developmental stage. Also, currently many innovative experimental approaches of ASIT are studied in animal models and human in vitro systems and will hopefully further broaden the range of allergies that can be treated by ASIT, with enhanced efficacy and further reduced side‐effects.

Summary Background Patients with severe atopic dermatitis (AD) not controlled with topical therapy have limited treatment options. Ciclosporin A (CSA) is a commonly used, broad immunosuppressant in AD, but treatment with CSA requires monitoring for potentially serious adverse effects. In a previous phase III trial, tralokinumab plus topical corticosteroids (TCS) as needed provided early and sustained improvements in AD signs and symptoms. Objectives To evaluate the efficacy and safety of tralokinumab plus TCS in adult patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA. Methods In this 26‐week, multicentre, parallel, randomized, double‐blind, placebo‐controlled, phase III trial, European adults with severe AD were randomized 1 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks plus TCS as needed. The primary endpoint was a 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Results In total, 277 patients were randomized. At week 16, more patients treated with tralokinumab plus TCS vs. placebo plus TCS achieved EASI 75 [64·2% vs. 50·5%; difference 14·1% (95% confidence interval 2·5–25·7); P = 0·018], which increased further up to week 26. Improvements in AD severity were accompanied by early improvements in patient‐reported outcomes, including Dermatology Life Quality Index, Patient‐Oriented Eczema Measure, pruritus and sleep interference. Tralokinumab plus TCS also showed a higher EASI75 response at week 16 among patients who had previously failed CSA therapy vs. placebo plus TCS (57% vs. 41%). The overall incidence of adverse events was similar between treatment arms. Conclusions Tralokinumab 300 mg plus TCS as needed was effective and well tolerated in patients with severe AD whose disease was not adequately controlled with CSA or who had contraindications to oral CSA.

The presence of ectopic breast tissue is reported in 2-6% of the general population with most cases being located in the axillary region. Although the same pathology occurs in both eutopic and ectopic breast tissue, primary carcinoma of ectopic breast tissue has been reported only in a small number of cases. Because an overlying accessory areola or nipple is often missing and because of a general lack of awareness among physicians and patients concerning these unsuspicious nodules, clinical diagnosis is frequently delayed. Histological diagnosis can also be delayed if ectopic breast tissue is not present or screened for in the biopsy specimens as apocrine glands of the breast and skin, respectively, exhibit striking similarities and immunohistochemistry is of limited help. Diagnostic delay is demonstrated by the case of a 56-year-old patient who underwent a series of four surgical excisions of a primary ectopic breast carcinoma and developed local lymph node metastasis until treatment with tamoxifen was started. As two-thirds of reported cases of primary ectopic breast carcinoma arose within the axillae, this case underlines the importance of a search for ectopic breast tissue in the context of axillary ductal carcinoma.

The utility of allogeneic hematopoietic stem cell transplantation is limited by graft-versus-host disease (GVHD), a significant cause of morbidity and mortality. Patients with GVHD exhibit cutaneous manifestations with histological features of interface dermatitis followed by scleroderma-like changes. JAK inhibitors represent a class of immunomodulatory drugs that inhibit signaling by multiple cytokines. Herein we report the effects of tofacitinib in a murine model of GVHD. Oral administration of tofacitinib prevented GVHD-like disease manifested by weight loss and mucocutaneous lesions. More importantly, tofacitinib was also effective in reversing established disease. Tofacitinib diminished the expansion and activation of murine CD8 T cells in this model, and had similar effects on IL-2-stimulated human CD8 T cells. Tofacitinib also inhibited the expression of IFN-γ-inducible chemoattractants by keratinocytes, and IFN-γ-inducible cell death of keratinocytes. Tofacitinib may be an effective drug for treatment against CD8 T-cell–mediated mucocutaneous diseases in patients with GVHD.