Review and feature article
Chronic urticaria: Pathogenesis and treatment,☆☆,

https://doi.org/10.1016/j.jaci.2004.02.049Get rights and content

Abstract

Patients previously designated as having chronic idiopathic urticaria are now divided into 2 groups: 40% to 50% with chronic autoimmune urticaria, and the remainder with chronic idiopathic urticaria. Patients in both groups may have concomitant angioedema (approximately 40%). The autoimmune subgroup has an association with antithyroid antibodies and is caused by IgG antibody to the α subunit of the IgE receptor (35% to 40%), usually reactive with unoccupied IgE receptors, or IgG antibody to IgE (5% to 10%). Complement activation augments histamine secretion by release of C5a. The IgG subclasses that appear to be pathogenic are IgG1, IgG3, and, to a lesser degree, IgG4, but not IgG2. Histology of chronic urticaria (both subtypes) reveals a perivascular non-necrotizing infiltrate of CD4+ lymphocytes consisting of a mixture of TH1 and TH2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited as a result of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules. Suggested therapy for patients with severe disease involves the use of high-dose hydroxyzine or diphenhydramine when nonsedating antihistamines are ineffective, supplemented by H-2 antagonists and leukotriene antagonists. The most severe patient may require protracted treatment with low-dose alternate-day steroid or cyclosporine. Cyclosporine can be steroid-sparing when side effects are encountered or when use of steroids is relatively contraindicated. Careful monitoring of blood pressure, BUN, creatinine, and urinalysis is required.

Section snippets

Autoimmunity and chronic urticaria: historical observations

The first suggestion that patients with chronic urticaria and angioedema might have an autoimmune diathesis was the observation that there is an increased incidence of antithyroid antibodies in such patients relative to the incidence in the population at large.10 These include anti-microsomal (perioxidase) and anti-thyroidglobulin antibodies, as are associated with Hashimoto thyroiditis.11 Patients might have clinical hypothyroidism, and a small number might have hyperthyroidism if thyroid

Functional assays of anti-IgE receptors

Assays for anti-IgE receptor antibody have included in vivo methods and in vitro assays. The autologous skin test,2., 15. as noted above, provided one of the first clues that a subset of patients with chronic urticaria have an autoimmune disorder. Basophils are frequently used as an in vitro surrogate for mast cells, and secretion of histamine as a result of incubation with patient sera or purified IgG was readily demonstrated19., 20., 21. but was not observed if the source of basophils was

Binding assays for anti-receptor antibody

Attempts to quantitate IgG antibody to the α subunit have, in general, been unsuccessful. Initial attempts to demonstrate the presence of the antibody by means of immunoblotting22., 29. have not proved useful because positive reactions might be seen in other autoimmune disorders29 or occasionally with sera22 from subjects with no history of urticaria. In addition, studies of the relationship of a positive immunoblot result with histamine release did not yield a significant correlation23; sera

The role of complement

The notion that complement might contribute to the histamine release observed with sera from patients with chronic urticaria was suggested by studies in which complement depletion or inactivation appeared to diminish histamine release.20., 29. A series of reports by Ferrer et al28 and Kikuchi and Kaplan23., 33. then documented not only a role for complement but also more specifically activation of the classical pathway and generation of C5a. First, we demonstrated that the addition of purified

The cellular infiltrate

Mast cell degranulation certainly initiates the inflammatory process in autoimmune chronic urticaria and is assumed to also do so in idiopathic chronic urticaria. However, no alternative mechanism for mast cell degranulation in the idiopathic groups has been suggested to date. Yet the histology of the 2 groups is virtually indistinguishable and differs only in minor ways. There is, however, considerable heterogeneity evident when individual patients are compared. Common to all biopsy specimens

Treatment considerations

A review of the treatment of chronic urticaria has been recently published,48 including a critical assessment of approaches that are evidence based. The mainstay of initial treatment is the use of antihistaminic agents active at the H1 receptor. Alternate-day steroids may be used for patients with severe disease,1., 48. and immunosuppressive agents, such as cyclosporine, can also be used for patients with severe disease.49., 50., 51. Cyclosporine also inhibits basophil and mast cell

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    (Supported by a grant from GlaxoSmithKline, Inc, Research Triangle Park, NC)

    ☆☆

    Series editor: Harold S. Nelson, MD

    Disclosure of potential conflict of interest: A. P. Kaplan—none disclosed.

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