The Journal of Allergy and Clinical Immunology: In Practice
Review and Feature ArticleChronic Spontaneous Urticaria: The Devil's Itch
Introduction
Chronic urticaria is defined as the presence of urticaria for a period exceeding 6 weeks, assuming the presence of symptoms for most days of the week. It is divided into chronic inducible urticarias (also called physical urticarias) and chronic spontaneous urticaria (CSU), previously termed chronic idiopathic urticaria.1, 2 Chronic inducible urticarias are identified on the basis of history of a consistent stimulus that initiates lesions, which are typically short-lived and fleeting, lasting a few minutes up to 2 hours. When biopsied, there is no cellular infiltrate. In contrast, the term CSU emphasizes that patients can experience urticaria independent of any exogenous stimulus even if one can define circumstances that may worsen symptoms. Thus, a search for such an external “cause” in CSU is a fruitless effort because the underlying abnormality is “intrinsic.” Approximately 40% of patients with CSU will report accompanying episodes of angioedema or deeper swelling of dermal or mucosal tissues, whereas 10% have angioedema as their primary manifestation.3, 4 In most cases, it is a self-limiting disorder, persisting for 2 to 5 years in most cases, although 20% of patients suffer for more than 5 years.5, 6, 7
The treatment for CSU that has evolved is based on double-blind, placebo-controlled studies whenever possible, but is not yet targeted at any particular pathogenic mechanism. Although the efficacy of omalizumab in disease has implicated IgE and IgE receptors in disease pathogenesis, a clear biomarker that segregates responders from nonresponders remains elusive. In this article, we will review the current status regarding pathogenesis, discuss what are the essentials of a diagnostic workup, and update the approach to treatment including consideration of published guidelines, our own experience, and guideline updates that are being prepared.
Section snippets
Pathogenesis
Wheals and angioedema in CSU appear to involve the degranulation of skin mast cells, which release histamine, proteases, and cytokines with generation of platelet-activating factor and other arachidonic acid metabolites (prostaglandin D2, leukotrienes C4, D4, and E4). These mediators induce vasodilatation, increase vascular permeability, and stimulate sensory nerve endings that lead to swelling, redness, and itch.8 A lesion site or wheal is characterized by edema, mast cell degranulation, and a
Future Considerations
Clearly, the various aspects of pathogenesis require further investigation. Although autoantibody titers may or may not reflect disease status (eg, antinuclear antibodies [ANAs] and rheumatoid factor do not, whereas c-ANCA levels do83), a role for IgG anti-FcεRI alpha in urticarial pathogenesis requires further clarification but does provide a mechanism for histamine release in those in whom it is present. Although the latter is not more than 45%, the responsiveness of CSU to antihistamine
Distinguishing Features of CSU Versus Other Urticarias
Inducible urticarias are usually suspected on the basis of history.84 In addition, there are particular characteristics that distinguish the appearance and duration of physically induced hives from those of CSU (Table II). Individual lesions of cold urticaria, local heat urticaria, cholinergic urticaria, dermatographism, solar urticaria, and aquagenic urticaria are fleeting and last from a few minutes up to 2 hours.85 When biopsied, there is no cellular infiltrate. They respond to high-dose
Diagnosis of CSU
In an otherwise healthy individual, very few tests need to be done for a proper evaluation. Skin testing for food allergy is not recommended.1, 2 The typical patient who suspects a food allergy as the cause may present with a lengthy list of suspected foods or has tried many different diet manipulations, none of which have made a consistent difference in clinical course. Laboratory tests are also kept to a minimum. A complete blood cell count with differential is helpful if eosinophilia is
Treatment of CSU
The treatment of this disorder has been virtually revolutionized with the discovery that omalizumab is effective even in the most complex, resistant cases.106 The earliest observation was a case report of 3 patients107 in which omalizumab was tried, and appeared to be successful. Because omalizumab was already approved for asthma, a typical “phase 1” study was not necessary. Instead, a “proof-of-concept” study by Kaplan et al108 enrolled 12 severe patients, all with evidence of autoimmunity
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S.S.Saini is supported by grant number R01AI116658.
Conflicts of interest: S. S. Saini receives research grant funding from the National Institutes of Health, ITN, and Novartis; and has been a paid consultant for Array, Allakos, AstraZeneca, Genentech, Medimmune, Novartis, Ono, Pfizer, Regeneron, Teva, and Uriach. A. P. Kaplan is chairman of the Genentech review committee for adjudication of allergic events or angioedema and has received lecture fees from Shire and CSL Behring.