American Journal of Clinical Dermatology

Urticaria - A ReviewTasneem Poonawalla; Brent Kelly

Posted: 05/08/2009; Am J Clin Dermatol. 2009;10(1):9-21. © 2009 Adis Data Information BV

Abstract and Introduction

Abstract

Urticaria is often classified as acute, chronic, or physical based on duration of symptoms and the presence or absence of inducing stimuli. Urticarial vasculitis, contact urticaria, and special syndromes are also included under the broad heading of urticaria. Recent advances in our understanding of the pathogenesis of chronic urticaria include the finding of autoantibodies to mast cell receptors in nearly half of patients with chronic idiopathic urticaria. These patients may have more severe disease and require more aggressive therapies. Extensive laboratory evaluation for patients with chronic urticaria is typically unrevealing and there are no compelling data that associate urticaria with chronic infections or malignancy. Pharmacologic therapy consists primarily of the appropriate use of first- and second-generation histamine H1 receptor antihistamines. Additional therapy may include leukotriene receptor antagonists, corticosteroids, and immunomodulatory agents for severe, unremitting disease. Despite our greater understanding of the pathogenesis of urticaria, the condition remains a frustrating entity for many patients, particularly those with chronic urticaria.

Introduction

Urticaria, commonly called 'hives,' has a long and rich history in documented medicine dating back at least to the 10th century B.C. when it was called 'Feng Yin Zheng' in China. [1] Many cultures have described urticaria in some capacity and the disorder has had many names. In the 4th century B.C., Hippocrates noted the similarities between urticaria, contact with stinging nettles, and insect bites and called the condition 'cnidosis' (nettle rash).[2] 'Uredo,' 'essera' (Arabic for elevation), 'urticatio' (derived from the Latin urere; to burn), and 'scarlatina urticaria' have all been used.[2] Use of the term 'morbus porcinus', which means pig's disease, resulted from a translational error of the intended term 'morbus pocellaneus,' which referred to the white color of the central wheal.[3] William Cullen was probably the first to use the term urticaria in 1769.

Nearly as many theories about the pathogenesis of urticaria have been described including, among others, a humoral theory (relating urticaria to body 'humors'), a metereologic theory in 1823 (suggesting that allergy was determined by the constellation of the stars), and a menstrual theory in 1864 (proposing that urticaria was related to endogenous hormones).[1] It was the discovery of the mast cell in 1879 by Paul Ehrlich that led to our current understanding of allergy pathogenesis, including urticaria. However, despite improvements in our understanding of urticaria, the condition remains a frustrating disorder for many patients, particularly those with chronic urticaria. This review attempts to classify urticaria and discuss the evidence-based pathogenesis and treatment options available, with particular emphasis on chronic urticaria.

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A MEDLINE search using Ovid was performed to obtain the articles reviewed. Search terms included 'urticaria' and 'hives' and were applied from 1950 to the date of review. Relevant articles, particularly those relating to history, pathogenesis, and treatment, were included in this review. Articles were excluded if they did not add to the known knowledge base of the subject. Additional relevant articles were obtained from citations in the reference sections of identified articles.

Clinical Features and Epidemiology

Urticaria consists of recurrent wheals that are usually pruritic, pink-to-red edematous plaques that often have pale centers. The wheals are transient, and in most types of urticaria last for <24 hours. [4] The wheals range in size from a few millimeters to several centimeters in diameter. They can, however, become confluent and form plaques. Urticarial wheals are generally paler than the erythematous surrounding skin because of the compressing effect of dermal edema on post-capillary venules. Wheals may be round or irregular and may occur anywhere on the skin, including the scalp, palms, and soles. They are quite pruritic with maximal intensity in the evenings and night-time and occasionally may be 'burning' or 'pricking' in quality. This itch is unique in that it is relieved more so by rubbing than by scratching, and purpura rather than excoriations are a more common consequence of urticaria.[5]

Urticaria is a worldwide disease and may present at any age. The lifetime occurrence of urticaria in the general population ranges from 1% to 5%.[6,7]

Classification

Classification of urticaria is most often based upon clinical characteristics rather than etiology (see Table I). Unfortunately, it is often difficult to determine the etiology or pathogenesis of individual cases of urticaria and many cases remain idiopathic. Six weeks of daily or nearly daily symptoms is a somewhat arbitrary, but nonetheless useful, time period for separating acute from chronic urticaria. Angioedema can, and often does, accompany the urticarial lesions. Angioedema without urticaria, however, should raise suspicion of an acquired or hereditary form (particularly complement [C]-1-inhibitor deficiency), which can often be more severe with laryngeal involvement. Other categories of urticaria include contact urticaria, urticarial vasculitis, and physical urticaria. Physical urticaria, a unique and often debilitating form of the disorder, results from a specific trigger. Subtypes include aquagenic, cholinergic, cold, delayed pressure, dermatographism-related, localized heat, and solar and vibratory urticaria.[4,5]

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Table I. Classification of Urticaria

Ordinary urticarias

Acute urticaria

Chronic urticaria

Contact urticaria

Physical urticarias

Dermatographism

Immediate

Delayed

Cholinergic urticaria

Vibratory angioedema

Exercise-induced urticaria

Adrenergic urticaria

Delayed-pressure urticaria

Solar urticaria

Aquagenic urticaria

Cold urticaria

Special syndromes

Schnitzler syndrome

Muckle-Wells syndrome

Pruritic urticarial papules and plaques of pregnancy

Urticarial bullous pemphigoid

Urticarial vasculitis

Acute Urticaria

Acute urticaria, by definition, is wheals occurring for <6 weeks. The individual lesions typically resolve in <24 hours, occur more commonly in the pediatric population,[4] and are often associated with atopy. Between 20% and 30% of patients with acute urticaria progress to chronic or recurrent urticaria. [8]

Etiologic data suggest that acute urticaria is idiopathic in about 50% of patients, due to upper respiratory tract infections in 40%, to drugs in 9%, and to foods in 1%. [4] Food allergies probably contribute more often than is reflected in these data, but are under-represented because patients often self-diagnose and then avoid the offending agent. Acute urticaria precipitated by foods, drugs (most notably, ß-lactam antibacterials), insects, contact with an external agent, or parasites is often IgE dependent. Opioids, muscle relaxants, radiocontrast agents, and vancomycin often cause urticaria via direct mast cell degranulation and proinflammatory mediator release. Complement-mediated acute urticaria can be triggered by serum sickness, transfusion reactions, and viral or bacterial infections. Finally, acetylsalicylic acid (aspirin) and NSAIDs can cause acute urticaria through their effects on the metabolism of arachidonic acid.[4]

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Chronic Urticaria

Chronic urticaria is defined as the development of cutaneous wheals that occur on a regular basis (usually daily) for >6 weeks with individual lesions lasting from 4 to 36 hours. The symptoms can be severe and can impair health-related quality of life.[9] Detailed epidemiologic studies are not available and published studies are problematic in that some include the physical urticarias and urticarial vasculitis while others do not. Additionally, establishing cause and effect is difficult and many cases remain idiopathic. By some estimates, the physical urticarias account for approximately 35% of all cases of chronic urticaria, while urticarial vasculitis makes up about 5%.[4] A small percentage of chronic urticaria is caused by an infection or pseudoallergy. Although many cases of chronic urticaria remain classified as idiopathic, recent evidence suggests that a significant portion of the so-called idiopathic urticarias may have an autoimmune etiology.[4,5] In general, chronic urticaria is more prevalent in female patients, occurring at a 2???1 female-to-male ratio.[4]

Contact Urticaria

Contact urticaria is defined as the development of urticarial wheals at the site where an external agent makes contact with skin or mucosa. Contact urticarias can be subdivided into allergic (involving IgE) or non-allergic (IgE-independent) forms. IgE-mediated allergic contact urticaria occurs in persons sensitized to environment allergens such as grass, animals, or foods or to occupational allergens such as latex gloves in healthcare workers. Non-allergic contact urticaria occurs as a result of the direct effects of urticants on blood vessels. Examples of common urticants are sorbic acid in eye solutions, cinnamic aldehyde in cosmetics, and chemicals from the stinging nettle (Urtica dioica), which include histamine, acetylcholine, and serotonin.[4]

Physical Urticaria

Of the various urticarial disorders, the physical urticarias may affect quality of life most severely.[4] The lesions of the physical urticarias are typically localized to the stimulated area and resolve within 2 hours with the exception of delayed pressure and delayed dermatographism.[10] If a patient has a history of wheals lasting for <1 hour, the presence of a physical urticaria should be considered. [4,5] Symptomatic dermatographism – the most common form of physical urticaria – is not associated with systemic disease, atopy, food allergy, or autoimmunity.[4] Conversely, patients with delayed-pressure urticaria may present with systemic symptoms such as malaise, influenza-like symptoms, and arthralgias. Delayed-pressure urticaria is distinguished by the development of deep erythematous swellings at sites of sustained pressure to the skin after a delay of 30 minutes to as long as 12 hours. Examples of sites typically affected include the waistline after the wearing of tight clothing and the area of the legs that makes contact with the elastic band of socks. Many patients with delayed-pressure urticaria also have concurrent chronic idiopathic urticaria.[5] Cholinergic urticaria – the second most common type of physical urticaria – is characterized by a wheal surrounded by an obvious flare in response to physical exertion, hot baths, or sudden emotional stress.[4] Adrenergic urticaria, in contrast to cholinergic urticaria, is characterized by blanched, vasoconstricted skin surrounding small pink wheals. Other categories of physical urticaria include cold urticaria, solar urticaria, aquagenic urticaria, pressure urticaria, and vibrating angioedema.

Challenge testing to confirm the diagnosis of a physical urticaria can be performed in the office setting. Cholinergic urticaria can be diagnosed with exercise or hot bath testing. The lesions of cold urticaria can be induced with the ice cube test. Aquagenic urticaria can be confirmed with application of water compresses. Testing for pressure urticaria can be performed by applying an 8-kg weight to the patient's thigh.[4]

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Special Syndromes

Schnitzler syndrome is a unique variant of chronic urticaria characterized by recurrent non-pruritic wheals, intermittent fever, bone pain, arthralgias or arthritis, an elevated erythrocyte sedimentation rate (ESR), and a monoclonal IgM gammopathy. IgM may play an important role in wheal formation as it has been demonstrated around dermal vessels and IgM autoantibodies directed against skin have been reported.[11] Some investigators believe that Schnitzler syndrome may be a variant of urticarial vasculitis rather than chronic urticaria. Interestingly, Saurat et al.[12] found that patients with Schnitzler syndrome had IgG antibodies directed against the cytokine interleukin (IL)-1. Biopsies of lesions from patients with clinical features of Schnitzler syndrome often demonstrate an increased polymorphonucleocyte count with occasional leukocytoclasia.[13]

Muckle-Wells syndrome, an autoinflammatory disorder associated with cold-induced autoinflammatory syndrome-1 gene mutations, is a rare entity characterized by urticaria, arthralgias, progressive sensorineural deafness, and amyloidosis. Familial cold autoinflammatory syndrome is a similar entity that seems to be related to changes in temperature.[14]

Pruritic urticarial papules and plaques of pregnancy (PUPPP), also known as polymorphic eruption of pregnancy, is the most common dermatosis associated with pregnancy. Its lesions are often urticarial and involve the trunk, particularly abdominal striae. PUPPP typically runs a benign, self-resolving course with an onset in the third trimester. It is important to differentiate this disorder from the more serious pemphigoid gestationis, a bullous pemphigoid like-disorder associated with pregnancy.[15]

Urticarial Vasculitis

The clinical presentation of urticarial vasculitis may be indistinguishable from that of chronic urticaria. Nonetheless, the characteristics of the wheals may be helpful in differentiating urticarial vasculitis from chronic urticaria. In contrast to chronic urticaria, the lesions of urticarial vasculitis tend to last longer than 24 hours and are associated with burning and pain in addition to itching. These lesions are also described as healing with purpura or petechiae; however, the most common cause of purpura after urticaria is probably scratching.[4,16] In patients with suspected urticarial vasculitis, histologic examination of a skin biopsy specimen typically shows evidence of leukocytoclastic vasculitis. Urticarial vasculitis is rare, with reported ranges of 1–10% in patients with chronic urticaria.[4,16] The incidence is probably closest to 1% in most experts' opinion. When it does occur, urticarial vasculitis is typically a component of a chronic systemic illness such as systemic lupus erythematosus, hypocomplementemic urticarial vasculitis syndrome, Sjögren syndrome, or mixed cryoglobulinemia.[17]

Etiology

Unfortunately, most cases of chronic urticaria remain idiopathic. Recent data suggest that 35–50% of chronic urticaria cases are related to autoimmunity, specifically the presence of autoantibodies to the high-affinity IgE constant fragment receptor-1 (FceR1) located on mast cells. [18] This results in chronic stimulation of these mast cells and release of vasoactive mediators. Although not widely used, an in vivo test known as the autologous serum skin test (ASST) can separate these patients from the remaining idiopathic cases. The ASST is a modified skin allergy test using the patient's own serum injected intradermally to elicit wheal formation.[18,19] This test and the importance of autoimmune chronic urticaria are discussed further in section 5.

In addition to autoimmune causes, other identifiable causes of chronic urticaria include IgE-dependent, complement-mediated, or immune complex deposition. Non-immunologic causes may include direct mast

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cell release, vasoactive stimuli, alterations in prostaglandin (PG) pathways as a result of intake of acetylsalicylic acid and other NSAIDs, dietary pseudoallergens (rarely), and alterations in the bradykinin pathway as a result of use of ACE inhibitors.[4,18,20]

Food allergy and food additives such as preservatives and coloring agents do not appear to be significant causes of chronic urticaria.[19] It is possible that impaired gastroduodenal barrier function may be of pathophysiologic importance in the development of pseudoallergic reactions, and despite the rare association of chronic urticaria with food allergies, some clinicians recommend that patients try an elimination diet at least once in their lifetime.[13,21] Most, however, feel that this approach is unnecessary and that food allergy can be ruled out as a cause by the history. Food allergies typically would cause a reaction within 30 minutes of ingestion.[22]

Both Hashimoto thyroiditis and Graves disease have been associated with chronic urticaria. Antithyroid antibodies, antimicrosomal antibodies, or both have been found in up to 27% of patients with chronic urticaria.[23,24] A recent study showed that patients with chronic urticaria who had a positive ASST result had significantly more autoimmune thyroid disease and abnormal thyroid function with abnormal thyroid microsomal antibodies and abnormal thyroid-stimulating hormone than ASST-negative patients.[25] Also, other investigators have found that patients with chronic autoimmune urticaria have significantly more antithyroid peroxidase antibody than patients with chronic idiopathic urticaria (p = 0.03). [26] About 19% of patients with chronic urticaria have abnormal thyroid function.[27] However, there is no evidence that the antibodies involved in thyroid disorders play a role in the pathogenesis of chronic urticaria; this association most likely represents parallel but unrelated autoimmune events.[19] Additionally, there is only anecdotal evidence that both refutes and supports treatment of urticaria with levothyroxine sodium in euthyroid patients. In patients with both chronic urticaria and autoimmune thyroiditis, the ASST can continue to be positive after remission of urticaria. This suggests that some component of thyroid disease can enhance a positive ASST. Almost all patients with autoimmune thyroiditis and no history of urticaria have a negative ASST,[28] which correlates ASST more with chronic urticaria than with thyroiditis. This phenomenon needs further study to verify the reliability of a positive ASST as a surrogate marker of circulating anti-FceRI and anti-IgE autoantibodies in patients with coexisting chronic urticaria and autoimmune thyroiditis.[28] Other autoimmune conditions associated with chronic urticaria include vitiligo, insulin-dependent diabetes mellitus, rheumatoid arthritis, and pernicious anemia.[29,30]

It has been proposed that Helicobacter pylori, which has an immunogenic cell envelope, may play an indirect role in the etiology of chronic autoimmune urticaria by reducing immune tolerance and inducing autoantibody formation, such as anti-FceRI.[19,26] Some investigators have found an increased frequency of H. pylori IgG antibodies in patients with chronic urticaria,[31] while others have not.[32] Whether eradication of H. pylori is effective in the treatment of chronic urticaria is a controversial issue, and the limited number of studies of this question have yielded conflicting results.[31] In a systematic review of published studies of the effects of H. pylori eradication on the rate of remission of chronic urticaria, Federman et al.,[33] in 2003, found that urticaria was more likely to resolve when antibacterial therapy successfully eradicated H. pylori than when eradication was unsuccessful. Since then, data have both refuted and confirmed improvements in urticaria with successful eradication of H. pylori.[34-36] Although many experts are not convinced of a causative role of H. pylori in chronic urticaria, an evaluation for its presence may still be considered, particularly since H. pylori infection is also associated with mucosa-associated lymphoid tissue lymphoma and gastric adenocarcinoma and an effective treatment is available.

There is no association between chronic urticaria and malignancy.[37,38] Although an association between urticaria and occult infections such as dental abscesses or gastrointestinal candidiasis has been proposed, there is little supporting evidence other than anecdotal reports.[38] A few case reports have described resolution of recalcitrant chronic urticaria after treatment of dental abscesses.[39] Parasitic infections such

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as intestinal strongyloidiasis may occasionally cause chronic urticaria in endemic areas. [37] The fish nematode Anisakis simplex has been implicated as a cause of chronic urticaria based on detection of IgG4 antibodies.[40,41] Although a study[42] from Japan suggested a possible link between hepatitis C and chronic urticaria, other investigations, including a large prospective study[43] conducted in France, have found no association between the hepatitis C virus and urticaria.[37] No conclusive evidence is available linking chronic urticaria with hepatitis B, Epstein-Barr virus, cytomegalovirus, or HIV.[39]

There is some evidence that genetic factors play a role in the pathogenesis of chronic urticaria. In a study of more than 1300 patients with chronic idiopathic urticaria, Asero [44] found that the prevalence of the disease was much higher among first-degree relatives of the study group than in the general population. O'Donnell et al.[45] have shown that, compared with control individuals, patients with chronic idiopathic urticaria have an increased frequency of HLA-DR4 and HLA-D8Q. HLA-DR4 is strongly associated with autoimmune chronic urticaria.

Pathogenesis

The mast cell is the principal effector cell of urticaria. Mast cells are distributed throughout the body but vary in their response to stimuli. All mast cells express high-affinity IgE receptors (FceRIs) that enable their involvement in IgE-dependent allergic reactions. The constant region domain of IgE, Ce3, is the major site of interaction with the IgE receptor. When IgE forms a complex with FceRI on the mast cell to which an allergen binds, degranulation occurs.[20] Mast cell degranulation also occurs through a variety of other mechanisms, including cross-linking of adjacent FceRI, binding of receptor-bound IgE by allergen, anti-IgE, and anti-FceRI antibodies. Non-immunologic stimuli such as opioids, C5a anaphylotoxin, and stem cell factor as well as neuropeptides such as substance P can cause degranulation via direct stimulation. These stimuli initiate calcium- and energy-dependent steps that cause storage granules to fuse with the cell membrane and externalize their contents, which include preformed and newly synthesized mediators of inflammation. FceRI stimulation also leads to upregulation of the synthesis and secretion of proinflammatory mediators.[4,19,20]

The key mediator is histamine. Preformed cytokines, including tumor necrosis factor (TNF)-a, IL-3, IL-4, IL-5, IL-6, IL-8, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF), are also released. Newly synthesized mediators from arachidonic acid include PGD2 and leukotrienes C4, D4, and E4.[4,19,20] Leukotriene C4 is 1000 times more potent than histamine in causing a wheal-and-flare reaction and thus can also be considered an additional mediator of urticaria.[46] Histamine, TNFa, and IL-8 upregulate the expression of adhesion molecules on endothelial cells and encourage migration of circulating inflammatory cells from the blood into the urticarial lesion.[4] IL-4 promotes further IgE production that causes positive feedback. One study has shown that the serologic immune profile of patients with chronic autoimmune urticaria is a mixed T helper-1 (Th1)/Th2 pattern with a slight Th2 predominance due to increased IL-13 production.[47] IL-13 shares biologic properties with IL-4 and may increase mast-cell FceRI expression and mediator release. Another study found evidence for a prevalent role of lymphocytes with a mixed Th1/Th2 response focally expressing interferon-? and IL-5 in autologous wheals.[48] The investigators also reported that the main infiltrating population was neutrophils with involvement of the chemokine pathway. Additionally, they found that uninvolved skin in persons with chronic idiopathic urticaria had latent inflammation with a lymphocytic and granulocytic cellular infiltrate with mediator upregulation, which may represent a prolonged and widespread urticarial state.[48]

Histology of chronic urticaria (both idiopathic and autoimmune) demonstrates a perivascular non-necrotizing infiltrate of CD4+ lymphocytes consisting of a mixture of Th1 and Th2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils.[49] Other observations include increased levels of matrix metalloproteinase-9 in patients afflicted with chronic urticaria, especially those with severe disease.

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In addition, there is evidence that CD4+ T cells are highly activated, with increased nuclear factor-?B (NF-?B) expression leading to increased B-cell lymphoma (bcl)-2 expression in the T cells of patients with chronic urticaria.[50] Substance P does not appear to play a noteworthy role in chronic urticaria, although it may occasionally function as an alternate mode of triggering urticaria.[51]

Initial evidence of autoimmune involvement in chronic urticaria was reported by Hide et al. [18] who showed autoantibodies of the IgG subclass against FceRI on mast cells and basophils. Only patients with chronic urticaria have been shown to manifest functional histamine-releasing anti-FceRI autoantibodies. These antibodies do not occur in physical urticarias, atopic eczema, or other diseases involving activated mast cells.[5] About 35–40% of patients with chronic urticaria have IgG antibodies to the a subunit of the FceRI, and 5–10% have IgG antibodies to IgE itself. Those autoantibodies that recognize the a2 domain on the FceRI compete with IgE for the binding site, whereas non-competitive autoantibodies are directed against the a1 domain and are able to bind even in the presence of IgE.[4,19]

Autoantibodies to mast cells may also initiate complement activation with generation of C5a anaphylatoxin leading to degranulation.[52] The antibodies involved are primarily IgG1 and IgG3, which are often considered to be involved in complement activation. IgG4 is also occasionally involved, although, unlike IgG1 and IgG3, it is not complement fixing.[53] It is interesting to note that only IgG in sera with complement will release histamine from dermal mast cells, which indicates that the release of histamine from dermal mast cells by FceRI is most likely augmented by complement activation. This finding is further supported by the fact that patients with severe autoimmune chronic urticaria do not experience bronchospasm because lung mast cells, unlike dermal mast cells, are devoid of complement receptors. One study, however, did show that patients with chronic urticaria had bronchial hyper-responsiveness to methacholine provocation on pulmonary function tests.[54] This hyper-responsiveness was not as severe as that observed in the asthmatic control patients.

In addition to autoantibodies, it is possible that other factors in sera or plasma may also contribute to mast cell degranulation and urticaria formation. For example, some have suggested that only half of patients with a positive ASST are able to induce histamine release from basophils in vitro.[55] Additionally, IgG-depleted sera were still able to maintain a wheal and flare. Some have suggested that components of the coagulation cascade, particularly thrombin, may play a role.[56] Thrombin has been shown to increase vascular permeability,[57] trigger mast cell degranulation and, indeed, may be equipotent to FceR1-mediated activation. Autologous plasma skin tests (which would still include clotting factors) are more frequently positive than ASST in patients with chronic urticaria, and serum levels of thrombin have been directly related to urticaria severity.[58]

Diagnosis and Work-up

Studies have shown that taking a detailed patient history is usually adequate to establish a diagnosis of chronic urticaria.[4,38,59-61] If laboratory tests are warranted, based on the history, an ESR and white blood cell count with differential should be considered. Although the ASST is helpful in distinguishing some cases of chronic autoimmune urticaria from chronic idiopathic urticaria,[4,38] this test is currently not widely used. If a cause for the urticaria is not found, some clinicians recommend screening for H. pylori infection. Thyroid function tests and tests for thyroid antibodies are necessary only when clinical findings suggest the presence of thyroid disease.[37] Challenge testing is indicated when a patient is being evaluated for a physical urticaria. Patients suspected of having urticarial vasculitis should undergo a skin biopsy to confirm the diagnosis. Patients with angioedema but without urticaria should have C4 levels measured to screen for C1-inhibitor deficiency; C1-inhibitor levels can be measured if the C4 level is low.[4,37,38]

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Distinguishing between autoimmune chronic urticaria and idiopathic chronic urticaria is clinically important because patients afflicted with the autoimmune form typically have a more aggressive disease course and are more resistant to treatment. Sabroe et al.[29] have shown that patients with autoantibodies have more wheals with a wider distribution, higher itch scores, more systemic symptoms, and lower serum IgE levels than patients without autoantibodies. In addition, they are more likely to require and benefit from immunosuppressive therapy. Establishing a diagnosis of autoimmune chronic urticaria is a difficult task because there are no reliable laboratory tests to aid the clinician. A decrease in basophils (basopenia) is a common feature of chronic urticaria and may be useful for screening for the autoimmune form of the disease.[62,63] However, there are no convenient and reproducible methods of counting basophils in the peripheral circulation. Unfortunately, no reliable direct antibody test is available and results with ELISA and immunobinding techniques have been disappointing.[5]

Currently the most useful test for evaluating chronic urticaria is the ASST. A sample of the patient's own serum (collected during a flare) is injected intradermally into uninvolved skin of the forearm. Saline and histamine controls are injected at the same time. A result is positive for autoimmunity if the diameter of the wheal at the serum-injected site is 1.5 mm greater than that of the bleb at the saline-injected site. The sensitivity of this test is estimated to be 65–81% and the specificity 71–78%. [19] If a positive reaction is observed, the result should be confirmed by in vitro testing (the gold standard), which demonstrates histamine release from target basophils and dermal mast cells from healthy donors. [19] The ASST has also been shown to be useful in monitoring the course of chronic urticaria, with a positive test being consistent with an exacerbation of symptoms and a negative test with remission of symptoms.[28]

The diagnosis of chronic idiopathic urticaria is established when a patient does not have any identifiable autoantibodies to mast cells. In these patients, the likelihood of identifying an underlying cause of the urticaria is rare. The clinical features of autoimmune chronic urticaria are indistinguishable from those of chronic idiopathic urticaria.

Treatment

The mainstays of managing urticaria include general measures to prevent or avoid triggers and pharmacotherapy. Management can be stratified into first-, second-, and third-line therapies.

First-line Therapy

First-line therapy includes patient education and general non-drug measures followed by a trial of histamine H1 receptor antihistamines if symptoms persist.[4] General measures include avoidance of aggravating factors such as overheating, stress, and alcohol.[38] Avoidance of acetylsalicylic acid, NSAIDs, and ACE inhibitors may also be advisable.[4,38] Cooling antipruritic lotions such as 1% or 2% menthol in aqueous cream or calamine lotion may be helpful.[37,38] It is important to keep patients well informed about the disease, using both verbal and written information. Specifically, patients should be informed about the benign course of the disease, the lack of a cure, and the fact that a cause often can not be found.[38]

Histamine H1 Receptor Antihistamines. Antihistamines are inverse agonists at H1 receptors. Stimulation of the H1 receptor activates G-protein-coupled receptors that in turn activate inositol triphosphate and diacylglycerol in addition to the transcription factor NF-?B, which prevents the production of many important mediators of inflammation such as P-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, inducible nitric oxide synthase, IL-1ß, IL-6, TNFa, and GM-CSF. [64] Antihistamines have the capacity to inhibit histamine release and prevent the actions of mast cell and basophil-derived histamine on its target organs. H1 receptor inhibition also reduces allergen-induced eosinophil accumulation. Investigators who examined the effects of two second-generation H1 receptor

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antihistamines, cetirizine and levocetirizine, reported that both drugs have well documented anti-inflammatory effects that include inhibition of platelet-activating factor (PAF)-dependent eosinophil chemotaxis, PAF-dependent eosinophil adhesion to the endothelium, and transendothelial migration through dermal endothelial cells.[65] Cetirizine has also been shown to downregulate NF-?B production.[65]

Receptor occupancy is a concept that suggests that predicting the efficacy of drugs in humans is a function not only of the in vitro affinity of a drug to a receptor and its half-life, but also of the drug concentration at the receptor site in vivo. For example, investigators have found that although desloratidine has a higher affinity for H1 receptors and a longer half-life than both fexofenadine and levocetirizine, its ability to inhibit a wheal and flare response are diminished because of decreased receptor occupancy in vivo.[66]

The efficacy of antihistamines in alleviating pruritus and decreasing the number of hives is well established, although not all patients will respond. Of patients treated with antihistamines at tertiary care clinics, only 40% experienced complete clearing of their symptoms.[4] In some patients, antihistamines only reduce the severity of pruritus and decrease the number and duration of wheals.[4] However, it is important to not assume therapeutic failure if one particular antihistamine does not resolve the urticaria; more than one antihistamine should be tried since efficacy is patient specific. Antihistamines are most effective if taken daily rather than on an as-needed basis.[4,38]

First-generation or classic H1 receptor antihistamines include hydroxyzine, diphenhydramine, cyproheptadine, and chlorpheniramine (chlorphenamine). These antihistamines are rarely used as monotherapy because of their adverse effect profile, which includes sedating and anticholinergic effects. However, they can be valuable adjunctive therapy, especially for patients whose sleep is disturbed by symptoms of urticaria.[4,38] Many believe that the adverse effect profile in patients with significant urticaria is attenuated and becomes less apparent if the medication is used long term (daily for more than 1 week); however, to our knowledge, this has not been shown in any well conducted studies.

A number of second-generation H1 receptor antihistamines have been developed over the last 15 years and are as efficacious as first-generation antihistamines. These include cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, ebastine, and mizolastine. A major advantage of second-generation antihistamines is their lack of significant CNS and anticholinergic adverse effects. Although antihistamines are often prescribed at doses higher than those recommended in the package insert in an attempt to achieve additional anti-allergenic and anti-inflammatory effects, there is no evidence to support this practice.[67] A recent study of fexofenadine, the active metabolite of terfenadine, showed that the recommended daily dose of 180 mg provided effective, well tolerated relief for patients with chronic urticaria.[68] A dose-finding study by Nelson et al.[69] showed that a twice-daily 60-mg dose of fexofenadine was only slightly less efficacious than higher doses (120 and 240 mg) in reducing pruritus severity and number of wheals. Fexofenadine is unique amongst second-generation H1 receptor antihistamines in that it is lipophobic and does not penetrate the blood-brain barrier; hence, it can be prescribed at doses of up 360 mg/day without risk of sedation.[5]

Desloratadine is an active metabolite of loratadine and has more potent antihistaminic and anti-inflammatory properties than loratadine.[70] Cetirizine is an active component of hydroxyzine with similar effects but less sedation.[71] Levocetirizine is the active enantiomer of cetirizine and is more potent than cetirizine. It has been shown to provide rapid relief of pruritus and wheals in patients with chronic urticaria.[72] Mizolastine, which is unavailable in the US, should be used with caution in patients also taking cytochrome P450 enzyme (CYP) inhibitors such as cimetidine, cyclosporine (ciclosporin), and nifedipine because of concern about cardiac arrhythmias (QT prolongation).[4]

H2 Receptor Antagonists. Because 15% of histamine receptors in the skin are of the H2 type,[73] H2

receptor antihistamines have been shown to be a helpful addition to H1 receptor antihistamines in some

10

patients with chronic urticaria.[4,73,74] However, H2 receptor antagonists should not be used alone since they have only minimal effects on pruritus. H2 receptor antagonists include cimetidine, ranitidine, nizatidine, and famotidine.[4] Overall, data supporting the efficacy of H2 receptor antagonists are limited.

Second-line Therapy

If urticarial symptoms are not controlled by antihistamines alone, second-line therapies should be considered, including both pharmacologic and non-pharmacologic measures. Results of phototherapy with UV light or photochemotherapy (psoralen plus PUVA [PUVA]) have been inconclusive, although some studies have shown increased efficacy for PUVA in managing physical urticarias but not chronic urticaria.[75] Studies of relaxation therapies have also reported inconclusive results.[38] Several classes of drugs may be useful in second-line therapy, including antidepressants, corticosteroids, calcium channel antagonists, levothyroxine sodium supplements, leukotriene receptor antagonists, and a variety of other drugs.

Antidepressants. The tricyclic antidepressant doxepin has potent H1 and H2 receptor antagonist activity[4,37] and has been shown to be more effective and less sedating than diphenhydramine in the treatment of chronic urticaria.[76] However, Goldsobel et al.[77] reported that sedation is a greater problem for doxepin than for diphenhydramine or hydroxyzine and limits the usefulness of this antidepressant. Because of its sedating properties, doxepin works best when taken at night. Furthermore, because doxepin is metabolized by the CYP system, it should be used with caution or avoided in patients taking other drugs metabolized by this enzyme, such as cimetidine, erythromycin, and cyclosporine. Doxepin may be especially useful in patients with chronic urticaria and coexisting depression. [37] Although the dosage of doxepin for the treatment of depression may vary from 25 to 150 mg/day, only 10–30 mg/day is recommended for chronic urticaria. Mirtazapine is an antidepressant that demonstrates significant effect on the H1 receptor and has antipruritic activity. It has been reported to be helpful in a few cases of physical urticaria and delayed-pressure urticaria at doses of 30 mg/day.[78]

Corticosteroids. Short courses of systemic corticosteroids can be prescribed for severe urticarial symptoms when the patient needs rapid and complete disease control. Although there is no doubt about the efficacy of corticosteroids, long-term therapy can not be recommended because of the likelihood of developing tolerance and numerous adverse effects such as hyperglycemia, osteoporosis, peptic ulcers, and hypertension. If prolonged corticosteroid therapy is necessary, it is imperative to use the lowest effective dose and incorporate corticosteroid-sparing immunosuppressive modalities.[4,37,38,74,79] Clinicians should be aware that antihistamine dosages, particularly of first-generation antihistamines given up to four times daily, should be maximized in an attempt to avoid corticosteroid courses.

Leukotriene Receptor Antagonists. Leukotrienes (C4, D4, E4) are potent mediators of inflammation and have been shown to elicit wheal and flare responses both in patients with chronic urticaria and in healthy individuals.[46] Leukotriene receptor antagonists such as montelukast, zafirlukast, and zileuton have been shown to be superior to placebo in the treatment of patients with chronic urticaria. [80,81] Leukotriene receptor antagonists such as montelukast may also be effective in controlling chronic urticaria in patients who are unresponsive to antihistamines alone.[74,82,83] There is also evidence that leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria.[84] Another study showed that montelukast in combination with desloratadine was superior to desloratadine alone in managing the symptoms of chronic urticaria.[85] Bagenstose et al.[86] also reported that addition of the leukotriene receptor antagonist zafirlukast to cetirizine therapy was significantly more effective than cetirizine alone in managing patients with chronic urticaria who were ASST positive, but not in those who were ASST negative. Despite these promising results, use of leukotriene receptor antagonists in the management of urticaria remains controversial and not all trials have shown a beneficial effect. For example, in a recent double-blind, placebo-controlled, crossover study of 52 patients with chronic

11

urticaria, monotherapy with zafirlukast 20 mg twice daily did not provide any significant benefit over placebo.[87]

Nifedipine. Nifedipine has been reported to be effective in decreasing pruritus and whealing in patients with chronic urticaria when used alone or in combination with antihistamines.[88] Many experts, however, have found the clinical effect of nifedipine disappointing.[38] The proposed mechanism of action is modification of calcium influx into cutaneous mast cells. A trial of nifedipine may be a reasonable option in patients with co-morbid hypertension, particularly if the patient is taking an ACE inhibitor or combination therapy that includes an ACE inhibitor and an alternative antihypertensive is desired.[4,38]

Third-line Therapy

Third-line therapy for patients with urticaria who do not respond to first- and second-line treatments typically involves the use of immunomodulatory agents, which include cyclosporine, tacrolimus, methotrexate, cyclophosphamide, mycophenolate mofetil, and intravenous immunoglobulins (IVIG). Patients who require third-line therapy often have the autoimmune form of chronic urticaria. Other third-line therapies that may be beneficial include plasmapheresis, colchicine, dapsone, albuterol (salbutamol), tranexamic acid, terbutaline, sulfasalazine, hydroxychloroquine, and warfarin.[4,16,37,38]

Immunomodulatory Agents. Several studies have shown that cyclosporine is effective in treating patients with refractory chronic urticaria.[5,89,90] Cyclosporine 3–5 mg/kg/day appears to benefit about two-thirds of patients with chronic urticaria who do not respond to antihistamines. [37] In a randomized, double-blind trial, 8 of 19 patients with severe chronic urticaria had a positive response to cyclosporine therapy versus none of the patients treated with placebo.[90] There was also a statistically significant decrease in the ASST response to serum histamine-releasing activity after cyclosporine therapy. Di Gioacchino et al. [89]

reported similar results with cyclosporine in a double-blind study of 40 patients with chronic idiopathic urticaria and a positive ASST. Greaves[5] states that >75% of patients that he treats have an excellent response to cyclosporine with one-third remaining in remission after withdrawal, one-third having a mild relapse, and one-third relapsing to pre-treatment levels. During treatment with cyclosporine, H1 receptor antihistamines should be continued and blood pressure and renal function should be monitored appropriately. Maintaining patients on long-term cyclosporine therapy should not be taken lightly because of the numerous adverse effects of the drug (e.g. hypertension, renal toxicity) and the potential for rebound after discontinuation.[4,37,74]

Experience with other immunomodulatory agents (tacrolimus, methotrexate, and cyclophosphamide) is more limited.[37,74] In a recent review of the literature, Stanaland[91] reported excellent results with a 20-µg/mL daily dose of tacrolimus in the treatment of patients with corticosteroid-dependent urticaria. A recent case report described the use of intravenous cyclophosphamide to achieve complete clinical remission in a patient with corticosteroid-dependent urticaria.[92] Methotrexate has been used successfully in the management of two ASST-negative patients with chronic urticaria refractory to conventional therapies.[74,93] A recent report by Shahar et al.[94] documented significant improvement in nine patients with chronic urticaria taking mycophenolate mofetil for 12 weeks. All patients were able to stop prednisone and no serious adverse events were noted.

IVIG appear to be effective in the management of patients with severe refractory autoimmune chronic urticaria.[4,37,74] Although the mechanism of action involved is unclear, it has been proposed that IVIG may contain anti-idiotypic antibodies that compete with endogenous IgG for H1 receptors and block histamine release or enhance clearance of endogenous IgG.[95] Why the effect would be sustained after initial therapy is not known. In a study by O'Donnell et al.,[96] nine of ten patients with severe autoimmune chronic urticaria experienced clinical benefit and a reduced ASST response after 5 days of high-dose IVIG

12

therapy. Three patients had prolonged remissions of 3 years. Another report described complete remission of refractory autoimmune urticaria within 48 hours after a high-dose infusion of IVIG. [95] Despite a negative ASST at 6 months, the patient's symptoms returned 7 months after IVIG therapy. Others have not found significant benefit.[97] Expense and potential morbidity remain concerns the use of IVIG, and controlled studies have not yet been conducted to evaluate this therapy for urticaria.[4,37,38,74]

Plasmapheresis. Plasmapheresis has been reported to be beneficial in the management of severe chronic autoimmune urticaria. In a case series report, plasmapheresis relieved the symptoms of six of eight patients with severe, treatment-resistant autoimmune chronic urticaria.[98] However, this approach can not be used long term or as monotherapy because of expense, potential morbidity, and early relapse of urticaria. Plasmapheresis alone is insufficient to prevent re-accumulation of histamine-releasing autoantibodies and needs to be investigated in conjunction with use of immunosuppressant pharmacotherapy.[4,37,38,74]

Other Drugs. Dapsone[99,100] and/or colchicine[4] may be beneficial in managing urticaria when predominantly neutrophilic infiltrates are seen histologically, but are probably most useful for urticarial vasculitis. Limited experience suggests that sulfasalazine may be beneficial in managing both chronic idiopathic urticaria and delayed-pressure urticaria;[4,37] however, many have not found this agent useful and it is probably best reserved for urticarial vasculitis. Hydroxychloroquine has also shown promising results in the treatment of chronic idiopathic urticaria; and has been associated with a good response in hypocomplementemic urticarial vasculitis.[37,74,101] Although the ß2-adrenoceptor agonist terbutaline has been evaluated for management of chronic urticaria, its use is generally not recommended because of adverse effects such as tachycardia, insomnia, and jitteriness that are not well tolerated by many patients.[79] A few studies have found that warfarin appears to have beneficial effects in some patients with chronic urticaria;[102,103] however, other investigators were not able to replicate this finding.[104] In the small, double-blind study conducted by Parslew et al.,[103] warfarin produced a response in some patients with ASST-negative chronic urticaria and angioedema who were resistant to antihistamines. These results suggest that their symptoms were not histamine dependent but more related to coagulation-dependent mediators such as kinins.[74]

The Future

Spector and Tan[105] recently reported on three patients with chronic urticaria who responded to omalizumab, a humanized monoclonal antibody that binds free IgE. Interestingly, not all of the patients had elevated IgE levels prior to therapy. The investigators speculated that downregulation of IgE receptors improved symptoms. It would be interesting to know if patients with autoimmune chronic urticaria (patients with anti-FCeR1 antibodies) would respond similarly.

Gimenez-Arnau et al.[106] reported that treatment with a novel non-sedating H1 receptor antihistamine, rupatadine, was associated with significant symptom improvement in 195 patients with chronic urticaria compared with control patients. It is claimed that this antihistamine has additional anti-inflammatory effects as a result of its anti-platelet activating factor properties and higher affinity for the H1 receptor.

Recently, H4 receptors on mast cells have been discovered. These may be more important in the pathogenesis of itch. Knockout mice for these H4 receptors have an attenuated itch response to histamine stimulation. Furthermore, a selective H4 receptor antihistamine, JNJ 7777120, reduced itch in mice more effectively than H1 receptor antihistamines.[107]

Conclusion

13

Urticaria can be diagnosed on the basis of the clinical presentation without extensive laboratory investigation and can be classified as idiopathic after allergic, infectious, physical, and drug-related causes have been ruled out. History and physical examination are crucial while undirected laboratory examination is typically fruitless. Although acute urticaria often has an identifiable trigger (foods, drugs, virus), chronic urticaria frustratingly tends to remain idiopathic. About 35–40% of patients with chronic idiopathic disease appear to have an autoimmune etiology in which setting the ASST is a somewhat sensitive and specific test for histamine-releasing autoantibodies. These patients with autoimmune chronic urticaria tend to follow a more aggressive course and often require more aggressive therapy. Non-sedating H1 receptor antihistamines represent the first-line therapy for urticaria, followed by combinations of H1

receptor antihistamines with other entities such as sedating antihistamines, antidepressants, or leukotriene receptor antagonists. For severe, recalcitrant chronic urticaria, short courses of corticosteroids can be beneficial followed by immunosuppressant therapies for patients with debilitating disease.

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Authors and Disclosures

Tasneem Poonawalla and Brent Kelly, University of Texas Medical Branch,  Galveston, Texas, USA

Disclosure: The authors have no conflicts of interest that are directly relevant to the content of this review.

Funding Information

No sources of funding were used to assist in the preparation of this review.

Am J Clin Dermatol. 2009;10(1):9-21. © 2009 Adis Data Information BV

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