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CHRONIC URTICARIA: DIAGNOSIS, THEORIES OF PATHOGENESIS, AND NATURAL HISTORY INTRODUCTION Chronic urticaria (CU) is defined by the presence

e of urticaria (hives), on most days of the week, for a period of six weeks or longer. No external cause can be identified in 80 to 90 percent of adults and children with CU [1-3]. There are several theories regarding the pathogenesis of idiopathic CU, none of which have been conclusively established. Terminology In this review, the terms chronic urticaria and chronic idiopathic urticaria are used synonymously. About 40 percent of patients with CU have accompanying angioedema, which typically affects the lips, cheeks, periorbital areas of the face, extremities, and genitals [4]. Here, the term CU includes patients with isolated urticaria, as well as those with accompanying angioedema. The epidemiology, diagnosis, and theories of pathogenesis of chronic urticaria will be reviewed here. The management of chronic urticaria and the various syndromes of physical urticaria are discussed separately. (See "Chronic urticaria: Standard management and patient education" and "Physical urticarias".) EPIDEMIOLOGY At any given time, CU affects up to 1 percent of the general population in the United States, and the prevalence is believed to be similar in other countries [5,6]. Both children and adults can develop CU, although it is more common in adults. Women are affected twice as often as men [6-12], and the condition typically begins in the third to fifth decades of life [6,8,11]. EVALUATION AND DIAGNOSIS CU is diagnosed clinically, by the recurrence of characteristic lesions for six weeks or longer. A detailed history and physical examination are essential in patients with persistent urticaria [13-16]. History The history should include the characteristics of the lesions (eg, pruritic, burning, appearance), duration of individual lesions, and accompanying angioedema. The duration of the lesions is often difficult for patients to assess, and we sometimes suggest that patients trace a circle in pen around a newly developed lesion and time the period of resolution. Patients should also be asked about whether the lesions resolve without any residual bruise or pigmentation (aside from bruising caused by scratching). Lesions lasting longer than 24 hours and those that are painful or leave residual bruising are suggestive of a vasculitic process (See 'Biopsy' below.) Appearance of lesions Patients whose symptoms have resolved sometimes have difficulty describing urticarial lesions in a sufficiently detailed manner to assist in diagnosis. In this setting, showing patients photographs of urticaria and asking if their lesions looked similar can be helpful (picture 1 and picture 2 and picture 3). No external cause can be identified in 80 to 90 percent of adults and children with CU, as mentioned previously [1-3,17]. Despite this, patients should be questioned about any newly administered drugs, including antibiotics, NSAIDS, and hormones [18,19]. Inquiries should be made about recent travel, infections, changes in health status, other atopic conditions, sexual history, and complete review of systems. The various identifiable causes of urticaria are discussed in more detail elsewhere. (See "New onset urticaria: Epidemiology, clinical manifestations, and etiologies".) Patients should be thoroughly questioned about signs and symptoms of systemic disease, such as fever, weight loss, arthralgias, arthritis, cold or heat sensitivity, abdominal pain, and bone pain [20,21].

Occasionally, urticaria or urticarial vasculitis will be a presenting feature of an underlying systemic disorder. (See "New onset urticaria: Epidemiology, clinical manifestations, and etiologies", section on 'Systemic disorders that may include urticaria'.) Laboratory evaluation A limited number of standard laboratory tests are indicated in the evaluation of a patient CU [22-25]. Investigational tests are discussed separately. (See 'Theories of pathogenesis' below.) In a systematic review of studies in which patients with CU were evaluated for underlying medical disorders, 29 studies including 6462 patients were examined [25]. Potentially causative internal diseases were identified in 1.6 percent, and there was no association between the number of tests ordered and the identification of an underlying disorder.In one study of 125 patients with CU, abnormal routine laboratory or radiographic studies were found in 21 percent of subjects [26]. The majority of these abnormalities were evident from the initial history and physical examination, although it was concluded that a CBC with differential and erythrocyte sedimentation rate (ESR) (or other measures of acute phase reactants) were cost-effective screening tests for systemic diseases. Both tests are normal in the majority of cases of chronic urticaria, although an elevation of ESR of a few points is also common in uncomplicated CU. Significant elevations in ESR or C reactive protein (CRP) should prompt further investigation for systemic diseases, such as autoimmune, rheumatologic, infectious, or neoplastic diseases. Such an evaluation may include measurement of antinuclear antibodies (ANA), thyroid peroxidase antibody, cryoglobulins, hepatitis B and C serologies, and a serum protein electrophoresis. (See "Acute phase reactants".)Another authority in the field has suggested that a thyroid stimulating hormone (TSH) level and a test of anti-thyroid antibodies (either antithyroglobulin or antimicrosomal) may be helpful to detect adult patients with associated thyroid autoimmunity [27]. Autoimmune thyroid disease is uncommon in children with CU [28]. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)".)Eosinophilia should prompt evaluation for an atopic disorder or parasitic infection. (See "Approach to the patient with eosinophilia".) Suggested tests Based upon the above studies and observations, we suggest initially obtaining a complete blood count with differential, a CRP or ESR, and a TSH level. Some clinicians also obtain both antithyroglobulin and antimicrosomal antibodies, while others do so only if the TSH level is abnormal. Further testing should be based upon the results of these tests [22,23]. Biopsy A three mm punch biopsy of an early lesion should be performed to rule out urticarial vasculitis in patients with one or more of the following features: Individual lesions that persist beyond 24 hours, are painful rather than pruritic, have accompanying petechial or purpuric characteristics, or leave residual pigmentation upon resolution [16,29]An elevated CRP/ESR and/or systemic symptomsSymptoms that are unresponsive to antihistamines Biopsy should also be obtained in patients with any features suggestive of cutaneous mastocytosis (see "Clinical manifestations, pathogenesis, and classification of mastocytosis (cutaneous and systemic)"). The biopsy sample should be obtained from a fresh lesion. Patients receiving glucocorticoids may need to discontinue these medications for several days in order to allow new lesions to form. Biopsy specimens should be submitted in formalin for routine hematoxylin and eosin (H&E) staining and in

those patients in whom urticarial vasculitis is a strong consideration, in Michels media or freshly snap frozen for direct immunofluorescence microscopy. Consider testing for immunoglobulins in lesional skin when vasculitis is a strong consideration and in perilesional, non-involved skin when considering autoimmune blistering disease. Biopsy findings The pathology of chronic urticaria is somewhat heterogeneous among patients, but consistently shows interstitial edema with a perivascular mixed infiltrate, consisting of lymphocytes, eosinophils, and in some areas, a few neutrophils or basophils. Lymphocytes are generally CD4+ T lymphocytes. B lymphocytes are not usually seen [4]. Neutrophil-predominant urticaria is a variant of chronic urticaria that is often refractory to standard pharmacologic treatments, but biopsy should not show vasculitis. The significance of neutrophil-predominant urticaria, in terms of treatment or prognosis, is not known. Angioedema, if present, often shows a similar infiltrate and is characterized by more prominent edema of the interstitial tissues. Leukocytoclasis should not be present in chronic urticaria. Leukocytoclasis is the fragmentation of neutrophils resulting in scattered nuclear fragments (nuclear dust) in the infiltrate, red blood cell extravasation within the lumen of affected vessels or in the interstitium, and fibrinoid degeneration of the endothelial cells resulting in a blunted vascular outline with fibrin deposits. If leukocytoclasis is seen, then the diagnosis of leukocytoclastic vasculitis and associated conditions must be considered. (See "Urticarial vasculitis", section on 'Histology' and 'Differential diagnosis' below.) A dense cellular infiltrate consisting almost entirely of neutrophils, combined with the finding of true leukocytoclasis, but not vasculitis, should prompt evaluation for the rare disorder neutrophilic urticarial dermatosis. (See "Neutrophilic dermatoses".) Several other disorders in the differential diagnosis for CU may also show a predominance of neutrophils, such as Schnitzler's syndrome, delayed pressure urticaria, and the Cryopyrin-Associated Periodic Syndromes (CAPS). Biopsies in these disorders may also mistakenly be interpreted as leukocytoclastic vasculitis. (see 'Differential diagnosis' below). DIFFERENTIAL DIAGNOSIS Several systemic disorders can present with urticaria-like lesions in the context of other signs and symptoms. Systemic lupus erythematosus Urticaria and urticarial vasculitis are among the many reported cutaneous manifestations of systemic lupus erythematosus. This disorder is reviewed in detail elsewhere. (See "Mucocutaneous manifestations of systemic lupus erythematosus".)Cryoglobulinemia Cryoglobulinemia causing cold-induced urticarial or vasculitic lesions can be seen in hepatitis C infection. Lesions are more prominent on the buttocks and lower extremities. (See "Overview of cryoglobulins and cryoglobulinemia" and "Cryopyrin-associated periodic syndromes and related disorders".)Urticarial vasculitis Urticarial vasculitis should be considered when the hives are painful rather than pruritic, last longer than 48 hours, leave residual pigmentation changes, or recur whenever glucocorticoids are tapered (picture 4 and picture 5). This disorder may occur in patients previously diagnosed with other systemic inflammatory diseases, such as Sjgren's syndrome or systemic lupus erythematosus (SLE). (See "Urticarial vasculitis".)Mastocytosis Mastocytosis includes a variety of disorders that are characterized by the overproliferation and accumulation of tissue mast cells. The cutaneous form of this disorder may present with lesions of urticaria pigmentosa (picture 6). These are pigmented papules that demonstrate the distinctive Darier's sign, wheals that appear with mild trauma, such as gentle stroking. Biopsy of these lesions reveals a focal collection of mast cells and

requires a thorough evaluation for systemic mastocytosis. (See "Clinical manifestations, pathogenesis, and classification of mastocytosis (cutaneous and systemic)".)Polymorphic eruption of pregnancy Polymorphic eruption of pregnancy (PEP, also called pruritic urticarial papules and plaques and papules of pregnancy or PUPPP) is a pruritic dermatitis affecting pregnant women, which typically presents as erythematous papules within abdominal striae with periumbilical sparing. The lesions then spread to the extremities and coalesce to form urticarial plaques. The face, palms, and soles are usually spared. Lesions may also be target-like. PEP is reviewed elsewhere. (See "Dermatoses of pregnancy".)Schnitzler's syndrome Schnitzler's syndrome has been described in patients with a monoclonal IgM or IgG component (monoclonal gammopathy) who have associated fever, weight loss, bone pain, adenopathy, and urticaria, presumably due to circulating immune complexes and complement activation [30,31]. (See "Cutaneous manifestations of internal malignancy".)Hypereosinophilic syndrome Hypereosinophilic syndrome refers to a group of disorders characterized by persistent overproduction of eosinophils that infiltrate and damage tissues. Cutaneous symptoms include recurrent urticaria and angioedema. The diagnosis requires blood eosinophilia of 1500/microliter, present for more than six months, signs and/or symptoms of eosinophil-mediated end-organ dysfunction, and no other apparent etiologies for eosinophilia, such as parasitic infection or allergic disease. (See "Clinical manifestations, pathophysiology, and diagnosis of the hypereosinophilic syndromes".)Cryopyrin-associated periodic syndromes The cryopyrin-associated periodic syndromes (CAPS) include two syndromes that involve urticarial eruption: Familial cold autoinflammatory syndrome and the Muckle-Wells syndrome. These are rare genetic disorders. Familial cold autoinflammatory syndrome presents with periodic fever, urticaria, leukocytosis, conjunctivitis, and muscle and skin tenderness after exposure to cold. The onset of symptoms occurs during infancy in most cases. This disorder is discussed elsewhere. The Muckle-Wells syndrome involves periodic urticarial eruptions and is associated with mutations in cryopyrin. It has a similar phenotype to familial cold autoinflammatory syndrome except that patients are not cold sensitive and experience frequent sensorineural hearing loss. These disorders are reviewed in more detail elsewhere. (See "Cryopyrin-associated periodic syndromes and related disorders".)Malignancy There are intermittent case reports of malignancies presenting with urticariallike lesions [32-34]. However, these patients rarely have simple urticaria and typically have urticarial lesions with prominent vasculitic properties, or they present with a variety of accompanying systemic symptoms. Diffuse and refractory pruritus or angioedema, without urticaria, represent other cutaneous manifestations of malignancy. (See "Cutaneous manifestations of internal malignancy".) THEORIES OF PATHOGENESIS None of the theories of pathogenesis of CU have been fully established [35]. The best-developed hypotheses include the autoimmune theory, theories involving histamine releasing factors, and the cellular defects theory. Hypotheses for which there is less evidence include abnormalities in the coagulation system and chronic infections. Autoimmune theory The concept that CU could represent an autoimmune disorder arose from the recognition that thyroid dysfunction and thyroid autoantibodies are more prevalent in patients with CU [21,36,37]. This led to a search for autoantibodies and other serum factors that could be responsible for increased release of histamine from cutaneous mast cells and basophils. Association with autoimmune disorders Thyroid autoantibodies, specifically thyroid peroxidase antibodies or antimicrosomal antibodies, are more commonly recognized among patients with CU (12 to 30 percent), compared to members of the general population (5 to 10 percent) [7,36-38]. Other autoimmune conditions, such as connective tissue diseases, vitiligo, and pernicious anemia, have also

been recognized in patients with CU [21,25,39]. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" and "Pathogenesis of Graves' disease".) The presence of urticaria does not necessarily correlate with thyroid function; patients who are euthyroid, hypothyroid, or hyperthyroid may have urticaria or angioedema [21,40]. The majority of patients with chronic urticaria who have circulating thyroid autoantibodies have normal thyroid function [37]. These patients are often poorly responsive to standard therapies for urticaria and may have more persistent disease [39]. The role of these autoantibodies in patients with normal thyroid function is not clear. Their presence may simply reflect an underlying tendency to develop autoantibodies [39]. Based upon the association between chronic urticaria and thyroid autoimmunity, several studies have examined the use of thyroid supplementation therapy in the treatment of CU, with mixed results. These studies are reviewed separately. (See "Chronic urticaria: Standard management and patient education".) Autologous serum skin test Another line of investigation suggesting that CU is an autoimmune disorder was introduced in the 1980s with the description of the "autologous serum skin test" (ASST) [41]. The ASST involves intradermal injection of patients' own serum [41,42]. In preparation for this test, patients must refrain from taking antihistamines for three to seven days (depending upon the half-life of the specific drug), which can cause an exacerbation in symptoms. In up to one-half of patients with CU, the intradermal injection of serum produces a wheal and flare reaction (ie, area of cutaneous edema and erythema) at the site of injection within 30 minutes (note that the time to maximal reaction is longer than 15 minutes seen in allergen skin testing) [43]. The ASST is proposed to provide an in vivo assay of serum factor-induced mast cell activation, since mast cells are difficult to collect and culture. (See "Mast cells: Development, identification, and physiologic roles".) Problems with the ASST The leading evidence against the clinical significance of the ASST is the fact that it is not unique to this CU [44-46]. In one study, positive ASSTs were found in 53 percent of patients with CU, 20 percent of patients with nonallergic asthma/rhinitis, and 56 percent of healthy controls [46]. In addition, the positivity of the ASST persists in patients with CU, even when the disorder is in clinical remission [47,48]. Finally, the ASST has not demonstrated clinical utility in identifying patients whose disease responds differently to treatment or carries a different prognosis [28,49]. Histamine releasing factors in the serum The sera of patients with CU and positive ASSTs are capable of causing in vitro histamine release from basophils collected from control subjects [41]. It was therefore proposed that an autoantibody or other histamine releasing factor was present in the serum of these patients. However, it is important to note that the in vitro manipulation of basophils poses several technical challenges. (See 'Problems in studying basophils' below.) Subsequent efforts to determine which component of the serum was responsible for the positive ASST revealed several possible candidate molecules [42,47,50,51]: Human IgG molecules directed against the IgE receptor alpha subunit (anti-FcR1alpha)Human IgG molecules directed against the Fc region of IgE (anti-IgE)Other low molecular weight molecules (10 to 15 kilodaltons)

The presence of autoantibodies to the IgE receptor or the Fc region of IgE can be demonstrated in as many as 30 to 50 percent of children and adults with CU [4,52-56]. These IgG molecules can trigger histamine release when incubated with normal basophils [50], and can activate mast cells, possibly through a mechanism involving complement [4,17,57-61]. However, the in vivo relevance of these autoantibodies has not been established [62], as IgG depleted serum can also induce a positive ASST [47]. In addition, autoantibodies to the IgE receptor or the Fc region of IgE have been identified in people without hives. (See 'Problems with the ASST' above.) In summary, several histamine releasing factors have been identified in the serum, both immunoglobulins and low molecular weight molecules, but no one factor has been shown to be essential for a positive ASST result. Histamine releasing factors in the plasma Histamine releasing factors in the plasma have also been proposed. Some patients with chronic idiopathic urticaria demonstrate excessive or abnormal production of platelet-derived clotting factors, such as thrombin, possibly resulting from activation of the extrinsic pathway of the clotting cascade [63-65]. In one study, the plasma of 28 patients with CU contained higher levels of the polypeptide F1+2, which is produced upon activation of prothrombin to thrombin, compared to control plasma [63]. The levels of this peptide correlated with the severity of the patients' urticaria. Thrombin, in turn, is capable of activating mast cells and basophils, and also increasing the permeability of blood vessels [66-68]. In addition, thrombin can stimulate the generation of C5a, which has been shown to enhance IgG-dependent mast cell histamine release in patients with CU [61]. Other groups have also found abnormalities in the coagulation system that correlate with CU severity [69]. The identification of abnormalities in clotting factors lead to the autologous plasma skin test (APST), a variant of the ASST in which sodium citrate-anticoagulated plasma is injected intradermally [63]. The APST has reported to be positive in 40 to 86 percent of patients with CU, and it is not clear if this test provides information that is different from that of the ASST [63,70]. The APST has not yet been studied in patients with other conditions or in normal controls. The finding that the extrinsic pathway of the clotting cascade activated in CU is consistent with reports of successful treatment of CU with the anticoagulant warfarin, in a small double-blind, placebocontrolled, crossover study of patients refractory to antihistamines [71]. Subcutaneous heparin was also reported to be effective in one patient [72]. (See "Chronic urticaria: Standard management and patient education", section on 'Other therapies for specific clinical situations'.) Evidence against histamine-releasing factors Similar to the ASST, anti-Fc RI-alpha antibodies have been identified in other autoimmune diseases, even in the absence of urticaria, including pemphigus vulgaris, systemic lupus erythematosus, dermatomyositis, and pemphigoid, suggesting that they may represent an epiphenomenon [57,73,74]. In addition, the levels of autoantibodies in chronic urticaria do not appear to change with the clinical activity of the disease [75]. Assays are commercially available for detecting anti-FcRI-alpha antibodies (eg, the Chronic Urticaria Index test; IBT labs), although these are based on poorly standardized basophil-activation tests and may be positive in healthy subjects [76]. (See 'Problems in studying basophils' below.) In addition from issues with testing for, and specificity of autoimmune factors in CU, it remains unclear why such serologic factors would activate only skin mast cells, rather than more generalized mast cell

and basophil activation leading to anaphylaxis, yet patients with CU are not at increased risk for anaphylaxis. Cellular defects theory The cellular defects theory generally proposes that patients with CU have defects in mast cell and/or basophil trafficking, signaling, and/or function. Mast cell numbers are normal in the skin of patients with CU, although the cells release histamine more readily than cells from healthy controls in response to compounds that trigger nonimmunologic mast cell degranulation, such as 48/80 and codeine sulfate [77,78].Peripheral blood basophil counts are low in patients with CU and lower with more severe disease, a finding attributed to increased migration of basophils to the skin [79-82].Several groups identified functional differences in basophils from patients with CU. Although the cells contained normal amounts of histamine [83,84], histamine release was reduced following in vitro activation through the IgE receptor, although not with activation through other receptors [78,85,86]. Subsequently, two basophil phenotypes were identified in patients with CU: one type with an apparently normal response to IgE receptor activation ("responders"), and another type of basophil that does not respond to IgE-mediated activation ("nonresponders") [83]. These phenotypes are present in approximately equal numbers in patients with CU, unlike in normals, where "nonresponders" comprise only about 10 to 15 percent of the whole. The nonresponder phenotype demonstrates elevated intracellular levels of regulatory proteins that normally inhibit signaling through the IgE receptor. Finally, normalization in basophil responsiveness has been demonstrated in patients with CU as their symptoms improve, unlike levels of autoantibodies or ASST status [75,86]. Problems in studying basophils Several issues arise in studying the basophils of subjects with CU: Patients' basophils are typically obtained for study from peripheral blood, although it has not been established that circulating basophils are fully representative of cutaneous basophils, and the two populations may have different characteristics in this disorder.Alternatively, basophils from normal donors may be used to test serum from chronic urticaria subjects, although this approach is also problematic due to the challenges in studying basophils: Different labs using different basophil donors will yield different results with the same tested serum.Basophils from individual donors can show variability in response to the same serum over time.There are no standardized procedures for handling basophils for use in serum testing, including uniform approaches to cell isolation, dilution of serum, or addition of a basophil priming cytokine (ie, IL3) to the assay mix.Histamine release from normal donor basophils in response to CU serum may be due to several factors, such as activated complement, chemokines, or even IL-3 in the tested sample. Thus, the readout of the assay itself represents a complex cellular response that can be elicited through a variety of mechanisms. Infectious agents Attempts have been made to associate some common chronic infections with CU, including Helicobacter pylori [87-90], hepatitis A [91], and hepatitis C [92]. However, the evidence is largely anecdotal [93]. Foods and food additives Up to 50 percent of adult patients with CU initially perceive food-associated reactions; however, in one study, only 10 percent of these individuals demonstrated signs or symptoms with placebo-controlled challenges [94]. IgE-mediated food allergy is far more likely to present with acute urticaria as part of generalized allergic reactions. In contrast, patients with CU will often report that rich meals, fermented foods, alcohol, and dramatic changes in diet will worsen the condition

temporarily. This may be related to the histamine content or innate histamine-releasing properties of these foods, as well as the vasodilatory effects of alcohol and certain spices. Food additives are rarely, if ever, confirmed to cause or contribute to flares of CU in carefully performed studies. Studies of food additives as an etiology of acute and chronic urticaria are reviewed elsewhere. (See "Allergic and asthmatic reactions to food additives".) NATURAL HISTORY AND PROGNOSIS CU is an episodic and self-limited disorder in most patients. The average duration of disease is two to five years [5,95]. In patients in whom no trigger or underlying disorder is identified, there is a rate of spontaneous remission at one year of approximately 30 to 50 percent [3,96]. However, symptoms persist beyond five years in nearly one-fifth of patients [9,97]. Duration of disease appears to correlate with symptom severity [95,97]. Symptoms persisted for longer in a prospective study of 228 patients with moderate to severe disease [95]. This study also found that in this subgroup, the presence of systemic hypertension was associated with longer disease duration. Among hypertensive patients, symptoms persisted for up to two and five years in 81 and 74 percent, respectively compared to 63 and 54 percent in normotensive patients. The type of antihypertensive medication administered did not appear to impact duration of urticaria. This finding warrants further study. Another prospective study followed 139 patients with CU of all severities for five years and assessed disease duration, the presence of angioedema, and various laboratory parameters [97]. CU persisted beyond one and five years in 70 and 14 percent of patients, respectively. A longer duration of symptoms was associated with increased severity, the presence of angioedema, thyroid autoimmunity, and a positive ASST [39,97]. However, other studies have not found an association between positive ASST and persistent disease [3]. Thus, symptom severity appears to correlate with duration of CU, but the predictive value of other clinical and laboratory features requires further study. SUMMARY AND RECOMMENDATIONS Chronic urticaria (CU) is defined by the presence of urticaria (hives), on most days of the week, for a period of six weeks or longer. CU prevalence is up to 1 percent of the general population. Adults are affected more often than children, and women, more often than men. (See 'Epidemiology' above.)The diagnosis is made clinically, based on the history and physical examination. No external cause can be identified in 80 to 90 percent of adults and children with CU. Laboratory studies are normal in most patients, although a complete blood count with differential, a CRP or ESR, and a TSH level are suggested. Biopsy of a fresh lesion is indicated in some circumstances. (See 'Evaluation and diagnosis' above.)Several theories regarding the pathogenesis of chronic idiopathic urticaria have been proposed, although the data for each are incomplete and none appears to be helpful for determining treatment or prognosis. The best developed hypotheses involve histamine releasing factors and defects in basophil signaling and/or function. (See 'Theories of pathogenesis' above.)Tests used in investigations of pathogenesis include the autologous serum and plasma skin tests, assays for autoantibodies directed against IgE or the FcepsilonRI receptor, and in vitro assessments of basophil function. However, these tests lack specificity and prognostic value for CU, are not standardized, and cannot be recommended for routine clinical use. (See 'Theories of pathogenesis' above.)CU is a self-limited disease. Spontaneous remission occurs in 30 to 50 percent of patients by one year, although nearly one-fifth of patients still have symptoms after five years. Those with more severe symptoms may have longer lasting disease. (See 'Natural history and prognosis' above.)

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CHRONIC URTICARIA: STANDARD MANAGEMENT AND PATIENT EDUCATION INTRODUCTION Chronic urticaria (CU) is defined by the presence of urticaria (hives) on most days of the week, for a duration of longer than six weeks. The prevalence of this disorder is up to one percent of the general population in the United States, and is believed similar around the world [1]. Associated angioedema occurs in about 40 percent of patients with CU and usually affects the lips, cheeks, periorbital areas of the face, extremities, and genitals [2]. The management of CU in most patients, as well as counseling of individuals with this disorder, will be discussed here. Treatment of CU that is refractory to standard management and the diagnosis, pathogenesis, and prognosis of CU are presented separately. (See "Chronic urticaria: Treatment of refractory symptoms" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".) Terminology In this review, the term CU refers to patients with isolated chronic idiopathic urticaria, as well as those with both urticaria and angioedema. Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CU (such as delayed pressure urticaria, cholinergic urticaria, or cold urticaria) are discussed separately. (See "An overview of angioedema: Pathogenesis and causes" and "Urticarial vasculitis" and "Physical urticarias" and "Cold urticaria".) Chronic autoimmune urticaria In the discussion below, the terms chronic urticaria and chronic idiopathic urticaria are used synonymously. Some studies distinguish between patients with and without positive autologous serum skin tests (ASST) or other laboratory indicators of an autoimmune process. This distinction is mentioned in the text only if a study found a difference between these two patient groups. The interpretation of a positive ASST in patients with CU is reviewed elsewhere. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history", section on 'Autoimmune theory'.) PATIENT EDUCATION Chronic urticaria causes marked distress to patients because it is physically uncomfortable, waxes and wanes unpredictably, interferes with work/school and sleep, and is often difficult to treat. The severity and duration of symptoms vary among individuals, and the underlying cause is not known in most cases. Furthermore, it can be misinterpreted by others to be infectious and patients may stay home to avoid embarrassment. All of these factors contribute to patient frustration and anxiety.

Reassurance Patients with CU are often frustrated and fearful, and reassurance is an important component of successful management. There are three important concepts to relay to patients with CU: Patients need to understand that CU is rarely permanent, and that almost 50 percent of patients undergo remission within one year [3].While acute urticaria and angioedema may be manifestations of allergic reactions that can be life-threatening, chronic urticaria is a different disorder that rarely puts the patient at any acute risk.The symptoms of CU can be successfully managed in the majority of patients. Avoidance of exacerbating factors No external cause can be identified in 80 to 90 percent of people affected by CU/angioedema. The evaluation and diagnosis of a patient with persistent urticaria are reviewed separately. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".) Once the diagnosis of chronic idiopathic urticaria/angioedema has been established, the clinician should begin educating the patient about management, including avoidance of things that can aggravate the condition, including: Physical factors A substantial subset of patients with CU have some flares that are triggered by physical stimuli. Educating patients about this can help them avoid these stimuli or simply make sense of their symptoms. As an example, heat (hot showers, extreme humidity) is a common trigger for many CU patients, and tight clothing or straps can also aggravate symptoms. In contrast, patients in whom physical factors are the main trigger for symptoms are more appropriately diagnosed as having a physical urticarial syndrome, such as cholinergic urticaria or delayed pressure urticaria. Physical urticarias are reviewed separately. (See "Physical urticarias" and "Cold urticaria".)Antiinflammatory medications and alcohol Nonsteroidal antiinflammatory drugs (NSAIDs) and alcohol worsen symptoms in many patients. Dietary manipulations It is particularly important to explain to patients that an undiscovered allergy to food or food additives is not likely to be responsible for their symptoms. IgE-mediated food reactions are not a cause of CU and testing for food allergy is not necessary [4]. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history", section on 'Foods and food additives'.) Although chronic urticaria is not a manifestation of IgE-mediated food allergy, food can cause fluctuations in the symptoms of CU that are noticeable to patients. This is believed to be due to the presence of "pseudoallergens," which are substances in food that exacerbate CU. Pseudoallergens include artificial preservatives and dyes in processed foods, as well as naturally-occurring aromatic compounds in certain foods (many fruits and vegetables, seafood, others). Diets free of pseudoallergens are difficult to follow because the array of foods that must be avoided is so broad (table 1). The utility of pseudoallergen-free diets in CU has been evaluated in uncontrolled studies. One study concluded that adherence to a diet low in pseudoallergens was helpful, since 73 percent of 64 CU patients had either cessation or a significant reduction of symptoms within two weeks of adopting a pseudoallergen-free diet [5]. However, only 19 percent of those who improved developed symptoms when subsequently challenged with individual pseudoallergens on provocation tests, suggesting that no one substance was responsible, and that benefit was dependent upon the strict avoidance of multiple foods. In contrast to the high rates of response in this study, a subsequent larger study of 140 patients placed on a pseudoallergen-free diet found that only 28 percent had a strong or partial response [6]. The foods and other substances that are prohibited in a pseudoallergen-free diet are listed in the table (table 1). Several weeks of adherence to this diet may be necessary for clinical improvement.

The limited clinical relevance of pseudoallergens in CU is also supported by the observation that patients in whom CU has remitted are able to eat anything without recurrence of urticaria [7]. In summary, we do not routinely advise CU patients to adopt pseudoallergen-free diets. However, if a patient is very motivated to try these diets, we do not object. AGENTS AND EFFICACY Most patients with CU are initially treated with antihistamines, often in conjunction with limited courses of oral glucocorticoids for refractory symptoms. However, long-term systemic glucocorticoids are associated with significant adverse effects, and persistent symptoms should be treated instead with other immunosuppressive, immunomodulatory, or steroid-sparing agents. The different medications used in the management of CU and studies of efficacy are discussed in this section. A stepwise approach to therapy, including recommended dosing and monitoring, is presented subsequently. (See 'Stepwise approach to treatment' below.) H1 antihistamines H1 antihistamines are the cornerstone of pharmacotherapy for CU and control symptoms to at least some degree in most patients [1,8-10]. Patients show variable responsiveness to antihistamines. The magnitude of effect is difficult to generalize, although in various reports, 50 to 95 percent of patients achieved satisfactory disease control with one or a combination of antihistamines, without other agents [9,11,12]. Several randomized, placebo controlled trials have demonstrated that both the first and second generation H1 antihistamines reduce the major symptoms of CU, (ie, pruritus, wheal (hive) formation, and disruption of sleep and daily activities) [2,13-16]. A systematic review concluded that nonsedating antihistamines improve quality of life for patients with CU [17]. The newer second generation agents (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine) are generally as effective and better tolerated (ie, less sedative and anticholinergic effects) than moderate doses of the older, first generation antihistamines (eg, hydroxyzine, diphenhydramine, chlorpheniramine, or mizolastine) [18,19]. A few trials have compared different second generation agents [20-23]. Cetirizine and levocetirizine were comparable in effectiveness and performed modestly better than other agents: Cetirizine and levocetirizine were comparable in efficacy in a trial of 50 patients [23].Levocetirizine (5 mg daily) produced a significantly greater reduction in pruritus severity and duration than desloratadine (5 mg daily) in a trial of 886 patients treated for four weeks [20].Cetirizine compared to fexofenadine was significantly more likely to induce clearance of hives (52 versus 4 percent) with a similar rate of improvement of hives (37 versus 42 percent) in 117 patients [22]. Dosing of second generation agents As mentioned above, the second generation H1 antihistamines (eg, cetirizine, levocetirizine, fexofenadine, loratadine, desloratadine) are generally as effective and better tolerated than the first generation agents. Doses of second generation antihistamines as high as four times the recommended dose are advocated in international guidelines on chronic urticaria, based largely upon expert opinion [9,10,24]. However,

the limited number of published studies evaluating this approach has not demonstrated a clear increase in efficacy [12,13,25]: A small observational study evaluated 21 CU patients with inadequate response after one to two weeks of cetirizine (10 mg daily) for improvement with cetirizine at a dose of 10 mg twice daily for an additional one to two weeks [26]. Subjects were then randomized to continue at a dose of either 20 mg daily or reduce to 10 mg daily for an additional two weeks. Both groups had improved urticarial scores on cetirizine 20 mg daily, but only the group that remained on the higher dose had continued improvement, with worsening symptoms in the group whose cetirizine dose was reduced.A randomized trial of 80 patients referred to a tertiary center for refractory CU assigned subjects to either levocetirizine or desloratadine [12]. Initial doses were 5 mg of either drug, and doses were doubled at weekly intervals if patients had not responded (with response defined as >50 percent improvement), up to maximal doses of 20 mg by week three. If patients did not respond to 20 mg of one drug, they were then changed to 20 mg of the other during week four. Subjects did not demonstrate increased somnolence with either agent. Among those patients who responded (as defined previously), improvement was achieved in 52, 65, and 74 percent with 5, 10, and 20 mg of levocetirizine respectively, and 41, 56, and 63 percent with the same doses of desloratadine. Of note, there were 13 patients who became symptom free on standard 5 mg doses of either medication, raising the issue of whether these "refractory" subjects had been adherent with previous therapies. There were seven subjects who did not respond to 20 mg of desloratadine, but did respond to 20 mg of levocetirizine. There were no patients who responded to desloratadine after failing levocetirizine, suggesting that levocetirizine was the more effective agent. However, about 15 percent failed to respond to the highest doses of either drug, and overall, only about one-half of patients achieved complete control of symptoms by the conclusion of the trial. In addition, there was no placebo arm. Thus, this approach of doubling the dose stepwise in patients whose symptoms are not controlled appears to be safe for patients, and allows the clinician to individualize treatment to some extent. This study suggests that higher doses of either desloratadine or levocetirizine may be more effective than standard doses. Studies of other second generation antihistamines have not shown improved efficacy at higher doses [13,25]: A multicenter randomized trial of 418 patients treated with fexofenadine at doses of 20 mg, 60 mg, 120 mg, or 240 mg twice daily found that the three higher doses provided better disease control than the lowest dose (which was below the lowest recommended adult dose), but there were no significant differences in effectiveness among the higher doses [13]. Another study of very similar design, also using fexofenadine, 20 mg, 60 mg, 120 mg, or 240 mg twice daily, found no difference in efficacy among the three highest doses [27].A small observational study of 22 patients found that increasing the cetirizine dose from 10 mg once daily to 10 mg three times daily improved disease control in only one patient [25]. Thus, the evidence for higher doses of second generation antihistamines is mixed and varies for different antihistamines. To summarize: Desloratadine and levocetirizine may be more effective at higher doses and do not cause clinically significant sedation.Fexofenadine is not more effective at higher doses.The evidence for the efficacy of higher doses of cetirizine in CU is conflicting and based on very low quality evidence. Information about sedation at higher doses is lacking.

Dosing of first generation agents Higher doses of first generation antihistamines have been recommended by several authors, particularly when second generation antihistamines do not produce an adequate response [10]. The primary concern with higher dose therapy is sedation and performance impairment, and clinicians should inform patients specifically about this side effect. In children younger than two years of age, first generation, sedating antihistamines should be avoided, as these drugs can cause paradoxical agitation and over-the-counter cold remedies containing them have been linked to a small number of deaths in this age group. (See "The common cold in children", section on 'Treatment'.) Studies of first generation antihistamines in adults, at usual doses, have shown tolerance to performance impairment after three to five days of therapy [28-30]. Studies in patients with CU given higher doses are lacking, although many patients with CU seem to tolerate high doses without difficulty. Based upon this information, some authors suggest a gradual titration of first generation antihistamines. As an example, hydroxyzine can be started at 10 to 25 mg daily and increased in 10 to 25 mg increments every five to seven days to a maximum of 25 to 50 mg four times daily [7,31]. Another approach is to administer first generation antihistamines as a single dose in the evening, in combination with a second generation antihistamine given in the morning [1,31]. First generation antihistamines typically have long half-lives and a single nighttime dose may reduce daytime sedation compared to frequent daytime dosing; however these proposed regimens have not been compared in terms of either efficacy or adverse effects in patients with CU. H2 antihistamines Patients whose symptoms are not adequately controlled on H1 antihistamines alone may experience modest improvement with the addition of H2 antihistamines [32,33]. Some studies of H1 and H2 antihistamine combinations have used agents that are metabolized by the same liver enzymes, raising the possibility that the benefit was largely due to increased serum concentrations of one or both drugs, rather than a true synergistic effect [34]. Thus, a trial of H2 antihistamines can be considered as additive therapy in patients whose symptoms do not respond adequately to H1 antihistamines alone. Topical agents While there are isolated, anecdotal reports that suggest benefit of some topical agents for CU, routine use is discouraged as they rarely result in sustained improvement and are rarely used as intended outside of clinical trials. Some of the agents that have been used include emollients that contain menthol, phenol or pramoxine, substances that are benign but minimally effective. Others contain high-potency topical corticosteroids, which can cause dermal atrophy, or topical antihistamines (eg, doxepin-containing preparations), which can cause contact sensitization [35]. Systemic glucocorticoids Systemic (usually oral) glucocorticoids are effective in controlling symptoms in most patients with CU. However, administration beyond several weeks is not justified for a disorder that, in itself, has an excellent long-term prognosis, since these agents have predictable and significant adverse effects. We view glucocorticoids as rescue therapy that should be used to attain temporary control of severe symptoms. (See "Major side effects of systemic glucocorticoids".) Most guidelines suggest that oral glucocorticoids be considered as an initial additive therapy for patients with symptoms refractory to one or more antihistamines [8-10]. One expert has advised that doses of prednisone not exceed 10 mg a day or 20 to 25 mg every other day, and that this be administered only as long as needed to gain control and then tapered [7]. In many cases, symptoms recur as

glucocorticoids are tapered or discontinued, and these agents are not believed to alter the long-term course of the disease. (See 'Systemic glucocorticoids for rescue therapy' below.) Leukotriene modifiers Leukotrienes are believed involved in the pathogenesis of urticaria. Activated mast cells generate and release leukotrienes in addition to histamine, and intradermally injected leukotriene D4 causes a strong wheal and flare response [36-38]. Antileukotriene medications include the leukotriene receptor antagonists, montelukast and zafirlukast, as well as the 5-lipoxygenase inhibitor zileuton. Available evidence suggests that these agents may be useful either as monotherapy or add-on therapy in some patients with CU. One subgroup that may respond more predictably to these agents is patients with CU that is exacerbated by ingestion of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs), since abnormal leukotriene regulation is believed to be important in the pathogenesis of this type of urticaria [39,40]. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions".) Case reports described the use of montelukast to block acute urticaria secondary to NSAIDs [41,42], and another described a patient with NSAID-exacerbated CU, who responded to both zafirlukast and zileuton [39].Two small randomized trials found montelukast to be superior to cetirizine and placebo in patients with NSAID-exacerbated CU [43,44]. Patients with the rare disorder of antihistamine-induced urticaria [45] might also benefit from antileukotriene agents. A case report described four such patients, three of whom responded to montelukast [46]. In unselected populations of patients with CU, the data in support of leukotriene modifiers are less robust: Montelukast (10 mg once daily), either alone or in combination with antihistamines, has demonstrated efficacy in randomized controlled trials [33,43,44,47,48]. However, not all trials were positive [49], and one found montelukast to be less effective than desloratadine for 160 patients with relatively mild CU [50].Studies of zafirlukast are mixed as well. The combination of zafirlukast and cetirizine was shown to be superior to cetirizine alone in a randomized trial of patients with a positive autologous serum skin test (ASST), but not in patients with a negative ASST [51]. This distinction was not confirmed in a separate open trial [52]. A second randomized trial was negative, showing no statistical difference between zafirlukast and placebo in 52 CU patients [53].Zileuton has not been formally studied in the treatment of CU. The only published experience with pranlukast described two patients who experienced an exacerbation during therapy [54]. No head-to-head studies have compared different leukotriene modifiers in the treatment of CU. Choice of agent and time to response The preferred agents are montelukast and zafirlukast, because these drugs are widely available and require no monitoring of laboratory studies. In contrast, zileuton use requires that liver function tests be followed. Time to benefit can be fairly rapid in some patients, while others appear to require several weeks of treatment [55]. One study suggested persistent drug-free remission [44], although most studies did not observe this outcome. OTHER THERAPIES FOR SPECIFIC CLINICAL SITUATIONS

Patients with concomitant borderline or elevated blood pressure Dihydropyridine calcium channel blockers may reduce the proliferation of stimulated T-lymphocytes and inhibit mast cell mediator release [56,57]. A small, randomized, controlled, crossover trial of 10 patients with CIU treated with nifedipine (up to 20 mg three times daily) demonstrated benefit in seven patients, with mild adverse effects [58]. Other evidence consists of case reports. Advantages of this agent include a relatively rapid therapeutic response, familiarity of clinicians with this class of drug, and wide availability. Thus, a trial of calcium channel blockers may be reasonable for patients who can tolerate the hemodynamic effects, or for those with concomitant hypertension. In addition, there is preliminary evidence that the presence of systemic hypertension is associated with longer CU duration, as discussed elsewhere. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history", section on 'Natural history and prognosis'.) Patients with hypothyroidism Thyroid autoimmunity, as determined by the presence of elevated levels of thyroid peroxidase antibodies or antithyroglobulin antibodies, is found in patients with chronic urticaria at a greater than expected frequency [59,60]. However, the patient's thyroid status does not necessarily correlate with the presence of urticaria. Patients with chronic urticaria/angioedema and evidence of thyroid autoimmunity may be euthyroid, hypothyroid, or hyperthyroid [59,61]. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".) Patients with thyroid autoantibodies and laboratory evidence of clinical hypothyroidism may benefit from thyroid hormone replacement. In contrast, the treatment of euthyroid patients with CU is controversial. There are several reports of apparently successful treatment of euthyroid patients with thyroid hormone at doses that suppress the level of thyroid stimulating hormone (TSH) [59-64]. We have seen some euthyroid patients with thyroid autoantibodies respond to thyroxine therapy without adverse effects, but the results are mixed and unpredictable. If this therapy is used, the uncertain benefits must be balanced with potential risks of iatrogenic hyperthyroidism and osteoporosis [65]. Pregnant or lactating women Pregnant women with urticaria with/without angioedema should be treated with the least amount of medication possible. Most patients can be treated with H1 antihistamines alone, with occasional short courses of oral glucocorticoids for severe flares. The safety of different antihistamines, leukotriene modifying drugs, and other agents in pregnancy and lactation is discussed separately. (See "Recognition and management of allergic disease during pregnancy", section on 'Urticaria and angioedema'.) STEPWISE APPROACH TO TREATMENT This section describes an approach to the treatment of chronic urticaria (CU) using the different medications discussed previously. This approach represents that of the author and editors of UpToDate. Practice Parameters for the management of CU have been published by expert panels of allergists/immunologists and/or dermatologists in the United States, United Kingdom, and Europe [8-10]. The approach described herein is relatively consistent with these practice parameters, although there are differences among these parameters and the best approach is not known. All doses listed are for adults, unless otherwise noted. Systemic glucocorticoids for rescue therapy Systemic glucocorticoids may be required periodically to gain temporary control of symptoms during severe exacerbations of urticaria that significantly impair quality of life. These rescue courses of glucocorticoids may be required at any point in therapy and are generally added on to the medications that the patient is already taking. However, long-term (eg,

months to years) of systemic glucocorticoid therapy should be avoided, as discussed previously. (See 'Systemic glucocorticoids' above.) The optimal dose and duration of glucocorticoids used for CU exacerbations has not been systematically studied, and recommendations vary among urticaria specialists. In addition, patients differ in their responsiveness to glucocorticoids in both the dose and duration of treatment required to control symptoms. We prefer to use relatively brief (ie, 3 to 10 day) courses of prednisone, and typically begin with a dose of 20 mg twice daily for two to three days. Occasional patients require higher initial doses. Once symptoms are controlled, the dose should be tapered down to 10 mg daily or less, which can typically be done in increments of 10 mg. Rebound worsening of urticaria may occur with tapering or discontinuation of systemic glucocorticoids and if this occurs, we return to the last effective dose and then try to taper again more gradually. Some authors suggest that once the dose has been reduced to 20 mg daily, the frequency of administration may be changed to every other day, and then the dose tapered further. Step 1: Second generation H1 antihistamine We administer a second generation antihistamine at standard therapeutic dose as initial therapy. We prefer cetirizine 10 mg once daily, but the following other agents are appropriate alternatives (see 'H1 antihistamines' above): Levocetirizine, 5 mg once dailyFexofenadine, 180 mg once dailyLoratadine, 10 mg once dailyDesloratadine, 5 mg once daily Step 2: Increase dose We instruct patients to increase the dose of the second generation antihistamine to twice daily if once daily does not control symptoms adequately within several days. Another option is to add a different second generation antihistamine (eg, fexofenadine 180 mg in the morning, and cetirizine 10 mg at night). This can be particularly helpful when patients develop increased sedation from higher doses of certain agents, such as cetirizine. (See 'Dosing of second generation agents' above.) Dosing up to four times standard doses may be considered with some agents, such as desloratadine and levocetirizine, although it is not useful with fexofenadine. (See 'Dosing of second generation agents' above.) Step 3: Add or substitute other types of antihistamines If increased doses of a second-generation H1 antihistamine do not control symptoms, we then either add or substitute a first generation H1 antihistamine at bedtime, or add an H2 antihistamine. We prefer to add one of the following potent H1 receptor antagonists: Hydroxyzine: This agent may be dosed once at bedtime, or alternatively in divided doses throughout the day. Adults may be given 10 or 25 mg initially at bedtime, and increased in weekly increments up to a maximum of 50 as a single before bedtime dose. Doses up to 100 to 150 mg daily may be given if divided every six to eight hours. Sedating antihistamines may be used in cautiously in children. Children six years of age may be given up to 50 to 100 mg per day in divided doses.Doxepin: Doxepin (in adults), may be initiated at 10 or 25 mg and increasing in weekly increments to 100 to 150 mg, given once at bedtime or alternatively in divided doses throughout the day. Doxepin is generally avoided in children <12 years of age due to limited clinical experience.(See 'H1 antihistamines' above.)Some clinicians add an H2

antagonist, such as ranitidine, 150 mg twice daily, to the patient's H1 antagonist. (See 'H2 antihistamines' above.) Step 4: Leukotriene modifier If symptoms are refractory to high-doses or combinations of H1 antihistamines and/or H2 antihistamines, or if patients experience excessive sedation or anticholinergic side effects, we then consider non-antihistamine therapies. Our preferred initial add-on therapy is a leukotriene modifier. We usually prescribe montelukast 10 mg daily, while maintaining the patient on the highest tolerated dose of H1 antihistamines. We allow at least four weeks to gauge the effect of the leukotriene modifier. If there is no improvement, we discontinue the medication. (See 'Leukotriene modifiers' above.) Step 5: Consider immunomodulatory and immunosuppressive agents For patients whose symptoms are refractory to the measures discussed so far in this review, additional therapies should be considered and are presented separately. (See "Chronic urticaria: Treatment of refractory symptoms".) Maintenance therapy Many patients with CU require multiple medications to control symptoms fully. Once symptoms have come under control, the patient should be maintained on those agent(s) for a period of time before withdrawal of medications is considered. The optimal duration of maintenance therapy in a variable disease like CU has not been studied. Patients whose symptoms were easily and completely controlled with one or two agents may begin to taper therapy after a month or two of well-controlled symptoms. For the majority of patients, we generally recommend three months of good control prior to tapering therapies, and we extend this longer for patients with one or more of the following characteristics: Symptoms that were present for years, were very severe, or were difficult to controlConcomitant physical urticarias, which tend to be longer-lasting than simple CUSymptoms that are mostly controlled, but still present at a low level We typically discontinue agents that have been deemed ineffective, including antihistamines in patients who are completely antihistamine resistant. In patients responsive to antihistamine therapy, we gradually reduce antihistamine doses every two to four weeks, beginning with first generation agents. Other agents can be tapered in a similar fashion. In patients dependent on systemic glucocorticoids, we reduce the dose as quickly as possible once their urticaria has been stabilized. SUMMARY AND RECOMMENDATIONS Patients with chronic urticaria (CU) are often frustrated and anxious. Education and reassurance are critical components of successful management and should begin as soon as the diagnosis is made. (See 'Patient education' above.)Systemic glucocorticoids should be reserved for short-term control of refractory symptoms. (See 'Systemic glucocorticoids for rescue therapy' above.)For all patients with CU, we recommend H1 antihistamines as initial therapy (Grade 1A). We recommend nonsedating second generation agents, rather than first generation agents (Grade 1B). We typically administer cetirizine, 10 mg once daily. (See 'H1 antihistamines' above and 'Step 1: Second generation H1 antihistamine' above.)For patients whose symptoms persist, we suggest either increasing the dose of the nonsedating H1 antihistamine (eg, cetirizine 10 mg twice daily) or adding a different second generation antihistamine (eg, fexofenadine 180 mg in the morning, and cetirizine 10 mg at night) (Grade

2C). (See 'Step 2: Increase dose' above.)For patients whose symptoms persist, we suggest adding or substituting a first generation H1 antihistamine (Grade 2C). It can be administered initially at bedtime, to avoid excessive daytime sedation. Alternatively, it can be given in divided doses throughout the day, starting at low doses and gradually increasing. The patient should be informed about sedation and anticholinergic side effects. Another option is the addition of an H2 antihistamine. (See 'Step 3: Add or substitute other types of antihistamines' above.)For patients whose symptoms persist, we suggest maintaining the highest tolerated dose of H1 antihistamines, and adding montelukast (10 mg daily) (Grade 2C). A month-long trial should be sufficient to assess response. (See 'Step 4: Leukotriene modifier' above.)Once symptoms are controlled, we continue the drug(s) required for control for a minimum of one to three months before attempting to taper doses or discontinue medications. We extend this maintenance period even longer in patients whose disease was particularly difficult to suppress. (See 'Maintenance therapy' above.)For patients whose symptoms are not controlled by the above stepwise approach, other immunomodulatory or immunosuppressant therapies may be needed. (See "Chronic urticaria: Treatment of refractory symptoms".) Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Kaplan AP. Clinical practice. Chronic urticaria and angioedema. N Engl J Med 2002; 346:175. 2. Goldsobel AB, Rohr AS, Siegel SC, et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1986; 78:867. 3. Kozel MM, Mekkes JR, Bossuyt PM, Bos JD. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol 2001; 45:387. 4. Bernstein, IL, Li, JT, Bernstein, DI, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol 2008; 100:S1. (Abstract). 5. Zuberbier T, Chantraine-Hess S, Hartmann K, Czarnetzki BM. Pseudoallergen-free diet in the treatment of chronic urticaria. A prospective study. Acta Derm Venereol 1995; 75:484. 6. Magerl M, Pisarevskaja D, Scheufele R, et al. Effects of a pseudoallergen-free diet on chronic spontaneous urticaria: a prospective trial. Allergy 2010; 65:78. 7. Kaplan AP. What the first 10,000 patients with chronic urticaria have taught me: a personal journey. J Allergy Clin Immunol 2009; 123:713. 8. Zuberbier T, Bindslev-Jensen C, Canonica W, et al. EAACI/GA2LEN/EDF guideline: definition, classification and diagnosis of urticaria. Allergy 2006; 61:316. 9. Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009; 64:1427. 10. Powell RJ, Du Toit GL, Siddique N, et al. BSACI guidelines for the management of chronic urticaria and angio-oedema. Clin Exp Allergy 2007; 37:631. 11. Humphreys F, Hunter JA. The characteristics of urticaria in 390 patients. Br J Dermatol 1998; 138:635. 12. Staevska M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010; 125:676. 13. Nelson HS, Reynolds R, Mason J. Fexofenadine HCl is safe and effective for treatment of chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2000; 84:517. 14. Ring J, Hein R, Gauger A, et al. Once-daily desloratadine improves the signs and symptoms of chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled study. Int J Dermatol 2001; 40:72. 15. Ortonne JP, Grob JJ, Auquier P, Dreyfus I. Efficacy and safety of desloratadine in adults with chronic idiopathic urticaria: a randomized, double-blind, placebo-controlled, multicenter trial. Am J Clin Dermatol 2007; 8:37.

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38. Wedi B, Novacovic V, Koerner M, Kapp A. Chronic urticaria serum induces histamine release, leukotriene production, and basophil CD63 surface expression--inhibitory effects ofanti-inflammatory drugs. J Allergy Clin Immunol 2000; 105:552. 39. Ellis MH. Successful treatment of chronic urticaria with leukotriene antagonists. J Allergy Clin Immunol 1998; 102:876. 40. Asero R. Leukotriene receptor antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria. Ann Allergy Asthma Immunol 2000; 85:156. 41. Prez C, Snchez-Borges M, Capriles E. Pretreatment with montelukast blocks NSAID-induced urticaria and angioedema. J Allergy Clin Immunol 2001; 108:1060. 42. Serrano C, Valero A, Picado C. Usefulness of montelukast to prevent adverse reactions to COX-2 selective inhibitors: a case report. J Investig Allergol Clin Immunol 2005; 15:156. 43. Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene receptor antagonist in chronic urticaria. A double-blind, placebo-controlled comparison of treatment with montelukast and cetirizine in patients with chronic urticaria with intolerance to food additive and/or acetylsalicylic acid. Clin Exp Allergy 2001; 31:1607. 44. Erbagci Z. The leukotriene receptor antagonist montelukast in the treatment of chronic idiopathic urticaria: a single-blind, placebo-controlled, crossover clinical study. J Allergy Clin Immunol 2002; 110:484. 45. Rodrguez del Ro P, Gonzlez-Gutirrez ML, Snchez-Lpez J, et al. Urticaria caused by antihistamines: report of 5 cases. J Investig Allergol Clin Immunol 2009; 19:317. 46. Catelain A, Freymond N, Queuille E, Nicolas JF. [Urticaria paradoxically aggraved by H1 antihistamines]. Ann Dermatol Venereol 2004; 131:451. 47. Nettis E, Dambra P, D'Oronzio L, et al. Comparison of montelukast and fexofenadine for chronic idiopathic urticaria. Arch Dermatol 2001; 137:99. 48. Nettis E, Colanardi MC, Paradiso MT, Ferrannini A. Desloratadine in combination with montelukast in the treatment of chronic urticaria: a randomized, double-blind, placebo-controlled study. Clin Exp Allergy 2004; 34:1401. 49. Godse KV. Oral montelukast monotherapy is ineffective in chronic idiopathic urticaria: a comparison with oral cetirizine. Indian J Dermatol Venereol Leprol 2006; 72:312. 50. Di Lorenzo G, Pacor ML, Mansueto P, et al. Randomized placebo-controlled trial comparing desloratadine and montelukast in monotherapy and desloratadine plus montelukast in combined therapy for chronic idiopathic urticaria. J Allergy Clin Immunol 2004; 114:619. 51. Bagenstose SE, Levin L, Bernstein JA. The addition of zafirlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results. J Allergy Clin Immunol 2004; 113:134. 52. Sanada S, Tanaka T, Kameyoshi Y, Hide M. The effectiveness of montelukast for the treatment of anti-histamine-resistant chronic urticaria. Arch Dermatol Res 2005; 297:134. 53. Reimers A, Pichler C, Helbling A, et al. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy 2002; 32:1763. 54. Ohnishi-Inoue Y, Mitsuya K, Horio T. Aspirin-sensitive urticaria: provocation with a leukotriene receptor antagonist. Br J Dermatol 1998; 138:483. 55. Mora PM, Gonzlez Prez Mdel C, Jimnez Villarruel M, et al. [Therapeutic options in idiopathic chronic urticaria]. Rev Alerg Mex 2005; 52:77. 56. Kotturi MF, Carlow DA, Lee JC, et al. Identification and functional characterization of voltagedependent calcium channels in T lymphocytes. J Biol Chem 2003; 278:46949. 57. Kim YY, Holgate ST, Church MK. Inhibition of histamine release from dispersed human lung and tonsillar mast cells by nicardipine and nifedipine. Br J Clin Pharmacol 1985; 19:631.

58. Bressler RB, Sowell K, Huston DP. Therapy of chronic idiopathic urticaria with nifedipine: demonstration of beneficial effect in a double-blinded, placebo-controlled, crossover trial. J Allergy Clin Immunol 1989; 83:756. 59. Leznoff A, Josse RG, Denburg J, Dolovich J. Association of chronic urticaria and angioedema with thyroid autoimmunity. Arch Dermatol 1983; 119:636. 60. Doutre MS. Chronic urticaria and thyroid auto-immunity. Clin Rev Allergy Immunol 2006; 30:31. 61. Rumbyrt JS, Katz JL, Schocket AL. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995; 96:901. 62. Dreyfus DH, Schocket AL, Milgrom H. Steroid-resistant chronic urticaria associated with antithyroid microsomal antibodies in a nine-year-old boy. J Pediatr 1996; 128:576. 63. Gaig P, Garca-Ortega P, Enrique E, Richart C. Successful treatment of chronic idiopathic urticaria associated with thyroid autoimmunity. J Investig Allergol Clin Immunol 2000; 10:342. 64. Monge C, Demarco P, Burman KD, Wartofsky L. Autoimmune thyroid disease and chronic urticaria. Clin Endocrinol (Oxf) 2007; 67:473. 65. Kisakol G, Kaya A, Gonen S, Tunc R. Bone and calcium metabolism in subclinical autoimmune hyperthyroidism and hypothyroidism. Endocr J 2003; 50:657.

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CHRONIC URTICARIA: TREATMENT OF REFRACTORY SYMPTOMS

INTRODUCTION Chronic urticaria (CU) is defined by the presence of urticaria (hives) on most days of the week, for a duration of longer than six weeks. Associated angioedema occurs in about 40 percent of patients. Standard management of CU primarily involves H1 antihistamines, often with a short course of glucocorticoids to control severe exacerbations. Leukotriene modifiers and H2 antihistamines are commonly used adjunctive therapies. (See "Chronic urticaria: Standard management and patient education".) Patients whose symptoms are not controlled over time using with these standard therapy may receive repeated courses of glucocorticoids, or extended periods of glucocorticoids exposure (ie, months of treatment). In this situation, the clinician should consider other antiinflammatory, immunomodulatory, or immunosuppressant agents, as the risks of long-term glucocorticoid therapy are well known. In addition, glucocorticoids are not believed to induce lasting remission or alter the natural history of CU, while some of the agents discussed in this topic review may have these properties. (See "Major side effects of systemic glucocorticoids".) There is no standardized approach to the management of refractory CU, and therapy must be individualized. The decision to use a certain medication should be based upon an assessment of risk versus benefit for that specific patient, taking into account concomitant medical conditions and patient preferences. Typically, the antihistamines and other standard agents that were clearly helpful to the

patient are continued while these more advanced treatments are tried. Any medications of uncertain benefit should be discontinued, so that medications do not accumulate. Therapeutic options for patients with refractory CU, as well as the evidence in support of the efficacy of each treatment, will be reviewed here. Standard management, as well as the diagnosis, pathogenesis, and prognosis of chronic urticaria, are reviewed separately. (See "Chronic urticaria: Standard management and patient education" and "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history".) TERMINOLOGY In this review, the term CU refers to patients with isolated chronic idiopathic urticaria, as well as those with both urticaria and angioedema. Disorders involving isolated angioedema, urticarial vasculitis, and specific physical forms of CU (such as delayed pressure urticaria, cholinergic urticaria, or cold urticaria) are discussed separately. (See "An overview of angioedema: Pathogenesis and causes" and "Urticarial vasculitis" and "Physical urticarias" and "Cold urticaria".) Chronic autoimmune urticaria In the discussion below, the terms chronic urticaria and chronic idiopathic urticaria are used synonymously. Some studies distinguish between patients with and without positive autologous serum skin tests (ASST) or other laboratory indicators of an autoimmune process. This distinction is mentioned in the text only if a study found a difference between these two patient groups. The interpretation of a positive ASST in patients with CU is reviewed elsewhere. (See "Chronic urticaria: Diagnosis, theories of pathogenesis, and natural history", section on 'Autoimmune theory'.) ANTIINFLAMMATORY AGENTS Agents Antiinflammatory agents that have been studied in the treatment of CU include dapsone, sulfasalazine, and hydroxychloroquine. Dapsone Dapsone is a sulfone antimicrobial agent. In CU, it may act by suppressing prostaglandin and leukotriene activity, interfering with release or function of neutrophil lysosomal enzymes [1,2], disrupting integrin-mediated neutrophil adhesiveness [3], inhibiting neutrophil recruitment and activation signals [4], and scavenging oxygen free radical intermediates [5]. Dapsone has traditionally been thought to be helpful in cutaneous diseases in which neutrophils play a prominent role [6]. Some cases of CU have a neutrophil-rich infiltrate on biopsy, although whether this histopathologic finding predicts response to dapsone in patients with CU is unproven. Studies of dapsone for the treatment CU include the following: A case series of 11 CU patients, refractory to antihistamines alone, reported clinical improvement in nine subjects within several weeks (ultimately allowing discontinuation of cetirizine therapy) with a low dose of dapsone (25 mg daily) [7]. In the two remaining patients, the dose was increased to 50 mg daily, which resulted in a complete response in one subject and partial response in the other. Seven patients had remission lasting variable periods of time after stopping use of the drug. We have also observed sustained remission in >50 percent of dapsone responders in our own practice.Preliminary, unpublished results from a randomized, crossover study performed at the author's center showed improvement in 15 of 22 CU patients taking dapsone, 100 mg daily [8]. Improvement was evident within days in some patients, whereas others required several weeks. Dapsone is generally well tolerated, widely available, and inexpensive. However, it can cause severe hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Therefore, it

is our practice to test for G6PD deficiency before initiating treatment. The various diagnostic tests for G6PD deficiency are discussed separately. (See "Extrinsic nonautoimmune hemolytic anemia due to drugs and toxins" and "Diagnosis and treatment of glucose-6-phosphate dehydrogenase deficiency", section on 'Diagnosis'.) Dapsone usually causes a small decline in hemoglobin (1 to 2 grams/dL), even in patients who do not have G6PD deficiency. We follow complete blood counts (CBC) monthly for the first three months of therapy and then every two to three months thereafter. We also follow liver function tests because hepatotoxicity is another uncommon side effect. Peripheral neuropathy, methemoglobinemia, and drug allergic reactions, such as the drug rash with eosinophilia and systemic symptoms (DRESS) are rare, but serious reactions that warrant immediate discontinuation of dapsone [9,10]. (See "Clinical features, diagnosis, and treatment of methemoglobinemia".) Sulfasalazine Sulfasalazine is an antiinflammatory 5-aminosalicylic acid (5-ASA) derivative. Mechanisms of action with possible relevance in CU include alteration of adenosine release [11], decreased leukotriene and prostaglandin synthesis, inhibition of IgE-mediated mast cell degranulation [12], attenuation of neutrophil respiratory burst [13], and inhibition of early-phase events in the proliferation and differentiation of B-lymphocytes [14]. Sulfasalazine is metabolized to sulfapyridine and 5-ASA within the gastrointestinal tract and most of the 5-ASA is degraded locally in the colon without much systemic distribution. Thus, the sulfapyridine may be largely responsible for its therapeutic activity in patients with CU. Limited data are available about the efficacy of sulfasalazine in CU: In the largest observational series, 19 patients with CU were treated with sulfasalazine and 14 experienced significant improvement, with four others showing modest benefit and one worsening [15]. Several patients were able to stop taking other medications, including glucocorticoids. Doses were increased in a stepwise fashion and response occurred within one month, although doses above 2 g daily had no additional clinical benefit in this group. Some patients experienced lasting remission after cessation of therapy.Other case reports successfully used doses between 2 and 3 grams daily [16,17]. Sustained remission was not described.Treatment failures are also reported [18]. Overall, sulfasalazine is well tolerated by most patients. Side effects include nausea, headache, mild or transient leukopenia, and transaminitis. Drawbacks include the advisability of gradual dose escalation, which may prolong the time to clinical response, as well as the need for laboratory monitoring. British guidelines recommend monitoring with CBC, blood urea nitrogen, creatinine, electrolytes, and liver function tests monthly during the first three months, then every three months thereafter [19]. Folate supplements should be co-administered to women who are pregnant or could potentially conceive. Hydroxychloroquine Hydroxychloroquine is an antiinflammatory drug and antimalarial agent. The relative safety and low cost of hydroxychloroquine make it a reasonable agent in the treatment of refractory CU. The major disadvantage is a relatively slow onset of action. Mechanisms of action include suppression of T-lymphocyte activation [20] and disruption of antigen processing and other cellular processes by alkalinization of intracellular vacuoles in macrophages and other antigen presenting cells [21]. In the best available study, 18 patients with CU were treated with a combination of therapies for CU (H1 antihistamines, H2 antihistamines, glucocorticoids, and doxepin) and randomized to receive either

hydroxychloroquine (5 mg/kg daily) or no additional drug [22]. After three months of treatment, patients in the hydroxychloroquine arm demonstrated improved quality of life. Hydroxychloroquine was well tolerated and there was a trend toward reduced medication use and urticarial activity that did not reach significance. Hydroxychloroquine rarely causes serious side effects. The most common adverse reactions are related to the gastrointestinal tract (nausea), skin (various macular lesions), and central nervous system (headache). Ophthalmologic problems, including corneal deposits (reversible) and retinopathy (potentially vision threatening) are possible, but rare with the low daily doses used in CU. The issue of ophthalmologic screening in patients taking hydroxychloroquine is reviewed separately. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.) Role in stepwise therapy The management of refractory CU is not standardized, as mentioned previously, and published guidelines only list options to be considered [23-25]. The approach presented here is that of the author and the editors of UpToDate. For patients whose symptoms are resistant to a regimen of H1 antihistamines and one or more of the other therapies discussed in the standard management topic review, and are requiring frequent or daily glucocorticoids, we suggest the addition of an antiinflammatory agent, specifically dapsone, sulfasalazine, or hydroxychloroquine. Any medications that did not appear to be helpful to the patient should be discontinued before others are added. A baseline CBC and chemistry panel with liver function tests should be obtained prior to initiation of these therapies. We consider the following in choosing among these agents: We most commonly start with dapsone, after additionally checking for G6PD deficiency. In adults, we start with a dose of 100 mg daily. In two weeks, we obtain a CBC and liver function tests and repeat these monthly for three months, and then less often. A 10 to 20 percent decline in hemoglobin or hematocrit is common and we do not stop therapy unless the decrease exceeds 25 percent. The dose can be reduced once there is a clear clinical response. A four to six week trial is usually sufficient to determine effectiveness. (See 'Dapsone' above.)We choose sulfasalazine instead in patients with underlying anemia or concomitant delayed pressure urticaria. In adults, we start with a dose of 500 mg twice a day for one week, and then increase to 1 gram twice a day. Laboratory monitoring with a CBC, liver function tests and urinalysis is performed every month for the first three months, and then less often. A four to six week trial is usually sufficient to determine effectiveness. (See 'Sulfasalazine' above.)We use hydroxychloroquine in patients who have suboptimal control of their CU, but only modest impairment in quality of life, as this agent is slow to work and patients with more severe disease may not be able to tolerate the duration of the trial. In adults, we start with a dose of 200 mg twice a day. A three month trial is usually required to determine effectiveness. (See 'Hydroxychloroquine' above.) Another strategy to circumvent the long latency time of hydroxychloroquine is the initiation of either dapsone or sulfasalazine at the same time. If the patient responds within a few weeks, the hydroxychloroquine can be discontinued as it was unlikely to have been responsible for the improvement. If no benefit is apparent with dual therapy after four to six weeks, the other agent (ie, dapsone or sulfasalazine) may be discontinued and the hydroxychloroquine continued for a total trial of 12 weeks.

We usually try two antiinflammatory agents before proceeding to immunosuppressant or immunomodulatory agents. Maintenance of successful therapy If the patient's symptoms are controlled, we usually maintain the effective dose of antiinflammatory agent while tapering and discontinuing glucocorticoids. If symptoms remain controlled on the antiinflammatory agent and antihistamines for a period of months, we then gradually begin reducing medications. If the patient is on sedating antihistamines or has not responded significantly to antihistamines, we taper these first and then the antiinflammatory is reduced over a period of several months as tolerated. IMMUNOSUPPRESSANT AND IMMUNOMODULATORY AGENTS If an antiinflammatory agent is not successful in controlling the disease, we discontinue it and consider immunosuppressant therapies next, such as cyclosporine, tacrolimus, sirolimus, or mycophenolate. However, in patients who are steroiddependent and already suffering from steroid-induced toxicity, we may elect to use an immunosuppressant prior to antiinflammatory therapy, as immunosuppressants seem to be more reliably effective in our clinical experience.

It is important for treating clinicians to be knowledgeable about potential adverse effects and monitoring when administering these medications for CU. Consultation with other specialists (eg, dermatologists, rheumatologists) may be appropriate depending on the medication, as well as the experience and comfort level of the treating clinician. Calcineurin inhibitors Calcineurin inhibitors, particularly cyclosporine, have been used successfully in chronic urticaria. These drugs inhibit calcium-dependent release of and responsiveness to histamine, leukotriene C4, and other mediators in mast cells and other cell types [26]. These agents also have anti-T lymphocyte activity [27]. Cyclosporine may also disrupt tumor necrosis factor alpha activity and secondarily inhibit neutrophil accumulation [28]. Tacrolimus has similar therapeutic effects. Cyclosporine Early studies of cyclosporine to treat CU described significant improvement with relatively high doses (6 mg per kg daily), but patients often discontinued therapy because of adverse effects, with relapse of their urticaria [29]. Mild adverse effects are frequent and dose-related, and dose reduction may eliminate these. Severe side effects are uncommon, but include hypertension and renal insufficiency. (See "Pharmacology and side effects of cyclosporine and tacrolimus".) Most subsequent studies have used lower doses (eg, 2 to 5 mg per kg daily), as well as the strategy of starting high and tapering down to the lowest effective dose [30-36]. This approach can achieve longterm benefit while minimizing significant side effects. Until more definitive studies are available, we suggest starting with a dose of 3 mg per kg, divided into two doses per day. Overall, randomized controlled trials support the effectiveness of calcineurin inhibitors in the treatment of CU, although these studies generally involved subjects who had failed only standard doses of antihistamines, so the severity of these patients' disease may have been overestimated. The following are representative studies: Thirty patients with "severe" disease were randomized to cyclosporine (4 mg per kg daily) or placebo for four weeks [37]. Initial non-responders were offered open-label cyclosporine for four weeks. Eight of 19 (42 percent) receiving cyclosporine improved, compared to none receiving placebo. In addition, 11 of 17

initial non-responders responded after an additional four weeks of open-label treatment. Adverse effects were common in this study (29 of 30 subjects) and most commonly involved paresthesias, gastrointestinal symptoms, and headache. All 30 patients in this study had positive autologous serum skin tests (ASSTs), but other studies found no correlation between ASST and cyclosporine response [38].Another randomized trial evaluated the effects of adding cyclosporine to cetirizine in 99 patients with CU [35]. The cyclosporine dose was 5 mg per kg daily for the first 28 days, which was then tapered to 3 mg per kg daily. All subjects were treated with cetirizine daily, plus either cyclosporine for 16 weeks, cyclosporine for eight weeks followed by placebo for eight weeks, or placebo for all 16 weeks. Symptom scores improved significantly in both groups receiving cyclosporine. Two patients discontinued treatment because of hypertension.Cyclosporine (5 mg per kg daily) was compared head-to-head with prednisone (20 mg once daily) in an eight week trial of 20 patients with CU refractory to antihistamines [39]. Nine of 10 patients receiving cyclosporine were symptom free within five days of starting therapy, and the last patient cleared within 15 days. Two patients suffered headache, tremors, and nausea, which resolved with lowering the dose to 3 mg per kg daily. No patient developed hypertension or renal function changes. Two patients had recurrent mild symptoms three months later. In comparison, all patients receiving prednisone also became symptom free "in a few days." One patient developed hypertension and two experienced weight gain. After the treatment period, four prednisone-treated patients promptly relapsed.A study of 54 children (9 to 16 years of age) with CU evaluated the use of cyclosporine for refractory symptoms [40]. Of the 54, seven children had symptoms that were not controlled with high dose antihistamines plus alternate-day prednisone and required daily oral prednisone. In these seven, cyclosporine (3 mg/kg/day divided into two doses per day) was added, and attempts were made to taper glucocorticoids. Cyclosporine levels were maintained 200 ng/mL to avoid adverse effects. Hives were completely controlled in all patients. This was achieved in one to four weeks for six subjects, and eight weeks for one. Once symptoms were controlled for one month, cyclosporine doses were reduced every two to four weeks and then discontinued. Four patients had relapses that again responded to cyclosporine, but all were eventually able to discontinue all medications with apparent remission of the disease. No children had significant side effects. Thus, cyclosporine appears to have several desirable properties, including rapid onset (sometimes within days) [31,33,41], a degree of efficacy comparable to prednisone [25], and the possibility of lasting remission [34,41,42]. Some authorities advocate the addition of cyclosporine for patients with prohibitive or persistent glucocorticoid requirements or who develop significant glucocorticoid side effects [43]. The optimal duration of therapy with cyclosporine is not known. Some studies indicate that a longer duration of therapy is more likely to induce sustained benefit [44], but other studies have found that the majority of patients respond within three months [36]. Blood pressure, blood urea nitrogen, and creatinine should be monitored monthly and fasting lipids periodically [19]. Serum levels may be followed to ensure that the dose is not excessive, although the optimal therapeutic level for CU has not been defined. In our experience, drug levels of calcineurin inhibitors have a poor correlation with overall effectiveness, and therefore we do not pursue a specific target drug level. Tacrolimus Experience with the use of tacrolimus in CU is limited. In one case series, 19 patients with severe CU were treated with low-dose tacrolimus [45]. Two patients discontinued tacrolimus due to side effects. At 12 weeks, 71 percent (12 patients) had responded to a significant degree, nine of whom were able to stop antihistamines, and three were able to stop glucocorticoids. One responder had a lasting drug-free remission and had previously failed cyclosporine, so there may be important differences

between the calcineurin inhibitors in the treatment of CU. The monitoring suggested with tacrolimus is similar to that with cyclosporine. Sirolimus Sirolimus (rapamycin) was reported to be effective in two of three patients in a case report [46]. The patients had previously failed multiple alternative therapies including montelukast, dapsone, hydroxychloroquine, colchicine, olsalazine, and mycophenolate mofetil. Of note, sirolimus and the related agent everolimus have been implicated in causing isolated angioedema [47-50]. Mycophenolate Mycophenolate acts as an antimetabolite selectively for lymphocytes and also impairs expression of adhesion molecules and secondary leukocyte migration [51]. Although unrelated to the calcineurin inhibitors, mycophenolate has some of the same properties with fewer reported adverse effects. The most common problems are gastrointestinal symptoms and leukopenia. (See "Mycophenolate mofetil: Pharmacology and adverse effects when used in the treatment of rheumatic diseases".) Very few studies are available on the use of mycophenolate in chronic urticaria. An open series evaluated nine patients with "severe" CU, defined as symptoms unresponsive over a six-week period to antihistamines and/or more than two week-long courses of oral glucocorticoids. Patients were treated with mycophenolate (1 g twice daily) for 12 weeks [52]. Six patients experienced marked improvement in urticaria scores, and the authors noted a steroid-sparing effect, since all patients were able to discontinue glucocorticoids by the end of the 12 week trial and improvement persisted for at least six months after discontinuation. No adverse effects or laboratory abnormalities were reported. If these findings are confirmed by future studies, mycophenolate would represent a highly attractive alternative to the calcineurin inhibitors, although further data are needed. Use in stepwise therapy and dosing Most patients with CU have relatively rapid responses (within days) to immunosuppressants. However, given the inherent variability of CU, a trial of one-month is typically adequate to determine efficacy. The following is one approach to administering these agents to patients with CU. Tacrolimus We prefer tacrolimus as an initial immunosuppressant. Although there are more data in support of cyclosporine, we prefer tacrolimus because most of our patients are women, and cyclosporine can cause hirsutism and gingival hyperplasia. Anecdotally, we have observed more frequent problematic side effects with cyclosporine than tacrolimus. Baseline laboratories including renal function are required prior to starting calcineurin inhibitors. We start tacrolimus at a dose of 1 mg twice daily for one week, and increase to 2 mg twice daily if no therapeutic benefit is seen within one to two weeks. In our experience, most patients will respond to doses 4 mg daily of tacrolimus. Higher doses can be used in patients who partially respond or have no response to lower doses and monitoring of tacrolimus levels and renal function is recommended to avoid renal toxicity. (See 'Tacrolimus' above.)Cyclosporine Cyclosporine may be started at 100 mg twice daily and increased to 5 mg per kg daily, given in divided doses. (See 'Cyclosporine' above.) Certain patients appear to respond better to either tacrolimus or cyclosporine, although if one of these agents has not helped, we generally try mycophenolate next.Mycophenolate mofetil Mycophenolate mofetil is typically started at 1000 mg twice daily and may be increased to 1500 mg twice daily after

several weeks if needed. (See 'Mycophenolate' above.)Omalizumab in patients with concomitant asthma In patients with CU refractory to antihistamines and leukotriene modifiers who have concomitant asthma, use of omalizumab earlier in the stepwise approach is reasonable. In most studies, omalizumab has been dosed based on established asthma dosing guidelines (ie, according to IgE level and body weight). Responses to omalizumab typically occur within days of the first dose, but we generally recommend two to three months of omalizumab to determine efficacy.Immune globulin Immune globulin is a reasonable choice of therapy in patients with CU that is refractory to the step wise approach above. It may be an appropriate earlier option in patients in whom an immunomodulator would be preferable to an immunosuppressive agent, such as those with a history of malignancy in the past. THERAPIES WITH SIGNIFICANT LIMITATIONS There are additional agents that can be useful in the management of CU, although each has limitations, including one or more of the following: The potential for serious adverse effectsLimited evidence of benefitInconvenience (eg, must be administered in a monitored setting)Intensive monitoring requirementsHigh cost Therapies that show therapeutic promise, but are costly and may not be reimbursed in third-party payer systems, include omalizumab and immune globulin. Therapies with significant side effects include methotrexate, cyclophosphamide, antifibrinolytics and anticoagulants, androgens, and plasmapheresis. Treatments with limited evidence of benefit include colchicine, methylxanthines, phototherapy, and autohemotherapy. Glucocorticoids remain the standard comparator for these therapies. Glucocorticoids have the advantages of high efficacy and low cost, and the disadvantages of predictable long-term toxicity and lack of disease-modifying effect. Omalizumab Omalizumab, a monoclonal antibody directed against IgE, shows significant promise in the treatment of CU. At the time of this review, omalizumab is only approved in the United States for treatment of asthma, An initial report described successful use in a patient with cold urticaria [53] and was followed by several more positive reports in patients with various types of refractory CU, including other physical urticarias and urticarial vasculitis, as well as patients with both positive and negative ASSTs [54-60]. Whether omalizumab has any disease modifying effects remains unclear. (See "Anti-IgE therapy".) A single-blind, controlled trial of 12 patients with CU with autologous antibodies involved a four-week placebo phase followed by omalizumab every two or four weeks for 16 weeks [55]. Seven patients had complete resolution, four had partial improvement, and one had no response. Expense, approval by third party payers, and inconvenience remain barriers to widespread application. However, patients with CU and concomitant asthma would be candidates for omalizumab. Immune globulin Immune globulin is an immunomodulatory agent that alters cell adhesion, immunoregulatory molecules, complement function, cytokine levels, autoantibody production, and antiidiotypic networks [61]. It can be administered intravenously (IVIG) or subcutaneously (SCIG), although the higher doses used in some studies of CU can only be administered intravenously. Adverse effects are generally predictable and manageable. Similar to omalizumab, barriers to use include expense, approval

by insurance carriers, and inconvenience. (See "General principles in the use of immune globulin" and "Intravenous immune globulin: Adverse effects".) Success in CU was first reported in an open trial of 10 patients who were treated with five days of IVIG (0.4 grams per kilogram per day) [62]. All had positive autologous serum skin test (ASST) and basophil histamine-release test results and many had failed glucocorticoids and various other agents. Responses occurred within days, ranged from modest transient benefit to complete and lasting remission. The three patients who exhibited complete remission (one after a second course) were symptom-free at least three years after the last course of IVIG. IVIG may be dosed in a several ways, and the optimal dose, number of infusions to administer, and schedule are unknown [63-69]: The lowest dose described was 0.15 grams per kg, given once every four weeks, in 29 patients [64]. Treatment duration ranged from 6 to 51 months. Twenty-six patients improved, including 19 who experienced complete remission.Another patient was treated with a 10-fold higher (2 grams per kg), infused once, and responded within 48 hours with improvement that lasted seven months [65]. However, repeating the infusion produced only moderate benefit that failed to persist.In two other reports representing a total of four patients, five-day infusions resulted in two complete responses, one partial benefit, and one failure [66,67].Other failures have also been reported [68,69]. Colchicine Colchicine may act to relieve CU by suppressing leukotriene generation or by decreasing leukocyte adhesiveness and migration [70,71]. However, evidence for effectiveness is lacking. Despite this, colchicine has a favorable safety profile at recommended doses, minimal requirements for monitoring, low cost, and a generally rapid onset of action. The single available randomized controlled trial evaluated 12 patients with delayed pressure urticaria, and failed to demonstrate any effect compared to placebo [72]. Evidence of benefit in patients with chronic idiopathic urticaria is limited to anecdotal reports [73,74]. Our clinical experience with colchicine in CU has been disappointing in that only a small number of patients seem to respond. Androgens Androgens, which are effective in the treatment of hereditary angioedema, have been studied in chronic idiopathic urticaria and angioedema [75,76]. A randomized trial of 58 patients with CU refractory to cetirizine compared stanozolol, 2 mg twice daily, with placebo over a 12-week period [76]. The stanozolol group had a greater clinical response with respect to frequency of marked improvement (65 percent versus 29 percent) and mean reduction in clinical scores. Short-term adverse effects were reported as "infrequent," with two patients having transient elevations in transaminases that normalized without treatment cessation. This study was criticized because both treatment groups showed continued reduction in urticarial activity that had not plateaued by the end of the study. The long-term adverse effects of androgens include hypercholesterolemia, hypertension, acne, mood disorders, and transaminitis, and monitoring is recommended. Although androgens may compare favorably with glucocorticoids in many patients, these side effects limit their use in children, women, and some men. (See "Prevention of attacks in hereditary angioedema", section on 'Attenuated androgens'.) Methotrexate Methotrexate reduces neutrophil accumulation in inflamed skin [77], diminishes activated leukocyte adhesiveness and other adenosine-mediated antiinflammatory properties [78],

decreases leukotriene synthesis [79], and alters cytokine activity [80]. Adverse effects can be serious and frequent monitoring is advised. These issues are reviewed elsewhere. (See "Major side effects of lowdose methotrexate".) Evidence of efficacy in CU is limited to case reports and small series [81-85]. One of the larger series described 16 patients, 10 with CU, 4 with urticarial vasculitis, and 2 with angioedema without urticaria [85]. Three of the CU patients also had delayed pressure urticaria. Of the 16 treated patients there were 12 that noted some benefit along with steroid sparing effects. The doses of methotrexate required ranged from 5 to 25 mg/week. Effects were typically observed after four weeks of therapy. The authors do not state whether patients could be removed from therapy. Negative studies also exist [68]. Cyclophosphamide Cyclophosphamide has generally been reserved for patients in whom multiple other alternative agents have failed. It is believed to act on plasma cell to reduce autoantibody production in autoimmune CU [86]. Evidence of efficacy is limited to case reports of patients with positive ASSTs who had failed multiple other therapies, including cyclosporine [87-89]. In one report, improvement began four weeks into the initial infusions and continued to complete resolution by six months [87]. The patient continued to be asymptomatic 12 months after the last infusion. Cyclophosphamide use is limited by expense, inconvenience, need for monitoring, and risk of serious adverse effects (including delayed secondary neoplasia and hemorrhagic cystitis). Antifibrinolytics and anticoagulants The inflammatory pathways believed relevant to urticaria/angioedema are interconnected with pathways of coagulation and fibrinolysis [53]. Agents acting on different points in these pathways theoretically shunt mediators along altered routes and reduce pro-urticarial factors. Antifibrinolytic agents (aprotinin and tranexamic acid) have long been used to treat disorders of angioedema, and their use in chronic urticaria was evaluated in the 1970s [90-92]. The anticoagulants warfarin and heparin were also studied in CU [93-98]. However, the risks of these agents generally outweigh the potential benefits. Methylxanthines The use of methylxanthines to treat CU has also been considered [99,100]. A double-blind, placebo-controlled study of 134 CU patients evaluated theophylline 200 mg twice a day for six months followed by 200 mg once a day for six months, compared to placebo, as add-on therapy to cetirizine [100]. Both groups experienced large improvements in all symptoms assessed, and the theophylline group had statistically significant improvement in overall urticaria scores. However, pruritus did not improve. Non-drug therapies Non-drug treatments that have been studied in CU include phototherapy, autohemotherapy, and plasmapheresis. Phototherapy Phototherapy has been administered to patients with CU [101,102], although it has been applied more often to the treatment of solar urticaria and other physical urticarias. Phototherapy is a reasonable option for patients able to commit to frequent visits or for those intolerant to systemic medications. Skin that is directly irradiated improves most dramatically, suggesting local mediators and cells as primary targets. Histamine release from mast cells may also be reduced [103].

A small randomized trial of 19 patients with CU compared two forms of phototherapy (PUVA and UV-A) and found that both modalities provided modest clinical benefit [102]. Phototherapy is discussed in greater detail separately. (See "Physical urticarias", section on 'Solar urticaria'.)Autohemotherapy Autohemotherapy involves parenteral injection of autologous blood in an attempt to desensitize patients to pro-urticarial factors in the patient's own serum. An initial report of this was promising [104]. Following that report, a single-blind placebo-controlled trial of 56 patients randomized to weekly subcutaneous injections of either autologous, whole, untreated blood, (2.5 mL the first week and 5 mL thereafter), or isotonic sodium chloride solution for eight weeks [105]. Patients with ASST positivity experienced some reduction in urticarial lesions, decreased antihistamine use, and improved quality of life, although the differences were not statistically significant. The ASST-negative patients did not have appreciable benefit. We do not use this treatment.Plasmapheresis Plasmapheresis removes a variety of proteins and other substances from plasma, and may have immunomodulatory effects through one of several mechanisms [106,107]. One study described eight patients with severe CU who underwent plasmapheresis. Two had complete resolution, two improved, and two did not change [108]. SUMMARY AND RECOMMENDATIONS CU should be considered refractory when symptoms are not controlled by antihistamines in combination with other standard therapies. (See "Chronic urticaria: Standard management and patient education".)Patients who require frequent and repeated courses of oral glucocorticoids, or extended periods of glucocorticoid treatment (ie, months at a time) are candidates for the other therapies presented in this review. The most effective combination of antihistamines and the lowest possible dose of glucocorticoids for that patient should be continued while trials of other agents are conducted. (See 'Introduction' above.)There is no standardized approach to the management of severe refractory chronic urticaria (CU), and therapy must be individualized. The effectiveness of the therapies discussed in this review is supported by low quality evidence in all cases.For patients without evidence of steroid toxicity, we suggest antiinflammatory agents (ie, dapsone, sulfasalazine, or hydroxychloroquine) in preference of other drugs as an initial intervention (Grade 2C). We usually begin with dapsone, after checking for G6PD deficiency. (See 'Antiinflammatory agents' above.)For patients with evidence of steroid toxicity, we suggest an immunosuppressant or immunomodulatory agent (such as cyclosporine or tacrolimus or methotrexate) in preference to antiinflammatory agents as an initial intervention (Grade 2C). The author usually begins with tacrolimus. (See 'Immunosuppressant and immunomodulatory agents' above.)There are a variety of other drugs and therapies for refractory CU, although each has one or more significant limitations. Despite this, there may be situations in which a certain therapy is indicated. As an example, patients with moderate to severe asthma who develop refractory CU are candidates for omalizumab. (See 'Therapies with significant limitations' above.) Use of UpToDate is subject to the Subscription and License Agreement REFERENCES 1. Bonney RJ, Wightman PD, Dahlgren ME, et al. Inhibition of the release of prostaglandins, leukotrienes and lysosomal acid hydrolases from macrophages by selective inhibitors of lecithin biosynthesis. Biochem Pharmacol 1983; 32:361. 2. Bozeman PM, Learn DB, Thomas EL. Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone. Biochem Pharmacol 1992; 44:553. 3. Booth SA, Moody CE, Dahl MV, et al. Dapsone suppresses integrin-mediated neutrophil adherence function. J Invest Dermatol 1992; 98:135.

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