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Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history

Chronic spontaneous urticaria: Clinical manifestations, diagnosis, pathogenesis, and natural history
Author:
Sarbjit Saini, MD
Section Editor:
Jeffrey Callen, MD, FACP, FAAD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Feb 2022. | This topic last updated: Nov 30, 2021.

INTRODUCTION — Chronic spontaneous urticaria (CSU) is defined by the presence of recurrent urticaria (also called hives or wheals), angioedema, or both, for a period of six weeks or longer [1]. There are several theories regarding the pathogenesis of CSU, none of which have been conclusively established. CSU is a self-limited disorder in most patients, with an average duration of disease of two to five years, although active CSU significantly impairs quality of life [1].

The clinical manifestations, epidemiology, diagnosis, theories of pathogenesis, and natural history of CSU will be reviewed here. The management of CSU is discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient education" and "Chronic spontaneous urticaria: Treatment of refractory symptoms".)

TERMINOLOGY — The term "chronic spontaneous urticaria" (CSU) refers to patients with recurrent urticaria for six weeks or longer well, as those with both urticaria and angioedema. Note that in a 2017 international guideline, isolated idiopathic angioedema, without urticaria, was included in the definition of CSU for the first time, provided that other angioedema disorders (especially those mediated by bradykinin) have been excluded [1]. Therefore, CSU presents with an urticaria-predominant phenotype in approximately one-half of patients, a mixture of urticaria and angioedema in about 40 percent, and mainly angioedema in 10 percent. However, there are additional diagnostic considerations in patients with isolated angioedema, which are discussed in more detail separately. (See "An overview of angioedema: Clinical features, diagnosis, and management".)

The term "spontaneous" is included to differentiate CSU from several forms of physical urticaria, which are hives triggered by physical stimuli, such as heat, cold, pressure applied to the skin, exercise, water, vibration, and sunlight. Physical urticaria is also called "inducible urticaria." Physical urticaria syndromes are discussed separately. (See "Physical (inducible) forms of urticaria".)

Other terms for CSU include "chronic idiopathic urticaria" and the general term "chronic urticaria." We favor the term CSU over the others, although it is not as familiar to nonspecialists.

EPIDEMIOLOGY — At any given time, CSU affects up to 1 percent of the general population in the United States, and the prevalence is believed to be similar in other countries [2-4]. Both children and adults can develop CSU, although it is more common in adults. Women are affected twice as often as men [3,5-11], and the condition typically begins in the third to fifth decades of life [3,7,10].

CLINICAL MANIFESTATIONS — The clinical manifestations of CSU may be limited to the skin, although some patients report accompanying systemic symptoms.

Cutaneous signs and symptoms

Urticaria — Urticarial lesions (also called hives or wheals) have three typical features [1]:

An area of central swelling of various size, usually with surrounding erythema, although erythema may be difficult to appreciate on darker skin tones (picture 1A-B)

An itching sensation

A fleeting time course for an individual lesion (usually 30 minutes to 24 hours) with the skin returning to normal without ecchymoses

Urticaria may be round, annular, or serpiginous (picture 1A-G). Any area of the body may be affected. Areas in which clothing compresses the skin (ie, under waistbands) or the skin rubs together (axillae) are sometimes affected more extensively. Patients with intense pruritus may occasionally injure their skin by scratching, resulting in excoriations (superficial erosions and crusts). The lesions may appear flattened if the patient is currently taking H1 antihistamines.

The pruritus of CSU may be severe enough to disrupt work, school, or sleep and is often most noticeable at night. Patients whose symptoms have resolved sometimes have difficulty describing urticarial lesions in a sufficiently detailed manner to assist in diagnosis. In this situation, showing patients photographs of urticaria and asking if the lesions looked similar can be helpful.

Individual lesions usually appear, possibly enlarge or merge, and then resolve within 24 hours. If the patient is having difficulty estimating how long an individual lesion lasts, he/she can trace a newly developed lesion with a pen and monitor the time to resolution. Lesions lasting longer than 24 hours and those that are painful or burning in nature or leave residual bruising are suggestive of a vasculitic process. (See 'Differential diagnosis' below.)

Angioedema — Angioedema, if present, is defined as episodic submucosal or subcutaneous swelling that is usually asymmetric in distribution and affects nondependent parts of the body, such as the lips, cheeks, periorbital areas of the face, extremities, and genitals [12]. It typically develops over minutes to hours and resolves gradually over one to three days, depending upon the initial severity. Affected areas typically feel slightly painful, numb, or tingling, rather than pruritic.

In contrast, angioedema involving the throat, tongue, or lips, without urticaria, should prompt consideration of drug-induced angioedema (such as that seen with angiotensin-converting enzyme inhibitors), hereditary angioedema, or acquired C1 inhibitor deficiency. Episodic abdominal pain due to angioedema of the intestinal mucosa is another distinguishing feature of these disorders. (See "ACE inhibitor-induced angioedema" and "An overview of angioedema: Pathogenesis and causes".)

Systemic symptoms — A subset of patients with CSU report systemic symptoms, including headache, fatigue, pain or swelling of joints, wheezing, flushing, gastrointestinal symptoms, and palpitations [13,14]. In a study of 155 CSU patients treated at a university allergy clinic, 103 reported systemic symptoms [13]. This subgroup had more severe and longer-lasting disease and significantly higher baseline tryptase levels, compared with CSU patients without systemic symptoms (5.1 versus 3.9 ng/mL, respectively). Although there was likely some referral bias in this study toward patients with more severe disease, clinicians should inquire about systemic symptoms in patients with CSU.

Note that in patients with urticaria or angioedema accompanied by fever or objective evidence of joint inflammation, urticarial vasculitis should be considered. (See 'Differential diagnosis' below.)

ASSOCIATED CONDITIONS — CSU is associated with various atopic and autoimmune disorders. There is a possible association with malignancies, although data are conflicting.

Allergic diseases — Strong associations with atopic disorders, including food allergy, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis, and asthma were demonstrated in a large cohort study of over 1 million Israeli adolescents [15]. These associations were not seen in the adult population, when studied by the same researchers. Instead, an association with autoimmune conditions was observed.  

Autoimmune disorders — Various autoimmune conditions are more prevalent among patients with CSU [5,16-19]. In the largest study, the prevalence of autoimmune disorders in nearly 13,000 patients with CSU was compared with over 10,000 control patients [5]. The following autoimmune disorders were more prevalent in patients with CSU: thyroid disorders, celiac disease, Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus, with considerable variability between males and females. Antinuclear antibodies were also more prevalent than in the general population [5]. Among patients with CSU, an autoimmune disorder was more likely to be diagnosed in the decade after the onset of CSU, rather than before it.

Thyroid disorders — In the larger study mentioned previously, hypothyroidism was diagnosed in 9.8 percent of CSU patients (versus 0.6 percent of controls) and hyperthyroidism in 2.6 percent (versus 0.5 percent of controls) [5]. A population-based Korean study found that individuals with autoimmune thyroid disease (Hashimoto thyroiditis and Graves' disease) had higher rates of CSU compared with controls (hazard ratio [HR] = 1.5, 95% CI 1.3-1.7) [20].

Thyroid autoantibodies, specifically thyroid peroxidase antibodies or antimicrosomal antibodies, are more prevalent among patients with CSU (12 to 30 percent), compared with members of the general population (5 to 10 percent) [6,21-23]. However, the presence of thyroid autoantibodies does not necessarily correlate with abnormal thyroid function, and the majority of patients with CSU who have demonstrable thyroid autoantibodies have normal thyroid function [22]. The role of these autoantibodies in CSU in patients with normal thyroid function is not clear. Their presence may simply reflect an underlying tendency to develop autoantibodies [18]. However, even in the absence of hypo- or hyperthyroidism, patients with thyroid autoantibodies are often poorly responsive to standard therapies for CSU and have more persistent disease [18].

The pathogenesis of autoimmune thyroid disease is reviewed elsewhere. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" and "Pathogenesis of Graves' disease".)

Based upon the association between CSU and thyroid autoimmunity, several studies have examined the use of thyroid supplementation therapy in the treatment of CSU, with mixed results. These studies are reviewed elsewhere. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Patients with thyroid autoantibodies'.)

Unclear association with malignancy — The association between CSU (without vasculitis) and malignancy is unclear. Guidelines do not suggest that malignancy screening be performed in patients with CSU, unless indicated by specific abnormalities in the clinical history or physical exam or the presence of unintended weight loss [1,24,25]. Studies that support this approach include the following:

No increased risk of malignancy was found in a study of 1155 Swedish patients with CSU, in which subjects were followed by academic dermatologists for an average of 8.2 years [26]. The incidence of malignant cancer during the period of observation was compared with the expected number of cancers from the Swedish Cancer Registry, yielding a relative risk (RR) of 0.88 (95% CI 0.61-1.12).

In a systematic review of 6462 patients described in 29 studies, underlying diseases were detected as an underlying cause of CSU in only 105 patients (1.6 percent) [16]. Within this group, there were 60 cases of urticarial vasculitis, 17 patients with thyroid disease, 7 with lupus, and 16 with other connective tissue disorders. Three patients had a paraproteinemia, four had polycythemia vera, and five had various malignancies (breast cancer, acute myeloid leukemia, renal cell carcinoma, and two unidentified cancers). Therefore, few malignancies were detected in this review, and no one type of cancer predominated.

In contrast to the two studies above, a possible association was detected in a study of 12,720 Taiwanese patients with CSU [27]. In this cohort, subjects were identified as having CSU based upon the International Classification of Diseases (ICD)-9-CM code for urticaria, combined with use of an antihistamine for at least six months over a two-year period. Patients with coexisting allergic disorders that could require chronic antihistamines, patients receiving immunosuppressant drugs for any reason, and those with pre-existing malignancies, rheumatoid arthritis, lupus erythematosus, or Sjögren syndrome, were excluded. The rate of malignancies diagnosed in this cohort over an average follow-up period of five years was compared with expected rates obtained from the Taiwan National Cancer Registry. The standardized incidence ratio for patients with CSU was 2.2 (95% CI 2.0-2.4). However, information about possible confounders (eg, smoking and alcohol use) was not included, and patients may not have been systematically evaluated for signs or symptoms of underlying disorders. In addition, the authors noted that there was no diagnostic code for urticarial vasculitis, which is known to be associated with malignancy, so this diagnosis would not have been easily distinguished from simple CSU. Therefore, this study may have overestimated cancer risk, although the association warrants further evaluation.

A case report and literature review described 26 patients in whom CSU preceded the diagnosis of a malignancy, usually by several months, and reported that treatment (ie, chemotherapy or surgical resection) led to resolution of the CSU in 88 percent of cases [28]. In three patients, return of urticaria signaled a recurrence of the malignancy.

Until the association between chronic idiopathic urticaria and malignancy is better defined, it seems logical to continue to perform additional testing only if indicated by the patient's clinical history and physical exam.

EVALUATION AND DIAGNOSIS — CSU is diagnosed clinically based upon the episodic and transient appearance of characteristic urticarial lesions, with or without angioedema, for a period of six weeks or longer. A detailed history and physical examination form the basis of the evaluation [1,29-32]. Several practice parameters have been published for the diagnosis of CSU [1,24,25,33,34]. The suggestions in this review are consistent with these, although some variation exists among guidelines.

History — The clinical history is an important element of the evaluation. The history should include the signs and symptoms associated with the lesions, duration of individual lesions, and accompanying angioedema. If signs and symptoms are consistent with CSU, then questioning should focus on identifying a possible underlying cause and on ensuring that the patient does not have evidence of a more serious systemic disease.

To exclude a specific cause, clinicians should question patients about any newly administered drugs, including antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), and hormonal therapies [35,36]. Inquiries should be made about recent travel, infections, changes in health status, other atopic conditions, sexual history, and complete review of systems. No external cause can be identified in 80 to 90 percent of adults and children with recurrent urticaria persisting longer than six weeks once these known causes are excluded [37-40]. The various identifiable causes of urticaria are discussed in more detail elsewhere. (See "New-onset urticaria".)

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 [17,41]. Occasionally, urticaria or urticarial vasculitis will be a presenting feature of an underlying systemic disorder, such as systemic lupus erythematosus. Systemic diseases that can present with urticaria accompanied by other signs and symptoms and disorders that involve urticarial vasculitis are reviewed in more detail separately. (See "New-onset urticaria", section on 'Systemic disorders that may include urticaria' and "Urticarial vasculitis", section on 'Associated conditions'.)

Aggravating factors — Although not the sole cause of symptoms, certain factors aggravate CSU in a substantial subset of patients (table 1). These include:

Physical factors – Some patients with CSU have some flares that are triggered by physical stimuli. As an example, heat (hot showers, extreme humidity) is a common trigger for many CSU 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 (inducible) forms of urticaria" and "Cold urticaria".)

Anti-inflammatory medications – NSAIDs worsen symptoms in 25 to 50 percent of patients with CSU [42].

Stress – Patients often report more severe symptoms during periods of physical or psychologic stress [43-50]. However, evidence that psychosocial factors are in some way causative is lacking [51].

Variations in dietary habits and alcohol – Although food allergy is a rare cause of CSU, some patients will report that variations in diet, particularly rich meals or spicy foods, will aggravate symptoms. Alcohol also aggravates symptoms in some. The interactions between diet and CSU are discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Dietary manipulations (controversial)'.)

Laboratory evaluation — Routine laboratory tests are unlikely to reveal abnormalities when the clinical history does not suggest an underlying allergic etiology or the presence of systemic disease [16,24,52-55]. Guidelines suggest initially obtaining a limited set of laboratories to screen for the systemic disorders that may involve urticaria [1,56-58]. The author and editors agree with limited testing and suggest the following:

A complete blood count with differential – This is usually normal in patients with CSU [59]. Eosinopenia (ie, an absolute eosinophil count of <50 cells/microL) was present in approximately 10 percent of patients with CSU in one large study of 1259 patients, and was associated with basopenia, more severe disease, autoimmunity, and poor response to treatment with second generation antihistamines and omalizumab [59]. Eosinopenia is present in about 5 percent of the general population, and has been linked to several disease states [60]. Eosinophil numbers should be assessed when the patient has not recently received glucocorticoids, which cause a rapid reduction in eosinophil counts.

Eosinophilia should prompt evaluation for an atopic disorder or parasitic infection. (See "Approach to the patient with unexplained eosinophilia".)

Basopenia has been associated with more severe disease [61]. (See 'Cellular defects theory' below.)

CRP or ESR – Both tests are normal in the majority of cases of CSU, although an elevation of erythrocyte sedimentation rate (ESR) of a few points is also common in uncomplicated CSU [54]. Significant elevations in ESR or C-reactive protein (CRP) have been correlated with more severe disease, quality of life impairment, and non-response to antihistamines [62]. Such elevations should prompt further investigation for systemic diseases, such as autoimmune, rheumatologic, infectious, or neoplastic diseases. Such an evaluation may include measurement of antinuclear antibodies, cryoglobulins, hepatitis B and C serologies, total hemolytic complement, and a serum protein electrophoresis. (See "Acute phase reactants" and 'Differential diagnosis' below.)

TSH level – Routine measurement of thyroid-stimulating hormone (TSH) was not endorsed by the 2017 international guidelines [1]. However, some clinicians measure TSH in adults with CSU and also obtain thyroid autoantibodies (antithyroglobulin, antimicrosomal antibodies, or both), while others do so only if the TSH level is abnormal [63]. Autoimmune thyroid disease is uncommon in children with CSU [64].

The utility of more extensive laboratory testing in patients with CSU was analyzed in the systematic review mentioned previously, which concluded that only ESR, complete blood count, and differential were useful screening tests. This review analyzed 29 studies (including 6462 patients), in which investigations for underlying medical disorders were performed [16]. Potentially causative internal diseases were identified in only 1.6 percent of patients, and there was no association between the number of tests ordered and the identification of an underlying disorder.

Investigational tests — Investigational tests include the autologous serum skin test, various tests of basophil activation, and tests for autoantibodies to the immunoglobulin (Ig)E receptor or the Fc region of IgE [1]. These tests are discussed separately. (See 'Theories of pathogenesis' below.)

Diagnosis — The diagnosis of CSU can be made in a patient with characteristic skin lesions of urticaria and/or angioedema, which appear and resolve repeatedly over a period of six weeks or longer. There should be no other signs of systemic illness, and laboratory testing is usually normal.

In patients with isolated angioedema, other angioedema disorders should be excluded. Measurement of complement component 4 (C4) is indicated because depressed C4 levels should prompt further evaluation for hereditary or acquired C1 inhibitor deficiency. In cases in which the history suggests a possible diagnosis of hereditary or acquired C1 inhibitor deficiency (ie, lack of response to antihistamines or positive family history), C1 inhibitor antigen and functional levels should also be measured. The evaluation of angioedema without urticaria is discussed elsewhere. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Evaluation'.)

Skin biopsy — Skin biopsy is not routinely needed for the diagnosis of CSU. However, a 3 mm punch biopsy of a newly formed lesion should be performed to exclude 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 [32,65].

An elevated CRP/ESR and/or systemic symptoms (eg, arthralgias, fever).

Symptoms that are unresponsive to appropriate doses of antihistamines. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'H1 antihistamines'.)

Biopsy should also be obtained in patients with any features suggestive of mastocytosis. Mastocytosis is a rare disease that would be suspected in a patient in whom CSU was accompanied by episodic signs and symptoms of systemic mast cell-mediator release, such as flushing, abdominal cramping and diarrhea, wheezing, lightheadedness, or syncope. (See 'Differential diagnosis' below and "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

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 staining. In addition, if there is a strong clinical suspicion for urticarial vasculitis, a sample should be submitted in Michel's media or freshly snap frozen for direct immunofluorescence microscopy. Also consider testing for immunoglobulins in lesional skin when vasculitis is a consideration and in perilesional, noninvolved skin when considering autoimmune blistering disease.

Biopsy findings — The biopsy findings of CSU vary somewhat among patients. Consistent features include 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 [12]. Angioedema, if present, often shows a similar infiltrate and is characterized by more prominent edema of the interstitial tissues.

Neutrophil-predominant urticaria, without vasculitis, is a variant of CSU that is often refractory to standard pharmacologic treatments. The significance of neutrophil-predominant urticaria, in terms of preferred treatment or prognosis, is not known [66].

Findings that are not characteristic of CSU include the following:

Several disorders in the differential diagnosis for CSU may also show a predominance of neutrophils, such as Schnitzler syndrome, delayed-pressure urticaria, and cryopyrin-associated periodic syndromes. Biopsies in these disorders may also mistakenly be interpreted as leukocytoclastic vasculitis. (See 'Differential diagnosis' below.)

Leukocytoclasis should not be present in CSU. 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 found, the diagnosis of leukocytoclastic vasculitis and associated conditions should be considered. (See "Urticarial vasculitis", section on 'Histology' and 'Differential diagnosis' below.)

Leukocytoclasis accompanied by a dense cellular infiltrate consisting almost entirely of neutrophils, without evidence of vasculitis, should prompt evaluation for the rare disorder, neutrophilic urticarial dermatosis. (See "Neutrophilic dermatoses".)

THEORIES OF PATHOGENESIS — None of the theories of pathogenesis of CSU have been fully established, and we do not suggest routine performance of any of the tests mentioned in this section outside of research settings [1,67]. The best developed hypotheses include the autoimmune theory, theories involving histamine-releasing factors, and the cellular defects theory.

Autoimmune theory — The concept that CSU could represent an autoimmune disorder arose from the recognition that thyroid dysfunction and thyroid autoantibodies are more prevalent in patients with CSU [5,17,21,22]. 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. A European taskforce panel of CSU experts published a statement in 2013 concluding that there was persuasive but not conclusive evidence for the existence of autoimmune CSU as a specific disease entity [68]. The evidence suggesting that CSU may be an autoimmune disorder in some patients is reviewed above. (See 'Autoimmune disorders' above.)

The autologous serum skin test — One area of investigation suggesting that CSU is an autoimmune disorder was introduced in the 1980s with the description of the autologous serum skin test (ASST) [69]. The ASST is proposed to provide an in vivo assay of mast cell activation induced by factors in the patient's serum. The ASST involves intradermal injection of the patient's own serum [69,70]. 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 CSU, 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) [71]. In vitro tests of mast cell activation are lacking because mast cells are tissue-based cells that are not easily collected or cultured. (See "Mast cells: Development, identification, and physiologic roles".)

The leading argument against the clinical significance of the ASST is that a positive test is not unique to patients with CSU [72-74]. In one study, positive ASSTs were found in 53 percent of patients with CSU, 20 percent of patients with nonallergic asthma/rhinitis, and 56 percent of healthy controls [74]. In addition, the positivity of the ASST persists in patients with CSU, even when the disorder is in clinical remission [75,76]. Finally, the ASST has not demonstrated clinical utility in identifying patients who respond differently to treatment or whose disease follows a different clinical course [64,77-79].  

Autoantibodies — The sera of patients with CSU and positive ASSTs are capable of causing in vitro histamine release from basophils collected from control subjects [69]. It was therefore proposed that an autoantibody or other histamine-releasing factor was present in the serum of these patients.

At least two candidate autoantibodies have been identified [70,75,80,81]:

Human IgG molecules directed against the IgE receptor alpha subunit (anti-Fc-epsilon-R1-alpha)

Human IgG molecules directed against the Fc region of IgE (anti-IgE)

The presence of IgG 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 CSU [12,68,82-86]. These autoantibodies can trigger histamine release when incubated with normal basophils [80] and can activate mast cells, possibly through a mechanism involving complement [12,40,87-91]. Assays are commercially available for detecting anti-Fc-epsilon-RI-alpha antibodies (eg, the Chronic Urticaria Index) [92], although the clinical utility of this test is not well-established, as discussed in the next section.

Conflicting evidence — Similar to the ASST, the autoantibodies described above are not specific to CSU. Anti-Fc-epsilon-RI-alpha antibodies have been identified in healthy subjects [93] and in people with other autoimmune diseases, including pemphigus vulgaris, systemic lupus erythematosus, dermatomyositis, and pemphigoid, suggesting that they may represent an epiphenomenon [87,94-96]. In addition, the levels of autoantibodies in CSU do not appear to change with the clinical activity of the disease [97], and the presence of these autoantibodies does not predict more difficult-to-manage disease [78].

Also problematic is the fact that commercial assays for anti-Fc-epsilon-RI-alpha antibodies are based upon basophil activation tests, for which there are no widely accepted standards across laboratories. When more stringent basophil activation studies were performed with additional controls, only 7 percent of CSU patients were found to have autoantibodies that triggered histamine release, as opposed to the 30 to 50 percent found in earlier studies [98]. The technical difficulties of studying basophils are reviewed below. (See 'Problems with basophil studies' below.)

Theories involving other serum or plasma factors — Several other factors in the serum or plasma have been implicated in the pathogenesis of CSU because of an ability to activate mast cells or basophils, either directly or indirectly. No single factor has been shown to be essential for a positive ASST, and it remains unclear why serologic factors would activate only skin mast cells rather than causing more generalized mast cell and basophil activation leading to anaphylaxis, yet patients with CSU are not at increased risk for anaphylaxis.

One study tested sera from patients with CSU and normal controls for the ability to induce endothelial cell permeability [99]. Although neither group's sera alone induced endothelial cell permeability, the majority of CSU sera caused mast cell degranulation when incubated with different mast cell lines, one of which lacked IgE receptors. Supernatants from activated mast cell cultures did increase endothelial cell permeability. This property persisted when the sera were depleted of IgG and was unrelated to the ability of the sera to cause a positive ASST.

The observation that many patients with CSU improve with anti-IgE therapy (omalizumab) implies that there may be an abnormal IgE present, which recognizes an unknown antigen(s) and activates mast cells and basophils. Studies of omalizumab for the management of refractory CSU are reviewed separately. A variation on this theory proposes that there are individuals with IgE against self-antigens, but there are limited data for this concept. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

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 [100-102]. In one study, the plasma of 28 patients with CSU contained higher levels of the polypeptide F1+2, which is produced upon activation of prothrombin to thrombin, compared with control plasma [100]. 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 [103-105]. In addition, thrombin can stimulate the generation of C5a, which has been shown to enhance IgG-dependent mast cell histamine release in patients with CSU [91]. Other groups have also found abnormalities in the coagulation system that correlate with CSU severity [106].

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 [100]. However, the APST does not appear to provide information that is different from that of the ASST [100,107-109]. Of note, one study showed that if a control solution of 0.105 mol/L sodium citrate was included as a negative control, then there were no patients with positive APSTs who did not also have positive ASSTs [109].

The finding that the extrinsic pathway of the clotting cascade is activated in CSU is consistent with reports of successful treatment with the anticoagulant warfarin in a small double-blind, controlled study, as well as a case report of patients with CSU refractory to antihistamines [110-112]. Subcutaneous heparin and the antifibrinolytic agent tranexamic acid were also reported to be effective in small numbers of patients [113,114].

A review examined the literature for serum measures that could distinguish patients with CSU from healthy subjects. Among the measures that showed promise were D-dimer, C-reactive protein, and mean platelet volume [115]. Although promising, prospective studies will be needed to validate these associations.

Cellular defects theory — The cellular defects theory generally proposes that patients with CSU have defects in mast cell and/or basophil trafficking, signaling, and/or function. The following observations support this concept:

Mast cell numbers are normal in the skin of patients with CSU, 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 [116,117]. Functional studies of mast cells from patients with CSU are difficult to perform because mast cells are tissue-based cells that are not easily collected or cultured. In 2015, a G-protein-coupled receptor, MrgX2, was recognized as the receptor for 48/80 on mast cells [118]. It has also been noted that the expression of this receptor is heightened in CSU skin tissue [119].

Peripheral blood basophil counts are low in patients with CSU and even lower with more severe disease, a finding attributed to increased migration of basophils to the skin [61,120-123]. Evidence supports that basophil counts normalize on therapy with omalizumab [124,125]. (See "Chronic spontaneous urticaria: Treatment of refractory symptoms", section on 'Omalizumab'.)

Several groups have identified functional differences in basophils from patients with CSU. Histamine release was reduced following in vitro activation through Fc-epsilon-RI, although not with activation through other receptors [117,126,127], even though the cells contained normal amounts of histamine [128,129]. Subsequently, two basophil phenotypes were identified in patients with CSU: one type with an apparently normal response to Fc-epsilon-RI activation ("responders") and another type of basophil that does not respond to IgE-mediated activation ("nonresponders") [128,130]. These phenotypes are present in approximately equal numbers in patients with CSU, unlike in normals where "nonresponders" comprise only about 10 to 15 percent of the population. The nonresponder phenotype demonstrates elevated intracellular levels of regulatory proteins that normally inhibit signaling through Fc-epsilon-RI. Of note, normalization in basophil responsiveness has been demonstrated in patients with CSU as their symptoms improve, unlike levels of autoantibodies or ASST status [97,127]. CSU patients with the responder phenotype have milder but more prolonged disease [61].  

Problems with basophil studies — Basophils are notoriously difficult to study for the following reasons:

Different laboratories 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, interleukin [IL]-3) to the assay mix.

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.

Sometimes basophils from normal donors are used to test serum from CSU patients, although histamine release 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.

Other theories — Theories about infectious causes and food additives (pseudoallergens) continue to draw periodic attention in the medical literature and lay news. However, the evidence for these theories remains anecdotal. It is possible that various sources of chronic inflammation may predispose susceptible patients to the development of CSU [131].

Infectious agents — Attempts have been made to associate some common chronic infections with CSU, including Anisakis simplex [132], Helicobacter pylori [133-136], hepatitis A [137], and hepatitis C [138]. However, case reports and small series have been conflicting [139].

A larger study illustrated the ambiguous relationship between chronic infections and CSU. In a large meta-analysis of 22 studies including 1385 patients, spontaneous remission of CSU occurred more often in patients who were negative for H. pylori compared to those who were positive (risk ratio 0.39; 95% CI 0.19-0.81) [140]. Among H. pylori-positive CSU patients, remission of urticaria was more likely following antimicrobial therapy for H. pylori, regardless of whether eradication of the infection was successful.

Foods and food additives — Allergies to foods or food additives are rarely identified as a cause of CSU [141,142]. IgE-mediated food allergy is far more likely to present with acute urticaria as part of generalized allergic reactions. Despite this, up to one-half of adult patients initially perceive a relationship between food and episodes of urticaria. Patients' suspicion about the role of foods and food additives is fueled by the fact that many will notice that dietary variations can cause temporary fluctuations in CSU symptoms. In particular, rich meals, spicy or fermented foods, alcohol, and dramatic changes in diet will often 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. However, when CSU is in remission, the same patients can eat these foods without symptoms.

Dietary factors that can aggravate CSU and lists of foods that are potentially problematic are discussed separately. (See "Chronic spontaneous urticaria: Standard management and patient education", section on 'Dietary manipulations (controversial)'.)

Studies of food additives as a cause of acute and chronic urticaria are reviewed separately. (See "Allergic and asthmatic reactions to food additives", section on 'Patients with chronic urticaria'.)

DIFFERENTIAL DIAGNOSIS — Several systemic disorders can present with urticaria-like lesions in the context of other signs and symptoms.

Urticarial vasculitis – Urticarial vasculitis should be considered when the hives are painful rather than pruritic, last longer than 48 hours, leave residual bruising or pigmentation changes, or recur whenever glucocorticoids are tapered (picture 2 and picture 3 and picture 4). Patients with urticarial vasculitis may also report fever, chills, and arthralgias. Urticarial vasculitis may occur in isolation or in patients previously diagnosed with other systemic inflammatory diseases, such as Sjögren syndrome or systemic lupus erythematosus. Skin biopsy is indicated if signs or symptoms of vasculitis are present. (See "Urticarial vasculitis".)

Systemic lupus erythematosus – Urticaria and urticarial vasculitis are among the many reported cutaneous manifestations of systemic lupus erythematosus (picture 5). However, patients with lupus should have some of the other manifestations of this disease, such as fever, weight loss, arthritis, lymphadenopathy, or renal, pulmonary, or cardiac manifestations. This disorder is reviewed in detail elsewhere. (See "Overview of cutaneous lupus erythematosus".)

Cryoglobulinemia – Cryoglobulinemia causing cold-induced urticarial or vasculitic lesions can be seen in hepatitis B or 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".)

Schnitzler syndrome – Schnitzler 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. (See "Cutaneous manifestations of internal malignancy" and "Urticarial vasculitis", section on 'Differential diagnosis'.)

Mast cell disorders – Mast cell disorders are characterized by the proliferation and accumulation of tissue mast cells or excessive activity of these cells. The best characterized disorders are systemic and cutaneous mastocytosis, which feature signs and symptoms affecting multiple organ systems (table 2). Skin findings in mastocytosis consist either of flushing and pruritus or a distinctive lesion called maculopapular cutaneous mastocytosis or urticaria pigmentosa (picture 6). Patients with mast cell disorders can have urticaria in the setting of other episodic symptoms, but recurrent hives most days of the week is not typical [143]. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

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 (picture 7). 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".)

Hypereosinophilic syndrome – Hypereosinophilic syndrome refers to a group of disorders characterized by persistent overproduction of eosinophils that infiltrate and damage tissues. Cutaneous symptoms can include recurrent urticaria, although angioedema or erythroderma are more characteristic. The diagnosis requires persistent unexplained blood eosinophilia of ≥1500/microliter, 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 "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)

Cryopyrin-associated periodic syndromes – The cryopyrin-associated periodic syndromes include syndromes that involve urticarial or urticaria-like skin eruptions: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disorder. These are rare genetic disorders that are discussed in more detail separately. (See "Cryopyrin-associated periodic syndromes and related disorders".)

The differential diagnosis of isolated angioedema is reviewed in detail separately. (See "An overview of angioedema: Clinical features, diagnosis, and management", section on 'Differential diagnosis'.)

NATURAL HISTORY AND PROGNOSIS

Duration — CSU is an episodic and self-limited disorder in most patients. The average duration of disease is two to five years [2,144]. 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 [39,145]. Remission rates in children may be somewhat higher [146]. However, symptoms persist beyond five years in up to 30 percent of patients, and disease duration in this subgroup is not as well-studied [8,147,148].

Factors associated with persistence — In a prospective study of 139 patients with CSU of all severity, disease severity, the presence of angioedema, and various laboratory parameters were assessed in relation to disease duration [147]. CSU persisted beyond one and five years in 70 and 14 percent of patients, respectively. A longer duration of symptoms was associated with more severe disease, the presence of angioedema, and thyroid autoimmunity. This study also found that a positive autologous serum skin test was associated with longer-lasting disease, although other studies have not found this correlation [39].

Other studies have also found that more severe disease tends to last longer [144,146]:

In a retrospective analysis of 117 patients with CSU who were not controlled on a standard dose of oral antihistamine, the remission rates (ie, no urticaria for one month in the absence of any medication) were 12 and 28 percent at one and five years, respectively [146].

In a prospective study of 228 patients with moderate-to-severe CSU, a correlation was observed between the presence of systemic hypertension and more persistent symptoms [144]. Among hypertensive patients, resolution was seen in 19 and 26 percent at two and five years, respectively, compared with 37 and 46 percent in normotensive patients. The type of antihypertensive medication administered did not appear to impact duration of urticaria. The association with hypertension warrants further study.

Peripheral blood eosinopenia and basopenia may be biomarkers for more severe disease that is refractory to antihistamines and omalizumab. (See 'Laboratory evaluation' above.)

Impact of pregnancy — The impact of pregnancy on CSU and chronic inducible urticaria was examined in an international questionnaire study of 288 pregnancies that found that just over one-half of respondents believed their urticaria improved during pregnancy [149]. The mean duration of chronic urticaria was seven years and 67 percent of patients had CSU. During pregnancy, 51 percent of patients believed that their symptoms improved, 29 percent, that they worsened, and 20 percent reported no change. After giving birth, 44 percent of respondents felt that their disease activity remained unchanged compared with during pregnancy. Patients with more than one pregnancy reported similar changes during each pregnancy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Urticaria and angioedema (excluding hereditary angioedema)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Chronic hives (The Basics)")

SUMMARY AND RECOMMENDATIONS

Chronic spontaneous urticaria (CSU) is defined by the presence of urticaria (hives), angioedema, or both for a period of six weeks or longer. It is estimated that about 1 percent of the adult population develops CSU at some point in their lives. Adults are affected more often than children, and women are affected more often than men. (See 'Terminology' above and 'Epidemiology' above.)

The diagnosis of CSU is made clinically, based upon the episodic appearance of characteristic urticarial lesions, with or without angioedema, on most days of the week, for a period of six weeks or longer (picture 1A-G). No specific cause can be identified in 80 to 90 percent of adults and children with CSU. A complete blood count with differential, a C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR), and possibly a thyroid-stimulating hormone (TSH) level are suggested at diagnosis, although these laboratories are normal in most patients who lack signs and symptoms of systemic disease. (See 'Evaluation and diagnosis' above.)

Skin biopsy is not needed for routine diagnosis of CSU, although it is indicated to exclude urticarial vasculitis if there are signs or symptoms consistent with a vasculitic process or in the rare patients with features of mastocytosis. (See 'Skin biopsy' above.)

Tests used in investigations of pathogenesis include the autologous serum and plasma skin tests (ASST/APST), assays for autoantibodies directed against immunoglobulin (Ig)E or Fc-epsilon-RI, and in vitro assessments of basophil function. However, these tests lack specificity and prognostic value, are not standardized across laboratories, and are not recommended for routine clinical use. (See 'Theories of pathogenesis' above.)

Several theories regarding the pathogenesis of chronic idiopathic urticaria have been proposed, although the data for each are incomplete, and none appear 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.)

CSU is a self-limited disease in the vast majority of patients. Spontaneous remission occurs in 30 to 50 percent of patients by one year, and the average duration of disease is two to five years. Up to 20 percent of patients still have symptoms persisting beyond five years. Those with more severe symptoms tend to have longer-lasting disease. (See 'Natural history and prognosis' above.)

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Topic 8108 Version 28.0

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119 : Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria.

120 : Flow cytometric analysis of basophil numbers in chronic urticaria: basopenia is related to serum histamine releasing activity.

121 : Blood basophil numbers in chronic ordinary urticaria and healthy controls: diurnal variation, influence of loratadine and prednisolone and relationship to disease activity.

122 : Chronic idiopathic urticaria: infiltrating cells and related cytokines in autologous serum-induced wheals.

123 : TH1/TH2 cytokines and inflammatory cells in skin biopsy specimens from patients with chronic idiopathic urticaria: comparison with the allergen-induced late-phase cutaneous reaction.

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126 : Serum and cell bound IgE in chronic urticaria.

127 : Defective histamine release in chronic urticaria.

128 : Basophil FcepsilonRI histamine release parallels expression of Src-homology 2-containing inositol phosphatases in chronic idiopathic urticaria.

129 : Anti-Fc(episilon)RI auto antibodies and basophil histamine releasability in chronic idiopathic urticaria.

130 : Functional and phenotypic analysis of basophils allows determining distinct subtypes in patients with chronic urticaria.

131 : Stress, pseudoallergens, autoimmunity, infection and inflammation in chronic spontaneous urticaria.

132 : Anisakis simplex hypersensitivity is associated with chronic urticaria in endemic areas.

133 : Etiologic aspects of chronic urticaria.

134 : Beneficial effects of Helicobacter pylori eradication on idiopathic chronic urticaria.

135 : Lack of correlation between Helicobacter pylori infection and autologous serum skin test in chronic idiopathic urticaria.

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137 : Chronic urticaria and infections.

138 : Chronic hepatitis C and skin diseases: a review.

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140 : Systematic review and meta-analysis: Effect of Helicobacter pylori eradication on chronic spontaneous urticaria.

141 : Food Allergy in Korean Patients with Chronic Urticaria.

142 : Prevalence of food avoidance and food allergy in Chinese patients with chronic urticaria.

143 : The utility of serum tryptase as a marker in chronic spontaneous urticaria.

144 : Effect of arterial hypertension on chronic urticaria duration.

145 : Natural course of physical and chronic urticaria and angioedema in 220 patients.

146 : Prognosis of chronic spontaneous urticaria in 117 patients not controlled by a standard dose of antihistamine.

147 : Clinical and laboratory parameters in predicting chronic urticaria duration: a prospective study of 139 patients.

148 : The natural history of chronic urticaria and angioedema in patients visiting a tertiary referral centre.

149 : Effects of pregnancy on chronic urticaria: Results of the PREG-CU UCARE study.