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Urticaria
Li‐Ping Zhao1 and Xing‐Hua Gao2
1 Department of Dermatology, General Hospital, Shenyang, China
2 Department of Dermatology, The First Hospital of China Medical University, Shenyang, China
Introduction
Urticaria (hives) is a relatively common condition, characterized by the presence of wheals which can be raised, circumscribed, or erythematous plaques with central pallor, presenting in different sizes and shapes (round, serpiginous, or annular). Hives are characterized by three main features: erythema and swelling, itching/burning sensation, and spontaneous resolution within 24 hours [1]. Angioedema is a deeper localized swelling often associated with urticaria. Urticaria is usually divided in two subtypes: acute urticaria if the condition persists for less than six weeks; and chronic urticaria (CU) if it has a duration longer than six weeks.
A point prevalence of urticaria is about 0.5%–1% [2]. The peak incidence is among patients 20–40 years old [3, 4]. Based on a survey conducted in Germany, the lifetime prevalence of CU was estimated to be 1.8% [5]. About half of all patients with urticaria have associated angioedema [6]. Symptoms of CU may last for several months or years [3, 7, 8] with up to 14% of patients continuing to experience recurrent outbreaks of symptoms for longer than five years [9, 10].
The international guidelines recognize two subtypes of CU: chronic inducible urticaria (CIU), and chronic spontaneous urticaria (CSU). CIU is perhaps more accurately described as intermittent urticaria, for which signs and symptoms arise following exposure to specific eliciting factors such as cold, localized heat, generalized heat (more commonly called cholinergic urticaria), solar radiation, aquagenic or sustained pressure, etc. [3, 8, 11]. Sustained pressure induces delayed pressure urticaria, i.e. onset 4–6 hours after exposure, in a small group of people. It is an inducible physical urticaria that differs from other types [12], in that the lesions are long lasting i.e. 12–36 hours, there is an inflammatory reaction on skin biopsy, and it does not respond to antihistamines well but responds to corticosteroids. This is the reverse of all the other inducible urticarias listed which arise a few minutes after the stimulus and mostly disappear within 30 minutes to two hours, have few cellular infiltrates on biopsy, and generally don’t respond to corticosteroids, but respond to antihistamines [13].
CSU generally accounts for the majority of cases of CU, with reported estimates ranging from 66% to 93%. The lesions appear unpredictably, are present on most days of the week, can arise on virtually any part of the body, are associated with angioedema (but not laryngeal edema) in 40% of patients, and respond to corticosteroids, albeit the dose and duration required is too great to recommend. About half of patients improve significantly with antihistamines and the remainder are resistant, regardless of dose. Radioallergosorbent test (RAST) or routine food skin testing is not recommended for evaluation, as no relevant stimulus has been clearly established [2].
Etiology and Pathology of Urticaria
The most frequent causes of acute urticaria, affecting up to 15%–25% of all individuals at some stage in their lives, are food allergies, viral infections (especially affecting the upper respiratory tract), and adverse drug reactions [4, 6]. Systemic disease, physical factors, or long‐term infection may also lead to urticaria/angioedema [7, 14]. The causes of CU are still poorly defined. Growing evidence indicates that different biological processes in inflammation, immunity, and coagulation may take part in the pathogenesis that eventually lead to mast cell and basophil degranulation and hence to wheal formation. Histologically, skin biopsy specimens from CSU often show increased number of mast cells, perivascular infiltrate of CD4+ lymphocytes [15], and variable numbers of monocytes, neutrophils, eosinophils, and basophils [16, 17].
Major Cells, Mediators, and Immunopathogenesis of Urticaria
Mast Cells
It is well known that mast cells are the major final effector cells in urticaria. Their degranulation causes immediate release of the preformed granular mediators such as histamine, chymase, tryptase, and proteases [18, 19]. These mediators in the skin cause the characteristic pruritus, increased vascular permeability, and edema. However, the underlying causes of mast cell activation in the disease are multifactorial.
Activated mast cells can also very rapidly synthesize and release prostaglandin D2 (PGD2), leukotrienes (LTs), thromboxanes, and platelet‐activating factor (PAF). These mediators are responsible for the increased vascular permeability, vasodilatation, and stimulation of sensory nerve endings in the skin, resulting in redness, swelling, and itchiness. Mast cells are also important sources of an array of growth factors, cytokines, and chemokines which may perpetuate and amplify the inflammatory state of urticaria. IgE‐mediated activation of mast cell is the major route, while mast cells may be activated by other pathways such as IgG‐dependent triggers or by several nonimmunological agents such as compound basic polypeptides (polyarginine, polylysine), morphine sulfate, the anaphylatoxin C5a, and substance P [18].
Basophils
In parallel to mast cells, basophils also appear to be involved in the pathogenesis of CSU. Basophils are dramatically reduced in the peripheral blood (basopenia) of CSU patients with high disease activity, and this may be due to their recruitment from the circulation into the skin lesions [20–23]. Basopenia reverses when urticaria remits or is successfully treated [24]. In fact, hyporesponsiveness of basophils to anti‐IgE [25] and alteration of signal transduction pathways have been reported in at least half of the patients with active disease [21, 25, 26]. For example, one of these pathways involves the histamine‐releasing factor/translationally controlled tumor protein (HRF/TCTP), a cytokine which directly induces histamine release from basophils, by signal transduction process involving Syk kinase, mimicking many of the events associated with IgE‐mediated activation [21].
Recent studies found that blood basophils from CU patients showed a reduced surface expression of CRTH2 (the chemoattractant receptor–homologous molecule expressed on TH2 cells), the receptor for PGD2. This phenomenon was possibly due to the engagement of CRTH2 in patients with CU, and subsequently in vivo PGD2‐mediated activation of basophils [27]. Basophils from CU patients show a subset of different activation responders (either responder or non‐responder, based on the degranulation response to polyclonal goat anti‐human IgE) that seem independent of the presence of IgG autoantibodies to IgE or FcεRI [23, 28]. Basophil activation is augmented by complement, [29] which appears due to the formation of C5a [30].
Eosinophils
The presence of eosinophils in biopsies from affected skin supports the view that several pathological features of CSU are shared with the allergen‐induced late‐phase allergic reaction [31]. Mediators released by skin mast cells following their degranulation may lead to activation, eosinophil recruitment, and survival, and the perpetuation of the clinical features of urticaria. How eosinophils and their mediators may directly contribute to the development of CSU is unknown. There were eosinophil‐derived major basic protein (MBP) in the lesional skin of CSU patients, and eosinophils may directly affect mast cell degranulation by MBP with consequent amplification and perpetuation of the local inflammation in CSU [31].
Histamine
Histamine plays a key role in the pathophysiology of allergic inflammation [32]. After exposure to an allergen, specific antibodies of the IgE type are produced in genetically predisposed individuals [32]. IgE interacts with receptors on the surface of basophils and mast cells. The consequence is a series of intracellular reactions culminating in exocytosis and the release of histamine and other inflammatory mediators such as cytokines and PAFs [3, 32]. Various drugs (e.g. morphine) can also cause direct displacement of histamine from its storage granules [32].
The consequences of histamine release include receptor‐mediated smooth muscle cell contraction in the respiratory and gastrointestinal tracts, vasodilation, sensory nerve stimulation, plasma extravasation, and cellular recruitment, for example, to urticarial lesions [3, 32]. These effects lead to, among other things, erythema, flushing, nasal congestion, and pruritus [32].
Histamines contribute to the late allergic response by stimulating the production of class II antigens, cellular adhesion molecules, and cytokines in addition to their mediatory activity in the early allergic response [32].
Four principal histamine receptor subtypes exist: H1, H2, H3, and H4. These are G‐protein‐coupled receptors that transfer extracellular signals via G proteins, which act as intermediaries between cell surface receptors and intracellular second messengers [32, 33]. H1 and H2 receptors are widely distributed throughout the cells of the body, but the H3 subtype is mainly located in the central nervous system (CNS) and the H4 subtype is located in hematopoietic cells [32]. The allergic response is primarily mediated by the H1 receptor subtype.
H1 receptors are ubiquitous and are found in the CNS, adrenal medulla, epithelial, endothelial cells and immune cells, heart, sensory nerves, and smooth muscle [32]. In the CNS, most of the postsynaptic actions of histamine are mediated by H1 receptors [32]. This leads to activity on sleep–wake cycles and probably causes the sedative effects noted with first‐generation antihistamines that cross the blood–brain barrier [14]. Via H1 receptors, histamine also causes smooth muscle cell contraction in the respiratory and gastrointestinal tracts and stimulation of sensory nerves. Outcomes include sneezing, pruritus, increased vascular permeability, and edema [32].
C‐Reactive Protein (CRP)
C‐reactive protein (CRP), belonging to classical short pentraxins, is an acute‐phase protein produced primarily in the liver under the stimulus of IL‐1, TNF‐α, and/or IL‐6. A prominently elevated ESR/CRP is seen in infections, autoimmune diseases, and malignancy [3]. Blood levels of CRP were found to be significantly higher in CSU patients compared to controls, which supported the inflammatory status of CSU [34].
Recent studies showed the coexistence of CU and metabolic syndrome (MS) in a Korean population [35]; patients with both chronic MS and urticaria had a more severe disease, and had higher levels of inflammation markers (i.e. tumor necrosis factor [TNF]‐alpha, eosinophil cationic protein [ECP], and complement). It was interesting that patients with MS were more frequently scored negative on the Autologous serum skin test (ASST) than those without MS [35]. In another Asian‐based population study, CU was more frequent among subjects with a prior diagnosis of hyperlipidemia [36]. Recently, CU patients were found to show increased levels of a series of adipokines (lipocalin‐2, TNF‐alpha, IL‐6, and IL‐10) but lower levels of adiponectin [37].
Pentraxin 3 (PTX3)
Parallel to CRP, the role of other members of the pentraxin family, in particular, PTX3, produced at the site of inflammation, have been investigated. The observation that PTX3 levels were increased in the plasma of CSU patients compared to healthy subjects suggested a local inflammation due to activation of leukocytes infiltrating the skin. Thus, the observed association between CRP and PTX3 in CSU patients suggests that these two pentraxins may be upregulated by the same mechanisms correlated with acute‐phase response [38].
Proinflammatory Cytokines
Besides an increase of inflammatory mediators in the skin, some independent studies demonstrate an increase of several proinflammatory cytokines in the circulation of CSU patients, although contradictory results exist. IL‐6 is increased in the plasma of CSU patients and decreased significantly upon spontaneous remission, which is associated with the clinical activity score of CSU. Thus, IL‐6 was suggested as a marker of disease activity [39, 40]. Proinflammatory cytokine IL‐18 of the IL‐1 family, which was initially identified as a major inducer of interferon‐γ (IFN‐γ) in Th1 and natural killer (NK) cells, was increased in CSU in both total and free forms [41]; while in the study by Tedeschi et al. no significant differences in IL‐18 levels between the CSU and control group was observed [42]. Parallel to IL‐1 family cytokines, a role of the IL‐23/IL‐17 axis and TNF‐α in the pathogenesis of CSU was hypothesized [43]. High serum levels of TNF‐α, IL‐23, and IL‐17 were detected in CSU patients; correlational analysis indicated that the levels of TNF‐α and IL‐23, but not that of IL‐17, were associated with the activity of the disease. It seems conceivable that the increase of proinflammatory mediators and the consequent increase of CRP, are hallmarks of an inflammatory condition in CSU patients [34].
Other Cytokines and Chemokines
The cytokine profile in CSU is characterized by an increase in IL‐4, IL‐5, and IFN‐γ, which is suggestive of a mixed Th1/Th2 response [17, 44]. Cytokines of Th2 cells such as IL‐25, IL‐33, and thymic stromal lymphopoietin (TSLP) are increased in lesional but not in uninvolved skin, which suggest that innate pathways might play a role in the pathogenesis of CSU by the activation of mast cells in the lesional skin [45]. IL‐13 and periostin are involved in allergic inflammatory processes. Some data demonstrated that IL‐13 was significantly increased and periostin was significantly reduced in CSU patients, especially in those with severe versus mild disease, suggesting that the two mediators may be independently related to the pathogenesis of CSU [46].
The chemokine signaling is mainly involved in the regulation of leukocyte trafficking and may lead to recruitment of inflammatory cells in the lesional skin of CSU [47]. For example, CCL2/MCP‐1, CCL5/RANTES, and CXCL8/IL‐8 are able to induce serotonin and histamine release by mast cells, suggesting their direct effect on mast cell degranulation that contributes to the development of urticaria [48]. Additionally, CCL5/RANTES plays a role in the recruitment of monocytes, eosinophils, and lymphocytes in the lesional skin [49], and induces the migration of progenitor mast cells, possibly mediated by CCR5, as chemokine receptors for CCL5/RANTES are also expressed on progenitor mast cells [48]. Thus, since CCL5/RANTES can be produced from circulating inflammatory cells following tissue infiltration and from mast cells in the tissue, its effects and its production in the skin of CSU can persist over time, leading to the perpetuation and amplification of the inflammatory process.
Immunopathogenesis of Urticaria
Exposure to exogenous or modified endogenous triggers, in conjunction with susceptibility factors, may result in immunological activation events, an immune‐mediated inflammatory disease, manifesting as CSU [50]. Disturbances of innate and adaptive immune response may result in the inflammatory cascade and the recruitment of immune cells into the derma [51]. The autoimmune or “autoallergic” reaction is, at least in a subpopulation of patients, give rise to CSU. In such a situation, autoreactive IgE antibodies react against auto‐allergens, or autoreactive IgG antibodies against the mast cell (or basophil) high‐affinity receptor FcεRI, IgE or both [52]. 35%–40% of patients have an IgG antibody to the α subunit of the high affinity IgE receptor (IgG anti‐FcεRIα) or membrane‐bound IgE (in a minority of patients) present on both mast cells and basophils [1353–56], while an additional 5%–10% have IgG against IgE [57, 58]. These interactions are functional and can induce histamine release from blood basophils or cutaneous mast cells [59].
Specific IgE for thyroid peroxidase (TPO) dsDNA and ssDNA has recently provided a different mechanism potentially able to promote the survival, proliferation, and activation of mast cells [60]. However, the proportion of patients in whom such IgE autoantibodies can be detected is limited, and TPO‐specific IgE autoantibodies are generally associated with the more common TPO IgG autoantibodies that characterize patients with Hashimoto’s thyroiditis which are found in a minority of patients [61]. Studies are underway with the expectation that other “auto‐allergens” will be detected in larger proportions of patients with CSU [52]. Recently, the autoimmune pathogenesis hypothesis has received new, indirect but strong support from the detection of circulating autoreactive CD4+ T cells that proliferate in response to FcεRI in >50% of patients with CU examined [62].
However, the observation that sera from a large part of patients with CSU induce significant activation of mast cells lacking the high‐affinity IgE receptor, irrespective of the autoreactivity status or of the presence/absence of circulating autoantibodies, suggests that other mechanisms may be involved in the pathogenesis of the disease [63, 64]. Studies showed that low‐molecular‐weight circulating factors (molecular weight about 30 kDa) may be involved in the activation of mast cells in CU patients, [65, 66].
In the US practice parameters, CIU is considered to have an autoimmune basis in many, but not all, patients. Other underlying causes of CIU have been proposed, including food intolerance, infections, and autoallergy [8, 52].
Role of Autologous Serum Skin Test (ASST)
Since the reactivity of ASST is mainly due to serum factors responsible for histamine release and vasodilatation that are controlled by antihistamines, ASST is widely used in the diagnosis of CU in order to evaluate an autoimmune origin of the disease. ASST seems sufficiently specific for CU, as normal subjects do not show skin reactivity [67], although they may score positive for CIU such as cold urticaria [68], multiple hypersensitivity, and multiple drug allergy syndrome to non‐steroidal anti‐inflammatory drugs [69, 70]. However, the ASST scores positive in only about one‐half of CU patients [71, 72], leaving almost another half of patients not showing any autoreactivity despite their potentially severe and/or ongoing disease. The role of ASST as a marker for the disease is controversial. Some studies claimed there was a longer duration of urticaria or higher disease activity in ASST‐positive patients than that in ASST‐negative patients; while other studies did not support this point in terms of disease duration, severity, and quality of life scores [973–75]. Interestingly, a study showed that ASST reactivity was a significant predictor of well‐controlled CU during the six‐month stepwise treatment, and the results of the ASST may be a useful parameter for monitoring therapeutic response and predicting response to treatment in patients with CU. The authors hypothesized that ASST‐positive patients are expected to achieve a well‐controlled state within six months of treatment [76].
Endothelium and Coagulation System in CSU
Besides the chemokine system, the endothelium plays a critical role in influencing cellular trafficking and controlling the passage of fluid into the tissue [77]. In the skin, endothelium dysfunction might increase vascular permeability before a proinflammatory response. The soluble forms of adhesion molecules, such as intercellular adhesion molecule (ICAM‐1) and vascular cellular adhesion molecule‐1 (VCAM‐1), are widely used as biomarkers of endothelial dysfunction, and their increase in skin biopsies and circulation [49] seems to reflect a proinflammatory endothelium phenotype in several skin diseases, including CSU [17, 49, 78, 79].
The detection of increased levels of prothrombin fragment 1 + 2, factor VIIa, and D‐dimer in CSU suggests that, following endothelial cell activation, tissue factors are released with consequent activation of the extrinsic coagulation cascade and secondary fibrinolysis [80, 81]. It is thus presumed that thrombin is a potent inducer of mast cell degranulation and can increase vascular permeability, at least in experimental models [82]. Furthermore, the plasma levels of D‐dimer are frequently elevated in patients with severe CSU and seem to decrease following treatment with omalizumab [83], suggesting a link between activation of coagulation, circulating autoantibodies, and fibrin degradation in severe CSU. The D‐dimer level is also significantly associated with acute urticaria, suggesting its role as a marker of disease severity in both forms of urticaria. [84]
The observation that the autologous plasma skin test (APST) may score positive in some ASST‐negative patients [85] has prompted investigation of the coagulation system in patients with CU. Specific studies have shown that the coagulation cascade is activated in CU and involves the extrinsic pathway first and the intrinsic pathway second [80–8285–87]. The process seems to be triggered by the high expression of tissue factors by activated eosinophils [88]. IgG autoantibodies to the low‐affinity IgE receptor FcεRII, present on the membrane of eosinophils, have been detected in quite a large proportion of patients (about 65%) with CU [89]; activation of such cells with subsequent release of MBP and other mediators cause mast cell degranulation. The activation of the coagulation cascade might play an important role in the pathogenesis if one considers that thrombin is a potent inducer of mast cell degranulation and can remarkably increase the vascular permeability in experimental models. The activation of the coagulation cascade occurs in other skin disorders characterized by an increase of vascular permeability, such as bullous pemphigoid and angioedema due to C1‐inhibitor deficiency [90, 91], and in a wide spectrum of systemic diseases, such as disseminated intravascular coagulation [92], endotoxemia [93], and deep venous thrombosis [94], all prothrombotic conditions that are not characterized by urticaria or edema.
Parallel to the coagulation/fibrinolysis pathways, an imbalance in pro‐ and anti‐inflammatory adipokines in CSU patients has been also observed. In particular, Lipocalin‐2 (LCN2) might be used as a marker not only of the clinical response to antihistamine treatment but also of disease activity [37], suggesting new approaches to response to therapy and monitor disease progression in CSU patients.
Role of Angiogenesis in CSU
Angiogenesis is the growth of new blood vessels from pre‐existing ones. It is a multistep and highly orchestrated process involving endothelial cell migration, vessel sprouting, tube formation, proliferation, and survival [95, 96]. Under physiologic conditions, angiogenesis depends on the balance of negative and positive angiogenic mediators within the vascular microenvironment and requires the functional activities of a number of molecules, including extracellular matrix proteins, angiogenic factors, proteolytic enzymes, and adhesion receptors [95, 96]. Angiogenesis is also correlated with pathologic conditions as a direct response to tissue demands, such as fibrosis, chronic inflammation, and tumor growth. [96]
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