Urticaria mast cells

Urticaria mast cells DEFAULT

Is chronic urticaria more than skin deep?

Clinical and Translational Allergyvolume 9, Article number: 48 (2019) Cite this article

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Abstract

Chronic urticaria is a disease characterized by the appearance of weals, angioedema or both longer than 6 weeks. Degranulation of cutaneous or submucosal mast cells leads to release of mediators including histamine resulting in redness, swelling and itch. Because mast cells are widely distributed throughout the body, the question is why they are not activated systemically or does systemic activation occur without overt end organ dysfunction? We have conducted an exploratory literature search for reports that have evidence of organ-specific dysfunction in chronic urticaria that might justify prospective observational studies. This search revealed some evidence of systemic effects of chronic urticaria in cardiac, respiratory, gastrointestinal, central nervous and musculo-skeletal systems. The relevance of these findings needs to be further determined. However, they justify prospective studies in larger numbers of patients and at different stages of disease activity.

Background

Chronic urticaria (CU) is a disease characterized by the appearance of weals, angioedema or both in which mast cells have a central role [1]. Degranulation of cutaneous or submucosal mast cells results in release of pre-formed and newly synthesised mediators including histamine and cysteinyl leukotrienes LTC4, D4 and E4 resulting in redness, swelling and itch [2]. Because mast cells are widely distributed throughout the body, the question is why they are not activated systemically or does systemic activation occur without overt end organ dysfunction? A possible explanation could be relative restriction of C5a receptor expression to cutaneous mast cells, with preferential activation after C5a generation [3]. Degranulation of human foreskin mast cells required binding of the FcεRI and activation of the classical complement cascade in vitro [4]. Total, but not mature (β), tryptase in the sera of CU patients was higher than healthy and atopic controls, particularly in a subgroup with autoimmune urticaria, and symptomatic rather than asymptomatic patients suggesting an increased systemic mast cell burden [5]. Increased levels of plasma histamine have been reported in CSU patients [6]. Increased plasma histamine could lead to concentration-related histamine-mediated symptoms such as increasing gastric acid secretion and heart rate, tachycardia, headache, flush, urticaria, pruritus, decreased arterial pressure, bronchospasm, and cardiac arrest [7].

Some chronic spontaneous urticaria (CSU) patients have gastrointestinal symptoms, flushing, joint pain or swelling, palpitations, headache/fatigue and wheezing during active urticarial flares suggesting systemic as well as cutaneous mast cell activation [8]. In an epidemiological study, extracutaneous symptoms were found in over a third of cases (39.4%) [9].

We have conducted an exploratory literature search using PubMed and Google Scholar before May 2019 for reports that have evidence of organ-specific dysfunction in CU (spontaneous and inducible) that might justify prospective observational studies. Because the terminology of CU has historically been inconsistent we have included the specific terminology used in each report, accepting that chronic idiopathic urticaria (CIU), chronic spontaneous urticaria (CSU) and even CU itself relate to the same patient population unless specific subtypes of inducible urticaria have been specified. We performed a literature search strategy for evidence including every organ system of the body (Table 1). Reports relating to acute urticaria, urticarial vasculitis, autoinflammatory syndromes, mastocytosis and bradykininergic angioedema were excluded. Many systemic reactions related to inducible urticarias for example laryngeal oedema due to cold urticaria were also excluded. Identified reports that are relevant are summarised in Table 2.

Full size table

Full size table

Respiratory system (search terms employed urticaria and ‘upper respiratory tract’, ‘lower respiratory tract’, ‘pharynx’, ‘larynx’, ‘nose’, ‘respiratory symptoms’, ‘pulmonary system’, ‘asthma’, ‘bronchial hyperresponsiveness’)

Zuberbier et al. reported dyspnoea, rhinorrhoea or irritation of the eyes in 9.1% of urticaria patients [9]. Tedeschi et al. reported two autoimmune/autoreactive CU patients in whom urticaria onset was associated with the simultaneous appearance of asthmatic symptoms [10]. The same Italian group investigated pulmonary function and bronchial hyperresponsiveness in a group of patients with CU [11]. They included 26 CU patients and 26 asthmatic patients as controls and performed pulmonary function tests with methacholine provocation during a phase of moderate disease activity. 5 out of 26 had hypersensitivity to grass, HDM, olive, ragweed. The authors found that 22/26 (85%) of CSU patients had asthma or abnormal bronchial reactivity. Airway hyperresponsiveness was not associated with gender, disease duration, intolerance of NSAIDs, positive autologous serum skin testing or respiratory allergy. They concluded that results of the present study are completely different in that 85% of the patients with CU were found to have bronchial hyperresponsiveness (BHR) or, in some cases, overt asthma; this proportion largely exceeded the one expected in a normal population (5–20%). Petalas et al. studied cholinergic urticaria patients and found that bronchial hyperresponsiveness (BHR) was present in 13 of 30 (43%) of them but in only 1 of 15 patients with CU (7%), and 1 of 14 healthy volunteers (7%); the observed difference was statistically significant. In addition, a statistically significant correlation was found between patient age and disease duration and between intensity and frequency of symptoms [12]. Henz et al. found increased BHR in subjects with symptomatic dermographism and proposed a link between cutaneous and bronchial hyperreactivity, which might be based on a subclinical activation of mast cells that would induce changes in receptor expression and responsiveness of resident bronchial and cutaneous tissue and infiltrating inflammatory cells [13]. Even though clinical observations suggest CSU does not involve larynx, Juhlin et al. reported 8 from 330 CU patients to have laryngeal edema [14].

Gastrointestinal system (search terms employed urticaria and ‘gastrointestinal system’, ‘gastrointestinal symptoms’, ‘esophagus’, ‘intestines’, ‘gastric’, ‘gut’, ‘colon’, ‘duodenum’ ‘liver’, ‘pancreas’, ‘gall bladder’)

Nausea, vomiting and epigastric abdominal pain are present in around 40% of CU patients; the term “Chronic Gastrointestinal Urticaria” has been used [14, 15]. Since the gut is frequently exposed to histamine from foods, the action of histamine on the digestive tract has been investigated. Kanny et al. examined duodenal biopsies from seven patients with CU before and after intraduodenal administration of histamine (120 mg). Five CU patients had clinical symptoms (diarrhoea, urticaria, headache, accelerated heart rate, and drop in blood pressure) within 1 h of duodenal histamine challenge (DHC). Ultrastructural changes, including oedema of the interstitial tissue, enlargement of the basal intercellular spaces, slight congestion of the endothelial cells and pericapillary oedema were observed in six patients 45 min after DHC. The authors concluded that histamine can induce oedema in the basal intercellular spaces of the duodenal mucosa and in the submucosa without evident change in the integrity of intercellular junctions [16]. Minnei et al. investigated if the mast cell number in the gastroduodenal mucosa is increased in CU patients compared to controls and found that CU patients demonstrated a significantly increased mast cell number in the stomach and the duodenum even if they did not have gastrointestinal symptoms [17]. Teramura et al. recently reported a patient with diarrhoea and urticaria in whom the symptoms were linked to intestinal oedema caused by urticaria itself [18].

Intestinal permeability studies were performed by Andre´ et al. who reported a slightly elevated lactulose/mannitol index in CU patients, whilst Guida et al. reported normal intestinal permeability in all patients with CU [6, 19, 20]. Buhner et al. designed a study to investigate whether disturbances of the gastrointestinal barrier function play a role in the pathomechanism of CU by enrolling 55 patients with CU. Gastrointestinal permeability was measured with an in vivo triple-sugar-test before and after 24 days of a low pseudoallergen diet. Sucrose served as marker of gastroduodenal permeability and lactulose/mannitol ratio for small intestinal permeability. They found that basal gastroduodenal and intestinal permeability were significantly increased in patients with urticaria by comparison with controls. In 29 of the 55 patients urticarial symptoms decreased or completely disappeared during the diet (responders). Compared to non-responders, responders had significantly higher gastroduodenal permeability before the diet, which decreased after the diet (0.17 ± 0.02; P < 0.001). The results of the study suggested that an impaired gastroduodenal barrier function may be of pathophysiological importance in the development of pseudoallergy in CU patients [21].

A case report from Turkey described a patient with cholinergic urticaria and erythematous pangastritis whose severe dyspeptic complaints did not resolve with proton pump inhibitors but with omalizumab [22].

The liver

Searching for “urticaria and liver” revealed a case of cholinergic urticaria with transient hepatocellular injury during attacks of cholinergic urticaria in a 25-year-old man with ulcerative colitis [23]. We could not find any other publications relating to liver dysfunction in CU but we found reports of “yellow urticaria” with high blood bilirubin levels due to various liver diseases. The unusual colour of the lesions was thought to be due to increased permeability of cutaneous blood vessels in urticaria resulted in exudation of bilirubin into the weals [24]. There were no reports of gall bladder dysfunction.

The pancreas

Barba et al. investigated the exocrine function of the pancreas in 25 patients with CU by analysing the quantitative or qualitative deficiency of pancreatic enzyme secretion. All the patients showed normal faecal chymotrypsin excretion and 23/25 had normal bentiromide (para-amino benzoic acid) and pancreolauryl tests [25]. The authors concluded that these findings did not support pancreatic deficiency in CU.

Cardiovascular system (search terms employed urticaria and ‘cardiac involvement’ ‘heart’, ‘cardiologic symptoms’ ‘hypertension’)

Histamine is found in high concentrations in the healthy heart and in very high concentrations in the coronary arteries of patients known to have died from coronary heart disease [26, 27]. Ginsburg et al. Demonstrated histamine to be capable of inducing coronary artery spasm [28]. In vitro studies of the human heart have revealed that the H1 receptors mediate contraction of coronary vascular smooth muscle, while H2 receptors mediate relaxation [29]. During hypersensitivity reactions or anaphylaxis, degranulation of cardiac mast cells will lead to release of vasoactive substances with reduction in coronary blood flow and depression in regional myocardial contractile function [30].

The concurrence of acute coronary syndromes with conditions associated with mast cell degranulation has been termed Kounis syndrome (KS) after his description in 1991 [31]. Three types of KS has been described: type I variant (most common variant, 72.6%) is characterized by the release of inflammatory mediators which induces coronary artery spasm with or without increase of cardiac enzymes and troponins. Type II variant (22.3%) is featured with the release of inflammatory mediators which induces coronary artery spasm together with plaque erosion or rupture manifesting as acute MI. Type III variant (5.1%) includes patients with coronary artery stent thrombosis as a result of an allergic reaction [32]. Allergic, anaphylactic and anaphylactoid reactions are associated with this syndrome [32]. Recently, Erxun et al. described a 31 year old patient with Kounis syndrome who had been suffering from chronic autoimmune urticaria for 3 years. Her urticaria became more serious 1 week before an emergency department (ED) visit with heart palpitations, precordial pain, chest tightness and excessive sweating. Prior to this acute presentation, her heart symptoms had tended to resolve about 2 h after the urticaria disappeared. She had repeated attacks of urticaria exacerbations with cardiac symptoms at follow up. An ECG showed ST-segment elevation and, on review of her ED visits, the ST-segment elevation was found to occur almost at the same time she was suffering from serious urticaria, but it returned to normal when her urticaria disappeared. Angiography was performed during and after heart symptoms; the results revealed a coronary artery spasm at the time of onset of her heart symptoms that returned to normal when her symptoms were relieved. The authors stressed that when severe chronic urticaria is accompanied by repeated heart symptoms, physicians should consider the possibility of Kounis syndrome [33]. A case of cold-induced urticaria complicated by Kounis syndrome during swimming in seawater was also reported who had a normal ECG but a high cardiac troponin [34]. Kounis syndrome has more commonly been reported in acute urticaria and anaphylaxis but it could also be more common in acute severe chronic urticaria outbreaks than is currently recognised [35,36,37].

Chang et al. reported that hypertension was associated with CIU. Their patient cohort had a 1.37-fold greater risk of developing subsequent hypertension than controls. They attributed this association to alterations in the blood coagulation and fibrinolysis pathways as well as systemic inflammation associated with CIU [38]. In another study, Nebiolo et al. reported that systemic hypertension was present in 42 of 228 patients (18.9%) and that hypertension is associated with extended duration of CIU [39].

Central nervous system (search terms employed urticaria and ‘brain’, ‘neurologic symptoms’, ‘central nervous system’)

The search for “urticaria and brain” revealed a case of cholinergic urticaria with seizures. Harada et al. reported a 10-year-old boy with cholinergic urticaria associated with epileptic seizures and abnormalities on electroencephalogram. They proposed that sweat-promoting stimuli, such as heat, exercise and tension stimulate the autonomic centre in the diencephalon or brain stem, and that excitation of the autonomic centre is transmitted to the efferent sympathetic nerves, causing cholinergic urticaria. When the intensity of stimulation is high, the autonomic centre exhibits abnormal activities and causes epileptic seizures [40]. Fumal et al. reported a patient with an unusual form of migraine with urticarial lesions on the chest at the end of each migraine attack outlasting the attack by 10 to 90 min, which was assumed to be related to a systemic release of serotonin or other vasoactive substances like histamine, bradykinin, or nitric oxide [41].

Wang et al. investigated the functional and structural alterations of the striatum in chronic spontaneous urticaria (CSU). They performed amplitude of low frequency fluctuations (ALFF), voxel-based morphometry (VBM), and seed-based resting-state functional connectivity (rs-FC) analysis on 40 CSU patients and 40 healthy controls to assess brain activity and related plasticity. They found that CSU patients had higher ALFF values in the right ventral striatum/putamen, which were positively associated with clinical symptoms as measured by UAS7; a higher gray matter volume in the right ventral striatum and putamen; and decreased rs-FC between the right ventral striatum and the right occipital cortex and between the right putamen and the left precentral gyrus. In summary, by using multiple-modality brain imaging tools, they demonstrated dysfunction of the striatum in CSU. The authors concluded that CSU may be associated with disrupted reward, motivation, and motor processing [42]. These investigators published a recent original article which demonstrated the altered cerebellar activity and cerebellum-reward-sensorimotor loops in CSU; these changes in cerebellar activity were shown to decline with treatment when urticarial activity is decreased [43].

Musculoskeletal system (search terms employed urticaria and ‘skeletal system’, ‘joints’)

A paper from 1989 reported four HLA-B51 positive patients with simultaneous urticarial and articular manifestations but without evidence of immune complex disease. The authors suggested that a common genetic background might be present in some cases of urticaria with articular complaints [44]. McNeil et al. described 9 patients with concurrent arthritis and/or arthralgia, urticaria and angioedema in whom routine laboratory studies were normal, including complement levels, humoral and cellular immunity. The absence of associated infection and connective tissue disease suggested this recurrent triad represents a distinct entity, which the authors designated the AHA (arthritis, hives and angioedema) syndrome [45]. A case report from 2007 described a patient with CU and mild arthritis associated with autoimmune thyroid disease who was successfully treated with l-thyroxine. Both urticaria and arthralgia responded to treatment [46].

Recently, an association between CU and osteoporosis was reported [47]. In this report, CU was associated with lower serum PTH, lower rates of hypocalcemia and higher rates of osteoporosis. Patients with osteoporosis and CU were younger more likely to be of male sex and had a higher prevalence of obesity than osteoporotic patients without CU, further strengthening the association between CU and osteoporosis.

Renal system (search terms employed urticaria and ‘renal involvement’, ‘kidneys’, ‘renal functions’) and genitourinary system (‘genitourinary system’ and ‘fertility’)

We found no reports of nephritis, proteinuria or haematuria associated with chronic urticarial activity. However, interference with micturition due to delayed pressure urticaria swelling after sexual intercourse has been reported [48].

Conclusions

Systemic consequences of urticaria could result from increased circulation of cutaneous mast cell mediators, generalized enhancement of releasability of mast cells, a reactive increase in mast cell numbers (as opposed to clonal in mastocytosis), increase in plasma histamine level or all of these. It might be expected that any systemic effect would be most obvious when the disease is most active. The natural history of CU is one of natural improvement followed by resolution so looking for evidence of dysfunction would be logical during the acute stage of the illness or during acute urticaria. Patients presenting acutely unwell with severe urticaria are often treated with short courses of systemic steroids that are likely to mask subclinical effects of the illness.

Searching for reports of organ-based dysfunction in patients with urticaria revealed some evidence in cardiac, respiratory, gastrointestinal, central nervous and musculo-skeletal systems (Fig. 1). The relative paucity of published reports does not exclude organ-based dysfunction if a relationship has not been looked for or written up in the medical literature. The relevance of these findings needs to be further determined. However, they justify prospective studies in larger numbers of patients and at different stages of disease activity.

Involved systems in chronic urticaria and relevant manifestations

Full size image

Limitations of this review include:

  1. 1.

    The possibility that relevant reports were missed in the literature search by using incomplete search terms.

  2. 2.

    The anecdotal reports may have been co-incidental rather than directly related to urticaria.

  3. 3.

    It was not possible to assess the effects of urticaria treatment on potential improvement of any organ-based dysfunction without it.

Availability of data and materials

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Abbreviations

amplitude of low frequency fluctuations

bronchial hyperresponsiveness

chronic urticaria

chronic spontaneous urticaria

chronic idiopathic urticaria

duodenal histamine challenge

emergency department

seed-based resting-state functional connectivity

voxel-based morphometry

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Affiliations

  1. Department of Dermatology, Koç University, School of Medicine, Istanbul, Turkey

    Emek Kocatürk

  2. St John’s Institute of Dermatology, Guy’s Hospital, London, UK

    Clive Grattan

Contributions

Conceived and designed the study: EK and CG. Wrote the manuscript: EK. Critically reviewed and revised the manuscript: CG. Final language editing: CG. Agreement with manuscript and conclusions: all. Designed the figures and tables: EK. Both authors read and approved the final manuscript.

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Correspondence to Emek Kocatürk.

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Emek Kocatürk has received honoraria for scientific advice or consultancy from Novartis. Clive Grattan has given talks for Novartis and SunPharma and has done consultancy work for CSL Behring.

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Kocatürk, E., Grattan, C. Is chronic urticaria more than skin deep?. Clin Transl Allergy9, 48 (2019). https://doi.org/10.1186/s13601-019-0287-2

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Keywords

  • Urticaria
  • Organ involvement
  • Systemic findings
  • Cardiac
  • Gastrointestinal
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Sours: https://ctajournal.biomedcentral.com/articles/10.1186/s13601-019-0287-2

Urticaria

Updated: July 2019
Updated: February 2014
Originally posted: September 2004


Allen P. Kaplan, MD
Medical University of South Carolina
Dept. of Medicine: Pulmonary 96 Jonathan Lucas Street
Charleston, SC 29425
USA


Definitions
Symptoms
Classification
Causes
Treatment

Urticaria and Angioedema: Global Overview

Definitions

Urticaria is a transient erythematous swelling of the skin, associated with itching, which usually resolves within 24 hours.  It is caused by degranulation of histamine containing cells (mast cells) in the superficial dermis.

Symptoms

Urticarial lesions itch, have a central white wheal that is elevated, and are surrounded by an erythematous halo. The lesions are typically rounded and circumscribed. Characteristically, hives should blanch with pressure; they generally resolve within 24 hours, and leave no residual scar or changes to the skin. The redness is due to dilated blood vessels in the superficial layers of the skin which have responded to histamine and is then augmented by a local neural reflex (axon reflex) initiated by the same nerve fibers that mediate itch.  The wheal is due to leakage of these vessels and as fluid extravasates, compresses the vessels beneath so that the central area appears clear.

Angioedema often accompanies urticaria as the swelling results from the same processes that cause hives but involves small blood vessels (venules) in deeper layers of the skin.

Classification

Urticaria is commonly classified by duration. If hives are present for less than six weeks, the process is considered “acute”.  If urticaria persists beyond 6 weeks, it is designated “chronic”.  The causes and mechanisms of hive formation are different in each instance, as is the prognosis and approaches to treatment.

Acute urticaria can be divided into two general types, depending on the rate at which hive formation occurs and the length of time it is evident. One type produces lesions that last 1-2 hours and is typically encountered in physically induced hives. The inciting stimulus is present only briefly, and there is prompt mast cell degranulation. Biopsy of such lesions reveals little or no cellular infiltrate. The second type produces a prominent cellular infiltrate, and individual lesions can last as long as 36 hours. This type is encountered with food or drug reactions, delayed pressure urticaria, chronic spontaneous urticaria, and urticarial vasculitis.

Chronic spontaneous urticaria is characterized by a non-necrotizing perivascular mononuclear-cell infiltrate (CD4 positive T lymphocytes and monocytes) with variable accumulation of eosinophils, neutrophils, and mast cells. Patients with vasculitis and urticaria appear to be a separate sub-population in whom the cause and pathogenesis of hive formation probably involves immune complexes, complement activation, anaphylatoxin formation, histamine release, and neutrophil accumulation, activation, and degranulation.

Causes 

Acute urticaria

Acute urticaria, which is an allergic (IgE-mediated) reaction, is common in both children and adults. This type of urticaria is a self-limiting process that occurs when mast cells in the skin are activated, degranulate, and secrete histamine, leukotrienes, platelet activating factor (PAF), enzymes such as tryptase and chymase, cytokines, and chemotactic cytokines (chemokines). When an allergen (for example, a food) to which the person is allergic arrives via the bloodstream to mast cells in the skin, it binds to the IgE, and the mast cells become activated, and degranulate. Allergens that can result in acute urticaria include foods, drugs (particularly antibiotics such as penicillin), and venoms from bee, wasp, yellow jacket, hornet, or fire ants. Virtually any allergen that can be disseminated throughout the body, and to which there is an IgE response, has the potential to cause generalized urticaria.

If an allergic reaction causes hives or swelling, it is usually ingested (food, oral drug) or injected (drugs, stings). If an allergen can penetrate the skin locally, hives will develop at the site of exposure. For example, contact urticaria may occur following exposure to latex gloves if sufficient latex penetrates through the skin.

Non-specific stimuli

Acute urticaria can result from "non-specific" stimulation of mast cells, when there is degranulation of mast cells in the absence of a defined allergen. An example is exposure to certain radiocontrast media which changes the osmolality of the environment in which the mast cell resides and can result in degranulation. Patients who develop acute urticarial eruptions can have other accompanying manifestations of a systemic anaphylactic reaction such as wheezing, laryngeal edema, cramps, diarrhea, and hypotension.

Acute viral illnesses in children can be associated with urticarial eruptions which last a few weeks and then spontaneously subside. This typically accompanies symptoms of viral rhinitis, pharyngitis, or bronchitis. When such patients are given an antibiotic, the cause of the hives becomes less clear because a drug reaction becomes an alternative possibility. If penicillin or related antibiotics have been given it is worth performing skin testing for penicillin and/or cephalosporin allergy, rather than making an unsubstantiated assumption that the child is "penicillin allergic." Hepatitis B, infectious mononucleosis (EB virus) and a large number of helminthic parasites may be associated with hives in all age groups.

Codeine and other opiate-derived medications can cause degranulation of mast cells by stimulation of opiate receptors. Urticaria and angioedema can result from agents that alter the metabolism of arachidonic acid, such as aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). These responses to NSAIDs have the potential to be fulminant with generalized hives and swelling.

The Inducible Urticarias

Physically induced hives and/or swelling share the common property of being induced by environmental factors such as a change in temperature or by direct stimulation of the skin by pressure, stroking, vibration, or light.  These hives are fleeting i.e. last less than two hours, the only exception being delayed pressure urticaria.  The stimulus results in mast cell histamine release and is not followed by any cellular infiltration i.e. no late phase component.

The physical urticarias

Physically induced hives and/or swelling share the common property of being induced by environmental factors such as a change in temperature or by direct stimulation of the skin by pressure, stroking, vibration, or light.

Cold-dependent disorders

Idiopathic cold urticaria is characterized by the rapid onset of pruritus, erythema, and swelling after exposure to a cold stimulus. The location of the swelling is confined to those parts of the body that have been exposed. When suspected, an ice-cube test can be performed in which an ice cube is placed on the subject's forearm for 4-5 minutes. A positive reaction leads to formation of a hive in the shape of the ice cube within 10 minutes after the stimulus is removed. The time course of this reaction (i.e., cold challenge followed by hive formation as the area returns to body temperature) demonstrates that a two-step reaction has occurred in which exposure to cold is a prerequisite, but hive formation actually occurs as the temperature increases.

One proposal to explain this phenomenon is that patients have an IgE autoantibody to a cold-induced skin antigen. Passive transfer (PK-testing) has been reported in which serum of the patient was injected into the forearm as one could to an intradermal skin test.  After 48 hrs. an ice cube test is done at the site and a small wheal is a positive test.  This was done in the pre-HIV era.  Fractionation of sera revealed IgE to be the pathogenic antibody and is not an IgE cryoglobulin, i.e. does not aggregate in the cold. Thus, sensitization might occur in the cold, and release of mediators proceeds as the cells warm. Studies to test this hypothesis (i.e. to identify a cold-inducible skin antigen) have thus far been negative.

Localized cold urticaria, in which only certain areas of the body urticate with cold contact, has been reported after predisposing conditions such as cold injury; it has also been reported at sites of intracutaneous allergen injections, ragweed immunotherapy, or insect bites.

Systemic cold urticaria yields severe generalized hive formation resulting from systemic cold challenge occurring over covered or uncovered parts of the body. Symptoms are unrelated to exercise or other activities, and the ice-cube test is negative.

Cold-dependent dermatographism demonstrates prominent hive formation if the skin is scratched and then chilled.

Exercise-induced disorders

Cholinergic or generalized heat urticaria is characterized by the onset of small (1 mm) punctate wheals surrounded by a prominent erythematous flare associated with exercise, hot showers, sweating, and anxiety. Typically, lesions first appear about the neck and upper thorax; when viewed from a distance, hives may not be perceived and the patient appears flushed. Pruritus is a prominent feature of the reaction. Gradually the lesions spread distally to involve the face, back and extremities, and the wheals increase in size. In some patients the hives become confluent and resemble angioedema. Although uncommon, symptoms of more generalized cholinergic stimulation such as lacrimation, salivation, and diarrhea may occasionally be seen. These various stimuli have the common feature of being mediated by cholinergic nerve fibers.  Sweat glands are a paradox; they are innervated by sympathetic fibers that release acetylcholine.   Cholinergic urticaria is the only form of hives in which emotional stimuli can, in some patients, initiate an urticarial reaction.  One study suggests that a subpopulation of patients has IgE antibody to an antigen in sweat.

Exercise-induced anaphylaxis was first described in a series of patients in whom combinations of pruritus, urticaria, angioedema, wheezing, and hypotension occurred as a result of exercise. The hives seen with exercise-induced anaphylaxis are large (10-15 mm), in contrast to the small punctate lesions characteristic of cholinergic urticaria. Subtypes of exercise-induced anaphylaxis have been described that are food-related. In one of these hives is seen only if exercise takes place within 5 hours after eating a food to which the patient is allergic. In a second subtype, hives occurs if exercise is within 5 hours of having eaten but the identity of the food is irrelevant.

Other physically induced forms of urticaria or angioedema

The remaining forms of physically induced hives or swelling are, with the exception of dermatographism, relatively rare disorders.

Dermatographism

Dermatographism, the ability to write on the skin, can occur as an isolated disorder that often presents as traumatically induced urticaria. It can be diagnosed by observing the skin after stroking it with a tongue depressor or fingernail are more quantitatively employing a dermographometer where the level of stimulus can be controlled. A white line secondary to reflex vasoconstriction is followed by pruritus, erythema, and a linear wheal, as is seen in a classic wheal-and-flare reaction. It is often an isolated finding of little clinical significance.  But symptomatic dermatographism can be very severe and debilitating.  It can also be confused with chronic spontaneous urticaria if symptoms are on-going all of the time.  Occasionally sensitivity is such that clothing rubbing along the skin during routine activites causes hive formation.

Pressure-induced urticaria/angioedema

Pressure-induced urticaria typically occurs 4-6 hours after pressure has been applied. Patients may complain of swelling secondary to pressure with normal-appearing skin (i.e., no erythema or superficial infiltrating hive), so that the term angioedema is more appropriate. Others are predominantly urticarial and may or may not be associated with significant swelling. Symptoms occur about tight clothing; the hands may swell with activity such as hammering; foot swelling is common after walking in patients with normal heart function; and buttock swelling may be prominent after sitting for a few hours.

Solar urticaria

Solar urticaria is a rare disorder in which brief exposure to light causes the development of urticaria within 1-3 minutes. Typically, pruritus occurs first, in about 30 seconds, followed by edema confined to the light-exposed area and surrounded by a prominent erythematous zone caused by an axon reflex. The lesions usually disappear within 1-3 hours.  Six subtypes can be defined based on the wave length of light that initiates a reaction.  Type I solar urticaria and possibly type IV are IgE antibody dependent.  Hereditary protporphyria is a photosensitive urticaria due to mutant protoporphyrin IX

Aquagenic urticaria

Patients develop small wheals after contact with water, regardless of its temperature.

Chronic Spontaneous urticaria and angioedema (CSU)

CSU is diagnosed when urticaria is present for more than 6 weeks and when it has been determined that an apparent protracted episode of urticaria is not the result of recurrent episodes of acute urticaria.  There typically is no identifiable food or medication causing it and the incidence of finding a food allergen as cause when urticaria persists for over six weeks, skin testing or RAST testing for food allergy is not recommended.  The lesions can very greatly in shape or size but are roughly circular.  They feel somewhat indurated (not flat) and individual lesions last 12-24 hrs.  This latter characteristic also distinguishes it from inducible urticarias except for delayed pressure urticaria.  Angioedema is present as well in about 40% of cases and may involve the lips, tongue, pharynx, extremities, but not the larynx, and asphyxiation is not a risk.  The spontaneous remission rate is 65% within 3 years, 85% within 5 years, and 98% within 10 years.

CSU is not associated with atopy, i.e. there is an increased incidence of atopic dermatitis, allergic rhinitis, or asthma compared to the incidence of these disorders in the absence of chronic urticaria although their IgE level, as a group, is higher than normal. Some patients are dermatographic, although this is usually of milder degree than is seen with the IgE-dependent dermatographism described earlier. The dermatographism may wax and wane, and the urticaria may vary from severe to mild or may intermittently subside. These individuals have a normal white-blood-cell count and erythrocyte sedimentation rate (ESR) and have no evidence of systemic disease. CSU does not appear to be an allergic reaction in the classic sense, even though IgE antibody may be involved and no external allergen is needed to initiate or perpetuate the process. It differs from allergen-induced skin reactions or from physically induced urticaria (e.g., dermatographia or cold urticaria) in that histologic studies reveal a prominent cellular infiltrate around small venules, with an increased number of mast cells.

Association with autoimmune thyroid disease

Patients with CSU have an increased frequency of Hashimoto's thyroiditis. An association has been noted with the presence of antibodies to thyroglobulin, or a microsomal-derived antigen (peroxidase) even if patients are euthyroid. The incidence of thyroid autoantibodies in patients with chronic urticaria is approximately 24%. Thyroid function and thyroid antibodies should be checked in all patients with chronic urticaria. There are no data to suggest that either of these antibodies are pathogenic in terms of hive formation and it is believed that these are associated, parallel, autoimmune events.

Autoallergy

There is an increased incidence of IgE antibodies to autoallergens that could have pathogenic significance.  Besides the aforementioned IgG antibody to thyroperoxidase and to thyroglobulin, there is also a hgh incidence of IgE antiperioxidase antibody.  Nevertheless to be pathogenically significant, thyroid antigen would need to be present in skin.  When gene screening was done for any IgE antibody that is not present in normal controls that is directed to self-antigens, a very large number were identified.  The most prominent was IgE anti-interleukin 27.  Interleukin 27 has; however, been found in skin but is epidermal and the epidermis is normal in CSU.  Examination in patients with atopic dermatitis would be of considerable interest.

Treatment 

Treatment of acute urticaria and angioedema

Identification of causative allergens, from the clinical history and blood testing or skin testing for specific IgE antibodies, will enable the individual with urticaria and angioedema to avoid pathogenic allergens. Where a reaction to medication has been implicated, for example, NSAID's or antibiotics, the physician should identify alternative drug groups for future treatment, and if possible perform skin testing with antibiotics to confirm or refute the diagnosis of specific antibiotic allergy. Acute attacks of urticaria or angioedema can be treated with H1 antihistamines. Treatment with 1% menthol in aqueous cream may suppress itching. As wheals can occur where tight clothing is in contact with the skin, loose clothing should be recommended. Itching is worse in warm conditions, and a cool temperature, particularly in the bedroom, is recommended. If urticaria and angioedema have occurred during a systemic anaphylaxis reaction, the patient should be prescribed an auto-injector of epinephrine to carry. Very often an episode of urticaria occurs without any explanation or lasting clinical significance, and without any risk of recurrence. Patients unresponsive to antihistamines can be treated with a tapering course of corticosteroid.

Physically-Induced Urticaria

Disorders such as cold urticaria, cholinergic (generalised heat) urticaria, and dermatographism can be treated with antihistamines such as cetirizine or loratidine. If so severe that responsiveness to these is insufficient, higher than normal doses can be used (example loratidine or cetirizine 10 mg up to 4 times a day). In some instances, when severe, a particular drug can be tried, eg, cyproheptadine 4-8 mg, 3-4 times a day, to treat cold urticaria or hydroxyzine 50 mg four times a day for cholinergic urticaria. Solar urticaria (light-induced urticaria) is treated with antihistamines and sun-screens, if sensitivity is to u.v. wavelengths. Sensitivity to visible light wavelengths is particularly difficult since symptoms can occur indoors as well as outdoors. Delayed pressure urticaria is an exception where symptoms more closely resemble CSU (with which it is commonly associated) and responds poorly to antihistamines.  It can be treated with omalizumab or cyclosporine.  It does respond to corticosteroid, but chronic use is not recommended.

Chronic Spontaneous Urticaria

First generation antihistamines are no longer necessary since we have excellent alternatives when antihistamine resistance is encountered.  The addition of 25-50 mg Hydroxamine or Diphendyramine at bedtime can help with sleeplessness or residual itch if urticaria is otherwise controlled such that additional agents are unnecessary.  H-2 receptor antagonists and leucotriene antagonists are no longer recommended; there is no good evidence of efficacy beyond the placebo effect.

When the response to antihistamines is unsatisfactory, the agent of choice is Omalizumab administered as a 150 mg or 300 mg subcutaneous injection monthly.  The UAS-7 instrument measures itch and urticaria on a 0 – 3 scale and multiplies by 7 days/week.  Thus a score of 42 is maximal (worst).  It is a useful tool for following the clinical course of patients and was employed in three, phase 3 studies of over 300 patients each.  A striking dimination of symptoms was observed in patients refractory to antihistaminics and leucotriene antagonists with a weekly score of 6 or less in about 60-70% of patients and complete control, i.e. a score of zero, in 40-50%. 


Figure - Symptom score demonstrating response to 300 mg Omalizumab vs placebo during a 6 month trial.

When therapy was discontinued after a 6 months trial, symptoms recurred, and later studies suggest that even 1 yr. is not sufficient to be able to stop the drug and have a significant number who do not relapse.  We do know that restarting omalizumab after a relapse has occurred leads to excellent disease control once again.  Angioedema or symptoms of delayed pressure urticaria respond along with the urticaria.

The rate of response suggests two groups of patients.  There are rapid responders i.e. with one week (i.e. one injection) while others show a slower, progressive diminution of symptoms over 16 weeks i.e. 4 injections.  IgE levels drop towards zero soon after administration, bound IgE (to mast cells and basophils), appears to dissociate in the presence of omalizumab, and the IgE receptor is downregulated.  Any or all of these may lead to mast cell desensitization accounting, depending on which effect predominates, for the rapid and slower responding subjects.  When the response appears to be unsatisfactory after at least 4 doses, one may increase further to 450 mg or even 600 mg or decrease the interval of a 300 mg dose to every 2-3 weeks.  This is based in part-marketing experience and has not been formally studied.  Although the 150 to 300 mg doses are approved, all studies demonstrated superior efficacy at 300 mg.

If antihistamines treat 45% of patients, and omalizumab is successful in the remaining 55%, it is estimated that both drugs should be effective in about 83% of patients with CSU.  When a response to omalizumab is not seen, the next drug of choice is cyclosporine.  A typical adult dose is 200 mg and it is recommended that 3.5 mg/kg not be exceeded.  Because of possible side effects on renal function and blood pressure; patients are checked every 4-6 weeks for BUN, creatinine, urine protein, and blood pressure.  The drug can be safely employed and most patients are free of adverse effects.  If cyclosporine is discontinued should an adverse effect on creatinine or blood pressure be encountered, it typically reverses within 3 weeks.  Frequent monitoring is key.  Its efficacy is also at least 70%, as is that of omalizumab and had previously been the medication of choice for anti-histamine resistant patients.  The estimated success rate employing all three medications in sequence i.e. after failing antihistamines and Omalizumab is 93%.

Should failure with all three be encountered, there are no studies that recommend what to do.  Agents tried previously that have not been clearly shown to have an effect on the disease beyond the 25-30% placebo effect include dapsone, sulfasalazine, hydroxychloroquin, IV gamma globulin, and methotrexate.  Tacrolimas is in the same drug category as cyclosporine and might be an alternative.  Corticosteroid can be used acutely, but not chronically, for particularly severe episodes.  Forty mg/day for 3 doses (stop without a taper) will treat angioedema.  A longer course that tapers by 5 mg/day (total of 10 days) can be ameliorative temporarily as one considers alternative agents.  Small numbers of patients (anecdotally) have responded to omalizumab and low-dose cyclosporine used in combination.

Urticarial vasculitis can be treated similarly but other agents (that are typically less effective for CSU) may be tried, such as dapsone, hyroxychloroquine, or colchicine. Hydroxychloroquine can be particularly helpful for the treatment of the hypocomplementaemic urticarial vasculitis syndrome. The various types of urticarial vasculitis account for less than 1% of all chronic urticarias.  Confirmation by skin biopsy is needed.  Clues to its presence are fever, organ involvement other than skin, petechiae and/or pupura, or lesions that scar or last 36 hrs. or more.

Education and Programs
Sours: https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/urticaria
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Basophils and mast cells in chronic idiopathic urticaria

Chronic idiopathic urticaria (CIU) is diagnosed in patients when urticarial eruptions recur for more than 6 weeks, and no specific cause is determined. Given that urticaria resembles the lesions induced by injection of histamine or allergen into the skin, a role for mast cells or basophils has been proposed in the generation of localized urticarial lesions. However, currently, the exact mechanisms governing regional mast cell or basophil activation are unknown. In the past decade, there has been mounting interest in viewing CIU as an autoimmune disease, given the presence of circulating autoantibodies to IgE or the alpha subunit of the high-affinity IgE receptor (FceRI) in a subset of patients. In this review, we propose that in addition to autoantibodies, specific differences in the expression of FceRI-signaling molecules in the basophils or mast cells of CIU patients may contribute to the generation of urticarial eruptions.

Sours: https://pubmed.ncbi.nlm.nih.gov/15967067/
Urticaria (Hives) and Angioedema – Pediatrics - Lecturio

Autoimmune Theories of Chronic Spontaneous Urticaria

Introduction

Urticaria, more commonly known as “hives”, is a prevalent disorder that affects between 15 and 25% of the population at some point during their lifetimes (1). The condition tends to be more common in adults than in children and in woman than in men with peak occurrence in the third to fifth decades of life. This condition is marked by the onset of pruritic “wheals,” which represent well-circumscribed areas of non-pitting edema with blanched centers and raised borders that involve only the superficial portions of the dermis and are seen in conjunction with surrounding erythema of the skin (2). Lesions can be as small as a few millimeters in diameter but can coalesce to form wheals as large as several centimeters wide. They often remit within 24 h since time of onset. Urticaria may be accompanied by the presence of angioedema, which is a similar process that occurs at submucosal surfaces of the upper respiratory and gastrointestinal tracts and deeper layers of the skin including subcutaneous tissue (3). Urticaria is classified as either acute or chronic depending on whether the onset of episodes lasts for less or >6 weeks in duration, respectively. In this review, we will focus specifically on the pathophysiology of chronic urticaria. Formerly referred to as chronic idiopathic urticaria, chronic spontaneous urticaria (CSU) refers to recurrent urticaria lasting more than 6 weeks that occur in the absence of an identifiable trigger. Urticaria that are incited by a well-defined eliciting factor (e.g., pressure, temperature, vibration) are referred to as inducible urticaria and will not be further discussed in this review. Prevalence of chronic urticaria is estimated to be anywhere from 0.5 to 5% in the general population but is not truly known, though incidence is thought to fall around 1.4% annually (4). Recent guidelines now include isolated idiopathic angioedema within the definition of CSU provided that other causes of angioedema, particularly those that are bradykinin mediated, have been excluded (5). Multiple studies have suggested that CSU may be an autoimmune condition in a substantial proportion of cases, but it is important to identify potential triggers of disease and exclude other differential conditions prior to making the diagnosis as outlined in Figure 1. In this article, we will discuss the pathophysiology of chronic urticaria and review the evidence surrounding its autoimmune etiology.

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Figure 1. Diagnostic workup of chronic urticaria.

Mast Cells and Basophils as Centralized Regulators of Chronic Spontaneous Urticaria

The pathophysiology of CSU is not well-understood, but it is clear that derangement of both mast cell and basophil activation and degranulation remains central to the process. Of these, mast cells are most widely accepted as the primary effectors of chronic urticaria. While other cell types including lymphocytes and polymononuclear cells (PMNs) have been observed within the inflammatory infiltrates of patients with CSU, it is well-established that histamine and other mast cell products are predominantly responsible for development of this condition [note that skin biopsies are seldom needed for the diagnosis but are occasionally useful to distinguish CSU from other inflammatory conditions such as urticarial vasculitis (5)]. The physical manifestation of urticaria can be attributed to the enhanced vascular permeability that results from the release of preformed mediators from mast cells (e.g., histamine, tryptase, leukotrienes) and their delayed generation of cytokines. Ongoing research continues to probe into the mechanisms by which mast cells are activated by blood-borne antigens, with recent data from murine in vivo studies suggesting that CD301b+ dermal dendritic cells (DCs) are actually first to sample antigen and then relay it to nearby mast cells through secreted microvesicles (6). However, the vast majority of cases of chronic urticaria are not triggered by any identifiable substance and are in fact idiopathic. In these cases, anaphylaxis does not occur though angioedema may be present.

Two major mechanisms have been put forward with regards to the pathogenesis of chronic urticaria. The first is not autoimmune in nature, but involves dysregulation of intracellular signaling pathways within mast cells and basophils that lead to defects in trafficking or function of these cells. The second involves the development of autoantibodies to FcεRIα or IgE on both mast cells and basophils and will be discussed in more detail in the following sections (7). Both of these mechanisms will be further explored here and are outlined in Figure 2.

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Figure 2. Model of the mechanisms underlying chronic urticaria. Pathologic activation of mast cells and basophils in patients with chronic spontaneous urticaria is thought to occur via two major mechanisms: intracellular signaling defects and autoimmune mechanisms. In the former, inappropriate activation of molecules such a spleen tyrosine kinase (SYK) or inhibition of negative regulators including the Src homology 2 (SH2)-containing inositol phosphatases (SHIP) promotes spontaneous degranulation of mast cells/basophils with subsequent release of histamine and other protein and lipid mediators. The more commonly accepted theory of pathogenesis in CSU includes antibody-mediated mast cell and basophil activation, which can occur via IgG- or IgE- mediated pathways. In the former, IgG molecules directed against the Fc portion of IgE or the FcεR1 promote spontaneous cellular degranulation. In patients with autoallergy, crosslinking of Fc epsilon R1 (FcεR1) via autoreactive IgE molecules directed against self-antigens such as thyroid peroxidase (TPO) promote mast cell/basophil degranulation.

Dysregulation of Intracellular Signaling Pathways can Predispose to Pathologic Activation of Mast Cells and Basophils

Activation of the high-affinity IgE receptor, FcεR1, is an important step in the development of allergic responses and in the development of urticaria. This receptor is composed of an α-, β-, and two γ subunits (8). Whereas the α-subunit binds to the Cε3 constant region of the IgE molecule, the β-, and γ- subunits contain cell immunoreceptor tyrosine-based activation motifs (ITAMs) which, when phosphorylated, promote activation of spleen tyrosine kinase (SYK) and downstream recruitment of a host of secondary molecules including those involved in the phosphoinositide-3 kinase (PI3K) pathway. This series of events is responsible for degranulation of mast cells and can predispose to pathologic mast cell activation when inappropriately upregulated. SYK is recruited to the FcεR1 upon antigen stimulation, and inhibition of this protein has been shown to inhibit mast cell degranulation and production of both lipid mediators and cytokine activity (9). When mast cells from CSU patients with active urticarial disease at the time of blood sample collection were compared to those from healthy human donors, they were unsurprisingly found to release significantly more histamine in vitro than their healthy counterparts (10). Yet when these CSU patients were further subdivided into responders vs. non-responders based on their ability to degranulate in response to anti-IgE (with responders showing >10% degranulation activity), SYK levels were shown to be higher in the responder group than in the non-responder group, suggesting that this protein is a major determinant of predilection toward spontaneous degranulation. SYK expression is highly variable among the general population and is thought to correlate with the degree of IgE-mediated degranulation. Intriguingly, the presence of autoantibodies to FcεRIα or IgE do not predispose to upregulation of basophil SYK expression (11).

Negative regulation of mast cell activation occurs through phosphoinositide lipid phosphatases which function as well-described negative regulators of hematopoietic cell activation and proliferation. Src homology 2 (SH2)-containing inositol phosphatases SHIP-1 and SHIP-2 associate with the FcεR1 β subunit and are activated upon stimulation with IgE or antigen (12). It is likely that dysregulation of these pathways that leads to an imbalance of positive signaling plays a pathogenic role in the development of CSU. One study demonstrated that when basophils from highly allergic IgE-positive donors (distinguished as having the ability to mount a response to human-recombinant histamine release factor, a complete stimulus for histamine release) were compared to those from healthy human donors, they contained lower levels of SHIP protein. As such, they demonstrated hyperresponsiveness (i.e., degranulation) in response to stimuli that did not appear to affect IgE-negative basophils (13). Similar results have been shown in mast cells from CSU patients highly sensitive to degranulation, with responders showing significantly lower levels of SHIP protein than both non-responders and healthy human donors (10).

The Autoimmune Theory of Mast Cell Activation in Chronic Spontaneous Urticaria

While cellular signaling defects may account for some cases of CSU, the autoimmune theory is the more widely accepted hypothesis to explain the inappropriate activation of mast cells and basophils in patients with chronic spontaneous urticaria. Up to 45% of cases of CSU are thought to be autoimmune in etiology. In a sentinel study conducted by Grattan et al., 12 patients with chronic urticaria were subjected to intradermal autologous serum injection (14). Seven of the 12 subjects (of whom six were female) mounted a positive wheal-and-flare reaction to this test, and fewer of these patients described a history of disease exacerbation with application of pressure when compared to patients with a negative injection test. This suggested that these patients with a positive result were less likely to have an inducible urticarial syndrome. Additionally, only one patient described a personal history of atopy, suggesting an alternative etiology for urticaria in the majority of cases. When the same serum was re-injected into the same subjects 1 year later, most of the patients with an initial positive test demonstrated a second positive result, though the same was not necessarily true when fresh serum was injected. In the small number of serum-positive patients who did not mount a second reaction at 1 year, the authors noted that their urticaria had cleared. On the contrary, the two patients who continued to mount a reaction with both original and fresh serum at the 1 year interval were noted to have continued disease activity. Ultimately, the authors concluded that many patients with chronic urticaria contain a “circulating mediator” in their serum which is capable of inducing urticaria. Over the past 30 years, the search has been ongoing to identify the mysterious culprit; multiple theories have since been put forth. However, it was these initial findings that opened the floodgates to the autoimmune theory of chronic spontaneous urticaria.

Though theoretically performed by Grattan et al. (14), the autoimmune etiology of CSU was further supported by formal development of the autologous serum skin test (ASST), an in vivo assay of mast cell activation that is induced by intradermal injection of a patient's serum into self. It has now been accepted that nearly 50% of patients with CSU will have a positive test in response to factors present within their own serum within 30 min of injection. Additional groups have suggested that such “factors” are indeed autoantibodies or histamine-releasing factors that are capable of inducing mast cell degranulation. Unfortunately, these data have been somewhat difficult to interpret, as positive ASSTs are not unique to patients with CSU and have been noted in a substantial proportion of patients with allergic or non-allergic rhinitis, multiple drug allergy syndrome, and even in healthy control subjects (15). Furthermore, the positivity of the test has been shown to persist even when CSU patients are in clinical remission, particularly in subjects with autoimmune thyroiditis (16). Interestingly, it has been shown that levels of autoantibodies in CSU do not vary with disease activity which may, in part, explain this finding (17).

Some individuals have suggested that the autologous plasma skin test may be more sensitive than ASST for the diagnosis of CSU (18), though this result has not been reliably demonstrated (19). Since plasma and serum have similar levels of autoantibodies, additional mechanisms beyond autoantibody production have been put forth to explain the pathophysiology of the disease. One such theory states that factors that are uniquely present in plasma may be involved in the development of urticaria, and indeed it was shown that levels of the prothrombin fragment 1+2 (a marker of thrombin generation) were significantly higher in CSU patients than in control subjects (18). This suggests involvement of the clotting cascade in the development of the urticarial reaction. While the role of the coagulation cascade in the pathogenesis of urticaria is beyond the scope of this review, thrombin has been shown to directly increase mast cell degranulation, activate protease-activated receptors on mast cells, and enhance vascular permeability through actions on endothelial cells (20). It should also be noted that autoantibodies against the low affinity IgE receptor FcεRII (CD23) have been demonstrated in a large percentage of CSU patients (21). Anti-CD23 autoantibodies can activate eosinophils to release major basic protein, which in turn can trigger histamine release from mast cells, and basophils. Curiously, in CSU patients eosinophils are also a major cellular source of tissue factor, a protein which promotes activation of the extracellular coagulation cascade and generation of thrombin (22).

It has also been speculated that activated lymphocytes may play a role in the pathogenic activation of mast cells. Indeed it has been demonstrated that mast cells release inflammatory mediators including TNF-α upon direct contact with activated T cells (23). This TNF-α release is responsible for upregulation of several mast cell genes, among which includes matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1). Intriguingly, MMP9 and TIMP-1 have both been found at higher levels in the plasma of patients with chronic urticaria, and levels of MMP-9 may correlate with disease severity (24).

Chronic Spontaneous Urticaria Is Associated With Development of Autoantibodies to IgE and the High Affinity IgE Receptor

Circulating mediators with the potential to induce wheal-and-flare reactions in nearly half of all patients with CSU have been demonstrated in response to ASST. The identify of those factors became apparent in the early 1990s. One landmark study demonstrated that antibodies present in the serum of patients with chronic spontaneous urticaria (but not in patients with dermatographism or pressure urticaria) were able to elicit histamine release from healthy donor peripheral blood leukocytes with similar kinetics as anti-IgE antibodies (25). Intriguingly, the authors noted that preincubation of basophils with either anti-IgE or chronic urticarial serum abolished subsequent histamine release upon incubation with urticarial serum or anti-IgE, suggesting that both anti-IgE and chronic urticarial serum stimulate degranulation via a similar mechanism. Removing surface-bound IgE from leukocytes prior to incubation with urticarial serum or anti-IgE reduced histamine release. These important results suggested for the first time that histamine-releasing autoantibodies present in the serum of patients with chronic urticaria act by cross-linking cell surface IgE receptors.

In addition to the aforementioned findings, the authors astutely noted that histamine release could be elucidated when chronic urticarial serum was incubated with basophils from donors with very low serum IgE concentrations but not with anti-IgE (25). These data implied that non-IgE-dependent histamine releasing factors are present in the serum of patients with CSU. Shortly after the publication of this initial study, the same group determined the presence of IgG antibodies against the α subunit of the high-affinity FcεR1 in a group of patients with CSU (26). In this subset of patients, IgG anti-FcεR1α pathologically induced histamine release irrespective of the degree of IgE sensitization of the basophils. As proof of concept, histamine release was effectively neutralized in a concentration-dependent manner by preincubating donor basophils with soluble fragment of FcεR1α prior to the addition of purified IgG from sera of patients with CSU.

The concept that circulating IgG antibodies against IgE and the high-affinity IgE receptor FcεR1 likely contribute to the pathogenesis of CSU has since become widely accepted. Approximately 40% of patients with CSU have circulating antibodies to one of these targets (27) with a higher frequency of positivity in CSU patients who are ASST positive (28). Anti-FcεRI antibodies are thought to be the more common of the two. FcεRI is found on the surface of both dermal mast cells and basophils, and autoantibodies to this receptor can provoke chronic stimulation and degranulation of these cells in an IgE-independent fashion (2). On the contrary, IgG-anti IgE antibodies may bind to and crosslink receptor-bound IgE on the surface of mast cells and basophils, thus leading to activation and degranulation of these cells. As is the case with many autoimmune conditions, the presence of autoantibodies does not necessarily result in a disease phenotype. The presence of FcεR1α autoantibodies have been noted in the sera of patients with other autoimmune skin conditions and even in healthy subjects, though these have not been shown to display pronounced histamine-releasing activity in individuals without CSU (29). The authors attribute this difference to the fact that anti-FcεR1α antibodies tend to be of the complement-fixing IgG1 and IgG3 subtypes in patients with chronic urticaria but of IgG2 and IgG4 subtypes in patients with other inflammatory skin conditions. Other groups have shown that in vitro basophil activation and subsequent histamine-releasing activity fails to correlate with the presence of autoantibodies to FcεR1α even among patients with chronic urticarial (27).

The presence of autoantibodies to IgE and to FcεR1α infers the presence of antigen-specific lymphocytes in individuals with chronic urticarial disease. FcεR1α-specific T lymphocytes are detectable in a large percentage of patients with CSU and these cells more typically adopt a Th1 cytokine profile with the largest percentage being INF-γ secretors (30). Intriguingly, the relationship between INF-γ and autoantibody responses to FcεR1α has been found to be inversely related, similar to that which has been observed for T cell and autoantibody reactivity to glutamic acid decarboxylase antigen in individuals at risk for type 1 diabetes mellitus (31). It remains unclear how T cell reactivity vs. antibody reactivity to FcεR1α affects pathogenesis of CSU. However, it has been demonstrated that markers of T cell activation are directly proportional to markers of mast cell degranulation in chronic urticaria patients, particularly in patients known to have positive antibodies against FcεR1 (32). Further evidence for the involvement of T lymphocytes in the pathogenesis of CSU stems from observed variations in protein tyrosine phosphatase 22 (PTPN22) in patients with CSU (33). PTPN22 is a strong susceptibility gene for a variety of autoimmune disorders and encodes lymphoid specific tyrosine phosphatase (Lyp), which normally serves as an inhibitor of T cell activation.

An increased frequency of the HLA-DR4 allele has been found in patients with CSU (34). Intriguingly, the HLA-DR4 has been found at an increased frequency in a variety of other autoimmune disorders including rheumatoid arthritis, type 1 diabetes mellitus, and multiple sclerosis. Patients with autoimmunological subtypes of CSU have been noted to have a particularly high likelihood of carrying this HLA class II allele (35). However, these data have not been replicable across a wide spectrum of populations, with other studies noting increased frequencies of HLA-DR9 (30) and HLADR12 (30, 36) among patients with CSU. Heterogeneity in allelic association with this disease likely indicates that FcεR1α contains a number of different epitopes which act as targets of autoreactive T lymphocytes.

The Overlap Between Chronic Spontaneous Urticaria and Other Autoimmune Diseases

The concept of “overlapping autoimmune diseases” suggests that disorders which are autoimmune in nature occur at increased frequency in patients with known autoimmune disease. Numerous autoimmune conditions including systemic lupus erythematosus, polymyositis, dermatomyositis, and rheumatoid arthritis have been associated with chronic urticaria (2).

One large population study of over 12,000 subjects derived from a large health maintenance organization in Israel determined that female patients with CSU demonstrate a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes, and systemic lupus erythematosus than patients without CSU (37). While men also demonstrated higher odds of having these autoimmune conditions when compared with control subjects, these numbers did not reach statistical significance. When further investigation into serologic markers of autoimmune disease was performed, it was determined that patients with CSU as compared to control subjects had significantly higher levels of anti-thyroid peroxidase (anti-TPO) antibodies, antinuclear antibodies (ANA), antithyroglobulin (i.e., antimicrosomal) antibodies, rheumatoid factor, anti-transglutaminase IgA antibodies, and anti-parietal cell antibodies with anti-dsDNA, and anti-cardiolipin antibodies trending toward significance. Moreover, the mean platelet volume (MPV) was noted to be abnormally high in 29% of CSU patients and only in 1% of control subjects. Elevations in MPV occur when the body produces platelets at a more rapid rate and tend to correlate with levels of systemic inflammation.

As this study was the first of its kind to examine the relationship between CSU and other autoimmune diseases, it has shed some light on some intriguing commonalities between these two conditions. As is the case with most autoimmune conditions, CSU tends to affect women more commonly than it does men, and women with CSU tend to have much higher odds of developing other autoimmune conditions vs. men. This sex difference is also mirrored by the observation that both CSU and autoimmune diseases on the whole tend to occur more commonly in young adulthood as opposed to in older, post-menopausal adults. Additionally, the high prevalence of the aforementioned autoimmune conditions in CSU patients at much higher frequencies than occurs in the general population adds more strength to the theory that the underlying pathology of CSU is autoimmune in nature. When overlapping autoimmune conditions did occur, they were frequently diagnosed within the first 10 years after onset of CSU and quite commonly within the first 6 months. A recently conducted systematic review of autoimmune comorbidities in individuals with CSU also noted that organ-specific autoimmune disorders are more common than systemic autoimmune disorders in patients with urticaria, with endocrine, hematologic and skin disorders being among the most common (38). The reasons for this discrepancy remain largely unclear.

The common pathogenic mechanism between these conditions is the presence of autoantibodies on a background of chronic inflammation. However, autoimmune disorders are incredibly heterogenous in nature and thus it is difficult to extrapolate whether the link between chronic urticaria and the aforementioned conditions truly stems from a common pathologic tie or is merely reflective of detection bias. If a true connection does exist, one would imagine that CSU would be found at a higher frequency in patients with established autoimmune disease, but this link has been difficult to definitively make. For example, the prevalence of CSU in patients with SLE ranges from 0 to 22% depending on the individual study (39).

Autoallergy in Chronic Spontaneous Urticaria

With regards to the idea of overlapping autoimmune diseases, the well-established link between chronic urticaria and autoimmune thyroid disease deserves particular mention. Even among euthyroid subjects, many patients with CSU have detectable levels of antibodies against thyroglobulin or microsomal-derived antigen (40). Furthermore, an increased prevalence of clinical hypothyroidism (i.e., Hashimoto's thyroiditis) as well as hyperthyroidism has been found among patients with CSU, with one study estimating a 23 times and seven times greater odds for hypothyroidism in female and male patients with chronic urticaria compared to control subjects, respectively (37). In 80% of these cases, the diagnosis of thyroid disease was made within 10 years, of the diagnosis of urticaria. The occurrence of IgG anti-thyroid antibodies in patients with CSU documented in studies where more than 100 patients were enrolled was noted to be anywhere from 3.7 to 37.1% with two-thirds reporting increased anti-thyroid antibody levels in >10% of patients (41).

Patients with CSU also demonstrate higher levels of IgE anti-thyroid peroxidase (anti-TPO) antibodies relative to healthy controls, though this distribution was found to be bimodal with 39% of CSU patients exhibiting IgE anti-TPO levels similar to control subjects (IgE anti-TPOlow) (42). It is theorized that autoallergic mast cell activation may contribute to the pathophysiology in CSU patients with detectable levels of IgE anti-TPO. IgE has a well-established role in the defense against helminthic infections and in recognition of exogenous allergens, but it was not until very recently that its potential role in autoimmunity has emerged. The term “autoallergy” refers to a type I, IgE-mediated hypersensitivity reaction against self-antigens which can, in turn, promote degranulation of basophils and mast cells. It was first put forth by Rorsman et al. as an explanation for urticaria-induced basopenia (43). Rorsman theorized that unlike in physical causes of urticaria, antigen-antibody interactions in non-physical causes of urticaria are likely to occur in both the skin and within the circulation (44). Autoallergic mast cell activation has been shown to occur in a variety of skin disorders including atopic dermatitis (45, 46) and bullous pemphigoid (47). In such disorders, IgE directed against skin antigens may bind to these cognate antigens and activate mast cells residing within the skin. On the contrary, TPO can be released from the thyroid into circulation, where it is free to bind to the surface of FcεR1-expressing cells. This extracutaneous nature of TPO may be one reason why the manifestations of CSU are not simply limited to the skin as they are in many other autoimmune skin disorders. Indeed it has been shown that anti-IgE TPO antibodies have the ability to induce basophil degranulation in vitro in the presence of TPO antigen and likely play a role in the pathogenesis of CSU (48). Recent findings have demonstrated that IgE anti-TPO antibodies are present at higher frequency and amounts in patients with CSU and have greater potential to induce TPO-mediated skin reactions in these subjects vs. in healthy controls (49). These results were validated by increased upregulation of basophil activation markers in CSU subjects upon exposure to TPO and ability of anti-TPO IgE to induce positive skin reactions upon passive transfer of this antibody from a patient with CSU to the skin of a healthy subject. In addition to IgE anti-TPO antibodies, IgE anti-dsDNA antibodies have also been noted at higher frequency in patients with CSU (50). However, no significant difference in IgE anti-dsDNA levels were observed between ASST-positive vs. ASST-negative patients, which suggests that these antibodies may be correlated with but are not likely to be involved in the pathogenesis of CSU.

IgE-mediated autoimmunity is becoming increasingly recognized as a possible contributor to the pathogenesis of a variety of systemic conditions including systemic lupus erythematosus and rheumatoid arthritis (51). A multicenter study in patients with SLE showed over half of all subjects had detectable levels of IgE against at least one common nuclear autoantigen (dsDNA, SS-A, SS-B, Sm) (52). This frequency increased during active disease and was strongly associated with the presence of active nephritis. There is still much to learn about the fields of autoallergy and IgE-mediated autoimmunity, which currently remain in their infancy, but it is likely that this will reveal a host of novel, targetable autoantigens. Over 200 IgE autoantigens were recently demonstrated in CSU subjects that were not present in healthy controls, among which included IL-24, which were detected in all patients with CSU (53). Further in vitro analyses demonstrated that IL-24 contributes to histamine release from human mast cells sensitized with IgE from CSU but not control subjects and that IgE-anti-IL-24 levels have reasonable predictive value for disease activity. The questions of why and how IgE autoantibodies develop and to what degree they contribute to CSU pathogenesis when compared to IgG autoantibodies has yet to be determined and is likely to be the focus of many future studies in this field.

Treatment of Chronic Spontaneous Urticaria

The primary treatment for chronic urticaria is to address the underlying pathology whenever possible and prevent mast cell activation. In any patient with chronic urticaria, elimination of potential triggers including drugs which can cause non-allergic hypersensitivity reactions (most commonly NSAIDs) should first be undertaken (5) Multiple guidelines have been put forth for management of CSU, though the EAACI/GA2LEN/EDF/WAO remain the most popular among practicing clinicians (5). If cases where no triggers can be identified, antihistamines (particularly the modern 2nd-generation antihistamines) are recommended as the mainstay pharmacologic treatment modalities for this condition. In patients who are poorly responsive to antihistamine therapy, it is recommended that the dosage be increased up to four times the normal limit prior to initiating a new agent. In cases of severe urticaria not adequately controlled with antihistamines alone, the EAACI/GA2LEN/EDF/WAO guidelines have recommended the addition of anti-IgE therapy, with cyclosporine being reserved for the most refractory cases of CSU. While short courses of prednisone do have a role in acute exacerbations of CSU, there is a strong recommendation against the use of long-term oral steroids given risk for adverse effects.

Evaluating the Use of Omalizumab for the Treatment of Chronic Spontaneous Urticaria

Omalizumab is an IgG monoclonal antibody against the Fc portion of the IgE antibody and prevents free IgE from binding to high-affinity FcεR1 receptors on mast cells and basophils. The first multicenter, placebo-controlled study evaluating omalizumab use in CSU examined efficacy of this therapy in subjects with IgE autoantibodies and found that 70% of omalizumab-treated patients who were otherwise refractory to standard antihistamine therapy were completely protected against wheal development (vs. 4.5% of placebo-treated subjects) (54). Another phase three study demonstrated that omalizumab given in three subcutaneous doses of either 150 or 300 mg over a 12 week period significantly reduced symptoms in antihistamine-refractory CSU patients without rebound of symptoms following discontinuation of the medication (55). Lack of relapse after discontinuation and very good safety profile have made omalizumab suitable for long-term therapy in patients with CSU, though cost still limits its use in many circumstances.

The mechanism by which omalizumab benefits patients with CSU has yet to be fully elucidated but the aforementioned results strongly argue for the contribution of IgE autoantibodies in the pathogenesis of CSU with rapid neutralization of these antibodies being an effective component of therapy. While the exact mechanisms by which omalizumab treatment benefits patients with CSU remain unclear, clearance of IgE autoantibodies is certainly likely to be of relevance. It has been well-established that omalizumab rapidly reduces levels of free IgE, which promotes downregulation of FcεR1 on basophils within the span of weeks and on mast cells within the span of months (56). The reason for this is because FcεR1 is effectively degraded when it is not stabilized by IgE binding (56, 57). Additionally, omalizumab has been shown to improve the genetic signature of lesional skin in patients with CSU to reflect non-lesional skin signatures by downregulating expression of genes involved in mast cell and leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8), oxidative stress, vascularization (CYR61), and skin repair (KRT6A, KRT16) (56). Notably, non-responders to omalizumab do not demonstrate these genetic alterations. Basophils are also thought to be recruited to the urticarial lesions of patients with active CSU (58). Post hoc analysis of randomized clinical trial data have demonstrated that omalizumab increases peripheral blood basophil counts by likely reducing recruitment of these cells to the skin (59) and may also help to regulate defective basophil IgE receptor pathways (57). Clinical trials are currently underway to better characterize the effects of omalizumab on basophil responses.

Treatment with omalizumab has been shown to decrease levels of both FcεR1- and IgE- positive skin cells in skin of patients with CSU (60). In theory, omalizumab may reduce the autoimmune effects of self-antigen by mediating this decrease in pathogenic IgE levels and/or IgE receptors on the mast cell surface. Recently, a great deal of attention has been placed on the utility of IgE levels for predicting responses to omalizumab. Patients who have lower IgE levels prior to receiving omalizumab and lower IgE levels 4 weeks after undergoing treatment tend to respond less well to this therapy than those with higher baseline and post-treatment IgE levels (61), suggesting that these laboratory tests may help to guide management of CSU patients being considered for second- and third-line treatment options (61, 62). Interestingly, total IgE levels have been shown to positively correlate with basophil FcεR1 expression, the latter of which tends to be higher in those who respond quickly to omalizumab therapy (62). Despite our poor knowledge of the precise role of basophils in CSU pathophysiology, it is becoming clear that the time to effect for omalizumab in CSU appears to correlate with the expected time for reduction of FcεR1 on basophils (54) as opposed to on mast cells. Similar results were noted in prior studies examining use of omalizumab for cat allergy, which demonstrated that reduction of nasal symptoms correlated directly with a reduction in basophil responsiveness as opposed to mast cell responsiveness (63).

The question of how omalizumab benefits patients whose disease is mediated by a type I hypersensitivity reaction (autoallergy) vs. a type II hypersensitivity reaction (autoimmunity) is still largely unclear, however, it does appear that patients with autoallergy experience faster response times when treated with omalizumab. In one study, subjects refractory to standard antihistamine therapy with IgE anti-TPO antibodies were randomized to receive omalizumab in 2 or 4 week intervals for a span of 24 weeks. Patients with anti-IgE TPO antibodies experienced early responses to omalizumab, suggesting that rapid neutralization of IgE is the major mechanism by which omalizumab benefits this particular cohort (54). On the contrary, subjects who display a slow response to omalizumab are thought to have IgG antibodies against FcεRI since downregulation of this receptor occurs only after free IgE is first complexed by the drug (64). The authors validated this hypothesis by demonstrating a high correlation between length of time to the onset of omalizumab efficacy and positive basophil histamine release activity, with the latter predicting slower response times to treatment (64). Basophil activation, which is more specific for the detection of histamine-releasing autoantibodies in CSU patients than the ASST, may thus be a useful test in assessing patient responsiveness to omalizumab (64). As such, patients with refractory CSU may benefit from longer, more “personalized” courses of omalizumab (65). Further investigation on the mechanisms by which omalizumab benefits patients with CSU is certainly in need as are biomarkers to predict the efficacy of responsiveness and likelihood of relapse among patients with various subtypes of CSU.

Conclusion

Chronic spontaneous urticaria is a common and complex disorder that occurs in the absence of any identifiable provoking factor. While there are many aspects regarding CSU that have yet to be understood, it is becoming increasingly clear that both autoimmunity (IgG-mediated disease) and autoallergy (IgE-mediated disease) can contribute to the pathogenesis of this disorder and predispose subjects to the development of additional autoimmune diseases. Subjects with IgE autoantibody-mediated CSU appear to have a faster onset of improvement in response to omalizumab than those with IgG-mediated disease due to the unique mechanisms by which this drug sequentially affects IgE levels and FcεR1 status. Further investigation is required to determine how the presence of unique autoantibodies can predict the disease course and comorbidities associated with various subtypes of CSU as well as overall responsiveness to therapy.

Author Contributions

SB and ASM conceptualized the topic of the review article and wrote the review. SA and ASM supervised the writing of this review.

Funding

ASM is supported by the Duke Department of Dermatology and receives research funding through the National Institutes of Health (1R01AI139207-01 to ASM). ASM acts a consultant for Silab that is on a different topic than the content of this review article.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: chronic spontaneous urticaria, chronic idiopathic urticaria, autoimmune urticaria, anti-IgE, anti-FcεR1, autoallergy, anti-TPO

Citation: Bracken SJ, Abraham S and MacLeod AS (2019) Autoimmune Theories of Chronic Spontaneous Urticaria. Front. Immunol. 10:627. doi: 10.3389/fimmu.2019.00627

Received: 23 January 2019; Accepted: 08 March 2019;
Published: 29 March 2019.

Edited by:

Ralf J. Ludwig, Universität zu Lübeck, Germany

Reviewed by:

Martin Metz, Charité Medical University of Berlin, Germany
Karoline Krause, Charité Medical University of Berlin, Germany

Copyright © 2019 Bracken, Abraham and MacLeod. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Amanda S. MacLeod (née Büchau), [email protected]

Sours: https://www.frontiersin.org/articles/10.3389/fimmu.2019.00627/full

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